Category Archives: HRT

THE NEGLIGENCE- MORTALITY AND MORBIDITY- OF WITHHOLDING APPROPRIATE HEALTHSPAN-EXTENDING PHYSIOLOGICAL HUMAN HRT FROM AGING MEN AND WOMEN

update 10 Dec 2015  a reader in Germany  responds:  “ Excellent! I wonder when lawyers will start suing for withholding hormone replacement. 
I think you have made a very strong point by stating that government, medicine and industry are more interested in disease than health.”
      HRT UPDATE 8 Dec 2015: THE NEGLIGENCE- MORTALITY AND MORBIDITY- OF WITHHOLDING APPROPRIATE PHYSIOLOGICAL HEALTHSPAN-EXTENDING HUMAN HRT FROM AGING MEN AND WOMEN :

its been a long time since this column last reviewed HRT for women (the KEEPS Trial) and for men, other than in the contexts of prevalent cancer phobiamongering.  Both our experience in practice, and longterm observational studies, are increasingly affirmative. Why should we be surprised?

Global pollution and overheating, antibiotic, alcohol and sugar abuse, and shortage of drinkable/arable water and therefore food are the dominant “natural” threats of the next decade let alone century. As a 2013 German-Chinese study says, Water-sustainability requires > 60% of arable land for soil water replenishment.
But thanks to worsening indoor living, sloth and food production policies, deficiency of antiinfection- anticancer antioxidant growth-promoting (not just rickets-and – goiter-preventing) microdose anabolic vitamin D3 and iodine have taken the lead , for the half of mankind who do not go hungry, in the essential needed mineral-vitamin microsupplements in life-and- lifequality-limiting micronutrient deficiencies for young and old. These micronutrient deficiencies are so easily and cheaply remedied for a few $ per person per year- but there is no incentive for high-tech profit-based government, medicine and industry to promote these since Only Disease Pays.

Now the recent October interview with leading Canadian andrologist Dr Alvaro Morales Testosterone Deficiency Focus of New Canadian Guidelines echoes what we have learned  the past 50 years over our career lifetimes about appropriate parenteral natural physiological HRT being as important for deficient aging men- testosterone replacement. This matches need for appropriate parenteral natural physiological HRT for postmenopausal women- for whom progesterone cream often suffices as the safe baseline, adding parenteral testosterone and parenteral estrogen only as selectively indicated.ie in both genders to conservatively restore physiological balanced baseline bloodlevels of healthy young adults. .
Its now 13 years since the USA hysterical banning (2002 then 2003) of all HRT after the badly designed and bad analyses and premature stopping of the Womens’ Health Initiative; which illogically tested unphysiological and long-discredited patent oral xeno- ie non-human hormones (premarin and medroxyprogestin) in mostly elderly women long past the Change- the midlife menopause and menopause symptom decade (ie late forties to late fifties).

Many of us in the International Menopause Society objected to this dangerous hysteria from 2002 onwards, but the Americans involved in the WHI refused to concede for a decade that they were wrong, since such admission would have opened them to culpable negligence claims.. . .

in 2013 co-editors Dr Nick Panay(UK) and Dr Ana Fenton (NZ) asked in the leading journal Climacteric about the Womens’ Health Initiative:WHI: have our worst fears come true? . This was based on ongoing analyses of studies eg by Drs Sarrell, Katz ea at Yale University that showed The mortality toll of estrogen avoidance: an analysis of excess deaths among hysterectomized women aged 50 to 59 years who were denied HRT.

Ongoing studies over 60 years (Schleyer-Saunders, Lee, Dalton, Greenblatt, Gelfand, Gambrell, Schneider, Davey, Shapiro, Cheifitz, Burger & Davis, Nieschlag & Behre, Notelowitz, Lunenfeld, Utian, Harman, Bhasin, Zitzman, Hader, Saad ea) have clearly confirmed what was apparent from experience in the 1940s, and Masters and Grody’s initial landmark HRT studies in the1950s in both sexes, that appropriate human parenteral balanced HRT (testosterone/ progesterone, plus estrogen for women) retard all risks of aging degenerative diseases in sex-hormone deficient aging people; and also extend both healthspan and longevity ie are antiaging.

           Now we have come full circle with longterm followup of stable physiological parenteral testosterone replacement- patches, fortnightly depotTT – or quarterly Nebido TUndecanoate – in 100 000s of men globally to a mean testosterone level around 18nmol/L (let alone to appropriate testosterone  replacement in women):

ongoing followup from a European observer personal communication last week is borne out by already published studies below: “there is no evidence from various registries of increased incidence and/or severity of prostate cancer with testosterone treatment.

      Increasing signals are that adequate testosterone treatment is protective, for the prostate as well as the immune, cardiovascular, nervous, musculoskeletal and cognitive-mood systems. One registry follows both hypogonadal men who refused testosterone treatment, and those on replacement. In 8 years follow-up of 296 elective hypogonadal men , 26% had major cardio-/vascular medical endpoints (21 deaths -19 = 6% cardiovascular, 30 =10% strokes, and 26 = 9% myocardial infarction, in total 77 events) . The elective Nebido testosterone replacement group (360 men) reported NO cardio/vascular endpoints ie no medical deaths, strokes, or heart attacks.(1 traffic accident death, 1 postsurgical complication death), q.e.d. p<0.0000…

REFS- in italics :
BOTH SEXES:
Clin Interv Aging. 2014 Jul 23;9:1175-86.. Off-label use of hormones as an antiaging strategy: a review. Samaras N1ea Geneva University Switzerland. Given demographic evolution of the population in modern societies, one of the most important health care needs is successful aging with less frailty and dependency. During the last 20 years, a multitude of anti-aging practices have appeared worldwide, aiming at retarding or even stopping and reversing the effects of aging on the human body. One of the cornerstones of anti-aging is hormone replacement. At present, women live one third of their lives in a state of sex-hormone deficiency. Men are also subject to age-related testosterone decline, but andropause remains frequently under-diagnosed and under-treated. Due to the decline of hormone production from gonads in both sexes, the importance of dehydroepiandrosterone (DHEA) in steroid hormone production increases with age. However, DHEA levels also decrease with age. Also, growth hormone age-associated decrease may be so important that insulin growth factor-1 levels found in elderly individuals are sometimes as low as those encountered in adult patients with established deficiency. Skin aging as well as decreases in lean body mass, bone mineral density, sexual desire and erectile function, intellectual activity and mood have all been related to this decrease of hormone production with age. Great disparities exist between recommendations from scientific societies and actual use of hormone supplements in aging and elderly patients. In this article, we review actual data on the effects of age related hormone decline on the aging process and age-related diseases such as sarcopenia and falls, osteoporosis, cognitive decline, mood disorders, cardiovascular health and sexual activity. We also provide information on the efficiency and safety of hormone replacement protocols in aging patients. http://www.ncbi.nlm.nih.gov/pubmed/25092967

     WOMEN: The latest of many are the Danish studies of up to 16 yearsfollowup ;        2008 http://eurheartj.oxfordjournals.org/content/29/21/2660.abstract

and
2012 http://www.ncbi.nlm.nih.gov/pubmed/?term=BMJ+%28Schierbeck+et+al+2012%3B345%3Ae6409,

the USA KEEPS RCT of lower-dose premarin vs estradiol patch +- parenteral progesterone in perimenopausal women by Harman, Naftolin ea http://www.keepstudy.org/publications/index.cfm,

and again
Clin Endocrinol (Oxf). 2014 Oct;81(4):621-8. doi: 10.1111/cen.12459. Epub 2014 May 5. Transdermal testosterone improves verbal learning and memory in postmenopausal women not on oestrogen therapy. Davis ea . Monash University, Australia. Randomized, placebo-controlled trial in which participants were randomized (1:1) to transdermal testosterone gel 300 mcg/day, or identical placebo, for 26 weeks. 92 postmenopausal women aged 55-65 years, on no systemic sex hormone therapy. Eighty-nine women, median age 60 years, were included in the primary analysis. Testosterone treatment resulted in statistically significantly better performance for the ISLT (improved verbal learning and memory) compared with placebo, adjusted for age and baseline score (mean difference 1•57; 95%CI 0•13, 3•01) P = 0•03 At 26 weeks, the median total testosterone was 1•7 nm (interquartile range (IQR) 1•1, 2•4) in the testosterone group and 0•4 nm (IQR 0•3, 0•5) in the placebo group. The small but statistically significant effect of testosterone treatment on verbal learning and memory in postmenopausal women provides the basis for further clinical trials.
Testosterone in women-the clinical significance. Davis & Wahlin-Jacobsen .Lancet Diabetes Endocrinol. 2015 (12):980-92. http://www.ncbi.nlm.nih.gov/pubmed/26358173.      Testosterone is as much an essential hormone for women, with physiological actions mediated directly or via aromatisation to oestradiol throughout the body. Observational studies indicate that testosterone has favourable cardiovascular effects measured by surrogate outcomes. Adverse cardiovascular effects have not been seen in studies of transdermal testosterone therapy in women. http://www.ncbi.nlm.nih.gov/pubmed/24716847

    MEN:
BJU Int. 2014;114:125-30. Long-acting testosterone injections for treatment of testosterone deficiency after brachytherapy for prostate cancer. Balbontin, Morgentaler ea With a median of 31-months follow-up, long-acting testosterone injections in men mean 62yrs with prostate cancer treated with brachytherapy produced significant clinical benefits. There were no cases of rising serum PSA, prostate cancer progression or recurrence.
J Urol. 2015;193:80-6. Incidence of prostate cancer in hypogonadal men receiving testosterone therapy: observations from 5-year median followup of 3 registries. Haider A1, Zitzmann M Yassin ea Germany In 3 parallel, prospective, ongoing, cumulative registry studies 1,023 hypogonadal men received testosterone therapy since 1996. Patients were treated when total testosterone was 12.1 nmol/l or less (350 ng/dl) with symptoms of hypogonadism. Maximum followup 17 years (1996 to 2013), median followup was 5 years. Mean baseline patient age was 58 years and 41 years. Patients received testosterone undecanoate injections in 12-week intervals. Prostate monitoring/ biopsies were performed according to EAU guidelines. RESULTS: A total of 11 patients were diagnosed with prostate cancer in the 2 urology settings at proportions of 2.3% and 1.5%, respectively. The incidence per 10,000 patient-years was 54.4 and 30.7 , respectively, ie mean 0.42% pa – well below that in the general population. No prostate cancer was reported by the andrology center. CONCLUSIONS:Testosterone therapy in hypogonadal men does not increase the risk of prostate cancer. If guidelines for testosterone therapy are properly applied, testosterone treatment is safe in hypogonadal men. http://www.ncbi.nlm.nih.gov/pubmed/?term=Incidence+of+Prostate+Cancer+in+Hypogonadal+Men+Receiving+Testosterone+Therapy%3A+Observations
Eur Heart J. 2015 Oct 21;36(40):2706-15. Normalization of testosterone level is associated with halved incidence of myocardial infarction and mortality in men. Sharma R1, ea University of Kansas retrospectively examined 83 010 male veterans with documented low TT levels http://www.ncbi.nlm.nih.gov/pubmed/26248567
Prostate Cancer Prostatic Dis. 2015 Dec;18(4):382-7. Preoperative low serum testosterone is associated with high-grade prostate cancer and an increased Gleason score upgrading.Pichon ea, France http://www.ncbi.nlm.nih.gov/pubmed/?term=Preoperative+low+serum+testosterone+is+associated+with+high-grade+prostate+cancer+and+an+increased+Gleason+score+upgrading+A+Pichon1%2C5%2C
Horm Mol Biol Clin Investig. 2015 Jun;22(3):101-9. Obesity and hypogonadism are associated with an increased risk of predominant Gleason 4 pattern on radical prostatectomy specimen. Neuzillet , ea France http://www.ncbi.nlm.nih.gov/pubmed/26047422
BJU Int. 2013;111:880-90. Prostate-specific antigen (PSA) concentrations in hypogonadal men during 6 years of transdermal testosterone treatment. Raynaud ea france http://www.ncbi.nlm.nih.gov/pubmed/23294726
Exp Clin Endocrinol Diabetes. 2015 Nov;123(10):608-13. The Effect of Metformin and Metformin-Testosterone Combination on Cardiometabolic Risk Factors in Men with Late-onset Hypogonadism and Impaired Glucose Tolerance.Krysiak ea Poland . No previous study has investigated the effect of metformin, administered alone or together with testosterone, on cardiometabolic risk factors in men with hypogonadism. The study included 30 men with late-onset hypogonadism (LOH) and impaired glucose tolerance (IGT) who had been complying with lifestyle intervention. After 12 weeks of metformin treatment (1.7 g daily), the participants were allocated to one of 2 groups treated for the following 12 weeks with oral testosterone undecanoate (120 mg daily, n=15) or not receiving androgen therapy (n=15). before and after 12 and 24 weeks of therapy with the final dose of metformin. Patients with LOH and IGT had higher levels of hsCRP, homocysteine and fibrinogen than subjects with only LOH (n=12) or only IGT (n=15). Metformin administered alone improved insulin sensitivity, as well as reduced 2-h postchallenge plasma glucose and triglycerides. Testosterone-metformin combination therapy decreased also total and LDL cholesterol, uric acid, hsCRP, homocysteine and fibrinogen, as well as increased plasma testosterone. The effect of this combination therapy on testosterone, insulin sensitivity, hsCRP, homocysteine and fibrinogen was stronger than that of metformin alone. The obtained results indicate that IGT men with LOH receiving metformin may gain extra benefits if they are concomitantly treated with oral testosterone. http://www.ncbi.nlm.nih.gov/pubmed/26600057
Swiss Med Wkly. 2015 Nov 24;145:w14216. Hypotestosteronaemia in the aging male: should we treat it? Christe N1, Meier CA1.Switzerland http://www.ncbi.nlm.nih.gov/pubmed/26599486 The term male hypogonadism is defined as the failure to maintain physiological concentrations of testosterone, a physiological quantity of sperm or the combination of both. Aetiologically, androgen deficiency can originate from the testes (primary hypogonadism) or from the hypothalamic-pituitary regulation of the testicular function (secondary hypogonadism). The causes of hypogonadism are very diverse .. But how about the aging male? It is known that there is a highly variable age-related decline in testosterone levels; whether this represents a variation of normality or has a true disease value requiring therapy has been disputed over more than a decade. The key questions surrounding this debate concern not only the age-dependent threshold for serum testosterone but, more importantly, the risks and benefits of testosterone replacement therapy in the aging male. randomised controlled trials of testosterone administration in aging males with a size of at least 100 patients and a follow-up of at least 6 months, identified eight studies. These studies mostly tried to evaluate the effect of testosterone on bone density, muscle strength and body composition, rather than clinically meaningful endpoints. Moreover, these trials have provided evidence for relevant cardiovascular adverse events in elderly men. This supports the need for further studies to define the treatment threshold for testosterone levels in the aging male, as well as with regard to the long-term risks and relevant benefits of testosterone therapy in this population. Until we have more solid data in aging males, testing for testosterone deficiency and testosterone replacement should remain reserved for patients with predisposing conditions, symptoms and signs of bona fide hypogonadism.
Rev Endocr Metab Disord. 2015 Nov 21. The complex and multifactorial relationship between testosterone deficiency (TD), obesity and vascular disease.Traish AM1, Zitzmann M2.Boston & Germany Univ. Testosterone deficiency (TD) is a well-established and recognized medical condition that contributes to several co-morbidities, including metabolic syndrome, visceral obesity and cardiovascular disease (CVD). More importantly, obesity is thought to contribute to TD. This complex bidirectional interplay between TD and obesity promotes a vicious cycle, which further contributes to the adverse effects of TD and obesity and may increase the risk of CVD. Testosterone (T) therapy for men with TD has been shown to be safe and effective in ameliorating the components of the metabolic syndrome (Met S) and in contributing to increased lean body mass and reduced fat mass and therefore contributes to weight loss. We believe that appropriate T therapy in obese men with TD is a novel medical approach to manage obesity in men with TD. Indeed, other measures of lifestyle and behavioral changes can be used to augment but not fully replace this effective therapeutic approach. It should be noted that concerns regarding the safety of T therapy remain widely unsubstantiated and considerable evidence exists supporting the benefits of T therapy. Thus, it is paramount that clinicians managing obese men with TD be made aware of this novel approach to treatment of obesity. http://www.ncbi.nlm.nih.gov/pubmed/26590935
Cancer Causes Control. 2015 Nov 20. Serum androgens and prostate cancer risk: results from the placebo arm of the Prostate Cancer Prevention Trial. Schenk JM1, EA USA & Australian Univ. examined whether pre-diagnostic serum androgens were associated with PCA risk in the placebo arm of the Prostate Cancer Prevention Trial. In this 3 yr nested case-control study, cases (n = 1,032) were primarily local-stage, biopsy-detected cancers, and controls (n = 1,025) were biopsy-confirmed to be PCA-free.. We found no significant associations between serum androgens, estrogen-to-testosterone ratios, or SHBG and risk of total, low (Gleason <7) or high-grade (Gleason 7-10) PCA. http://www.ncbi.nlm.nih.gov/pubmed/26589415
by contrast,

seer.cancer.gov/statfacts/html/prost.htm reports:
In recent years, the number of prostate cancer deaths IN USA was 21.4 per 100,000 men per year ie 0.021%pa . c/f apparently no prostate cancer deaths in the TRT studies. These rates are age-adjusted and based on 2008-2012 cases and deaths. Lifetime Risk of Developing Cancer: Approximately 14.0 percent of men will be diagnosed with prostate cancer at some point during their lifetime, based on 2010-2012 data

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UPDATE: COLORECTAL CANCER SCREENING IN LOWRISK PATIENTS- NO BENEFIT ON ALL-CAUSE MORTALITY. IS IT ANYTHING BUT A HUGE EXPENSE- AND RISK?

neil.burman@gmail.com

21 Dec 2014 Update: No response has been received from or published by  Annika  Steffens ea  of Australian universities in the past 2 months on the allcause mortality difference by CRC screening in their massive colorectal  cancer CRC screening study in an older population. .

But a number of autopsy studies the past 40 years throw more light on how infrequent CRC actually is elsewhere , Australia apparently having one of the highest rates at 0.125% pa.

As regards apparently undiagnosed cancer found at autopsy: colon cancer is very infrequent, and its import drops with age; and is no more common in sudden death potential organ donors than in others. In Japan over 20 years, the incidence of unsuspected colon cancer in 3600  routine autopsies  was only 0.03%pa. In Singapore in 1000 random autopsies on the other hand, incidental CRC was found in 10 ie a prevalence of 1%. In the Connecticut Cancer registry over 50 years, one cancer trebled the risk of a second cancer- especially  high risk of cancers of lung, larynx, mouth, pharynx; breast;colon, uterus,  ovary, cervix; suggesting a common etiology involving  smoking & HPV? , ie an intriguing link  between female genital tract, breast, airway  and colon but not prostate.. However studies since at least 2005  including from RSA 2007, do indicate a link between HPV and prostate cancer, the latest from Crete University 2014.

So smoking, alcohol and  STDs- especially HPV- are a deadly triad in   male-dominated  permissive countries like South Africa – but  likely worse in strict Islamic countries that keep citizens (subjugated women even more than men) overdressed ie minimize sunshine and thus lifegiving vitamin D3 levels.  .

refs: A  new study   from France asks:  Are suicide rates higher in the cancer population? An investigation using forensic autopsy data.  Med Hypotheses. 2014  de la Grandmaison,  Charlier ea Versailles Saint-Quentin University,    note previous population-based studies have identified increased suicide rates among cancer patients.  In total, 232 cases were included in both the suicide and the control groups.  Cancer was significantly more often found in the suicide group than in the control one (8.6% vs. 3.9%, p=0.03).  the presence of cancer increased the risk of suicide. Moreover, cancer was not known to the deceased in 70% of cases, while the most frequent mental disease found in cancer-related suicide cases was depression (75%). In the 20 cancer-related suicide cases analysed herein, it was difficult to ascertain whether malignancy was the only motive for committing suicide, as cancer could be considered to be either a major causative factor for suicide or an incidental finding.

Crit Rev Oncol Hematol. 2012 Cancer prevalence and mortality in centenarians: a systematic review. Pavlidis ,  Audisio  ea  Univ of Ioannina,Greece.   Data analysis demonstrates how cancer incidence and cause of death present a threefold decrease after age 90 and reach 0-4% above age 100. In addition, the number of metastatic sites are remarkably less and incidental malignant tumours or multiple primary cancers are more frequent, indicating that cancer in centenarians carries a more indolent behaviour. Cancer in the very elderly is relatively uncommon as a disease and as a cause of death. It is characterized by a slow growth and a modest life-threatening potential.

Arch Pathol Lab Med. 2009 Unexpected neoplasia in autopsies: potential implications for donor tissue  safety. Sens, Cooley ea University of North Dakota.-Medical examiner cases are increasingly used as tissue donor referral sources to meet ever-growing need for transplant tissues. Assumption is often made that traumatic and sudden deaths have minimal risk of unsuspected neoplasia.-A retrospective, 5-year review of 412 autopsies from a regional, primarily forensic, autopsy service to determine the incidence of unsuspected neoplasia, potential donor referral suitability. Unsuspected neoplasia rate at autopsy was 7% (29 of 412 patients); cancer was the cause of death in 41% (12 of 29 patients) of these individuals. In patients with a history of cancer, the discordance of cancer diagnosis was 44% (4 of 9 patients [11 patients with known cancer, 2 who refused medical evaluation were excluded from the study]). Nearly 60% (17 of 29 patients) of the unsuspected cancer cases had no apparent reason for deferral of tissue procurement before the autopsy examination.

Ueyama,Tsuneyoshi ea  Kyushu University, Japan.  During the past 20 yr, 17 colorectal carcinomas (0.47%) were incidentally detected among 3,638 autopsied patients without clinically evident colorectal carcinoma, including 2,232 males and 1,406 females, more than 40 yr old. Among the 15 male and two female index subjects, six (0.33%) were detected in the first and 11 (0.60%) in the second decade.

Cancer. 1988 Mar 1;61(5):1059-64.  Incidental carcinoma of the colorectum at autopsy and its effects on the incidence and future trends of colorectal cancers in Singapore.   Lee YS1 Ten incidental invasive carcinomas (two early carcinomas involving the submucosa, and eight advanced carcinomas involving the muscularis propria or beyond) of the large intestine were discovered in a series of 1014 consecutive autopsies. All occurred in Chinese aged 60 years and older, constituting a prevalence rate of about 3% in this age group. If unsuspected colorectal carcinomas in Chinese Singapore residents aged 60 years and older exist in those who died in 1984 to the same extent as that noted in this autopsy study, it was estimated that 146 additional cases would have been added to the Cancer Registry in that year. This would constitute 47.9% of the total number of colorectal cancers diagnosed in this age group in 1984. This potential contribution has to be taken into consideration in epidemiologic studies on the incidence and future trends of colorectal cancers in Singapore. It was observed further that incidental carcinomas were found predominantly in the ascending colon. With more frequent use of colonoscopy, the incidence of right-sided cancers of the large bowel may be expected to increase.

Natl Cancer Inst Monogr. 1985  Summary: multiple primary cancers in Connecticut, 1935-82.  Curtis,  Fraumeni ea   The risk of developing a second primary cancer was evaluated in over 250,000 persons reported to the Connecticut Tumor Registry (CTR) during 1935-82. The CTR has collected data on cancer incidence longer than any other population-based tumor registry and thus provided researchers with a unique opportunity to investigate the occurrence of second cancers among persons followed for long periods, in some cases for more than 40 years. When compared with the general Connecticut population, cancer patients had a 31% increased risk of developing a subsequent cancer overall and a 23% elevated risk of second cancer at a different site from the first. Little variation in risk was seen for the first 20 years of follow-up, although the risk for females averaged twice that for males (41% vs. 18%). Persons who survived more than 20 years after the diagnosis of their first cancer were at highest risk: 51% for females and 45% for males. Over 1 million person-years of observation were recorded, and the excess risk of developing a new cancer was 3.5 per 1,000 persons per year. Common environmental exposures seemed responsible for the excess occurrence of many second cancers, particularly those related to cigarette smoking, alcohol consumption, or both. For example, persons with epithelial cancers of the lung, larynx, esophagus, buccal cavity, and pharynx were particularly prone to developing new cancers in the same or contiguous tissue throughout their lifetimes. A notable finding was the high risk of cancers of the lung, larynx, buccal cavity, and pharynx observed among cervical cancer patients, which suggested a common etiology involving cigarette smoking. The intriguing association previously reported among cancers of the colon, uterine corpus, breast, and ovary was confirmed in our data, which indicated the possible influence of hormonal or dietary factors. Incidental autopsy findings were largely responsible for the observed excesses of second cancers of the prostate and kidney, and heightened medical surveillance of cancer patients likely resulted in ascertainment bias and elevated risks for some tumors during the early period of follow-up, most notably cancers of the thyroid. Interestingly, patients with prostate cancer were the only ones found to be at significantly low risk for second cancer development. However, this might be an artifact of case-finding because advanced age at initial diagnosis of prostate cancer was associated with an underascertainment of second cancers.

J Am Geriatr Soc. 1979   Cancer in the aged: an autopsy study of 940 cancer patients.    Ishii, Hosoda ea  In an autopsy study of 940 elderly cancer patients, 1,030 cancers were identified. The prevalence rate for overall cancer declined after age 85 in men and after age 75 in women. The chief sites of major cancers were the stomach, lung, esophagus, liver, and pancreas, in that order. Incidental cancers (chiefly of the prostate, thyroid, and colon) were found more often in patients over 80 years old. For multiple primary cancers, the prevalence rate was relatively constant until the age of 70, when it rose to a peak in the 80–84 age group before declining to the original level

4 Nov 2014  update: a new POSTAL study Colorectal cancer CRC  screening and subsequent incidence of colorectal cancer: results from the 45 and Up Study. by Steffen ea, from Australian universities shows the usual ~50% reduction BY SCREENING  in colorectal cancer occurrence, in a population mean age 60yrs followed for a mean of 3.78yrs in 741 000 screened pts , mean 60yrs at screening, mean BMI 27kg ie a high-risk population . .   But it glaringly omits  mentioning the most important data:     what was the allcause mortality reduction if any in the screened versus the unscreened cohorts after 3.78years? By this strange data omission, it must be assumed that the study showed no such benefit?.

All that the study confirmed is that it detected about 1000 new colon cancers in about 200 000 older people followed for almost 4 years ie an annual incidence of ~ 1 in 400 000 or 0.125% per year . This rate is similar to  the 0.12% cases pa ie per year  of early breast or  prostate cancer   claimed  in USA SEER data;  but the Australian CRC cancer rate reported is strangely almost three times the overall USA CRC incidence rate of about 0.04%pa found in USA men and women combined, similar to the lung cancer incidence reported there. . If the Australian data presented is correct, there must be something colotoxic (Perhaps their high beer and barbeque  intake?)  in the Australian diet compared to the European and USA population, since the great majority of all such citizens are of European “Caucasian”  origin?

This compares to South Africa where the latest stats for the whole population (NRC/CANSA 2007)   (assuming only maybe <1/4 of the population are 45yrs and up) are : prostate or breast 0.05%pa, lung or  CRC 0.01%pa, and cervix (much younger- due to abuse and STD) 0.05%pa. That study reported the lifetime risk of CRC in RSA as 1:115 in men, 1:199 in women, compared to , prostate 1:26 and breast 1:35, cervix 1:42,  uterus 1:176,  lung men 1:91  women  1:250.

There remains  no good evidence of lives saved ie reduction in all-cause mortality by such hugely costly population cancer screening for these commonest cancers. All that it achieves is the knowledge of previously silent cancer,  which would mostly have been buried unknown with the patient dying of other common causes- ie creating the worried well who have become “cancer survivors”.

we await response from the authors  on this primary issue .

Do any   studies show that there is   meaningful survival benefit from  costly mass screening for internal disease  of adults not at high risk, except for hypertension?  Mass CRC screening of people not at increased risk ( from family history, bowel symptoms or disease) is like breast and prostate screening, no apparent benefit on the most crucial issue, all-cause mortality.

19 Sept 2014   .    is there anything to update? CONCLUSION: not really. Conservatism urges avoidance of screening anyway in those with short lifespan from other major disease, or age eg above 75years- UNLESS there is good evidence of meaningful life extension. As we concluded in 2011, is such screening worth perhaps  1 month life extension in old age?

So far there is still no good evidence to support regular mass population screening in apparently well adults without risks for any degenerative disease  EXCEPT for hypertension;  glaucoma;   malignant melanoma; and  women at risk of cervix cancer ie sexually active at a younger age.

Health benefits and cost-effectiveness of a hybrid screening strategy for colorectal cancerDinh T,  Levin TR  ea 1Archimedes Inc, San Francisco  present a model rationale for FOBT screening from age 50yrs, with a single elective colonoscopy at 66yrs if FOBT remains negative – at a cost of US$10000 per putative QALY gained. .   Colorectal cancer (CRC) screening guidelines recommend screening schedules for each single type of test except for concurrent sigmoidoscopy and fecal occult blood test (FOBT). We investigated the cost-effectiveness of a hybrid screening strategy that was based on a fecal immunological test (FIT) and colonoscopy.   METHODS:  We conducted a cost-effectiveness analysis by using the Archimedes Model to evaluate the effects of different CRC screening strategies on health outcomes and costs related to CRC in a population that represents members of Kaiser Permanente Northern California. The Archimedes Model is a large-scale simulation of human physiology, diseases, interventions, and health care systems. The CRC submodel in the Archimedes Model was derived from public databases, published epidemiologic studies, and clinical trials.  RESULTS:   A hybrid screening strategy led to substantial reductions in CRC incidence and mortality, gains in quality-adjusted life years (QALYs), and reductions in costs, comparable with those of the best single-test strategies. Screening by annual FIT of patients 50-65 years old and then a single colonoscopy when they were 66 years old (FIT/COLOx1) reduced CRC incidence by 72% and gained 110 QALYs for every 1000 people during a period of 30 years, compared with no screening. Compared with annual FIT, FIT/COLOx1 gained 1400 QALYs/100,000 persons at an incremental cost of $9700/QALY gained and required 55% fewer FITs. Compared with FIT/COLOx1, colonoscopy at 10-year intervals gained 500 QALYs/100,000 at an incremental cost of $35,100/QALY gained but required 37% more colonoscopies. Over the ranges of parameters examined, the cost-effectiveness of hybrid screening strategies was slightly more sensitive to the adherence rate with colonoscopy than the adherence rate with yearly FIT.    .  CONCLUSIONS:  In our simulation model, a strategy of annual or biennial FIT, beginning when patients are 50 years old, with a single colonoscopy when they are 66 years old, delivers clinical and economic outcomes similar to those of CRC screening by single-modality strategies, with a favorable impact on resources demand.  Clin Gastroenterol Hepatol. 2013 Sep;:1158-66.

16 Sept 2014: PREVENT INSTEAD OF SCREEN: Dr  Ng  from DANA FABER CANCER INST, BOSTON MASS asks in .  Vitamin D for Prevention and Treatment of Colorectal Cancer: What is the Evidence?   Vitamin D insufficiency is highly prevalent in the U.S, particularly among colorectal cancer (CRC) patients- – studies suggest that higher vitamin D levels are associated with lower risk of incident CRC as well as improved survival in patients with established CRC. There remains a great need to improve prognosis for patients with CRC, and investigating vitamin D as a potential therapeutic modality is an attractive option in regards to safety and cost, particularly in this era of expensive and often toxic anti-neoplastic agents.  Curr Colorectal Cancer Rep. 2014 Sep 1;10:339-345

But as we know well from many studies, conventional “high” doses of vitamins C (eg  hundreds of  mgs/d)  and D (a few hundred to a few thousand iu/d)  have only modest benefit for prevention and against existing disease-  it requires about 10-15fold higher vit D3 ie 80-100iu/kg/day, and 100 to 500 more vit C ie a few to a few score gms vit C a day to have major impact. These must not be in isolation, as they may be limited by conditioned deficiency of other micronutrients especially vits K2. . We know well from eg the ATBC trial of vits A and E that too much and too late may be harmful, especially if these are not in natural balanced forms of all the vits A and E groups.

14 Sept 2014   A colleague is surprised that  at 72yrs I have never had a screening scope.

so I recheck the evidence after 3 years, since my 2011 review. Even The USA National Cancer Institute review of colon cancer screening  (updated to 24 July 2014) agrees  that Based on solid evidence, there is little evidence that screening for colorectal cancer (CRC) reduces all-cause mortality, possibly because of an observed increase in other causes of death, although in some studies it may reduce CRC mortality;   and there is always serious risk of harms. Overall, the NCI concludes that  On initial (prevalence) examinations, from 1% to 5% of unselected persons screened  with stool gFOBT guaiac faecal occult blood test (collected over 3 days, repeated up to yearly )   have positive test results ie 30 per 1000 recalled; of whom on imaging  2% to 10% have cancer and approximately 20% to 30% have adenomas,[26,27] depending on how the test is done.That translates to colon cancer detected in  about 3% of 6%  = 0.18% of the target population screened  – of whom 74% occur between 55 and 84 yrs. .

As a recent Spanish team review last year says, No strategy, whether alone or combined, has proven definitively more effective than the rest:   Economic evaluation of colorectal cancer (CRC) screening   Cruzado J1Carballo F. ea  1Colorectal Cancer Prevention Program for  Instituto Murciano de Investigación Biosanitaria,  Murcia, Spain Because of its incidence and mortality colorectal cancer represents a serious public health issue in industrial countries. In order to reduce its social impact a number of screening strategies have been implemented, which allow an early diagnosis and treatment. These basically include faecal tests and (then) studies that directly explore the colon and rectum. No strategy, whether alone or combined, has proven definitively more effective than the rest, but any such strategy is better than no screening at all. Selecting the most efficient strategy for inclusion in a population-wide program is an uncertain choice. Here we review the evidence available on the various economic evaluations, and conclude that no single method has been clearly identified as most cost-effective; further research in this setting is needed.. Best Pract Res Clin Gastroenterol. 2013 ;27:867-80.  

BUT:  Is aging per se a real risk factor for suffering colon cancer? No good evidence yet.  all cancers do increase with aging. But there is still no hard evidence of meaningful life extension from colon, breast or prostate  screening for silent risks in those without other cancer risk factors.

The NCI found four completed  trials of FOBT faecal occult blood testing since 2004 – in Minneapolis(46500), Denmark (31000), Sweden(68000) and UK(151000) – ie 300 000 older lowrisk adults- these   find no benefit in terms of increased length of life. The longest, –  30 year followup in Minneapolis – looks at the longterm mortality benefit of CRC screening– and as with breast and prostate screening for silent cancer in those without significant risk factors.   So organized mass population screening eg every 1  or 10 years from age 50 years does not save lives in the elderly at low risk ie no colon symptoms- at an enormous cost in the scores  of well people  – about 1.2 per 1000- needed to screen, with about 3% of these found positive needing imaging- at major risk of unforseen problems-  to find one cancer, shorten the lead time, save a life from silent cancer. We all die from something eventually. 99.82% of the population screened did not develop colon cancer.

In firstworld people the risk of colon cancer is generally below that of breast and prostate cancer respectively: Wiki sums it up-                                                                    Based on rates from 2007-2009, 5% of US men and women born today will be diagnosed with colorectal cancer during their lifetime.[95] The median age at diagnosis for cancer of the colon and rectum in the US was 69 years of age. Approximately 0.1% were diagnosed under age 20; 1.1% between 20 – 34; 4.0% between 35 – 44; 13.4% between 45 – 54; 20.4% between 55 a-64; 24.0% between 65 – 74;  25.0% between 75- 84; and 12.0% 85+ years. Rates are higher among males (54 per 100,000 c.f. 40 per 100,000 for females). about 20% of such cancer patients have a familial genetic risk.

so faecal screening would be the mass screening method of choice, with about 25% recall rate for costly colon imaging to find the 1.2  cases per 1000 in the target population. But that is supposed to uncover silent colon cancer 2 years earlier, allowing expected drastic reduction in the 75% mortality of clinically presenting colon cancer. So why do no trials of  colon cancer screening show reduction in all-cause mortality? Perhaps its because the lethal colon cancers occur  and present clinically younger in those with lethal genetic risks eg Lynch syndrome, or predisposing colon inflammation eg ulcerative colitis, Crohn’s; or those with multiple polyposis  who are more likely to bleed early.

But we know that real chronic colonic  disease is par excellence a western Saccharine Disease ie of our urban fastfood high sugars,  low fibre diet, inadequate water intake,  and slothful low sunshine ie couch potato  low vitamin D  constipated  lifestyle; with often smoking and alcoholism. . Naturally the Wiki review, written to favour regular screening to find profitable more  silent cancers (like breast and prostate screening) , does not mention this. .

Shaukat A1, Church TR ea  (in N Engl J Med. 2013;369:1106-14  Long-term mortality after screening for colorectal cancer    Minneapolis VA Health Care System USA).  In randomized trials, fecal occult-blood testing FOBT  reduces mortality from colorectal cancer. However, duration of the benefit is unknown, as are the effects specific to age.  METHODS:  In the Minnesota Colon Cancer Control Study, 46,551 participants, 50 to 80 years of age, were randomly assigned to usual care (control) or to annual or biennial screening with fecal occult-blood testing. Screening was performed from 1976 through 1982 and from 1986 through 1992. We used the National Death Index to obtain updated information on the vital status of participants and to determine causes of death through 2008.  RESULTS:  Through 30 years of follow-up, 33,020 participants (70.9%) died. A total of 732 deaths 2% were attributed to colorectal cancer: 200 of the 11,072 deaths (1.8%) in the annual-screening group, 237 of the 11,004 deaths (2.2%) in the biennial-screening group, and 295 of the 10,944 deaths (2.7%) in the control group. Screening reduced colorectal-cancer mortality (relative risk with annual screening, 0.68; 95% confidence interval [CI], 0.56 to 0.82; relative risk with biennial screening, 0.78; 95% CI, 0.65 to 0.93) through 30 years of follow-up. No reduction was observed in all-cause mortality (relative risk with annual screening, 1.00; 95% CI, 0.99 to 1.01; relative risk with biennial screening, 0.99; 95% CI, 0.98 to 1.01). The reduction in colorectal-cancer mortality was larger for men than for women in the biennial-screening group (P=0.04 for interaction).     CONCLUSIONS: The effect of screening with fecal occult-blood testing on colorectal-cancer mortality persists after 30 years but does not influence all-cause mortality. The sustained reduction in colorectal-cancer mortality supports the effect of polypectomy.

For mass Sigmoidoscopy screening,   Five sigmoidoscopy screening RCTs have reported incidence and mortality results.- Norway 2 trials;  and  United Kingdom; Italy; and the U.SA, in 166,000 participants in the screened groups and 250,000 controls. Follow-up ranged from only 6 to 13 years.   There was an overall 28% relative reduction in CRC mortality (RR, 0.72; 95% CI, 0.65–0.80), an 18% relative reduction in CRC incidence (RR, 0.82; 95% CI, 0.73–0.91), and a 33% relative reduction in the incidence of left-sided CRC (RR, 0.67; 95% CI, 0.59–0.76). There was no effect on all-cause mortality.

For mass colonoscopy screening, no trials have been completed to give any evidence of longterm mortality benefit.

One group proposes a screening program based on  periodic stool FIT faecal immunological test , with a single colonoscopy at 66yrs.  Dinh , Levin ea Archimedes Inc, San Francisco,( Clin Gastroenterol Hepatol. 2013 ;11:1158-66   Health benefits and cost-effectiveness of a hybrid screening strategy for colorectal cancer)  In our simulation model, a strategy of annual or biennial FIT, beginning when patients are 50 years old, with a single colonoscopy when they are 66 years old, delivers clinical and economic outcomes similar to those of CRC screening by single-modality strategies, with a favorable impact on resources demand.

UPDATE  20 Oct  2011 A chiropracter asks: what is the recommendation regarding screening colonoscopy, mammography, prostate for cancers? would MD’s and DO’s get one and if so in what circumstance?

My answer:

The only link between breast, prostate, bowel, ovary and womb cancers is that these organs (unlike cervix cancer) are genetically linked through common sex hormone influences; and (apart from the breasts) coincidentally abut ..

Prostate cancer associates with higher estrogen and DHT levels. As for usually estrogen-dependent breasts and  breast cancer screening in low-risk breasts discussed previously, the overwhelming evidence favours no screening at all without symptoms  or risk factors. Unlike for breast cancer,  treatment for prostate cancer (as for  colon cancer) seems to make no difference except when there is obstruction or bleeding. For asymptomatic PRCA the rule remains: watchful waiting. Like women and breast cancer, many men have undiagnosed ie asymptomatic prostate cancer at autopsy for other causes of death.

Colon cancer is different.   it is less common in women with estrogen replacement.

But unlike prostate and breast cancer where invasive screening of all lowrisk patients likely causes more harm  (including despondency) than good,  it is hard to find good colon cancer studies of asymptomatic lowrisk people that show no benefit of screening colon imaging. Studies of colon cancer imaging are inevitably by practitioners who have  a major commercial vested interest in such imaging.

But how many studies have been done comparing colon screening with no screening in patients who truly have none of the risk factors –  – heredity, meat diet, smoking, overweight, bleeding,  inflammatory bowel disease, polyps, diabetes?

Few articles are against such colon screening ie rationalize or philosophize against it .

A 2011 Medscape review from a New Jersey University team concludes cautiously: “In particular, education and intervention efforts for colon imaging should be focused on patients that have risk factors eg diabetes, obesity, or are former/current smokers. This population represents a sub-group of patients who are having CRC screening at a rate lower than the average-risk population. Significant reductions in CRC incidence and mortality might be possible by providing targeted screening interventions to increased-risk individuals and by educating physicians on the importance of recommending screening to these patients even in the face of multiple competing demands”. ie it  encourages  colon screening in  increased risk individuals. 

Search of Pubmed for “incidental colon cancer at autopsy” reveals only three  studies, >20 years ago,  two in the orient.

Ueyama ea, Kyushu University, Japan in Am J Gastroenterol.1991    Colorectal carcinomas incidentally detected in 3,638 autopsied cases and inpatients  during the past 20 yr.   17 colorectal carcinomas (0.47%) were incidentally detected among autopsied patients without clinically evident colorectal carcinoma, including 2,232 males and 1,406 females more than 40 yr old. Among the 15 male and two female index subjects, six (0.33%) were detected in the first and 11 (0.60%) in the second decade. During their survival periods, fecal occult blood studies were performed in 14 cases and positive in 12 (86%); however, two of them had gastric ulcers which were responsible for the occult blood. During the recent 11 yr, six cases (0.48%) of colorectal carcinoma (four of them males; two, females) also were detected among 1,249 inpatients who were examined by barium enema and/or colonoscopy, including 816 males and 433 females, 40 yr old, or more, in the Department of Radiology. Fecal occult blood was detected in four cases (67%) before colonic investigation. Compared with 708 surgically resected carcinomas, the incidental lesions from both sources were smaller, consisted of higher percentages of Dukes’ A type, and arose predominantly from the sigmoid colon and, rarely, from the rectum. These results indicate that the prevalence of colorectal carcinoma and its predominance in the sigmoid colon have not only apparently but actually increased in Japan, apart from improved diagnostic capabilities, and that false-negative rates with occult blood tests were surprisingly low in these autopsied cases and inpatients.

 Lee YS in Cancer 1988 studied Incidental carcinoma of the colorectum at autopsy in Singapore. . . Ten incidental invasive carcinomas (two early carcinomas involving the submucosa, and eight advanced carcinomas involving the muscularis propria or beyond) of the large intestine were discovered in a series of 1014 consecutive autopsies. All occurred in Chinese aged 60 years and older, constituting a prevalence rate of about 3% in this age group. If unsuspected colorectal carcinomas in Chinese Singapore residents aged 60 years and older exist in those who died in 1984 to the same extent as that noted in this autopsy study, it was estimated that 146 additional cases would have been added to the Cancer Registry in that year. This would constitute 47.9% of the total number of colorectal cancers diagnosed in this age group in 1984. This potential contribution has to be taken into consideration in epidemiologic studies on the incidence and future trends of colorectal cancers in Singapore. Incidental carcinomas were found predominantly in the ascending colon. With more frequent use of colonoscopy, the incidence of right-sided cancers of the large bowel may be expected to increase. The current underdiagnosis of ascending colon carcinomas has to be taken into consideration when any future increase in right-sided cancers of the large bowel is observed. 

Suen ea Cancer. 1974 studied Cancer and old age – autopsy study of 3,535 patients over 65 years old, in New York from 1960 to 1970 ie a decade earlier than the above oriental studies; they showed that men had cancer nearly twice as frequently as women (40% vs. 24%); and more incidental ie less aggressive neoplasms as age advanced. The most frequent cancers were those of the prostate (12% of men), gyne (7.5% of women- breast 3%) , kidney 3.5%, and colon 5.6%.. 70% of the cancers were already diagnosed in life ie 30% were incidental findings. Cancer tended to metastasize less frequently in the elderly.  The most common sites of latent asymptomatic cancer reported by Berg et al The prevalence of latent cancers in cancer patients. Arch. Pathol 1971. in their study of 5636 cancer patients with ages ranging from the teens to over 80,were prostate, thyroid, colon, and kidney. They further emphasized that cancer of the colon and kidney were the ones most easily missed clinically. In our study, the most frequent sites of incidental cancer, among the common cancers, were prostate (incidental 67%), kidney (51%), colon (31.5%), and breast 16.6%.

And  researchers from the Universities of California, North Carolina and Harvard –  Walter ea show in 2005  Screening for colorectal, breast, and cervical cancer in the elderly: Am J Medicine  that “characteristics of individual patients that go beyond age should be the driving factors in screening decisions… in one study -Selby ea A case-control study of screening sigmoidoscopy and mortality from colorectal cancer . N Engl J Med . 1992; .”For colorectal cancer screening, fecal occult blood testing has the strongest evidence of benefit in elderly patients, while flexible sigmoidoscopy reduces mortality from colorectal cancer by 59% .Flexible sigmoidoscopy has fewer complications than colonoscopy, with perforations occurring in less than 0.1 of 1000 examinations; .” But they did not report data on benefit of colorectal screening of lowrisk adults in terms of actual overall life extension ie reduction in all-cause mortality- which benefit has not been shown in rigorous analysis of xray screening mammography or screening blood and digital exams of lowrisk men for prostate cancer. .

Lack of significant life extension by breast and colon screening was shown by Rich and Black from Vermont USA in Clin Pract. 2000 When should we stop screening? Given a starting age of 50 years, screening throughout life has a maximum potential life expectancy benefit of 43 days for breast cancer and 28 days for colon cancer.

These 1 month extensions in life expectancy do not justify screening the entire population of older persons- surely only those of us with significant risk factors need be screened.

CONCLUSION: from the above references from autopsy series, the prevalence  of   incidental ie asymptomatic colon cancer at routine autopsy  in older deaths varies between about 0.5% and 3% in oriental and New York patients. So since I dont have any symptoms or risk factors listed, after 50 years in medicine I havent had colon or prostate imaging for a potential 4 week gain in life expectancy. I will do so promptly if I get colon symptoms.

I tell my older lowrisk patients the dubious potential benefit of cancer screening, and the serious risks, from overdiagnosis- polyps and lowgrade cancers that might never present in lifetime, to perforation ; while explaining to them that well-patient  breast, prostate  and colon cancer screening is hugely profitable universal policy.

For non-emergency consultations and especially costly and invasive procedures, doctors and patients need reminding that it’s the patient’s choice, not the doctors’..

This brings us to one of the ethical dilemmas of medicine: when our experience, and careful sifting of the hard evidence, conflicts with conventional wisdom- which is often based on belief and vested interests- evidence slanted hy bias- surely we practitioners have both a right to express our evidence-based personal conviction, and a duty to do so. Thus we surely have a duty  to give the patient the hard evidence both for and against- be it about the power of prayer and belief, about contraception and abortion, for and against statins for mild-moderate lipidemia, or in the low-risk patient, screening mammography, prostate or colon screening.

 

 

The Nonscience Witch Hunt Against HRT for Deficiency Syndromes Must End: An A4M Position Paper on Physician-Prescribed HRT

Our Oct 2014 cover
The Nonscience Witch Hunt Against Hormone Replacement Therapies for Deficiency Syndromes Must End
An A4M Position Paper on Physician-Prescribed HRT

Introduction  “Unless we put medical freedom into the Constitution, the time will come when medicine will organize into an undercover dictatorship to restrict the art of healing to one class of Men and deny equal privileges to others; the Constitution of the Republic should make a Special privilege for medical freedoms as well as religious freedom.”~Benjamin Rush (1745–1813), physician, writer, educator,
humanitarian, and Founding Father of the US

Since the inception of the anti-aging medical movement in 1991, various establishment parties have ruthlessly leveraged their positions of power in academic, political, and regulatory arenas for the purpose of attempting to limit the use of hormone replacement therapies (HRT) in adults with documented clinical deficiencies. For over 15 years, a prolonged and calculated campaign of deceit, fraud, and suppression has threatened physician licensures and liberties to treat and prescribe life-improving therapies, leading potentially to the direct compromise of patients’ health and longevity. Dozens of physicians have been sanctioned and punished with loss of license and academic standing. This pernicious abuse of position and power is particularly prevalent with regard to recent challenges made against human growth hormone (HGH), testosterone (TRT), and DHEA replacement therapies that are trumpeted by the mainstream media. Biased reporters frequently – and inappropriately – demonize legitimate physicians and clinical compounding pharmacies that are reluctantly positioned on the frontline of a decades-old agenda to limit freedom of choice and information, and the physicians’ most essential responsibility to select the best course of therapy and medication for their patients.

This conflict is being played out of late in the arena of anti-aging medicine, a clinical specialty that has flourished in its 22 year long history, garnering the support of more than 100,000 physicians and scientists worldwide who practice or research life-enhancing, life-extending interventions today. Prof. Dr. Imre Zs.-Nagy, of the University of Debrecen Medical and Health Science Center (Hungary), and founder of the Archives of Gerontology and Geriatrics (published by Elsevier), observes: “In my role as a basic and clinical scientist, I have had an opportunity to witness more than four decades of advances and declines in the arena of preventive medical care … there has been little else as dramatic, important, beneficial, and significant as the anti-aging medical movement.”1
   
Continual vigilance is necessary to countermand those whose financial and professional successes depend on repeated, calculated attempts to discredit the science and substance of anti-aging medicine.
   
Remarks Tanjung Subrata, MD, of Udayana University School of Medicine (Indonesia):
Anyone who does not believe in evil is not paying attention to the recent affairs of the past twenty years. We are living in a time of unprecedented tribulation and changes at-large – and in health care, in particular. All that is necessary for evil to prevail is for men of good will to do nothing. In this modern age of zero tolerance for alternatives to establishment medicine, and the willingness of our governmental officials to resort to police state tactics to suppress innovative schools of thought, progress in medicine halts and dies.2

A4M Position
The American Academy of Anti-Aging Medicine (A4M), its numerous worldwide affiliated scientific and medical societies, and befriended organizations support the judicious application of modern and advanced medical technologies to address the changes in chemical, hormonal, physical, and nutritional needs that occur with aging. Such repletion includes the restoration of hormones to an optimal physiological state when deficiency is determined by objective assessment.
   
Hormone replacement therapy (HRT) is an essential and extensively documented protocol for clinical intervention in the disorders of aging. HRT maintains an unblemished safety and efficacy profile that has been documented by 20 years of clinical application. Yet, a perfect storm of misguided media, combined with biased parties whose livelihoods hinge on disparaging the anti-aging medical movement, has grossly compromised access to HRT, placing the lives of hundreds of thousands of patients worldwide in potential jeopardy.
   
Experienced anti-aging physicians have been prescribing HRT for more than 20 years. PubMed contains more than 20,000 peer-reviewed studies of HRT, of which a preponderance document the life-enhancing and/or life extending benefits of HRT in aging adults. See Appendix A “Literature Review,” which presents a selection of such studies that represent the objective evidence that supports the A4M position.

The Anti-Aging Medical Movement
The goal of anti-aging medicine is not to merely prolong the total years of an individual’s life, but to ensure that those years are enjoyed in a productive and vital fashion. As established in 1991 by the physicians of the American Academy of Anti-Aging Medicine (A4M), the field of anti-aging medicine developed as a direct extension to the science of elite sports medicine of the 1980s. Just as sports medicine aims to keep the athlete’s body functioning at its optimum level, anti-aging medicine seeks to keep the human physiology performing at its peak. In other words, the similar principle, of extending and maximizing the healthy human lifespan, is at the core of both anti-aging medicine and sports medicine.

The Official Definition of Anti-Aging Medicine
The clinical specialty of anti-aging medicine thus is defined as follows:      Anti-aging medicine is a clinical specialty is founded on the application of advanced scientific and medical technologies for the early detection, prevention, treatment, and reversal of age-related dysfunction, disorders, and diseases. It is a health-care model promoting innovative science and research to prolong the healthy lifespan in humans. As such, anti-aging medicine is based on principles of sound and responsible medical care that are consistent with those applied in other preventive health specialties. The phrase “anti-aging,” as such, relates to the application of advanced biomedical technologies focused on the early detection, prevention, and treatment of aging- related disease.

Anti-aging medicine utilizes diagnostic protocols that are supported by scientific evidence to arrive at an objective assessment upon which effective treatment is assigned. Physicians who dispense anti-aging medical care are concerned with the restoration of optimal functioning of the human body’s systems, organs, tissues, and cells. Attempting to rebrand what they cannot deny, those in positions of power in academic, political, and regulatory arenas are inventing new catchphrases including longevity medicine, successful aging, healthy aging, and the like, in an effort to dilute and absorb the A4M’s original definition of anti-aging medicine. To implement this campaign, we suspect that these individuals have pejoratively solicited major media outlets to denigrate the A4M, its officers, and its members.
   
Anti-aging medicine is, in essence, a euphemism for early detection and advanced preventative medicine. It is a health-care model that emphasizes personalized, patient-focused, high-quality metabolic-specific medical care.

Critics with A Dark Agenda (Political Elites)
Scientifically based and well documented in leading medical journals, anti-aging medicine is among the fastest-growing medical specialties throughout the world. As an innovative model for advanced preventive health care that cannot be denied, anti-aging medicine has been disparaged by individuals with their own political and financial agendas in attempts to restore monopolistic control over the field of aging intervention. Critics of the science of anti-aging medicine most commonly hail from academia: as such, these naysayers many times have little or no medical training in aging intervention and may be nonclinicians.
   
Perhaps the most inconceivable reality is that at the very highest levels of academia, government, and science, truth and objective scientific method are not at all sacred to the political elites. We in clinical medicine via our training, discipline, and conditioning naively believe and act in the public interest, for the good of our patients’ health, and by professional standards of medical ethics. The (elite) medical establishment operates contrary to this position, reports investigative reporter Tim Bolen (www.bolenreport.com), who for 30 years has amassed data and evidence exposing a calculated effort to deride innovative medical therapeutics. Bolen observes:  Without a doubt, a stealthy control group – a cabal, if you will, in status-quo medicine exists. Approved by Big Pharma, parts of academia, and segments of the government, this group exerts its control in many different ways. I have uncovered information showing anonymous, and not-so-anonymous, funding of groups, loosely describing themselves as “Quackbusters or Skeptics” whose only purpose is to attack cutting-edge health care offerings. Those groups, in turn, train, and fund sub-groups. Data suggests that the “Quackbusters or Skeptics” donated over $1 Million US to Wikipedia to purchase control over pages with medical content. More, the Skeptic training camps teach their recruits how to operate together to control that same Wikipedia and Search Engines. Further, these covert groups drive media on issues particularly pertaining to alternative health care, in an effort to limit coverage of innovative discoveries and to vilify therapies that are not part of AMA/FDA/Big Pharma establishment medicine health care.

There are TWO main “skeptic” organizations – the James Randi Educational Foundation (JREF) and the Center For Inquiry (CFI). Both are well funded from secret sources.

JREF reported, in 2010, a total income of $999,971.00 and a Total Asset claim of $1,736,101.

The Center For Inquiry, Inc (CFI), based in Amherst, New York shows on their Form 990 that they took in $5,242,304 in Total 2009 Income, and they had, that year, Total Assets of $3,017,144. Their Schedule B ANONYMOUS contributions totaled $2,318,652.

More, CFI claimed that they received, in 2009, in addition to their anonymous contributions, a so-called “Management Fee Income” of $2,458,156. What do you suppose they managed? And who paid them to manage it? Maybe they manage Wikipedia health care articles? How about Search Engine Optimization (SEO) bringing skeptic, including Stephen Barrett’s (Quackwatch), articles to the first page of Google?

Much more – This cabal minimizes and delays innovative medical advancements by lodging anonymous complaints to state licensing boards against cutting-edge practitioners. Their insidious campaign also controls grant monies and research funding, somewhat silencing the voices of innovative medicine in favor of mainstream views. By leveraging control of the media in direct jeopardy of journalistic integrity, this control group seeks to suppress all in medicine that is not fully controlled by the establishment. To permit this level of manipulation and disinformation is wrong and ethically corrupt. The fate of a valuable avenue of medical innovation for the public interest – anti-aging medicine – stands at-risk.3

A JAMA commentary purported to address the legality of human growth hormone (HGH, GH) treatment by physicians for growth–hormone deficient (GHD) patients.4 It is the view of A4M that the commentary contained a number of incorrect, misplaced references and studies, and multiple basic scientific errors, in an apparent attempt to damage the anti-aging medical profession and the physicians practicing solid, evidence-based medical health care focused on improving and maintaining patients’ quality of life. It is A4M’s further opinion that the authors selected self-serving studies, in which they failed to qualify the conclusions in an effort to bolster what A4M believes is a disinformation campaign. It is A4M’s opinion, for example, that they incorrectly intermingled Internet sales of homeopathic pseudo-“GH” sprays, amino acids, and sports nutritional over-the-counter products in order to inflate their incorrect claims suggesting an illegal diversion of HGH by physicians and pharmacies, implying a black market in FDA-approved prescription injectable HGH for hormone replacement treatments by anti-aging physicians where none exists.

Misrepresentation in Competitive Sports
As an unfortunate consequence of media confusion and outright deception aiming to deliberately misrepresent anti-aging medical care, the reality of the clinical practice of hormone replacement therapy has become muddled. A recent Sports Illustrated article states: “In the sports world, the term ‘anti-aging’ has often come to signify therapy that uses hormones – usually testosterone and HGH – and … DHEA.”5 This erroneous definition grossly misrepresents the legal and ethical physiological use of hormones and supplements as being synonymous with the inappropriate use of hormones for sports enhancement. The A4M is squarely opposed to this myopic interpretation of “anti-aging” and urges reference to the official definition of anti-aging medicine as presented above.

Page 1, 2, 3, 4, Appendix/Notes

29 SEPT 2014 OVARIAN CANCER UPDATE: PROGESTERONE REPLACEMENT IS IDEAL; WHY USE ORAL HT? WHEN ESPECIALLY LONG TERM PROGESTINS GREATLY INCREASE RISK OF OVARIAN AS WELL AS BREAST CANCER.

: ABSTRACT:  since last review in  this column 5 years ago, what progress has there been with ovarian cancer OvCa? On Pubmed there are 81000 references,  45500 reviews on OvCa

5 Oct 2014:  Ovarian Cancer Often Arises from Precursor Endometriosis    Frontline Medical News, 2014 Sep 29, B Jancin

   29 Sept 2014  The good news is that if ovariectomy is not done at hysterectomy, then at least salpingectomy should be done- it does not cause earlier menopause.  And the modern fashion for progesterone cream as baseline hormone balancing in this age of estrogen dominance, the feminization of nature,  also adds major protection for heart, bone, memory, mood,  and against cancer, without the risks of estrogen.

Before this month’s update,  the latest, an Australian cancer review  Mette ea 2013, shows that cigarette smoking increases the risk of OvCa by 30% to 60%.

The latest   review 2013 Modugno ea at Univ Pittsburgh/Mayo Clinic  Hormone response in ovarian cancer: time to reconsider as a clinical target?   said “Ovarian cancer is the sixth most common cancer worldwide among women in developed countries and the most lethal of all gynecologic malignancies. There is a critical need for the introduction of targeted therapies to improve outcome. Epidemiological evidence suggests a critical role for steroid hormones in ovarian tumorigenesis. There is also increasing evidence from in vitro studies that estrogen, progestin, and androgen regulate proliferation and invasion of epithelial ovarian cancer cells. Limited clinical trials have shown modest response rates; however, they have consistently identified a small subset of patients that respond very well to endocrine therapy with few side effects. We propose that it is timely to perform additional well-designed trials that should include biomarkers of response.The most consistently reported reproductive and hormonally related factors found to protect against EOC are use of oral contraceptives (OCs), increasing parity, and having a tubal ligation. In contrast, increasing age and nulliparity have been consistently shown to increase EOC risk. 

    Recent studies, including the prospective Women’s Health Initiative (WHI) (Anderson et al. 2003) and the Million Women Study (Beral et al. 2007), report an increase in risk for both estrogen-only (ET) and estrogen–progestin (EPT) formulations, although the risk associated with EPT was lower than that of ET. A recent meta-analysis of 14 published studies found risk increases 22% per 5 years of ET use compared with only 10% per 5 years of EPT use, suggesting that risk differs by regimen (Pearce et al. 2009).               Exogenous androgens may be associated with EOC. One case–control study found that use of Danazol, a synthetic androgen commonly used in the treatment of endometriosis, significantly increased EOC risk (Cottreau et al. 2003), although this finding has not been replicated (Olsen et al. 2008). Ever use of testosterone (tablets, patches, troches, or cream) has been associated with a threefold increase in EOC (Olsen et al. 2008).             

     Reproductive disorders and other reproductive factors :  Factors affecting childbearing have also been shown to be associated with EOC. In most studies, infertility has been associated with an increased risk, which may be greatest among women who fail to conceive (Vlahos et al. 2010). In general, infertility treatment does not appear to increase EOC risk, although the subset of treated women who remain nulliparous may be at an increased risk (Vlahos et al. 2010).

         Endometriosis, defined as the presence and growth of endometrial tissue outside the uterine cavity, has also been associated with EOC. A recent pooled analysis of 13 case–control studies showed a threefold increase in the incidence of clear cell EOC and a twofold increase in endometrioid EOC among women with a self-reported history of endometriosis (Pearce et al. 2012).

    An increased risk of EOC was reported by one case–control study (Schildkraut et al. 1996) among women with polycystic ovary syndrome (PCOS), a condition associated with menstrual dysfunction, infertility, obesity, the metabolic syndrome, hyperandrogenism, and insulin resistance. However, the finding was based on a small number of cases (n=7) and the association was limited to nonusers of OCs and thin women. Further case–control and prospective studies have failed to confirm this relationship (Pierpoint et al. 1998, Olsen et al. 2008, Brinton et al. 2010).

   Tubal ligation has been consistently shown to be associated with reduction in EOC risk (Cibula et al. 2011). This protection appears similar in magnitude to OC use and child bearing (about 30%) and is protective in high-risk women (i.e. BRCA1/2 carriers) as well. Hysterectomy has also been shown to reduce EOC risk, although the magnitude of the association is not as great nor as consistent as that reported for tubal ligation (Riman et al. 2004). Finally, reproductive factors associated with other hormonally linked cancers, such as age at first menarche, age at menopause, and length of reproductive years, have not been consistently associated with EOC (Riman et al. 2004).

    Estrogens and androgens –  The evidence linking these  to EOC are mixed. The majority of women who develop ovarian cancer are postmenopausal at the time of diagnosis. In postmenopausal women, the major source of circulating estrogen is from the peripheral conversion (in skin and adipose tissue) of androstenedione by the enzyme aromatase.

    Progesterone and progestins- Epidemiological data suggest that progestins and progesterone may have a protective role against EOC. Importantly, there is some evidence that progesterone might synergize with chemotherapeutic drugs to induce apoptosis.

Now this month  comes exciting news about  a  Paradigm Shift: Prophylactic Salpingectomy for Ovarian Cancer Risk Reduction   Frontline Medical News, 2014 Sep 24, B Jancin     :   Removing the fallopian tubes at the time of pelvic surgeries as a potential means of reducing ovarian cancer risk appears to be a movement that’s picking up steam in clinical practice.
       A recent survey of 234 U.S. gynecologists showed prophylactic bilateral salpingectomy is catching on when performed in conjunction with hysterectomy, but far less so for tubal sterilization, Dr. Austin Findley observed at the annual Minimally Invasive Surgery Week.                                                                       A total of 54% of respondents indicated they routinely perform salpingectomy at the time of hysterectomy in an effort to reduce the risk of ovarian cancer as well as to avoid the need for reoperations. However, only 7% of the gynecologic surgeons said they perform salpingectomy for tubal sterilization, even though 58% of respondents stated they believe the procedure is the most effective form of tubal sterilization (J. Minim. Invasive Gynecol. 2013;20:517-21).
  “In my experience at various hospitals, I think these numbers are a pretty accurate reflection of what folks are doing,” commented Dr. Findley of Wright State University in Dayton, Ohio.
     The prophylactic salpingectomy movement is an outgrowth of the tubal hypothesis of ovarian cancer.
    “There is now increasing and dramatic evidence to suggest that most ovarian cancers actually originate in the distal fallopian tubes. I think this is a concept most people are unaware of or are just becoming accustomed to. The tubal hypothesis represents a major paradigm shift in the way we think about ovarian cancers. The previous belief that excessive ovulation is a cause of ovarian cancer is no longer regarded as accurate,” he explained at the meeting presented by the Society of Laparoscopic Surgeons and affiliated societies.
      Ovarian cancer is the No. 1 cause of mortality from gynecologic malignancy, accounting for more than 14,000 deaths per year, according to National Cancer Institute data. The lifetime risk of the malignancy is 1.3%, with the average age at diagnosis being 63 years.
       Only 10%-15% of ovarian cancers occur in women at high risk for the malignancy because they carry a BRCA mutation or other predisposing gene. The vast majority of ovarian cancer deaths are caused by high-grade serous tumors that have been shown to be strongly associated with precursor lesions in the distal fallopian tubes of women at low risk for the malignancy.
            There is no proven-effective screening program or risk-reduction method for these low-risk women. However, with 600,000 hysterectomies and 700,000 tubal sterilizations being performed annually in the United States, prophylactic salpingectomy has been advocated as an attractive opportunity to potentially reduce ovarian cancer risk. Other common pelvic surgeries in which it might be used for this purpose include excision of endometriosis and laparoscopy for pelvic pain. It also has recently been shown to be feasible and safe post partum at cesarean or vaginal delivery (Obstet. Gynecol. 2014 [doi: 10.1097/01.AOG.0000447427.80479.ae]).
   But the key word here is “potentially.” It must be emphasized that at present the ovarian cancer prevention benefit of prophylactic salpingectomy remains hypothetical; in theory, the procedure should reduce ovarian cancer risk, but there is not yet persuasive evidence that it actually does, Dr. Findley emphasized at the meeting, presented by the Society of Laparoendoscopic Surgeons and affiliated societies.
            In contrast, one well-established ancillary benefit of prophylactic salpingectomy is that it eliminates the need for future reoperation for salpingectomy. This was demonstrated in a large Danish cohort study including close to 10,000 women undergoing hysterectomy and a similar number undergoing sterilization procedures. Among the nearly two-thirds of hysterectomy patients who had both fallopian tubes retained, there was a 2.13-fold increased likelihood of subsequent salpingectomy, compared with nonhysterectomized women.
        Similarly, Danish women who underwent a sterilization procedure with retention of the fallopian tubes – typically tubal ligation with clips – were 2.42 times more likely to undergo subsequent salpingectomy, most often because of the development of hydrosalpinx, infection, ectopic pregnancy, or other complications (BMJ Open 2013;3 [doi:10.1136/bmjopen-2013-002845]).
     The most commonly cited potential risk of prophylactic salpingectomy – decreased ovarian function – now appears to be a nonissue. This was demonstrated in a recent retrospective Italian study (Gynecol. Oncol. 2013;129:448-51) as well as in a pilot randomized controlled trial conducted by Dr. Findley and his coworkers (Fertil. Steril. 2013;100:1704-8), which appears to have answered many skeptics’ concerns. Indeed, Dr. Findley’s coinvestigator Dr. Matthew Siedhoff said he has recently been approached by researchers interested in collaborating in a larger confirmatory randomized trial, but all parties eventually agreed it was a no-go.
    “It’s a little hard to demonstrate equipoise for a larger randomized controlled trial. We’re beyond that now, given that prophylactic salpingectomy really doesn’t seem to make a difference as far as ovarian function,” according to Dr. Siedhoff, director of the division of advanced laparoscopy and pelvic pain at the University of North Carolina, Chapel Hill.
         Another oft-expressed reservation about salpingectomy as a means of reducing ovarian cancer risk in women seeking sterilization is that salpingectomy’s irreversibility may lead to “tubal regret” on the part of patients who later change their mind about further pregnancies. However, Dr. Findley cited a recent editorial whose authors criticized colleagues who made that claim. The editorialists argued that the tubal regret concern indicates surgeons weren’t really listening to their patients’ true desires during the informed consent conversation.
     “We should not have started thinking about salpingectomy for female sterilization only once a decrease in ovarian cancer risk became part of the equation,” they declared (Obstet. Gynecol. 2014;124:596-9).
           Dr. Findley noted that Canadian gynecologists are leading the way forward regarding prophylactic salpingectomy as a potential method of ovarian cancer prevention. The Society of Gynecologic Oncology of Canada in a 2011 policy statement recommended patient/physician discussion of the risks and benefits of bilateral salpingectomy for patients undergoing hysterectomy or requesting permanent sterilization. The Society of Gynecologic Oncology followed suit with a similar clinical practice statement in late 2013.
        Additionally, the Canadian group declared that a national ovarian cancer prevention study focused on fallopian tube removal should be a top priority.
    Gynecologic oncologists in British Columbia recently reported the eye-catching results of a province-wide educational initiative targeting gynecologists and their patients. In 2010, all British Columbia gynecologists had to attend a course on the role of the fallopian tubes in the development of ovarian cancer, during which they were advised to consider performing bilateral salpingectomy for ovarian cancer risk reduction.
              Surgical practice changed dramatically in British Columbia in response. In 2009 – the year prior to the physician education initiative – salpingectomy was utilized in just 0.3% of permanent sterilization procedures. In 2010, it was 11.4%. By 2011, it was 33.3%.
           Similarly, only 7% of hysterectomies performed in British Columbia in 2009 were accompanied by bilateral salpingectomy. This figure climbed to 23% in 2010 and jumped further to 35% in 2011. Meanwhile the rate of hysterectomy with bilateral salpingo-oophorectomy remained steady over time at 44% (Am. J. Obstet. Gynecol. 2014;210:471.e1-11).
     This project was conducted in collaboration with the B.C. Cancer Agency, which maintains comprehensive province-wide registries. Over time, it will be possible to demonstrate whether prophylactic salpingectomy is indeed associated with a reduction in the incidence of ovarian cancer. “I think this study demonstrated that there’s a lack of awareness on this issue, but also [that there’s] potential effectiveness of introducing an educational initiative like this in changing our practice patterns. As we start talking more about this issue amongst our colleagues and our patients, we’re more likely to see a practice pattern shift in the United States as well,” Dr. Findley commented.

17 July 2009     A new cancer study of  over 7 million women years is another major coffin for unopposed estrogen ET, for progestin Pg, and for oral  sex hormone therapy SHT.

Danish  Universities prospectively document  the incidence of ovarian cancer OvCa in a million postmenopausal women PMW  from 1995 through 2005.  Compared to non-users, use of HT increased OvCa (mean age 62yrs) by about 40%   for up to 2 years after stopping Ht, ie increased the absolute incidence  of clinically diagnosed OvCa from ~ 0.04 to ~0.052% ie per 100 patient yrs.

Transdermal TD ET alone  increased risk by 13%; vaginal ET by 23%;                                            Oral ET alone increased  risk by  34%; oral E+ progestin Pg by  48%;          TDE+Pg by 67%.

Thus the relative incidence of OvCa rose about 33% by 7 years on HT, to 48% if HT continued beyond 7years.

In 2004 Glud ea reported an increase risk of 31% for OvCa in Danish women on OHT use – total ET dose of ~5gm ie for about  for 15yrs – at a time when the standard premarin  dose was 0.625mg/d (equivalent to l mg E2)  if not double that .

For perspective,  the relative incidence of cancers in similar mostly 1st world European women from the  the USA SEER data for 2006 age over 50  years  are: BrCa 0.33%,  uterus 0.07%, ovary o.03%(ie very similar to the baseline Danish figure of 0.04% above), colon 0.15%,and cervix 0.01%. The new (Norwegian)  analysis in the latest BMJ suggests that screening mammography may result in overdiagnosis of BrCa by up to 50% (the other 50% may arguably never have been clinically significant-diagnosed- during life) , so the provocative could argue that the relative incidence of clinically significant BrCa to OvCa is more like eg BrCa 0.2 to ovary 0.03 ie just below 10:1. But OvCa is notoriously about 70% fatal within a few years, so  the absolute  mortality rate – at age 60-64yrs-  from  the same SEER  source and period are as relevant: BrCa 0.063%, uterus 0.011%, ovary 0.033%, colon 0.03% & cervix 0.005%. ie new OvCa may be only 1/10th as common as newBrCa, but BrCa  kills only twice  as many PMW as OvCa.

And finally the 2007  survey by  Rossing ea of  Menopausal Hormone Therapy and Risk of Epithelial Ovarian Cancer in women in Washington State 2002-2005 showed that  ET -mostly premarin (but not ET + progestin- MPA medroxyprogesterone provera) – especially in  low-parity  younger slim women increased OvCa compared to non-users, and that this risk  was highest- up to 90%-  in  users of OET  for more than 6 years.

By comparison – BREAST CANCER BrCa and HT: Hoover ea  1976  are the first on Pubmed to report doubling in  risk of breast cancer  BrCA after 15yrs on premarin in USA ie at least 5gm cumulative dose.

In Denmark by 1994 Ravn ea reported that if there was a risk of BrCa from OHT, it was small, and only after prolonged use of estrogen (15-20 years).  But by 2004 -2005 Tjønneland ea , Stahlberg ea  and Ewertz ea  found increased risk for BrCa  of 61 to 112%  associated with current use of HT.  Stahlberg ea already in 2003 concluded from recent studies from both the USA and Europe that the combined treatment regimens with estrogen and progestin increase the risk of BrCa  beyond the risk of unopposed estrogen.

In Norway, a recent Tromso study suggested that the dominant HT therapy used in Norway was oral estradiol E2 plus the progestin norethisterone acetate. . An earlier Tromso study in only 35000 PMW was too small- it showed that use of such OHT for >5yrs trebled the incidence of breast cancer BRCa, but did not influence that of OvCa.

Apart from smokers’ lung cancer, the commonest cancer in older women- BrCa- clinically affects perhaps 5% of PMW  lifelong – but  with prompt therapy after clinical presentation kills as few as 5% of sufferers- and with appropriate OHT (premarin +- provera)  for up to 8years in the Women’s Health Initiative both the incidence of and mortality from BrCa, and all-cause mortality,  were reduced by about one-third. Hence appropriate HT saves many from both BrCa and from premature death and disability from the commonest degenerative diseases- vascular, dementing and fracturing. 75% of women who develop BrCa  die with it –  not from it but from far more prevalent degenerative diseases after an  otherwise normal lifespan. But the Danish evidence is that combined OHT will increase OvCa by >50%.

Ovarian Ca kills 70% of victims, and is it so rare compared to BrCa? .

Hence with the perhaps 2/3  lower incidence of OvCa, it is a relatively trivial problem for women overall- except for the 4  in  10 000 women  who develop it, who have <50% 5year survival, ie 3 out of 4  of whom it will kill within a few years- compared to <25% of breast cancer victims who will be killed by the BrCa.

However, it becomes clear that these hormone-dependent cancers are both  duration-  and total-dose HT related; but even more important, that unopposed OET is a risk if persisted more than about 12 yrs; and even if used in far lower dose parenterally, the risk of OvCa is far higher if combined with the European fashion of androgenic synthetic progestins Pg – even parenterally; whereas the American MPA for up to 8years at least apparently if anything mitigates the OvCa risk of ET..

By contrast this column has repeatedly reviewed evidence that balancing physiological ERT with physiological testosterone replacement TRT eliminates the risk  for BRCA and endometrial cancer of unopposed ERT +- PRT in PMW.  Intuitively this should also apply to ovarian cancer.

Hence the message strengthens that PMW should not be exposed for  any length of time at any stage to the much higher oro-hepatic HT doses (needed for symptom control) or OET+- Pg; but as in all other endocrine replacement for permanent  multisystem prevention – let alone sexual function-  patients with gonadal deficiency should have physiological sexhormone balance restored  ie with balanced parenteral  human androgen, estrogen and progesterone replacement.

It is common cause that (reproductive cycles and pregnancy aside) all the physiological  prime sex hormones-DHEAdehydroepiandrosterone, P4, T, E2, E3 – are as important as all other human hormones, essential life long  for optimal health; and that estrogen dominance (due to inadequate  androgen and progesterone levels) is deleterious. Hence most PMW require both physiological progesterone and androgen replacement- sometimes to balance excessively high endogenous estrogens, usually to accompany necessary ERT for full balance.

ndb

COMBATTING THE INCREASING OCCURRENCE OF BREAST CANCER IN YOUNGER WOMEN.

UPDATE: 2 Mar  2014: PARACETAMOL ACETAMINOPHEN, DIGOXIN AND SPIRACTIN are ESTROGENIC: even the most popular and perhaps safest synthetic designer painkiller paracetamol acetaminophen (Tylenol, Panado) discovered in 1877   has again been shown  (Harvard University 2014- the Nurses’ Health Study from 20 years ago) to be ( like the 250year old biological human hormone digitalis/digoxin, and the 50year old synthetic antihormone  spironolactone), a weak estrogenic ie they proliferate the breasts and thus cancer potential.                       Acetaminophen use was positively associated with total Estrogen Metabolites (2+ days/week vs. non-use: 236 vs. 198 pmol/mg creatinine; p difference = 0.02, p trend = 0.11),  Thus like its cousin phenacetin (never mind alcohol and smoking)  after decades of fraudulent promotion as safe,  paracetamol’s harms outweigh its utility

     Thus while it  is fairly safe in adults in moderation,  like all designer synthetic drugs eg NSAIDs and synthetic/xenohormones,  like even lowdose aspirin, paracetamol  has many risks (even for the eyes)  and doesnt cure anything- whereas digoxin and spiractin may have lifesaving benefits in serious heart/ hypertensive disease. .

As always, for pain best stick to physical cure by eg manipulation, massage, rest and exercise, heat or cold, acupuncture; or some natural safe biological analgesic/antipyretic combination– massage with   arnica/menthol/coconut oil/ DMSO/cayenne/Lugol’s iodine/magnesium oil;     or these orally with eg fish oil; vitamins C (eg citrus), D3 (sunshine) and B esp B5 (meat, whole grain, avocado, brassica);  magnesium, manganese, copper, iodine, selenium; GABA (but not gabapentin and pregabalin – Bad Medicine);  plant extracts eg  boswelia, bromelain, buchu,  catsclaw, curcumin, dandelion,  MSM, nettle, ginger, caffeine, ecchinacea, sage, cherries, Oregano, rosemary, thyme, mint, cannabis, angelica, valerian;  and  cartilage eg glucosamine-chondroitin .

Oct 2013:  BREAST PAIN,  CHEST PAIN AND HORMONE CONTRACEPTION.

CHEST/BREAST  PAIN: In men and women, nontraumatic pain in the front , back and sides  of the chest (and abdomen)  is mostly neuromusculoskeletal, and easily diagnosed  by  the history (absence of cough, central deep pain radiating especially to the jaw , back  or left shoulder, breathlessness, fever, heartburn),  and  physical examination –absence of  systemic signs or  significant  changes in pulse and bloodpressure);

and appropriate assessment of the neck and thoracic spine since these are so often where root pain (around the shoulder girdle, trunk and limbs)  originates and can be simply relieved ie cured and thus diagnosed.

    This is crucial in daily busy  primary care ie general practice where patients –especially the younger fitter ones without the common high  risks – want a quick opinion and fix so they can move on, not have to undergo xrays,  heart-  and blood-tests that specialists and hospitals, medical schemes, politicians and civil servants  thrive on..

    Older women of  course  usually have the   major extra anterior chest organs – pendulous  breasts – to  consider.  But the same  history and physical exam as in men  quickly mostly  sorts out the source and thus the cause of the pain:  a mammary cause eg hormonal congestion diffuse tenderness,  discharge, or tender  lump or gland, or root cause, is  quickly  apparent.

CASE REPORTS: at yesterday’s breast clinic we saw the usual spread of middle-age issues  in the eight  (mean age 45yrs, 32 to 65yrs) who booked  for breast prescreening imaging :

HORMONE CONTRACEPTION vs NECESSARY (PRO)HORMONE SUPPLEMENTS:

TWO IN THEIR FORTIES  ON DEPOT PROGESTINS:

CHEST PAIN: clerk Ms  booked herself for screening with almost constant  discomfort in her left breast for about 10weeks.. Like her and her doctors’ examinations, mammography a  month earlier found nothing abnormal.. She had no history of trauma or pain elsewhere, just slight neck discomfort. Her last period was years earlier, still on contraception  progestin injections. Examination and  mechanical tactile breast imaging confirmed tender full breasts; with maximal palpation tenderness midthorax laterally  at the site of her complaint.          Pressure and rotation elicited no discomfort elsewhere.  Gentle traction manipulation of her neck halved the ‘breast’ discomfort, which disappeared with a final satisfying click with gentle prone rotational pressure on her appropriate upper thoracic vertebra – confirming the root  source of her pain had been cured; and obviated further concern , tests and  analgesia.

 Manageress  also on  longterm depot hormone contraception (Mirena), with growing breasts,    rising weight despite careful diet,   and  concern about hip osteoporosis on DXA screening that was not improving but worsening the past 3 years on some routine vitamins C, D3  2000iu/day. K2 and calcium supplements. Her husband (not she) observed that she had severe night sweats.

       Both of the  ladies on synthetic progestin contraception   were reminded that such depot synthetics  suppress the ovaries ie cause artificial menopause with all its longterm subtle adverse effects, and that such hormones are known to slightly increase the risk of breast cancer, fattening and osteoporosis.    Both   were recommended progesterone cream, vitamin D and metformin as well as the other almost 20 bone supplements, for (pro)hormone balance and to assist with body fat  and thus all-risk reduction

        Ms   mid-60s with no complaints except stress vertebral fracture from osteoporosis now on opioid patch!  mother died of breast cancer at 78yrs; she has had 10 mammograms;  just dense lumpy breasts;; advised vigorous vit D, Super C, K2; Triple Bone-Pain – antiarthritic blend; metformin; DHEA and melatonin 20mg/d;

    Ms  early  50s  with menopausal symptoms, hypertension ( on perindopril)   and lumpy breasts, now off Nuristerate, ,   was advised to take appropriate supplements including progesterone cream. There is a new report from Holmes ea Canada http://www.ncbi.nlm.nih.gov/pubmed/24075077  that ACEi/ARBs use eg perindopril  was associated with significant 22%  increased deaths from  breast cancer (95% CI: 1.04-1.44), let alone the risk with such drugs of recurrent persistent cough and insidious nephropathy; so is advised to swop over to the safest best and cheapest 1st-line antihypertensive regime of lowdose  reserpine with low dose amilozide,

Ms  mid-30s with a child despite endometriosis and  PCOS , 4 years after removal of Mirena (7 years) , had lumpy breasts. Advised metformin,  vits  D and Supervit C, minerals and vitamins.

Ms  early 30s with PCOS , two aunts in their 50s with breast  cancer, her granny from the other parent having died of breast cancer at 76years.. with  lumpy breasts; she was advised the supplements including progesterone cream, melatonin, and metformin.

TWO IN THEIR 30S HAD KNOWN BREAST CANCER:

 Ms   mastectomy and DXRT 2011, now off Nuristerate ,  given weeks to live 18 mo ago with brain metastases that have shrunk with chemoradiotherapy and her zealous work as a cancer counselor;  lumpy other breast; now advised metformin, sutherlandia, melatonin 20mg/d,  vigorous vit  K2,  D and Supervit C, DIM, mushroom, astragulus, selenium, minerals and vitamins within her means.

Ms   had lumpectomy and 3 positive glands/12 removed in 2011, refused further oncology/ radiochemotherapy.   Lumpy breasts confirmed . Advised metformin,  sutherlandia, melatonin 20mg/d,  vigorous vits K2,  D and Supervit C, DIM- I3C, mushroom, astragulus , selenium, minerals and vitamins;  if not Iscador, cesium, TCM,  and pancreas/gene therapy  within her means.

BREAST PREVENTION REGIME: apart from optimizing diet and lifestyle with appropriate obesity-reducing diet and avoidance of estrogenic foods and drugs,

Based on published evidence and our experience from patients of analgesics and anticancer benefit, all were advised to try  triple breast massage daily with coconut oil, Lugols iodine then DMSO  for a few weeks, and if they want reassurance, return in a month or two  for followup breast imaging to show the shrinkage in all lumps that  most show. Those with higher risks are advised to take the oils by mouth as well, and if iodine depleted, oral iodine , for their global benefits.

      However, short of  avoiding  sex, or use condoms and barrier creams, or ill-advised sterilization or dependence on coitus interruptus,  their contraceptive method is hard to improve, short of relying on the oldfashioned intrauterine device without any contraceptive hormone. The oldest naturally occurring pregnancy we have seen was at 55 years, so women have to take care past this age…Natural human contraception with depot human progesterone and estrogen was developed decades ago, but naturally not made available commercially because only synthetics are patentable and thus commercially viable raincheck drugs that profit Big Pharma, health professionals and politicians. .

     Instead, women are advised simply to protect the breasts, womb, brain, heart, skeleton,  face etc, and stop menopause symptoms, by adding just enough human  progesterone cream daily to their face makeup (+- vaginally); (testosterone cream sparingly  if indicated for frailty, depression  and poor sex) , and take a sensible daily blend of the twenty other natural bone and multisystem antioxidant anabolics  (as this website www.healthspanlife.wordpress.com details under osteoporosis) including vitamin D about 2500iu/kg/month ie about 150 000 to 200 000 iu/month for an average size adult.

         In people rapidly fattening due to lifestyle, stress and the bad marketed adverse food chain, wiser choices have to be promoted-which does not suit most  politicians, Big Business or the Disease Industry for whom Only Disease Pays-  Prevention Doesn’t Pay.. So to protect against fattening and insulin resistance perils, metformin to sensible tolerance is also an inevitable recommended  natural albeit prescription supplement until healthy robust lean weight can be maintained without it.

      The supplements listed  above – (fish oil, appropriate parenteral human sexhormone replacement and the other antioxidants/anabolic vitamins, minerals and natural biologicals including the prohormones metformin and vitamin D) also mostly obviate the deplorable high-risk use (for commercial profiteering) of risky synthetics eg  statins, bisphosphonates, psychotropes, analgesics, NSAIDS, patented xenohormones and chemotherapy   etc – none  of  which address the underlying stress, deficiency  and pollution ie primary causes of  disease.

UPDATE: FIGHTING THE TIDE  OF  BREAST CANCER, DISEASE  in YOUNGER WOMEN: 

16 June 2013 A new review by Carolanne Wright reviews how to combat estrogen overload – How environment and lifestyle contribute to hormonal imbalance while devastating the health of both men and women.

27 May 2013 Wikipedia reports that in 2008,  about half a million women   died from  breast cancers (out of some billion older women worldwide ie 0.5 per 1000 women, an annual deathrate of 0.05% pa),  23% of cancer deaths in women; with cancer overall accounting for about 13% of deaths -the commonest being stomach-colon-liver 2.8%;  lung cancer 1.4%, then breast 0.46%  of deaths. So breast cancer – mostly undetected globally  by the luxury of mammography till it presents clinically-  kills only perhaps  1:2000 older women per year, ie perhaps <25%  of the  perhaps  1:500 older women who develop clinical breast cancer-  995/1000 of older women’s deaths being from other causes than breast cancer.

These figures dispel the  dangerously fraudulent  fearmongering  lie  of the USA Radiological and Breast Cancer Associations and Curves International that “(screening) mammography saves lives”. Its good to see in the current Curves South Africa website that in this Celebrating Mothers’ Week at Curves, they have dropped the Mammography saving lives myth of 3 years ago that started this particular theme column.  That hasnt stopped USA doctors  from continuing to propogate the lie.

But some there  eg Dr Lissa Rankin MD – daughter of a mammography radiologist- are still brave enough to refute the lie. And even the American Cancer Society chief medical officer doesnt make such ludicrous  claims but points out how complex the issue of prescreening detection is. .

Johnson and Bleyer reported Feb 2013    from the SEER study  that advanced breast cancer in young USA  women 25-39yrs has doubled between 1976 and 2010.

South Africa (religion mostly African Christian) has the distinction  of being one of Earth’s  most corrupt and illiterate  countries,  with strange bedfellows –  Latin  America (mostly Catholic),  Egypt Lebanon & Pakistan(Islamic), and  South Korea(mixed religions)-  that follow the USA in defying evidence – in this case  of danger to cows and humans – and allow the use of rBGH recombinant Bovine Growth Hormone ; and  sex hormones   in dairy and meat production. The evidence of harm, eg  carcinogenicity and feminization  is so strong that such  use has been banned in many  countries for decades .

MORTALITY TREND AND CANCER IN RSA AND GLOBALLY: Breast cancer is usually a disease of postmenopausal women-who till a centry ago on average barely lived to that age. In South Africa at the   peak of the untreated AIDS epidemic around 2000, with average lifespan drastically fallen, of all deaths, overall infections (HIV  TB, pneumonias etc)  caused about 39%, external causes  12%, cardio/vascular disease 11%,  cervix cancer 1.4% and breast cancer 1.3%.    But Statistics SA report last month that by 2010, with antiretrovirals, life expectancy  had risen about 5years, and that of all deaths,  HIV+TB  deaths had  at least halved   to  15% (17% in Africans, 9% in coloureds, 2.4% in Indians), cardio/vascular deaths were 12% in blacks but 27.8% in whites; external causes down to 9%, cancers 9% (mostly digestive and respiratory); with only 20 breast cancer deaths ie 0.00% reported in RSA.

Breast cancer is still rare in a mostly young population with mean age of survival of women still half of that of the first world,  with virtually a generation gap due to the carnage of the untreated AIDS era and institutionalized male violence especially against women, children and minorities- xenophobia.

But meat  and dairy milk (in South Africa widely containing added rBGH and sex hormones) are  among widely used foodstuffs likely contributing, as Joe Mercola notes,  to the increasing occurrence of breast cancer in younger women. Never mind deadly  sugars, smoking and alcohol consumption on the rise here in RSA.

AVOIDING CANCER AND MASTECTOMY:
To   improve immunity,  insulin receptor sensitivity
,  lessen obesity and excessive estrogenization (from both outside your body,  and your own fat production):

  • Exercise;  Maintain a healthy body weight  -BMI < 24kg; waist girth<about 85- 90 cm; earthing- walk barefoot.
  •    AVOID:- added or concenrated sugar, (especially fructose- commercial fruitjuice; cornstarch, white flour); charred fats; smoking; alcohol;  unfermented soy products; licorice; GE genetically engineered foods. .  
  • BUT those with asthma, leaky gut/IBD, epilepsy or bad arthritis should also try excluding for a few weeks WHEAT; DAIRY; AND NIGHTSHADEs (potato, tomato, peppers/cayenne, eggplant).
  •              —synthetic sexhormones (progestins, xenoestrogens eg in meat, commercial milk, birth control and HRT,   BPA, phthalates, pesticides); spironolactin Spiractin; digoxin; and . 
  •              –physical trauma eg underwire bras;                        xray (eg airports and xray screening mammography), electromagnetic fields eg electroblankets.
  •              -other toxin overload –  aspartame,  marketed designer drugs (eg  painkillers, statins, psychotropes, bloodthinners, antiinflammatories- even paracetamol Panado acetaminophen Tylenol);                         and      –overload metals  (eg iron, fluoride, bromide, chloride,  aluminium, lead, mercury, – consider detox.
  •    Do (Lymphatic) breast massage with eg anticancer coconut oil, DMSO, Lugols iodine; 
  •   Breastfeed your babies;
  • &  To avoid common deficiencies (on our depleted polluted GMO-fastfood diet, especially with increasing longevity), which contribute to all common diseases,                             take plenty of
  •      –sunlight; melatonin & enough restful natural sleep and relaxation!
  •      -organics eg green/coloured  vegetables/ juice daily. .
  •      –fish oil ie marine  omega-3  (dont fry  in  Om6 plant oil)
  •      -for lipidemia,  overweight, diabetes, the prime insulin sensitizer-weight/appetite reducer galega/metformin to tolerance;
  •      –iodine as eg kelp, or Lugol’s iodine.
  •      -vitamin D3:  with cancer, target  blood vitamin D level 70 to  100 ng/ml ie we need about  70-100iu/kg/day – and   sunshine and food cant provide this. . .
  •      –natural vitamin A – organic eggs, raw butter, raw whole milk, and beef or chicken liver, or a supplement.
  •      -buffered vitamin C about 50mg/kg/day    up  to tolerance;- with acute infection/inflammation/cancer  in an  adult, this may be 1/2 up to >2gm hourly till better, or diarrhoea, then (like metformin) just enough to avoid diarrhea;
  •      -virgin coconut oil & DMSO each 1(-15) tsp/day;
  •      -magnesium about 5 mg/kg/d; calcium phosphate;
  •      -zinc, chromium, selenium, manganese, boron;  and
  •      –vits Bco, CoQ10, &  K2.
  •      -natural estrogen-aromtase inhibitors to lower adverse estrogen dominance, raise  the  2OH:16OH estrone balance to about 2:1 – eg exercise; lecithin/choline (from eg  eggs/seeds);  oranges/lemons, red grapes, passionfruit;  celery, parsley, basil, artichokes, avocado,coconut, onions, garlic, olives, olive leaves; asparagus, squash, cauliflower, broccoli/cabbage/spinach/Brussels (provide I3C/DIM di-indole methane), yams, milk thistle,  sawpalm, diet fibre,  black radish, mushroom-astragulus, sutherlandia, beet, dandelion, curcumin turmeric, cinnamon, ginger, honey, garlic,  black pepper; taurinemethionine; zinc, selenium, vits C/D3/E/K2; and/or balancing  progesterone/ testosterone – or just 7ketoDHEA in the elderly..

Just this  month, a major trial from UCLA (Smith, Kurzer ea) confirmed that in healthy sedentary young women, moderate exercise 2.5 hour a week significantly beneficially  lowered the risky  estrone level  and raised  the             2OH:16OH estrone ratio.

These preventative steps may remove justification for therapeutic mastectomy (which is known to reduce survival)  for localized breast cancer , let alone preventative bilateral mastectomy even in women with high penetration BRCA genes, as publicized this month  by filmstar Angela Jolie .

THE 2014 VIRUS SEASON DAWNS: URGENT UPDATE: AVOIDING THE SEMMELWEIS REFLEX; natural antibiotics- Vitamins C & D3 – avoiding vitamin denialism.

update 22/3/2014the March equinox:Vaccines and antivirals for preventing   and  treating  influenza in healthy adults have  very modest benefit.  as  the seasonal flu epidemic wanes in the northern hemisphere and approaches in the south, Authorities eg the US CDC  continue relentlessly to promote mass flu vaccination. The South African Authority NICD recommends vaccination for anyone at high risk ie the elderly, infants or the sick, and carers. It also recommends antivirals eg Tamiflu for infection- but the BMJ recently publishes  Study claiming Tamiflu saved lives was based on “flawed” analysis. a 2012 BMJ  report by the samemedical journalist   Zosia Kmietowicz   notes Cochrane group rejects Roche’s offer of “advisory board” to discuss analysis of oseltamivir data. The 2011 Cochrane question remains unresolved:  Does Oseltamivir Tamiflu  Really Reduce Complications of Influenza?

But current Cochrane review of controlled trial publications to 2013 confirms  Vaccination of pregnant women is recommended internationally, while healthy adults are targeted in North America. The overall efficacy of inactivated vaccines in preventing confirmed influenza has a NNV of 71 (95% CI 64 to 80). . Live aerosol vaccines have an overall effectiveness corresponding to a NNV 46 (95% CI 29 to 115). Vaccination had a modest effect on time off work and had no effect on hospital admissions or complication rates. Inactivated vaccines caused local harms CONCLUSIONS: Influenza vaccines have a very modest effect in reducing influenza symptoms and working days lost in the general population, including pregnant women.  This review includes 90 studies, 24 of which (26.7%) were funded totally or partially by industry. Out of the 48 RCTs, 17 were industry-funded (35.4%).

A current German review  Methodological quality of systematic reviews on influenza vaccination.   Fourty-six systematic reviews fulfilled the inclusion criteria. Average methodological quality was high  but variability was large (AMSTAR range: 0-11). Quality did not differ significantly according to vaccination target group. Cochrane reviews had higher methodological quality than non-Cochrane reviews (p=0.001).  this was due to better study selection and data extraction, inclusion of unpublished studies, and better reporting of study characteristics (all p<0.05).

20/1/2014   Protecting us from the new year northern hemisphere viruses:   natural antibiotics- Vitamins C & D: avoiding vitamin denialism as cause of more deaths.

Abstract: The Semmelweis  Reflex is about rejecting, deriding important new scientific discoveries or any serious sincere statement/action.    I didnt  fully appreciate the importance of that  age-old human  (mostly male) evil – mocking, martyrdom  and murder by denialism-  until I started this review of the current flu season threat and the role of supplements, and researched  pioneer medical martyrs Drs Ignaz Semmelweis, Jack Drummond  and Linus Pauling  as  paradigms of the scourge of modern vested-interest denialism and falsehoods, in medicine as much as politics, religion etc..

In fact,  just as it is negligence to deny (as Semmelweis’s persecutors did) gloving up or  properly washing  hands between examining patients , or ensure that every adult has bloodpressure checked occasionally, it is clearly bad practice  not to ensure that everyone – especially the young and old,  takes a multinutrient plus extra vigorous dose vitamins D3 and C, plus some protective herbs- garlic, cinnamon, ginger, origanum; and fish oil and/or coconut oil if not both; and drastically cut down sweetness intake- especially fructose, sucrose  and aspartame that now pervade all mass- produced food and drinks..

update 21 January 2014 : URGENT: THE 2014 FLU EPIDEMIC:     “High H1N1 prevalence and mortality rates a concern:    Type A (H1N1) influenza, the  commonest flu virus in Canada this year, has a higher  than anticipated mortality rate  causing some to wonder if it’s virulence has increased.             The worrisome factor  “is the reported mortality rate,” says  McGill University. As of Jan. 13, there were twenty confirmed deaths in Canada   attributed to H1N1. “There are more deaths than what we expect for the regular H1N1 influenza, The strain this year could be more virulent . 96% of this year’s lab -confirmed influenza is H1N1. The virus is unusual in that it appears to affect younger people more than other strains of seasonal influenza. People  20 to 65 are being hit harder than usual, comprising 52% of flu cases.                                  However, if you look at Europe,  it’s still H3N2. Its an example of how   you never know what the flu is going to do.”           Alberta confirmed a death  on Jan. 8, due to the virus H5N1, an avian virus. The  deceased woman had recently returned from China. The mortality rate is higher with H5N1 than H1N1, “but fortunately, it’s not an easy virus to transmit”. So far, it seems that there are no cases of H5N1 transmission from human-to-human. It seems   like the cases of H5N1 are few and far between and related to contact with birds in  China.     Patrick Janukavicius, Montréal, Quebec.  In the same period, at least 20 children have reportedly died of the same strain in USA.

update 12 Jan 2014  THE ANTIFLU VACCINE DECEPTION: this review by Doc Joe Mercola     stresses the disease-mongering myths,  futility and risks in real life of flu vaccination  and antiflu drugs eg Tamiflu ; and the overwhelming importance of natural immune boosters like Vit D3 & C, zinc, selenium,  herbs, and hygienic prevention.

1 Jan 2014  CURRENT INFLUENZA STATUSThe  22 December  solstice is the sun at its southern nadir seen from planet Earth, the onset respectively of real winter in the Northern hemisphere, and real summer in South Africa. Last year   the Gregorian New Year heralded a fierce flu season in the northern hemisphere, and as usual feathered- and jet-propelled  air travel brought the corresponding surge at the bottom of Africa.

And ominously, the Plagues & Pandemics   (Howard Phillips 2012) of temperate climates  that did so much historically  to mould global demography not least  the past 360 years in South Africa ( –STDS- pox, bubonic, polio, cholera, influenza, and now  tuberculosis, Mad Cow disease, and   HIV-AIDS). and especially antibiotic-resistant germs – are all on the increase despite (or because of) the increasingly futile $trillion armamentarium of 20th century designer vaccines and other antimicrobials.. 

Pneumonia is a welcome   friend of the old, often rapidly relieving prolonged degenerative incapacity;  such ending mostly by virus respiratory infection  the gateway for the  final bacterial infection.  

Unlike the  selflimited coronavirus common cold, breath-and hand-borne type A  influenza, although usually mild in the well,  is the commonest trigger in the frail.  Many  of us in our (grand)parents’ time lost relatives in the 1918/1919 “Spanish”  H1N1  flu pandemic. But that was a unique  global catastrophe because it killed mostly  armies  of healthy men, and then  young working adults, apparently from cytokine storm, with 30 % of the workforce out for up to3 weeks if not  20% mortality.  This is harrowingly described in the recently published   Letters ( to his Mother) of Dr Arthur Conan Doyle, who lost – apart from his first wife to TB- more young relatives to the  flu  than to warfare.

The recent spring  months here – apart from seasonal allergies -have seen declining viral respiratory illness in Cape Town, with the  upper respiratory accent often shifted down to more gastritis-enteritis .

But New Year 2014   UK and northern North America forecast  and are having a  wet if not white New Year.  ‘Flu rates are reported already high  and rising  in USA and Canadamostly influenza A H1N1(swine-avian flu-the main 1918/19 killer); including already 6 deaths in USA and 3 in Canada.

but not in Europe, where  the influenza (A > B) prevalence is still low and slightly more H3N2 than H1N1;  in UK there has rather been been increase in RSV respiratory syncytial virus bronchitis in infants. .  .

In fact by 28 December the exploding H1N1 deathtoll had hit 13 in Texas alone; especially in youths; with increasing Tamiflu resistance reported eg in Missisippi.. On 24 Dec the USA CDC mailed an emergency Advisory Notice to Clinicians: Early Reports of pH1N1-Associated Illnesses for the 2013-14 Influenza Season: From November through December 2013, CDC has received a number of reports of severe respiratory illness among young and middle-aged adults, many of whom were infected with influenza A pH1N1 pdm09 virus. Multiple pH1N1-associated hospitalizations, including many requiring intensive care unit (ICU) admission, and some fatalities have been reported.  While it is not possible to predict which influenza viruses will predominate during the entire 2013-14 influenza season, pH1N1 has been the predominant circulating virus so far. For the 2013-14 season, if pH1N1 virus continues to circulate widely, illness that disproportionately affects young and middle-aged adults may occur. 

Our  regional  South African Communicable Diseases Institute says H1N1 was documented here from April to September. But of 2566 pts with severe respiratory illness for January to October 2013 enrolled and tested at the five sentinel sites, only 6% were positive for influenza – mostly virus -H1N1. A pneumonia case in Cape Town was found to be due to Leigionnaire’s.

Now from China 147 human cases of avian influenza H7N9 have been confirmed including 48 deaths. – especially from poultry contact. No vaccine is currently available for avian influenza (H7N9) virus.

SAPA–AFP, 10 December 2013:  Resistant flu virus keeps contagiousness.  A mutant form of the H7N9 flu virus that is resistant to frontline drugs is just as contagious as its non-resistant counterpart, according to a study, published inthe journal Nature Communications.  The virus has claimed dozens of  lives since its outbreak in February. H7N9 is believed to have spread to humans from poultry, where it circulates naturally. The World Health Organisation (WHO) said on its website that “so far”, no evidence has emerged of  “sustained” transmission of H7N9 among people.

And H7N1 and H7N7 has broken out in ostriches in South Africa,

So never mind the  common cold  coronaviruses and many other prevalent infections, increased caution is due against all common diseases at this season- both the USA H1N1 swine flu circulating the past few years,  and now the Chinese H7N9 flu. . And the MERS-Co Virus Middle-East SARS-type outbreak has not gone away… 9 new cases reported the past week or two  from the KSA alone .the-deadly-middle-east-coronavirus-outbreak/

A  current NEJM  has a new report of a trial of quadrivalent Vaccine for Prevention of Mild and Moderate-to-Severe Influenza in Children by vaccine manufacturers GSK. The vaccine reduced severity by perhaps 70%- but at a cost of 1.5% serious adverse events, 50% more than the control group (hepatitis A vaccine only).                                                                                    The question remains- why risk  flu vaccine’s ~1.5% serious adverse events when a single high dose of vitamin D3  300 000iu  even just annually, and regular vitamin C with a multivite  including zinc and selenium (at trivial cost ) largely cover one  against a multitude of infections including AIDS and TB, and all degenerative health   problems?

PRECAUTIONS:

Is it coincidence, or divine evolution, that we have had available at low cost  for about 60 year (never mind zinc,  selenium, iron, iodine, vitamins A and vitamin E) two safe natural major antimicrobials in vigorous safe dose   –  vitamins  C and D3?  Medico-Pharma Big Business and governments have been heavily discrediting and ruthlessly suppressing these  for their own profiteering vested interest  even as plagues of HIV, TB,  influenza rage, and Big Business determinedly profits hugely from killer  smoking and alcohol sales despite increasing  marketing restriction?   South Africa- a major producer of alcohol and tobacco-smoke, and fossil-fuel-burning power stations, factories and motorvehicles – continues to lead the world with  the highest road and respiratory death rates  despite zealous attempts to reduce their lethal  use.

Apart from optimal hygiene including  avoiding livestock  and poultry contact, smoking, alcoholism and pollution including  swimming and sick buildings- air-conditioning-           what can we take  to minimize avoidable influenza  ie immune depletion risk? apart from enough  sunshine, exercise, rest, sleep, walking barefoot, not carrying a cellphone,   and good mixed fresh organic diet? The clinical benefit of influenza vaccines is anything but proven, and the adverse risks appreciable.

Big Business and thus governments  and the media  profit from illness, so they keep publishing articles promoting Big Business: new antibiotics, vaccines  and other synthetic drugs that do not prevent or cure but if anything perpetuate chronic degenerative obesity-diabetes-vascular-respiratory,- digestive-arthritic-cancer diseases; – and  GMO-genetically modified preserved  food  and bottled drinks stuffed with slow poisons like refined cornstarch – fructose; salt; sucrose and cereals, soya,  Roundup, antibiotics, preservatives, estrogenics,  aspartame,  and especially boiled and baked omega6 and sugars;  instead of marine omega3 and MCT- medium chain triglyceride virgin coconut oil, and unrefined cereals eg oats, wholewheat bread etc..  

Big Business and it’s cash-cow  Disease Industry decries  the natural healthgiving lowsugar Asian/ Mediterranean  diet-organically pastured and grown livestock meat and dairy products, lightly cooked if not raw (oily)  fish,  fruit and nuts, coloured veggies,  and plenty of  oils in their natural plant form. These were  the norm till food processing became Big Business in our lifetime post WW2, and the developed world was bluffed by Organized Medicine, the Food Barons and Big Pharma  with the masterly fiction of Ancel Keyes, into jettisoning the natural longevity “sea and farm” diet of the east eg Japan, and West eg Mediterranean (fresh produce & cholesterol-rich dairyproducts, meat and fish)  for the Diet Deception (Gary Taubes, Tim Noakes) and Bad Pharma ( James le Fanu, Ben Goldacre) of Ancel Keyes‘  low-fat high-refined cereals, margarine; and  the cholesterol -busting and psychotropes/ painkillers /antidementia/antivascular/ antidiabetic disease Designer Drugs-for-all  myths.

It spends multimillions promoting alcohol,  smoking and ever-newer designer prescription drugs and vaccine, and  disinformation on old well-proven cheap drugs like  reserpine, amilozide, metformin,  natural physiological  human hormone replacement,  natural antioxidants and anti-inflammatories ,  and decrying  ineffective but deliberately lowdose and isolated or imbalanced  vitamins and minerals .

The ATBC vits A+E trial  (isolated highdose vits A and E) was  one such  farce in very high risk smokers in an icy climate. . Others have been the recent Norwegian trial using only up to 1000iu vit D supplement a day,

and the current Annals Int Medicine editorial  review of three new articles condemning multisupplements: , on which Mike Howard publishes a scathing critique

*a commercial multisupplement in the TACT  post-heart attack trial – but the composition of the multisupplement  included only deficiency-disease prevention microdoses of micronutrients including 100iu vitamin D3/d and equally negligible vitamin K-  not pharmacological doses of key vitamins eg vits B, C, D & K2 that are well proven to greatly reduce infections and chronic degenerative diseases ;

* the  Physicians’ Health Study  randomized elderly professional men  to placebo or combinations of vitamin C (500 mg synthetic ascorbic acid), vitamin E (400 IU of synthetic alpha-tocopherol), beta-carotene (50 mg Lurotin), and a multivitamin (Centrum Silver – this included  anti-deficiency disease low dose of all common vits and minerals BUT   only 400iu Vit D3),   .

* The third study- on lowdose (traditional anti-deficiency disease) Vitamin and Mineral Supplements in the Primary Prevention of Cardiovascular Disease and Cancer was simply a literature review of 26 best-quality  published trials of microdoses – not pharmacological safe macrodoses.

ie these  three trials published in this  Annals Internal Medicine issue to please Big Pharma advertisors to discredit supplements shared the usual problem of now well-known futile lowdose supplement doses  at least of vitamins D3 and K, if not also vitamin C in the multigram dose scientifically promoted by the Drs  Stone- Klenner-Pauling followers.

Sir Jack Cecil  Drummond (1891-1952) was one of the world’s pioneer 20th century  biochemists and nutritionists in UK,  from  1916- 1952 discovering or defining  and promoting  under his world-famous biochemist professors Rosenheim, Halliburton and Funk the role especially  of vits A, B, C  and E. Thanks to his and Churchill’s forceful vision and foresight, he oversaw  food supply and diet  and thus keeping Britons healthy through and after WW2. He was  so successful in promoting healthy cheap and unpatentable micronutrients and natural fresh food  (in the face of the mushrooming megaprofit  processed food  and designer drug industry) that it  speculatively led to his and his family’s  1952 assassination by competing interests  in France The Vitamin Murders, Fergusson 2007. .

        MURDER BY DENIALISM: It is incontrovertible   common cause that irrational and often jealous medical denialism costs endless lives:
* Scurvy prevention:  Dr James Lind (who did the first ever recorded clinical trial) showed by 1750 that sailors’ scurvy on long sea voyages  was preventable; but  despite his pioneer discovery, the British navy cost the lives of thousands more seamen from scurvy when the Admirals  neglected for 50years until the Napoleonic Wars to supply the fresh produce-  eg limes – that rapidly cured and prevented the lethal scourge.

This despite the fact that another UK navy surgeon Dr John Woodall had already over 130 years earlier- by 1617 – published in UK  The Surgeon’s Mate stating We have in our owne country here many excellent remedies generally knowne,- Scurvy-grasse, Horse-Reddish roots, Nasturtia Aquatica, Wormwood, Sorrell, and many other good meanes… to the cure of those at home…and Sea-men returned from farre who by the only natural disposition of the fresh aire and amendment of diet, nature herselfe in effect doth the Cure (of scurvy- for which antiscorbutic citrus had been known since antiquity) without other helps. the Lemmons, Limes, Tamarinds, Oranges, and other choice of good helps in the Indies… do farre exceed any that can be carried tither from England.

* Childbed fever prevention:  in 1865  Dr Ignaz Semmelweis (1818 -’65) an AustroHungarian Roman Catholic ob-gyne in Vienna, was locked up, and beaten to death  within weeks, because he showed – to the outrage of his peers- that handwashing with chlorinated lime eradicated the epidmic puerperal fever (three times that in the midwives’ ward)  in  the  doctors’ labour wards; 70years before Thir Reich terrorists took charge, his senior colleagues reacted violently to his progressive promotion of (what was already more advanced British and  French) hygiene and science, and his urging them to wash their hands after examining corpses before examining women in labour..  .  Tragically for Semmelweis and new mothers in the Hapsburg empire then,  Pasteur (b 1822) and Lister (b 1827) ‘s germ antiseptic discoveries  were already being implemented further west, but  had not yet been publicized.

    *metformin after centuries of use as an antidiabetic herb galega officinalis,  and its extraction as an antidiabetic in 1922, came into increasing use globally from the 1950s as the best treatment for type 2 diabetes, but the USA- to protect their own new patent antidiabetic  drugs – ruthlessly suppressed  its use there (like that of the natural salt lithium for manic depression)  for 40years till the mid-1990s.

     *AIDS and ART denialism: until  5 years  ago in South Africa   the  overwhelming-majority “people’s”  government  (with the country’s vast resources),  and its successive  “health”  ministers,   cost the lives of an estimated 300 000  AIDS victims through sufferers  – indigent state dependents-  being denied  antiretroviral ART  drugs, (never mind still till now denied quality education and civil  security,  and thus    adequate basic nutrition, and meaningful housing,  jobs and thus hope.)  Genocidal AIDS denialism about which the still-ruling (since 1994) leadership cadre did nothing until under  intense  international pressure and repeated Constitutional Court orders, combined with political rival factioneering in the ruling party,   they  ousted the denialist president and his denialist Disease Minister in 2008.

DENIALISM TARGETS IN NUTRITION: 

VIGOROUS VITAMIN C ASCORBIC ACID  PHARMACOTHERAPY : Much effort and Big Pharma money  has been  spent to denigrate the irrefutable science-based work   (between their advocacy years shown) of Drs Irvine Stone (1934-1984), Fred Klenner(1948-74) and Linus Pauling (1970-1991) of  antibiotic dose >50 to 1000 mg/kg/d pure vitamin C (not the antiscurvy  10mg/d)  – as a universally needed essential in primates. We primats,  like guineapigs and a few birds and fish species,  are among the few  that do not make their own since we  lost the needed gene and thus enzyme in our evolution..

It took about 150 years after Lind’s publication for the antiscorbutic factor to be named as vitamin C by Dr Jack Drummond, another 10 years for it to be assayed and its structure proven- but despite the pioneering clinical work of Dr Fred Klenner in the 1950s proving the lifesaving benefit of tens of grams a day intravenously, it took another 20 years before Dr Linus Pauling  took up Dr Irvine Stone’s conviction and put highdose vitamin C  on the world Nobel prize map; just on Pubmed,  vitamin C has >51 000 citations  since 1921, and intravenously in 763 entries  since 1946, with  Dr Fred  Klenner reporting  it intravenously  asmajor antibiotic in the Southern Medical journal from 1948..

The 2009 book  Injectable Vitamin C and the Treatment of Viral and Other Diseases collection  of  medical journal papers from the 1930s to 2006 details the exhaustive scientific evidence proving the uniform benefit of even 1gm a day vit C both as an antimicrobial antiinflammatory antioxidant  and immunomodulator against major crippling / lethal diseases from polio to tuberculosis, pneumonia, hepatitis, rabies, encephalitis, neuritis, poisoning, cancer, and pancreatitis;                                                                                   

          and the persistent resistance of the FDA and other multinational Regulators to recognize (so as to protect their domestic patent drug manufacturers- Big Pharma and their politician and civil service lobbyists )- such uniquely safe and effective natural drug therapy.         The final chapters of that 2009 book pose the crucial questions of overwhelming vested interest by the organized medical – hospital –pharmaceutical mega-industry and governments in not eradicating preventable disease, the Big Pharma banning of natural effective remedies-  The Origin of the 42-Year Stonewall of Vitamin C, and Medical Resistance to Innovation,

The  University of Oregon,  the  Riordan-Gonzalez group and more recently Hemila and Chaker‘ and Ullah et al’ s 2012 reviews have  published much  validating what Drs Goodall, Lind, Drummond, Stone, Klenner, Pauling and Cameron started.

VIGOROUS   VITAMIN D3 CHOLECALCIFEROLPHARMACOTHERAPY  costing wholesale ~ <US$0.5/month for ~200 000iu /month  in South Africa)  reduces serious infection by perhaps 90% ie 9fold: . eg 80iu/kg/d – 500iu/d (15000u/month) for an infant, 50 000iu/wk or 200 000iu/mo for an adult; who if obese, may need two  to three times the average dose, to achieve the (?) optimal 25OH vit D level of around 70ng/ml for health, higher for any acute or chronic chronic illness.

The modern prophets of vitamin D3 have been the three pre-WW2 doyens :

Prof Chris E Nordin (MB ChB 1950) working in bone physiology for 60 years now; 84 papers on vitamin D on Pubmed 

Prof Walter Stumpf (1927-2012; MD 1952) the recently deceased  professor at North Carolina University, neuropsychiatrist and radiobiologist  in his 60year medical career with over 500 publications (76 on Vit D on Pubmed) including early discovering that vitamin D targets all systems and diseases; professor-walter-e-stumpf-ahead-of-his-time/ and https://healthspanlife.wordpress.com/tag/stumpf-dr-walter/

paralled by Prof Robert Heaney (MD 1951) at Creighton University, osteoporosis and nutrition authority with 119 vitamin D papers on Pubmed since 1982, over 400 publications to date;

succeeded by Prof Mike Holick (PhD 1971, MD 1976) with 391 publications on vitamin D since 1970 on Pubmed, who has done more than most to show that the maximum daily body production of vitamin D3 with plenty of sunlight is enough to prevent rickets and reduce all disease, but nowhere near the pharmacologically therapeutic 80iu/kg/d needed to maintain a vigorous all-disease protective bloodlevel of 60-100ng/ml.

and Dr John Cannell (MD 1976, registered psychiatrist from 1993, nutritionalist), a  legendary whistleblower .   who successively campaigned against  #cigarette smoking; and  uncovered:   # the cigarette-smoking  (Black Lung) compensationitis fraud of miners’ pneumoconiosis;          #the fictitious inflated “above national average” school results (Lake Woebegone)  that all states were inventing and  reporting (as is still happening – mass government deception- in South Africa) ;  then the  
# recovered memory therapy (RMT) scandal – a form of psychotherapy in which patients recovered memories of abuse that they had no previous memory of. Such therapy resulted in false memory syndrome (FMS) of events that never occurred as well as an epidemic of multiple personality disorder (MPD), a rare disorder historically conceived of as being a hysterical disorder.  Unfortunately, many MPD patients believed the psychiatrist conducting the RMT and went home to falsely accuse their parents and others of horrendous acts that never occurred. Cannell teamed up with two Harvard professors to write a peer reviewed paper on RMT, debunking the witch-hunt;                                                                               then since the 1990s researching and promoting  # vitamin D deficiency as major cause of much psychopathology including autism, and vigorous vitamin D therapy to correct multiple diseases, through the Vitamin D Council. He has (co)authored some 13 papers, and published a book. .

Now a major longterm German Cancer Research screening program has just publishd   the 2002-2013 ESTHER study (Perna ea) of 10 000 citizens followed with serial 25OH vit D  levels; to assess the association of apparently unsupplemented vit D levels with fatal and nonfatal CVD in the same study population.  Follow-up data, including survival status, up to over 9  years. Comparing subjects with 25(OH)D levels below 12ng/ml and above 20ng/ml resulted in the lower vitamin D level cohort showing a higher hazard ratio of 1.27 (95% confidence interval = 1.05-1.54) for total CVD and 1.62 (1.07-2.48) for fatal CVD in a model adjusted for important potential confounders. No significant association for nonfatal CVD was observed. In dose-response analysis, we observed an increased cardiovascular risk at 25(OH)D levels below 30ng/ml. Results for CHD and stroke were comparable to the results obtained for the composite outcome CVD. Our results support evidence that low 25(OH)D levels are associated with moderately increased risk of CVD, BUT  the observed association is much stronger for fatal than for nonfatal events.

But the benefit of sunlight in healing tuberculosis has been used for well over a century; while the Google antibiotic benefit of calciferol on Pubmed goes back at least to 1950.

In a prospective 16 mo trial in press from Australia, vit D3 even just 60 000iu/month (ie 2000iu/day) halved antibiotic use in seniors.  (Tran, Neale  ea 2014) Effect of vitamin D supplementation on antibiotic use: a randomized controlled trial.

Since the toxic dose of vitamin D long term  reportedly may be as high as 600 000iu/day or a blood level well >150ng/l , imagine how much better the antimicrobial benefit of vitamin D3 at 80 to 100iu/kg/day or pro rata – even higher eg 10 000+iu/day for obese people who sequester more vit D in fat. .

Dr Robert F  Cathcart wrote 30 to 20 years ago in  Med Hypotheses. 1981 Vitamin C, titrating to bowel tolerance, anascorbemia, and acute induced scurvy   The amount of oral ascorbic acid tolerated by a patient without producing diarrhea increase somewhat proportionately to the stress or toxicity of his disease. Bowel tolerance doses of ascorbic acid ameliorate the acute symptoms of many diseases. Lesser doses often have little effect on acute symptoms but assist the body in handling the stress of disease and may reduce the morbidity of the disease. However, if doses of ascorbate are not provided to satisfy this potential draw on the nutrient, first local tissues involved in the disease, then the blood, and then the body in general becomes deplete of ascorbate (Anascorbinemia and Acute Induced Scurvy). The patient is thereby put at risk for complications of metabolic processes known to be dependent upon ascorbate.                     1984 Vitamin C in the treatment of acquired immune deficiency syndrome (AIDS). evidence is that massive doses of ascorbate (50-200 grams per 24 hours) suppress the symptoms of the disease and can markedly reduce secondary infections. In combination with usual treatments for the secondary infections, large doses of ascorbate will often produce a clinical remission which shows every evidence of being prolonged if treatment is continued. .. despite continuing laboratory evidence of helper T-cell suppression. There may be a complete or partial destruction of the helper T-cells during an initial infection that does not necessitate a continuing toxicity from some source to maintain a permanent or prolonged helper T-cell suppression. However, it is possible ascorbate may prevent that destruction if used adequately during that prodrome period. Emphasis is put on the recognition and treatment of the frequent intestinal parasites. Food and chemical sensitivities occur frequently in the AID syndrome and may aggravate symptoms considered to be part of the AID syndrome. A topical C-paste has been found very effective in the treatment of herpes simplex and, to a lesser extent, in the treatment of some Kaposi’s lesions.  Increasingly, clinical research on other methods of treating AIDS is being “contaminated” by patients taking ascorbate.                                                     1991 A unique function for Vitamin C is as reducing substance,  electron donor. When vitamin C donates its two high-energy electrons to scavenge free radicals, much of the resulting dehydroascorbate is re-reduced to vitamin C and therefore used repeatedly. Conventional wisdom is correct in that only small amounts of vitamin C are necessary for this function because of its repeated use. The point missed is that the limiting part in nonenzymatic free radical scavenging is the rate at which extra high-energy electrons are provided through NADH to re-reduce the vitamin C and other free radical scavengers. When ill, free radicals are formed at a rate faster than the high-energy electrons are made available. Doses of vitamin C as large as 1-10 g per 24 h do only limited good. However, when ascorbate is used in massive amounts, such as 30-200+ g per 24 h, these amounts directly provide the electrons necessary to quench the free radicals of almost any inflammation, and reduces NAD(P)H and therefore  provide the high-energy electrons necessary to reduce the molecular oxygen used in the respiratory burst of phagocytes. In these functions, the ascorbate part is mostly wasted but the necessary high-energy electrons are provided in large amounts.

A recent review from Atlanta Kearns ea found 30 papers which aggregate to show that annual vitamin   D3 dose (not D2) of  optimally 300 000 to 500 000iu (wholesale cost ~R5 in South Africa)  for deficient adults is best for avoiding poor patient compliance with minimal risk and major benefit.

THE INFERIORITY OF VITAMIN D2 SUPPLEMENT: It should be noted that the long-used Lennon’s Strong Calciferol datasheet  (1974 updated 2004) does not indicate that this 50 000iu tablet labelled ‘calciferol’  is in fact vitamin D2 (ergocalciferol), not the fourfold more potent cholecalciferol D3 formed by sunlight in the skin. This is disclosed only on the Lennons website.. and in the South African Medicines Formulary.  So ‘Strong Calciferol’ in South Africa (actually  the D2 not D3 form of calciferol) is convenient but seriously deceptive mislabeling-  much weaker than the ideal vitamin D3, and therefore its effect unpredictable compared to D3- in fact Dierkes ea Norway show that  giving D2 may actually lower 25OH vit D level in the blood..   Sadly, despite this being reported to the local manufacturers and authorities, no correction of the clinically serious misperception created by the Strong Calciferol label and insert has been issued  to health practitioners by the Medicines Control Council and the manufacturer Aspen-Lennons. 

A recent 8yr study in Cape Town blacks   Reciprocal seasonal variation in vitamin D status and tuberculosis notifications in South Africa Martineau, Nhamoyebonde ,Wilkinson ea   confirmed that vitamin D deficiency (serum 25(OH)D <20 mg/L) is associated with susceptibility to tuberculosis (TB) in HIV-uninfected people in Cape Town as it is Europe. Vitamin D deficiency was present in 62.7% of 370 participants and was associated (OR ~5.4)  with active TB in both HIV-uninfected  and HIV-infected -(P < 0.001) people. Vitamin D status varied according to season:  25(OH)D concentration was double in summer-January- March compared to winter (23 vs 12ng/l; P < 0.001). Reciprocal seasonal variation in TB notifications was observed:lowest in autumn  and highest in spring October through December (4,2 vs. 5; P < 0.001). Vitamin D deficiency is highly prevalent among black Africans in Cape Town and is associated with susceptibility to active TB both in the presence and absence of HIV infection.

Antimicrobial implications of vitamin D is detailed by Youssef,  Peiris ea (USA  Dermato-Endocrinol  2011)   against all microorganisms – viruses, fungi, bacteria, protozoa  (except perhaps leishmaniasis)  as both profound prevention and therapy; in many cases without commercially invented marketed antimicrobials to which there is growing and deadly  microbial resistance, let alone toxicity.. There is evidence that seasonal vitamin D deficiency  status contributed greatly to the 1918/19 flu-pneumonia pandemic (Grant & Giovannucci 2009).

and finally, a month ago JAMA published from Marianna  Baum,  Richard Marlink ea the universities of Miami, Harvard and Florida  Effect of Micronutrient Supplementation on Disease Progression in Asymptomatic  Antiretroviral-Naive HIV-Infected Adults in Botswana A Randomized Clinical Trial,  that Micronutrient deficiencies occur early in human immunodeficiency virus (HIV) infection, and supplementation with micronutrients may be beneficial; however, its effectiveness has not been investigated early in HIV disease among adults who are antiretroviral therapy (ART) naive.  2 year supplementation with either daily vitamins BCo,  C and E, selenium alone, or B,C,E with selenium vs placebo: study  conducted in 878 patients infected with HIV subtype C with a CD4 cell count greater than 350/μL who were not receiving ART between  2005 and July 2009.  Results  participants receiving the combined supplement of vitamins plus selenium vs placebo had half the  risk of reaching CD4 cell count 250/μL or less (adjusted hazard ratio [HR], 0.46); and secondary events of combined outcomes for disease progression  or AIDS-related death, whichever occurred earlier [adjusted HR, 0.56); . There was no effect of supplementation on HIV viral load. Multivitamins alone and selenium supplementation alone were not statistically different from placebo for any end point. Reported adverse events were adjudicated  unlikely  related to the intervention, and there were no notable differences in incidence of HIV-related and health-related events among study groups.Conclusions and Relevance  In ART-naive HIV-infected adults, 24-month supplementation with a single supplement containing vitamins BCo,C,E and selenium was safe and significantly reduced the risk of immune decline and morbidity. Micronutrient supplementation may be effective when started in the early stages of HIV disease.

THE PARADOX OF THE GLUCOSE- ASCORBIC ACID- CHOLESTEROL- STEROID CASCADE:              Is it coincidence, or  evolution, that the basic animal fast-energy circulating anabolic substrates are glucose, fatty acids and aminoacids?   from which basic glucose C6H12O6 ( from ingested  fructose C6H12O6 and sucrose C12H22O11, or fats or protein)  the liver manufactures the basic cardinal steroid  cholesterol C27H46O.     Then from cholesterol we metabolize by adding or splitting off carbon molecules  the crucial anabolic and regulating  human hormones-                                                                                                                    1. ouabain C29H44O12  the  adrenal hormone  made also  in the hypothalamus and heart ; adrenal),                                                                                                                                           2.  active calciferol C27H44O the strengthening and reproductive secosteroid;                                                                                                                                   3 the prime sex/ reproductive steroids  pregnenolone C21H32o2,  and thence progesterone C21H30O2,  testosterone C19H28O2, DHEA C19H24O2. and thence estradiol C18H24O2. and                                                       4 the prime adrenal mineralo/glucocorticoid steroids  cortisol C21H30O5, aldosterone C21H28O5.

But we primates and a few other species lost the ability to synthetise on demand in quantities of grams a day the crucial vitamin C ascorbic acid C6H8O6 that is key to all the above.                                                                                            And vested interests in the Disease Industry want us to believe the biological nonsense  heresy  that we must ingest minimal unprocessed foods- cholesterol, fats (especially dairy, marine oil Omega3 and medium-chain triglyceride- coconut oil)   and abundant vitamins C and D3, but eat abundant processed foods-  refined plant Omega6,  refined carbs- fructose,  sucrose, fruit juice,  cooldrinks, cereals, confections- which overload causes insulin resistance and thus lipidemia,  obesity- metabolic syndrome -diabetes, cancer and cardiovascular disease.

The Semmelweis reflexA current Wiki essay sums up the current genocidal problems of deliberate deceptions/denialism in Diet, Vitamins and causality  – for ruthless profit and possibly cynical eugenics: “The Semmelweis  effect is a metaphor for the reflex-like tendency to reject new evidence or new knowledge because it contradicts established norms, beliefs or paradigms.The term originated from the saga of Dr Ignaz Semmelweis, who discovered that childbed fever mortality rates reduced ten-fold when doctors washed their hands with a chlorine solution before examining  patients. His hand-washing suggestions were rejected by his contemporaries, often for non-medical reasons. For instance, some doctors refused to believe that a gentleman’s hands could transmit disease (see Contemporary reaction to Ignaz Semmelweis).   In his book The Game of Life, Timothy Leary provided the following polemical definition of the Semmelweis reflex: “Mob behavior found among primates and larval hominids on undeveloped planets, in which a discovery of important scientific fact is punished”. The expression has found way into philosophy and religious studies as “unmitigated Humean skepticism concerning causality“.[2]”

Idealism, ethics may evolve; but the  problem of  human bigotry, self-interest and subjective ie personal bias do not diminish, they spread.  It is classic that Semmelweis  (1818-1865) the observant innovative  Catholic medical scientist of his time (before microbes and antiseptics   were known) was fatuously condemned  not just by his jealous  competing Vienna colleagues,  but even by his progressive and reformist  Copenhagen  contemporary obgyn Prof Carl Levy (1808-1865)- who outlived him by only 4 months;

ironically at the same time that their Copenhagen contemporary Dr Soren Kierkegaard (1813-1855) was increasingly  isolating himself on the lonely ethical journey  against the convenience lazzez- faire  tide, writing for ethical life and religion against the hypocrisy  of the Church and becoming the father of both reformist theology and psychology. But unlike Semmelweis who was way ahead of the bioscience  and humanity of his time, Kierkegaard stuck to and isolated himself in   promoting the incompatible ie  blind-faith-based   religion – the dilemma of Abraham’s conviction (or delusion)  to sacrifice his son-  and ethical morality;

and closely followed by    Rudolph Steiner (1861-1925) another more  profound European  thinker who bridged  science, spirituality, progressive education, architecture, agriculture, natural medicine, nutrition,    and   social  reform;

contrary to the rationalists of the 19th Century “Age of Enlightenment” and since, like   British historian-philosopher -ethicist  Winwood Reade (1838 – 1875)  who published the enduring secularist’s bible The Martyrdom of Man (1872), of which  Churchill wrote  25 years later  “he was right but wrong to say it” on the book’s critique of the wrongs of war and religion, of mankind’s selfishness, corruption  and destructiveness (by the greedy aggressive acquisitive minority)  against the  weak masses and the environment) that carries on worse in the 21st century than even the 20th century;                                                                                                                                          and    150 years later bioscientist and philosopher Stephen Jay Gould (1941-2002) rationalized sadly   the non-overlapping Magisteria of Science and Faith, objective “provable” science – which in fact is seldom immutably constant as is mathematics-  and purely faith-based  “unprovable” religious belief.

It was only a year ago that Richard Conniff published his column on   Strange Behaviours, The Medical Martyrs. And the medical  hero martyrs in this review-  Semmelweis,  Margaret Sanger, Drummond  and Pauling –  never made it onto his list.

But then nor did  the modern medical  freedom fighters  Steve Biko,  Agostinho Neto,  Che Guevera. Jonas Savimbi, Neil Aggett, and the living spouse of Steve Biko, Dr Mamphele Ramphele….

Women of the Century apart (like Margaret Sanger, Marie Curie, Eleanor Roosevelt, Golda Meir, Indira Gandhi,  Helen Keller, Benazir BhuttoMother Theresa, Aung San Suu Kyi -many of whom have been martyred),                 it is a philosophical debate whether among the men  the medical martyr  Semmelweis (1818-1865) ranks with  his  19thC contemporaries-   Lincoln (1809-1865), Kierkegaard(1813-1855), Pasteur (1822-95), Lister (1827-1912)  ;  and his successors (and 20th C  leading achievers): Koch(1843-1910), Edison(1847-1931), Steiner (1861-1925), Gandhi(1869-1948),  Weizmann(1874-1952), Churchill (1874-1965), Einstein (1875-1955), Jung (1875-1961), FD Roosevelt(1882-1945), JK Galbraith(1908-2006), Martin Luther King (1929-68), Pauling and Mandela   as arguably giant enduring male leaders -innovators-  teachers and achievers  of the past two centuries.

Unlike eg Socrates, Hippocrates  and Jesus of Nazareth, one of the  five greatest polymath medical and ethical sages of all time Rabbi Dr Moses Maimonides (RamBam)  avoided martyrdom by burying himself in practicing selfless medical service for sultan and peasants alike, and jurisprudence   for his GreekoRoman based  Islamic-Sephardic   times and philosophy, like his guru predecessor Avicenna and his contemporary savant Averroes. .

CONCLUSION:   Today it can  be argued that the denial of effective phamacotherapeutic doses of especially  vitamins C and D3, let alone supportive doses of balancing vits (A, B1,3,5,6,9 & 12, E and K2); the often-crucially  deficient minerals (eg magnesium, sulphur, phosphate, iodine, zinc and selenium), and biologicals like human transdermal balanced HRT, coenzyme Q10, alphalipoic acid, milk thistle, cinnamon, fish oil, chondroglucosamine, DMSO, coconut oil,  is a repetition of denialism of the germ theory,  and of optimal physiological human micronutrition as well as macronutrition. .

      – especially when patients are poor and thus malnourished, and plagued by diarrhoea and stress, TB, lipidemic vascular disease and cancer; and when antiretroviral ART- although life-saving- is even more diabetogenic and neurotoxic  than untreated AIDs.

Even transdermal administration is  better than nothing, perhaps  better  (for the frail and noncompliant eg oldies) than oral or injection eg of vitamins D3 & C and progesterone , metformin, (in addition to the usual magnesium chloride, vits A, BCo & E)  may be beneficial whether by patch or cream for both healing, infection, calming,  heart, circulation, infection, arthritis, osteoporosis,   and neuritis, applied under coconut oil,  codliver oil and DMSO as further analgesic, anti-inflammatory,  memory and absorption enhancers.

REFERENCES:     New reviews bear out the major benefits of micronutrient supplements selenium,  zinc, silver, vits A, B, C, D, E;  and DMSO, sutherlandia and aloe  against HIV-AIDs. and co-infection;

Micronutrient supplementation for children with HIV infection. Irlam JH,  Rollins NC ea . Cochrane Database Syst Rev. 2013 Oct 11;10:CD010666.

Effect of micronutrient supplementation on disease progression in asymptomatic, antiretroviral-naive, HIV-infected adults in Botswana: a randomized clinical trial.Baum MK,  Marlink R ea .JAMA. 2013 Nov 27;310(20):2154-63. .

Preliminary trial of aloe vera gruel on HIV infection.Olatunya OS,  Oyelami OA. ea, J Altern Complement Med. 2012 Sep;18(9):850-3. doi: 10.1089/acm.2010.0735.

In vitro effects of Sutherlandia frutescens water extracts on cell numbers, morphology, cell cycle progression and cell death in a tumorigenic and a non-tumorigenic epithelial breast cell line.Stander A,  Joubert AM. ea, J Ethnopharmacol. 2009 Jul 6;124(1):45-60

Sulfur in human nutrition and applications in medicine.Parcell S.Altern Med Rev. 2002 ;7(1):22-44.

Coconut (Cocos nucifera L.: Arecaceae): in health promotion and disease prevention.DebMandal M, Mandal S.Asian Pac J Trop Med. 2011 Mar;4(3):241-7

below  are some of the  most recent  94 studies  of vitamin D and human infectionin   published just  in 2013:

New insights on the role of vitamin D in the progression of renal damage: Kidney Blood Press Res. 2013;37:667-78. . Lucisano S, Santoro D.ea  Many studies indicate relationship between hypovitaminosis D and survival, vascular calcification, bone mineral metabolism, immune, cardiovascular and endocrine. Vitamin D analogs reduces proteinuria, in particular through suppression of the renin-angiotensin-aldosterone system (RAAS) and exerts anti-inflammatory and immunomodulatory effects. In particular vitamin D deficiency contribute to an inappropriately activated RAAS, as a mechanism for progression of chronic kidney disease (CKD) and/or cardiovascular disease. Human and experimental models of CKD showed that vitamin D may interact with B and T lymphocytes and influence the phenotype and function of the antigen presenting cells and dendritic cells, promoting properties that favor the induction of tolerogenic T regulators rather than T effectory. Interstitial fibrosis may be prevented through vitamin D supplementation. .

Should vitamin D supplementation be a regular part of asthma care? Gordon BR.Otolaryngol Clin North Am. 2014 Feb;47:97-108. .Vitamin D (vitD3) deficiency occurs frequently and has profound effects on health, especially asthma.

Vitamin D in asthma and future perspectives.Huang H,  Zarogoulidis K. ea Drug Des Devel Ther. 2013 Sep 23;7:1003-13.

 vitamin D deficiency associated with development of Acinetobacter baumannii infections in critically ill patients?; Türkoğlu M, Aygencel G et al.; Journal of Critical Care 28 (5), 735-40 (Oct 2013)

Association between vitamin D and hepatitis C virus infection: a meta-analysis. Villar LM, Romero-Gomez M. ea World J Gastroenterol. 2013 Sep 21;19(35):5917-24.

Association between prehospital vitamin D status and hospital-acquired bloodstream infections. Quraishi SA, Christopher KB. Ea, Am J Clin Nutr. 2013 Oct;98(4):952-9.

Human parvovirus B19 associated dilated cardiomyopathy. Jain P, Jain A, Khan DN, Kumar M. BMJ Case Rep. 2013 Aug 5;2013.

The role of vitamin D supplementation in the risk of developing pneumonia: three independent case-control studies. Remmelts HH,  van de Garde EM ea  .Thorax. 2013 Nov;68(11):990-6.

Correlation between serum vitamin D level and severity of community acquired pneumonia in young children   Ren J, Sun B, Miao P, Feng X. Zhongguo Dang Dai Er Ke Za Zhi. 2013 Jul;15(7):519-21. Chinese. http://www.ncbi.nlm.nih.gov/pubmed/23866270

Role of vitamins D, E and C in immunity and inflammation. Shaik-Dasthagirisaheb YB, Pandolfi F. J ea Biol Regul [Correlation between serum vitamin D level and severity of community acquired pneumonia in young children].Homeost Agents. 2013 Apr-Jun;27(2):291-5.

Pre-hospital vitamin D concentration, mortality, and bloodstream infection in a hospitalized patient population.Lange N, Christopher KB ea. Am J Med. 2013 Jul;126(7):640.e19-27.

Vitamin D deficiency in HIV infection: an underestimated and undertreated epidemic. Pinzone MR, Nunnari G. eA Eur Rev Med Pharmacol Sci. 2013 May;17(9):1218-32.

Vitamin D deficiency and sudden unexpected death in infancy and childhood: a cohort study.Cohen MC, Offiah A, Sprigg A, Al-Adnani M. Pediatr Dev Pathol. 2013 Jul-Aug;16(4):292-300.

Serum 25-hydroxyvitamin D3 and the risk of pneumonia in an ageing general population.Aregbesola A, Tuomainen TP. ea J Epidemiol Community Health. 2013 ;67:533-6.

Treatment of pulmonary tuberculosis.Nunn A, Phillips PP, Abubakar I.Curr Opin Pulm Med. 2013 ;19(3):273-9.

Role of vitamin D in children with respiratory tract infection.Esposito S, Baggi E, Bianchini S, Marchisio P, Principi N. Int J Immunopathol Pharmacol. 2013 J26(1):1-13.

Tuberculosis incidence correlates with sunshine: an ecological 28-year time series study.Koh GC, Dedicoat M. PLoS One. 2013;8:e57752.

Improving outcomes in patients with psoriasis.Tidman MJ. Practitioner. 2013 ;257:27-30, 3.

vitamin C refs & infection:

Authors’ perspective: What is the optimum intake of vitamin C in humansFrei B, Birlouez-Aragon I, Lykkesfeldt J.  Crit Rev Food Sci Nutr. 2012;52(9):815-29.

Micronutrients at the interface between inflammation and infectionascorbic acid and calciferol. Parts 1 & 2: .Ströhle A, Wolters M, Hahn A. Inflamm Allergy Drug Targets. 2011 ;10:54-74- FULL TEXT IS ON LINE. .

Vitamin C for preventing and treating tetanus Cochrane Database Syst Rev. 2008 Apr 16;(2):

MODERN SYNTHETIC PALLIATIVES- ANTIDEPRESSANTS,ANTIPSYCHOTICS, ANALGESICS, STATINS AND ANTI-INFLAMMATORIES – ARE RISKY NON-CURATIVE ESTROGENIC /FERTILITY ie METABOLIC ENDOCRINE DISRUPTORS

Accompanying his 32year old partner (with like her mother  BRCA+ breast cancer ), a   young man this week complains sorrowfully  of total erectile failure within three  days every time he resumes fluoxetine for longstanding depression.

This may suit those patients who eschew sexuality, who knowingly choose chemical castration.. But the drug doesnt fix the causes of depression, merely palliates, often no better than a placebo, sometimes worse- compared to natural multibeneficial  antidepressant supplements.

We already long  live in a sea of estrogenic endocrine disruptors decimating many species including humans,  like pesticides and PCBs, as so aptly described by Deborah Cadbury and Prof Nils Skakkebaek in classic books  eg The Feminization of Nature and The Estrogen Effect.

The commonest prescription  drugs (synthetics- antidepressants; major psychotropes;  amoxicillin,   oxidants ( betablockers eg atenolol;  nonsteroidal anti-inflammatory NSAID (which block antidepressant effects –the Paul Greengard hypothesis 2011 Rocherfeller Inst NY);  statins (cholesterol -steroid and insulin disruptors), and patent synthetic sex hormones-  are  now routine if not mandatory prescription  worldwide due to ruthless relentless marketing pressure-  disease-mongering for profit-  even in children, and worse,  in patients with cancers. The  commonest cancers- breast, prostate, uterus-  are estrogen-driven.

Such environmentally and biologically hostile designer patent drugs-for-profit   are increasingly detectable in surface wastewater globally  from human excretion, and thus drinking  water supplies .

Endocrine disruption studies of antidepressants  (eg fluoxetine Prozacs, mianserin Lantanon (its commercial analogue successor is now Remeron), Bupropion Wellbutrin Zyban;  Venlafaxine Effexor  and desimipramine)  in surface water in Canada,  USA,  Mexico, Brazil and Belgium since 2006, and longer for antipsychotics, statins  and NSAIDS, show estrogenic  ie antiandrogenic risks  for eg gender development and thus for breast/prostate cancer,   for  virility and fertility..

Doctors  mostly blithely  ignore that reproductive young females  have by evolutionary reproductive  necessity  100fold  lower androgenic:estrogenic balance (eg 3:1) than men (eg 300:1), and are also far more prone  than males both to estrogenic contraception prescription harm, and  to common  major depression and autoimmune disease like rheumatod arthritis and lupus, and thus to  the double peril of mutiple estrogenic  prescription.

Recently common NSAIDs eg ibrufen, diclofenac  and mefanemic acid have been shown to be estrogenic in fish.

But such elective  prescription of ( endocrine disruption) cancer- and infertility- promotors (antidepressants, NSAIDS, hormone contraception and HRT etc) ,  is hardly desirable or ethical  at any age, especially when patients and their parents  are not informed of the grave risks of these drugs with no proven longterm benefits (except for contraception).

new reviews  gives more insight  from a plastic surgeon into prevention, including the harms of xray mammography.

and into the gross dangerous overprescription  of diabetogenic depressing  hepato-nephro-myotoxic  statins for all.

Popular painkillers eg opioids like oxycodin, fentanyl, tramadol on the other hand are similarly also  powerful longacting hypoandrogenism–inducing drugs   promoting estrogen dominance – which further complicates the misery and depression of those in chronic pain or depression,  including from  cancer, especially in women as well as men;  who thus  require monitoring of gonadal hormone levels and, if deficient, testosterone replacement. Aloisi ea Univ Siena 2012.

ndb

Reprod Toxicol. 2012:34:80-5. In vivo and in vitro estrogenic activity of the antidepressant fluoxetine.Müller JC, Imazaki PH, Boareto AC, Lourenço EL, Golin M, Vechi MF, Lombardi NF, Minatovicz BC, Scippo ML, Martino-Andrade AJ, Dalsenter PR.  University of Paraná,  Brazil.     .Recent years have seen an increase in the use of antidepressant drugs, especially fluoxetine (FLX), in sensitive populations, such as pregnant and lactating women. Although some evidence suggests a possible endocrine action of FLX, no specific studies have been performed to investigate this hypothesis. In the present study, we investigated the possible (anti)androgenic and (anti)estrogenic actions of FLX using Hershberger, uterotrophic (0.4, 1.7, and 17mg/kg), and reporter gene (7.6-129μM) assays. In the Hershberger assay, no differences were observed in androgen-dependent organ weights. However, the uterotrophic and gene reporter assays indicated a possible estrogenic action of FLX. Uterine weight increased in the 1.7 and 17mg/kg/day groups in the 3-day uterotrophic assay in immature rats. Additionally, noncytotoxic concentrations of FLX induced estrogenic responses and increased the estrogenic response of estradiol in MCF-7 breast cancer.    Recent years have seen an increase in the use of antidepressant drugs, especially fluoxetine (FLX), in sensitive populations, such as pregnant and lactating women. Although some evidence suggests a possible endocrine action of FLX, no specific studies have been performed to investigate this hypothesis. In the present study, we investigated the possible (anti)androgenic and (anti)estrogenic actions of FLX using Hershberger, uterotrophic (0.4, 1.7, and 17mg/kg), and reporter gene (7.6-129μM) assays. In the Hershberger assay, no differences were observed in androgen-dependent organ weights. However, the uterotrophic and gene reporter assays indicated a possible estrogenic action of FLX. Uterine weight increased in the 1.7 and 17mg/kg/day groups in the 3-day uterotrophic assay in immature rats. Additionally, noncytotoxic concentrations of FLX induced estrogenic responses and increased the estrogenic response of estradiol in MCF-7 breast cancer cells transfected with luciferase.
Pharmacol Biochem Behav. 2013103: 659-65..Participation of estrogen receptors in the antidepressant-like effect of prolame on the forced swimming test. Lemini C, Cruz-López B, Martínez-Mota L  Universidad Nacional Autónoma de México, Mexico.Estrogen therapy may produce antidepressant-like actions, but the side effects, such as thromboembolic events, may restrict its use among women. The 17β-aminoestrogens (AEs) [prolame [17β-(3-hidroxy-1-propylamino)-1,3,5(10)-estratrien-3-ol)], butolame [17β-(3-hidroxy-1-butylamino)-1,3,5(10)-estratrien-3-ol)], and pentolame [17β-(5-hidroxy-1-pentylamino)-1,3,5(10)-estratrien-3-ol)] induce estrogenic and anticoagulant actions, effects that could prove advantageous in an estrogen therapy; however, their antidepressant-like effects have not been described. The objective of this study was to determine the effect of these 17β-AEs (prolame, butolame and pentolame) in the forced swimming test (FST), an animal model sensitive to antidepressant drugs, and to establish the role of estrogen receptors in such actions. Ovariectomized female rats treated with prolame (10-200 μg/rat) showed a reduction in immobility and an increase in active behaviors in the FST, while this effect was not produced by butolame and pentolame (10-200 μg/rat). The antidepressant-like effect of prolame was similar to that of 17β-estradiol (E2, 5-20 μg/rat), sharing with it a biphasic profile but at higher doses. Antidepressant-like actions of prolame and E2 were not associated with changes in locomotor activity. With respect to a control group tamoxifen (15 mg/kg) by itself produced no changes in all behavioral evaluations, but canceled the antidepressant-like effect of prolame and E2. It is concluded that estrogen receptors participate in antidepressant-like effect of both estrogens in the FST. Antidepressant-like activity of different AEs is discussed considering their differences in chemical structure and the schedule used. Our results show additional central actions of prolame besides its pro-sexual, anti-coagulant, estrogenic and anxiolytic activity.
Aquat Toxicol. 2011:104::38-47. Selective uptake and biological consequences of environmentally relevant antidepressant pharmaceutical exposures on male fathead minnows. Schultz MM, Painter MM, Bartell SE, Logue A, Furlong ET, Werner SL, Schoenfuss HL  The College of Wooster, OH   USA   Antidepressant pharmaceuticals have been reported in wastewater effluent at the nanogram to low microgram-per-liter range, and include bupropion (BUP), fluoxetine (FLX), sertraline (SER), and venlafaxine (VEN). To assess the effects of antidepressants on reproductive anatomy, physiology, and behavior, adult male fathead minnows (Pimephales promelas) were exposed for 21 days either to a single concentration of the antidepressants FLX, SER, VEN, or BUP, or to an antidepressant mixture. The data demonstrated that exposure to VEN (305 ng/L and 1104 ng/L) and SER (5.2 ng/L) resulted in mortality. Anatomical alterations were noted within the testes of fish exposed to SER and FLX, both modulators of the neurotransmitter serotonin. Additionally, FLX at 28 ng/L induced vitellogenin in male fish–a common endpoint for estrogenic endocrine disruption. Significant alterations in male secondary sex characteristics were noted with single exposures. Effects of single compound exposures neither carried over, nor became additive in the antidepressant mixtures, and reproductive behavior was not affected. Analysis of brain tissues from the exposed fish suggested increased uptake of FLX, SER and BUP and minimal uptake of VEN when compared to exposure water concentrations. Furthermore, the only metabolite detected consistently in the brain tissues was norfluoxetine. Similar trends of uptake by brain tissue were observed when fish were exposed to antidepressant mixtures. The present study demonstrates that anatomy and physiology, but not reproductive behavior, can be disrupted by exposure to environmental concentrations of some antidepressants. The observation that antidepressant uptake into fish tissues is selective may have consequences on assessing the mode-of-action and effects of these compounds in future studies.

Aquat Toxicol. 2010 ;100:354-64    .Waterborne fluoxetine disrupts the reproductive axis in sexually mature male goldfish, Carassius auratus.nMennigen JA, Lado WE, Zamora JM, Duarte-Guterman P, Langlois VS, Metcalfe CD, Chang JP, Moon TW, Trudeau VL  University of Ottawa, Ontario, Canada.    Fluoxetine (FLX) is a pharmaceutical acting as a selective serotonin reuptake inhibitor and is used to treat depression in humans. Fluoxetine and the major active metabolite norfluoxetine (NFLX) are released to aquatic systems via sewage-treatment effluents. They have been found to bioconcentrate in wild fish, raising concerns over potential endocrine disrupting effects. The objective of this study was to determine effects of waterborne FLX, including environmental concentrations, on the reproductive axis in sexually mature male goldfish. We initially cloned the goldfish serotonin transporter to investigate tissue and temporal expression of the serotonin transporter, the FLX target, in order to determine target tissues and sensitive exposure windows. Sexually mature male goldfish, which showed the highest levels of serotonin transporter expression in the neuroendocrine brain, were exposed to FLX at 0.54μg/L and 54μg/L in a 14-d exposure before receiving vehicle or sex pheromone stimulus consisting of either 4.3nM 17,20β-dihydroxy-4-pregnene-3-one (17,20P) or 3nM prostaglandin F₂(α) (PGF₂(α)). Reproductive endpoints assessed included gonadosomatic index, milt volume, and blood levels of the sex steroids testosterone and estradiol. Neuroendocrine function was investigated by measuring blood levels of luteinizing hormone, growth hormone, pituitary gene expression of luteinizing hormone, growth hormone and follicle-stimulating hormone and neuroendocrine brain expression of isotocin and vasotocin. To investigate changes at the gonadal level of the reproductive axis, testicular gene expression of the gonadotropin receptors, both the luteinizing hormone receptor and the follicle-stimulating hormone receptor, were measured as well as expression of the growth hormone receptor. To investigate potential impacts on spermatogenesis, testicular gene expression of the spermatogenesis marker vasa was measured and histological samples of testis were analyzed qualitatively. Estrogen indices were measured by expression and activity analysis of gonadal aromatase, as well as liver expression analysis of the estrogenic marker, esr1. After 14d, basal milt volume significantly decreased at 54μg/L FLX while pheromone-stimulated milt volume decreased at 0.54μg/L and 54μg/L FLX. Fluoxetine (54μg/L) inhibited both basal and pheromone-stimulated testosterone levels. Significant concentration-dependent reductions in follicle-stimulating hormone and isotocin expression were observed with FLX in the 17,20P- and PGF₂(α)-stimulated groups, respectively. Estradiol levels and expression of esr1 concentration-dependently increased with FLX. This study demonstrates that FLX disrupts reproductive physiology of male fish at environmentally relevant concentrations, and potential mechanisms are discussed.

Pharmacol Biochem Behav. 2008 ;88:332-40.Estrogens participate in the antidepressant-like effect of desipramine and fluoxetine in male rats.Martínez-Mota L, Cruz-Martínez JJ, Márquez-Baltazar S, Fernández-Guasti A  Instituto Nacional de Psiquiatría  Mexico City In male rats, the antidepressant-like effect of fluoxetine (FLX) and desipramine (DMI) in the forced swimming test (FST) is reduced by orchidectomy and partially restored by testosterone (T). It is unknown if this modulation of T is produced by its estrogenic metabolites. The objectives of this study were to evaluate if the aromatase inhibitor, formestane, interferes with the antidepressant-like effect of DMI and FLX in intact male rats, and to analyze if 17beta-estradiol (E2) modifies the FST and interacts with the antidepressants in orchidectomized (Orx) males. Intact males received DMI (1.25-5.0 mg/kg) and FLX (2.5-10 mg/kg) alone or in combination with formestane (17.5 mg/kg). Orx rats received E2 (5, 10, 20 and 40 microg/rat) or the combination of E2 [at sub-threshold (5 microg/rat) and optimal (10 microg/rat) doses] plus sub-effective doses of DMI (2.5 mg/kg) or FLX (10 mg/kg). Serum testosterone and estradiol levels were measured in intact-control and -formestane treated animals as well as in castrated males replaced with various doses of E2. Formestane in intact males lacked of an action in the FST, but cancelled the antidepressant-like effect of DMI and FLX. E2 at the supra-physiological doses of 10 and 20 microg/rat produced antidepressant-like effects. E2 at 5 microg/rat (that re-established the levels of this hormone to physiological levels) and at 10 microg/rat restored the antidepressant-like action of DMI and FLX in Orx rats. It was concluded that estrogens participate in the antidepressant-like effect of DMI and FLX in the FST.

Chemosphere. 2006:;65:1836-45.. Effects of the antidepressant mianserin in zebrafish: molecular markers of endocrine disruption.van der Ven K, Keil D, Moens LN, Hummelen PV, van Remortel P, Maras M, De Coen W. University of Antwerp,  Belgium.    Due to their environmental occurrence and intrinsic biological activity, human pharmaceuticals have received increasing attention from environmental and health agencies. Of particular, ecotoxicological concern are drugs that affect nervous- and endocrine-systems. Zebrafish genome-wide oligo arrays are used to collect mechanistic information on mianserin-induced changes in gene expression in zebrafish. Gene expression analysis in brain and gonad tissue clearly demonstrated the estrogenic activity of mianserin and its potency to disrupt normal endocrine (estrogenic) signaling, based on induction of molecular biomarkers of estrogenicity (e.g., vitellogenin1 and zona pellucida proteins). The possible mechanism underlying this estrogenic activity of mianserin is disturbance of the Hypothalamo-Pituitary-Gonadal (HPG) axis by direct interference of mianserin with the serotonergic and adrenergic systems in the brain of zebrafish. Taking into account the importance of the HPG-axis, and considering the concept of ‘critical window of exposure’, our results reveal the importance for more elaborate testing of endocrine disruptive effects of aquatic antidepressants at different lifestages and during longer exposure periods (e.g., life cycle studies). Although there is a low concordance between the gene expression results in this study and previous cDNA microarray hybridizations, the global mechanistic expression patterns are similar in both platforms. This argues in favor of pathway-driven analysis of gene expression results compared to gene-per-gene analysis.

 

J Hazard Mater. 2013 Jun 15;254-255:242-51. .Effects of non-steroidal anti-inflammatory drugs on hormones and genes of the hypothalamic-pituitary-gonad axis, and reproduction of zebrafish.  Ji K, Liu X, Lee S, Kang S, Kho Y, Giesy JP, Choi K. Seoul National University,  Korea.This study was conducted in two experiments, to identify non-steroidal anti-inflammatory drugs (NSAIDs) with high endocrine disruption potentials, and to understand consequences of exposure to such NSAIDs in fish. In the first experiment, the effects of five NSAIDs on hormones and gene transcriptions of the hypothalamic-pituitary-gonad (HPG) axis were evaluated after 14 d exposure of adult zebrafish. Ibuprofen and mefenamic acids were identified to increase the concentrations of 17β-estradiol and testosterone in females significantly, while decreased those of testosterone among male fish. Significant up-regulation of fshβ, lhβ, fshr and lhr were observed in females, whereas down-regulation was observed in males exposed to each NSAID. In the second experiment, ibuprofen was chosen as a model chemical. Adult zebrafish pairs were exposed to ibuprofen for 21 d, and the effects on reproduction and development of offspring were examined. The egg production was significantly decreased at ≥1 μg/L ibuprofen, and parental exposure resulted in delayed hatching even when they were transferred to clean water for hatching. The results demonstrated that ibuprofen could modulate hormone production and related gene transcription of the HPG axis in a sex-dependent way, which could cause adverse effects on reproduction and the development of offspring.

University of Algarve, Portugal  .buprofen (IBU) is one of the most sold over-the-counter non-steroidal anti-inflammatory drugs (NSAID) and widely detected in the aquatic ecosystems. Nevertheless, the information regarding IBU effects in biota is still sparse. The goal of this study was to assess IBU potential effect as oxidative stress and endocrine disruption inducer in mussel Mytilus galloprovincialis applying a battery of biomarkers. Over two weeks of exposure to IBU (250 ngL(-1)), superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), phase II glutathione S-transferase (GST) activities and lipid peroxidation (LPO) levels were determined in the digestive gland and alkali-labile phosphates (ALP) were carried out in sex-differentiated mussels’ gonads. The results confirm a transitory induction of antioxidant activities responses concomitant to lipid peroxide formation outline and an increase of ALP levels over time, particularly in exposed males which may lead to mussels’ reproductive fitness impairment highlighting a higher impact of IBU as an endocrine disruptor than as a short-term reactive oxygen species (ROS)-generator.

 

Aquat Toxicol. 2011 ;105:264-9..Non-steroidal anti-inflammatory drug (NSAID) ibuprofen distresses antioxidant defense system in mussel Mytilus galloprovincialis gills.Gonzalez-Rey M, Bebianno M   University of Algarve,  Portugal.Active pharmaceutical ingredients (APIs) are presently considered an emergent class of environmental contaminants. Ibuprofen (IBU) is one of the most applied non-steroidal anti-inflammatory drugs (NSAIDs) in the world. Several authors report the occurrence of IBU in influents and effluents of waste water treatment plants (WWTPs), surface, river and public tap water in numerous countries. However, very little is known about the risks and chronic effects of IBU exposure in non-target organisms. This approach undertakes the assessment of several oxidative stress biomarkers responses through the analysis of antioxidant enzymes activities (superoxide dismutase – SOD, catalase – CAT, glutathione S-transferase – GST, glutathione reductase – GR) and lipid peroxidation (LPO) levels in sentinel species mussel Mytilus galloprovincialis gills exposed for 2 weeks to an environmental realistic concentration of IBU. Results clearly show the significant induction and positive correlation between SOD activity and LPO in exposed gills, concomitant to an antioxidant defense depletion of CAT, GR and GST compared to controls. The integration of all biomarkers in mussels’ gills separates non- and exposed groups supporting the breakdown of the redox defense system and IBU’s pro-oxidant action. Further studies are needed to test possible endocrine disruption effects in mussels’ reproduction fitness as IBU is involved on prostaglandins biosynthesis inhibition.

BMC Med. 2013; 11:57..  The effect of statins on testosterone in men and women, a systematic review and meta-analysis of randomized controlled trials. Schooling CM, Au Yeung SL, Freeman G, Cowling BJ. CUNY School of Public Health  York, .Statins are extensively used for cardiovascular disease prevention. Statins reduce mortality rates more than other lipid-modulating drugs, although evidence from randomized controlled trials also suggests that statins unexpectedly increase the risk of diabetes and improve immune function. Physiologically, statins would be expected to lower androgens because statins inhibit production of the substrate for the local synthesis of androgens and statins’ pleiotropic effects are somewhat similar to the physiological effects of lowering testosterone, so we hypothesized that statins lower testosterone.   METHODS:A meta-analysis of placebo-controlled randomized trials of statins to test the a priori hypothesis that statins lower testosterone. We searched the PubMed, Medline and ISI Web of Science databases until the end of 2011, using ‘(Testosterone OR androgen) AND (CS-514 OR statin OR simvastatin OR atorvastatin OR fluvastatin OR lovastatin OR rosuvastatin OR pravastatin)’ restricted to randomized controlled trials in English, supplemented by a bibliographic search. We included studies with durations of 2+ weeks reporting changes in testosterone. Two reviewers independently searched, selected and assessed study quality. Two statisticians independently abstracted and analyzed data, using random or fixed effects models, as appropriate, with inverse variance weighting.RESULTS:Of the 29 studies identified 11 were eligible. In 5 homogenous trials of 501 men, mainly middle aged with hypercholesterolemia, statins lowered testosterone by -0.66 nmol/l (95% confidence interval (CI) -0.14 to -1.18). In 6 heterogeneous trials of 368 young women with polycystic ovary syndrome, statins lowered testosterone by -0.40 nmol/l (95% CI -0.05 to -0.75). Overall statins lowered testosterone by -0.44 nmol/l (95% CI -0.75 to -0.13).    CONCLUSIONS:  Statins may partially operate by lowering testosterone. Whether this is a detrimental side effect or mode of action warrants investigation given the potential implications for drug development and prevention of non-communicable chronic diseases. See commentary article here http://www.biomedcentral.com/1741-7015/11/58.

 

Chemosphere. 2009 ;77 :1285-91.Occurrence and fate of rosuvastatin, rosuvastatin lactone, and atorvastatin in Canadian sewage and surface water samples.  Lee HB, Peart TE, Svoboda ML, Backus S. Aquatic Ecosystem Protection Research Branch, Environment Canada      Rosuvastatin (RST) and atorvastatin (ATO) are prescription drugs and members in the statin family used for the treatment of elevated cholesterol levels. A method using solid-phase extraction and liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the determination of ATO, RST and its metabolite rosuvastatin lactone (RSTL) in sewage and surface water samples has been developed. In the influent and effluent samples collected from 11 sewage treatment plants located in Ontario, Canada, ATO, RST, and RSTL were detected in all samples with median concentrations of 166 ng L(-1) (influent) and 77 ng L(-1) (effluent) for ATO, 448 ng L(-1) (influent) and 324 ng L(-1) (effluent) for RST, as well as 158 ng L(-1) (influent) and 41 ng L(-1) (effluent) for RSTL. Due to the inter-conversion between RST and RSTL, the total concentration of RST and RSTL in a sewage sample should be reported. The median removal rate by wastewater treatment was 66% for ATO and 22% for RST and RSTL combined. These statins were quite persistent in sewage. After a storage period of 21 and 62 days, there was only a slight decrease in ATO concentration and no change in the total RST concentrations. These three compounds were also detected in a number of surface water samples at low ng L(-1) concentrations. This is the first reported occurrence and fate of RST and RSTL in the Canadian aquatic environment.
Ecotoxicol Environ Saf. 2011;74:1216-25. Chronic exposure to diclofenac on two freshwater cladocerans and Japanese medaka.Lee J, Ji K, Lim Kho Y, Kim P, Choi  Seoul National University,  Korea.
Consequences of long-term exposure to diclofenac up to 3 months were evaluated using freshwater crustaceans (Daphnia magna and Moina macrocopa) and a fish (Oryzias latipes). Marked decrease of reproduction was observed at 25 mg/L for D. magna, and at 50 mg/L for M. macrocopa. Three-month exposure of fish to 0.001-10 mg/L of diclofenac resulted in significant decreasing trend in hatching success and delay in hatch. The hatching of the eggs produced from the fish exposed to 10 mg/L was completely interfered, while fertility of the parent generation was not affected. Gonadosomatic index (GSI) of female fish was also affected at 10 mg/L. Predicted no effect concentration of diclofenac was estimated at 0.1 mg/L, which is a few orders of magnitude greater than those observed in ambient water. Therefore direct impact of diclofenac exposure is not expected. However its bioaccumulation potential through food web should warrant further evaluation.\
J Toxicol Environ Health A. 2009;72(10):633-41. Life-cycle exposure of fathead minnows to a mixture of six common pharmaceuticals and triclosan.Parrott JL, Bennie DT Water Science and Technology Directorate, Environment Canada,Fathead minnows were exposed for a life cycle to environmentally relevant concentrations of a mixture of six common pharmaceuticals and one personal care product (nominal concentrations: 1,000, 300, 100, 30, or 10 ng/L). Mean measured concentrations of each chemical in the highest fish exposure aquaria were: naproxen 793 ng/L, gemfibrozil 662 ng/L, diclofenac 331 ng/L, ibuprophen 217 ng/L, triclosan 115 ng/L, salicylic acid 67 ng/L, and acetaminophen (chemical analysis inconclusive, nominal 1000 ng/L). Fish exposed for a life cycle even to the highest concentrations of the six pharmaceuticals and personal care product (PPCP) mixture showed no significant changes in growth and development compared to control. Length, weights, condition factors, liver weights, and gonad weights of PPCP-exposed fish were similar to water and solvent controls (0.000005% ethanol v/v). There were no marked effects of PPCP mixture exposure on external sex characteristics of the fish or on egg production. The only parameter that appeared to be affected was percent larval deformities in F1, which showed a significant increase in the 100- and 300-ng/L (nominal) PPCP mixture. Larvae from control fish had 4.7% (water controls) and 3.4% (solvent controls) deformities, compared to 9.3% in the 100-ng/L (nominal) PPCP mixture and 9.2% deformities in the 300-ng/L (nominal) PPCP mixture. Chronic exposure to environmentally relevant concentrations of seven PPCP most often detected in Canadian municipal wastewater effluents (MWWE) did not appear to affect fathead minnow survival, growth, or egg production, although it produced quantitative increases in deformities in the F1 generation.
Hum Reprod. 1993 Aug;8(8):1168-72.Autonomic nervous modulation and effects of a prostaglandin synthase inhibitor on human cervical secretion.Jonsson B, Hammarström  Karolinska Hospital, Stockholm, Sweden.Modulation of cervical secretion at ovulation time was studied in 10 women with regular menstruations. In an in-vivo model with repeated collection of mucus samples during three 90-min periods, the amounts of mucus in a control cycle and in three experimental cycles were compared. Drugs interacting with the autonomic nervous system and a prostaglandin synthase inhibitor were administered at time of ovulation. The cholinomimetic drug carbacholine significantly increased cervical secretion, while the anticholinergic drug butylscopolamine markedly inhibited this secretion. A long-lasting decrease in secretion was seen after administration of the prostaglandin synthase inhibitor diclofenac. Beside regulation of cervical secretion by the ovarian hormones, these results suggest an autonomic nervous modulation of cervical secretion, and in addition an impact on cervical by a prostaglandin synthase inhibitor. The effects on fertility regulation in the female are discussed.
Water Res. 2010 Jan;44(2):555-66.   Oxidative transformation of micropollutants during municipal wastewater treatment: comparison of kinetic aspects of selective (chlorine, chlorine dioxide, ferrate VI, and ozone) and non-selective oxidants (hydroxyl radical).Lee Y, von Gunten U. Federal Institute of Aquatic Science and Technology, Duebendorf, Switzerland.  Chemical oxidation processes have been widely applied to water treatment and may serve as a tool to minimize the release of micropollutants (e.g. pharmaceuticals and endocrine disruptors) from municipal wastewater effluents into the aquatic environment. The potential of several oxidants for the transformation of selected micropollutants such as atenolol, carbamazepine, 17 alpha-ethinylestradiol (EE2), ibuprofen, and sulfamethoxazole was assessed and compared. The oxidants include chlorine, chlorine dioxide, ferrate(VI), and ozone as selective oxidants versus hydroxyl radicals as non-selective oxidant. Second-order rate constants (k) for the reaction of each oxidant show that the selective oxidants react only with some electron-rich organic moieties (ERMs), such as phenols, anilines, olefins, and deprotonated-amines. In contrast, hydroxyl radicals show a nearly diffusion-controlled reactivity with almost all organic moieties (k>or=10(9)M(-1) s(-1)). Due to a competition for oxidants between a target micropollutant and wastewater matrix (i.e. effluent organic matter, EfOM), a higher reaction rate with a target micropollutant does not necessarily translate into more efficient transformation. For example, transformation efficiencies of EE2, a phenolic micropollutant, in a selected wastewater effluent at pH 8 varied only within a factor of 7 among the selective oxidants, even though the corresponding k for the reaction of each selective oxidant with EE2 varied over four orders of magnitude. In addition, for the selective oxidants, the competition disappears rapidly after the ERMs present in EfOM are consumed. In contrast, for hydroxyl radicals, the competition remains practically the same during the entire oxidation. Therefore, for a given oxidant dose, the selective oxidants were more efficient than hydroxyl radicals for transforming ERMs-containing micropollutants, while hydroxyl radicals are capable of transforming micropollutants even without ERMs. Besides EfOM, ammonia, nitrite, and bromide were found to affect the micropollutant transformation efficiency during chlorine or ozone treatment.
Toxicol Appl Pharmacol. 2007 Dec 1;225:142-53. .Modulation of steroidogenic gene expression and hormone production of H295R cells by pharmaceuticals and other environmentally active compounds.Gracia T, Hilscherova K, Jones PD, Newsted JL, Higley EB, Zhang X, Hecker M, Murphy MB, Yu RM, Lam PK, Wu RS, Giesy JP.Michigan State University,       The H295R cell bioassay was used to evaluate the potential endocrine disrupting effects of 18 of the most commonly used pharmaceuticals in the United States. Exposures for 48 h with single pharmaceuticals and binary mixtures were conducted; the expression of five steroidogenic genes, 3betaHSD2, CYP11beta1, CYP11beta2, CYP17 and CYP19, was quantified by Q-RT-PCR. Production of the steroid hormones estradiol (E2), testosterone (T) and progesterone (P) was also evaluated. Antibiotics were shown to modulate gene expression and hormone production. Amoxicillin up-regulated the expression of CYP11beta2 and CYP19 by more than 2-fold and induced estradiol production up to almost 3-fold. Erythromycin significantly increased CYP11beta2 expression and the production of P and E2 by 3.5- and 2.4-fold, respectively, while production of T was significantly decreased. The beta-agonist salbutamol caused the greatest induction of CYP17, more than 13-fold, and significantly decreased E2 production. The binary mixture of cyproterone and salbutamol significantly down-regulated expression of CYP19, while a mixture of ethynylestradiol and trenbolone, increased E2 production 3.7-fold. Estradiol production was significantly affected by changes in concentrations of trenbolone, cyproterone, and ethynylestradiol. Exposures with individual pharmaceuticals showed the possible secondary effects that drugs may exert on steroid production. Results from binary mixture exposures suggested the possible type of interactions that may occur between drugs and the joint effects product of such interactions. Dose-response results indicated that although two chemicals may share a common mechanism of action the concentration effects observed may be significantly different.