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Ross & Henderson’s sentinel (JAMA 1980) paper on the strong relationship between long term oral premarin  total dose and breast cancer was  largely ignored:  that  with cumulative premarin dose >1,500 mg (ie 7yrs) the breast cancer  risk  was estimated to be 2.5 in women with ovaries (vs  0,7 sans ovaries); the risk ratio for a high cumulative dose (ie after about 15years, >3mg premarin)  rose to 5.7 relative to nonusers with normal breasts.

But at the same time, Finnish papers in Maturitas showed why, because of non-physiological high E1>E2 even on oral E2,  systemic ERT is preferred:

Punnonen R ea: (in E2V 2mg/d  & the Renin-Aldost system: 1980:2:91-4) that  “on oral E2v the E2 levels rose to normal and (unlike  on oral premarin, EE2) caused  no rise In BP, aldost, renin; they thus preferred such natural  ERT which does not activate the biliary, RAS renin-angiotensin system, and thrombosis”;

 but Heinonen  PK et al (1982:4: 273-6 Estrogen levels on oral E2) showed that  on E2v  4mg/d orally, blood   E2 rose 5X and  E1 rose 25X; so they recommended avoiding   oral ERT.

Thus the Womens’ Health Initiative confirmed three facts: 

1. starting OHT well after age 60yrs and continuing even modest dose cyclic  (premarin 0.625mg plus MPA 5mg) does more harm than good; THIS SAYS NOTHING ABOUT APPROPRIATE PHYSIOLOGICAL BALANCED COMBINED PARENTERAL TESTOSTERONE-PROGESTERONE-ESTRADIOL HRT FROM ANY POSTMENOPAUSAL AGE HAVING ANY  LIFELONG RISKS WHATSOEVER.

2. starting the same OHT regime soon after menopause - especially premarin alone- reduces  all major diseases and mortality by about a third, except for rare cases of deep vein thrombosis and cholelithiasis;  this outcome was confirmed in the 9year RCT in Finland (Heikkinen ea 2006) in which women on oral estradiol 1mg/d +- MPA 2.5mg from menopause had zero major adverse events.  BUT THIS SPEAKS ONLY FOR AT MOST THE 9 YEARS THAT  THESE WOMEN WERE IN THE TRIALS.

There are  so far some seven  major functional types of steroid hormones  in humans: calciferols; androgens; estrogens; progestins; glucocorticoids; mineralocorticoids; and  endogenous digitalis- natriuretic hormone (eg Goldstein  2006, Weidemann 2005; Kurup ea 2003) .

     Apart from  gender-reproduction-childhood growth promotion (ie androgens, estrogens & progestins), their actions fall into many other systemic classes; which in conventional “replacement” doses  the literature and experience suggests may be compared as follows:

+=increase;    - = lessen; n = apparently neutral?  AS=anabolic steroids.

The active hydroxycalciferols are in a sense exocrine ie are produced from ingested  vitamin D3 and cholesterol in the skin and kidneys, not from dedicated endocrine glands; but while their synthesis needs no more than an hour of sunlight a week in sunny climates, and modest kidney function, calciferol deficiency is increasingly recognized in those who take little dairy products, and little sunshine. Thus the pituitary, skin,  parathyroids, adrenals  and  gonads are the primary  endocrine glands of growth.

The other steroid hormones (like the other major anabolic hormones- insulin and human growth hormone HGH) are endocrine ie are vulnerable to both intrinsic endocrine failure (Hypothalamic-Pituitary-Adrenal- pancreatic-Gonadal ),  and to  endocrine gland decrease and blockage by infections, cancer, major stress, auto-antibodies or direct trauma.

       All these anabolic  hormones  if swallowed are destroyed  by digestion/  1^st-pass hepatic metabolism; thus to achieve the same systemic effect,   comparative doses are reported as follows:                 

The vulnerability  of oral steroid therapy is illustrated by oral contraception: where taking eg an oral antibiotic can compete for absorption, reducing   blood SH levels so that accidental conception occurs. Similarly, a postmenopausal  patient with rheumatoid arthritis, on oral (E+P HRT), reports that  her analgesic  requirements  rise while she is on antibiotics.

     One  needs to go back to a standard textbook of Pharmacology of  1958, (Kranz & Carr: Pharmacological Principles of Medical Practice: Balliere, London) to find the corollary:  eg “cortisone acetate implant, or im  2-5mg daily injection as replacement for  Addisons’ Syndrome”: “For menopausal symptoms, combined E+TT is often employed…”;  “oral synthetic estrogens (have replaced natural ones due to availability,  oral form & lower cost; but) produce undesirable: nausea, cramps, migraine and male breasts.    Estrogen + TT are additive, and E doses may therefore be reduced   since the combination gives smoother transition:  73% of patients remain  symptom free.    TT 10mg imi 3 x/week may control  functional uterine bleeding better than progesterone”!.

      It is widely overlooked that  TT is converted irreversibly by aromatase to E2 in the tissues; but   giving E2 does not do the reverse – it  suppresses the  HPAG and   TT production. Thus women need to be given TT with estrogen, but  men do not need to be given estrogen -  giving them TT increases their E2 levels by about 1/3. This source of E2 may not be enough for balance in women, but reduces their needed dose of administered estrogen;  hence in women  on a standard 20:1 TT:E2  injection combination, or on combined implants eg TT 50mg + E2  20mg/6months,  the blood TT level should be monitored to check that the mean TT is in the physiological range of  1-3.5nmol/L, but the E2 level need  not be above perhaps 0.1nmol/L – in fact, to avoid excess fat deposition and breast cancer stimulation, it must  not , since TT is supplying E2 direct in target organs.

     Hence Ginsberg J & Prevelic GM  at Royal Free Medical School  ( Drug Therapy & Reproductive Endocrinology: London: Arnold 1996) note that in BRCA, androgen + prednisone give good results;  they advise: parenteral> oral ERT: eg  E2 patch 50u/d;  or Implants eg TT 50mg + 20mg E2 /6mo (= 300mcg TT + 110mcg E2/ day)..

In TOPICS IN O & G 1998: (ed Julian Bassin: Julmar Communications, Jbg 4^th Ed 1998: sponsored by all the RSA gyne Drug Suppliers):  Schnitzler CM wrote that “ERT should be given for life, from as early as possible, but even from 80yrs; the elderly not exposed to the sun needing >2000u vit D/day. Sonnendeker on HRT wrote that oral  HRT raises both coagulation & renin substrates acutely; EE2 should not be used for ERT; thus he prefers oral ERT except  if coagulopathy, liver/biliary/ triglyceride/ or vascular headache  problems, when he uses non-oral ERT. Indications for androgens are: poor libido; persistent tiredness & OP; preferring the 25mg TT pellet to oral androgens or imi esters”.

Finally, the physiological logic of parenteral  (as opposed to oral) HRT- in this case sex hormone replacement) was already well recognized and marketed over 60 years ago – even in South Africa- in eg the handbook Sex Endocrinology (Schering, New Jersey, 1944) which recommended and listed creams, injections and implants as well as tablets.

William Masters and colleagues followed this up with the first apparent RCT of HRT published in 1953,  who showing  in a 13month titration RCT that biweekly ie shortacting  esters  imi TT 20mg  + E2 1mg    (= T ~2.8mg/d + E2 ~0.14mg/d, ie a ratio of 20:1 to 22:1 – as in Schering’s Primodian Depot or Organon’s Mixogen)  restored 70% of geriatric women in their mid70s to selfcare; allowing the nursing staff on the unit to be halved. Overall the women had ~one brief menstrual bleed  after about 5weeks, thereafter on follow-up biopsy all maintained endometrial atrophy. Some  needed initial T:E dose titration (between eg 30:1 to 15:1)  for individual variation in response. As a result  both Schering and Organon to this day sell this preparation as a 100mg TT ester + 5mg estradiol ester ial, to be given as desired every 3 – 6 weeks.

     We have found for the past  ~10 years that, just as hypogonadal men do optimally  on about 200mg depotrone subcutaneously sc  every fortnight (= 10mg TT a day), women do well on  Masters’  20:1  TT:E2 hormone ratio, the optimal regime being on average 0.2ml 20mg of hormones by domestic  subcutaneous selfinjection every 2 weeks ie TT 1mg/day and E2  0.05mg/day,  – the average resultant  blood levels being TT round 2.5nmol/L - but of course the testosterone itself delivering far more estradiol extra- and intracellularly.

  With this regime we have never seen a breakthrough bleed in postmenopausal women, for the simple reason that follow-up endometrial ultrasound uniformly shows endometrial atrophy. We have also never seen increasing changes on follow-up screening mammography since it is common cause that testosterone suppresses female glandular breast proliferation.  

These  results with arenteral HRT  have been abundantly confirmed in women followed for up to  40years on parenteral HRT by leading menopause clinics such as Greenblat  & Ganbrell(Augusta); Gelfand(Montreal); Schiff(Boston), Buster(Houston), Notelovitz (Florida), Vliet(Tucson), Lichten(Michigan), Shippen(Philadelphia), Karpas(Atlanta); Schleyer-Saunders, Whitehead and Studd(London UK); Tvedegard Moller & Hansen(Copenhagen); Burger & Davis, Zhou & Dimitrikakis (Australia); and our Cape Town group under Davey;

and

most important of all:  since longterm trials beyond the necessary critical 20 years  will never be carried out in humans due to the cost, the results of primate studies by Thomas Clarkson ea at Wake  Forrest University  showing  that starting even oral premarin at castration in young  female monkeys and continuing it for the human equivalent of 15 years blocked onset of atheromatous disease ; but premarin alone or with MPA  produced breast proliferation;  but like endometrial proliferation, this was suppressed by testosterone replacement.

       The greatest myth (if not drug industry  hoax) of the past 30 years may be the claim that postmenopausal women (or for that matter women needing contraception) need a patent estrogen and a synthetic progestin for endometrial  and breast protection and contraception; when it was shown decades ago that depot estradiol plus depot progesterone- or better still,  depot estradiol plus depot  testosterone plus depot progesterone - do best for both contraception and HRT  and all-system protection against all the degenerative diseases of aging. 

The fevent hope and effort  of the patent designer drug industry is that they can buy off enough practitioners, academics, researchers, Regulators and politicians so that the widespread avilability, low cost - and massive all-disease prevention- of such natural supplements as human hormones as well as the dozens of other proven biologicals including vitamins and mineral is never appreciated and utiized. They cannot curb their insatiable lust   for immediate endless profits no matter how much suffering it causes - disaster capitalsm- by recognizing that if they now promote such safe cheap proven panaceas to both the poor and the prosperous consumers, they will extend healthspan by decades, producing far more survivors who will later rather than sooner still need/want to buy their designer products.

4. to follow: THE IMPORTANCE OF THE SITE OF PARENTERAL INJECTIONS

DOES THE SOURCE,  MEASUREMENT, DOSE, BALANCE, and  ROUTE OF ADMINISTRATION OF SEX HORMONE THERAPY HRT MATTER?

Chapter 

1.      THE IMPORTANCE OF THE MEASUREMENT OF BLOOD LEVELS OF SEX HORMONES

          While urologists,  andrologists and internists  demand blood hormone  levels to diagnose male hypogonadism ,  adrenal, thyroid  or other endocrine dysfunction ,  many gynecologists still apparently  give postmenopausal HRT without ever measuring levels.

           Do baseline and achieved sex hormone levels matter ?

           Older authorities(mostly male or trained by men) did not believe so; hence we still see women presenting  on  eg implants or Premarin up to 2,5mg/day for years, with Estrogen  levels of well above 3nmol/L ->10 times what is necessary and safe),  or SHBG levels well over 200nmol/L; some of them grossly bloated and dysfunctional if not with mushrooming breast cancers or  the obesity metabolic syndrome.

      The textbook HORMONE REPLACEMENT THERAPY HRT (A Wayne  Meikle ed: Humana Press, USA  1999: p266) says  in Men’s Sex Hormone Replacement SHR: “the  general principle of SHR  is to normalize the (TT) level”.  “The safe course is to duplicate normal physiology as much as possible:  HRT  should allow self-administration, be convenient, affordable, minimal discomfort, with predictable responses. TT-cypionate  or TT-enanthate  100mg/week maintains physiological levels between 16-32 ie mean 24nmol/L.   Mixtures of short-and-long-acting TT  (eg Sustanon) are  thus  not recommended”.

At p412 Davis & Burger, for TT Replacement  in women, say:  “replace TT levels to at least the UPPER level of  normal physiological range for young ovulating women”.

     Meikle’s  authoritative  Textbook thus stresses the importance of  duplicating  normal human  physiology .  This  requires  using human systemic (ie not oral) hormones which can  and  must  be measured before and periodically on SHR -

 ie  using only systemic TT in men, systemic TT + E2 + Progesterone in women.

The 2000 Management of the Menopause Millenium Review (Studd JW ea, London) strongly promotes measuring hormone levels and balance in both sexes: ”calcium loss decreases with serum E2> 72pmol/L; vasomotor symptoms at >126-252pmol/L; and lipids changes at  250pmol/L- whereas breast cancer BRCA cells responds  to  E2>36pmol/L”  but does not say how these interact with TT levels;  so it is  important to monitor the serum E2, to keep it in the therapeutic window above about 100 but below 250pmol/L ie mean about 200pmol/l;  many women do not feel better on solo ERT – so few persist  on it; Studd ea  thus recommend “E2 patch rather than orally, for less hypertension, gallstones, DVT & hepatic protein formation.”      “it  is mandatory to measure BMI and % body fat;   the single best screen for Insulin resistance is a  fasting glucose/insulin(G:I) ratio below 4,5.

       “Depression is the commonest functional disorder of aging men, in whom aging sexhormone changes - PEDAM(Partial Endocrine  Deficiency of Aging  Men)-  include falling androgens, rise in SHBG, arteriosclerosis  & CVD,  and decrease in brain hormones & wellbeing – with especially decrease in melotonin & sleep, muscle strength, RBC, cognition, bone,  immunocompetence,  &  erection.”

       The Johannesburg gynecologist editor of Wyeth’s Menopause Update August 2001 certainly advocates frequent E2 measurements to titrate the frequency and dose of E2 implants, “aiming for a blood level of 0.35-0.45nmol/L: side effects occur when the dose exceeds the patient’s needs”.  Kopenhager in the same issue promotes “lowdose ERT – 1mg/day oral E2 causing less side-effects like headache, swelling or mastalgia, without increase in body mass”; but he overlooks the fact that 0.05ug of E2/day systemically will often suffice, that body weight says nothing about the steady gain in fatmass and loss in muscle  mass with aging and unopposed estrogen.   Prof  Frank Guidozzi from Johannesburg in the same issue makes the  point about TT replacement even for men – 250mg ester/ fortnight intramuscularly ie  a mean 12mg TT/day, or 5mg/day by patch, or 120mg undecanoate/day orally..

          As Fritz Schumaker said, there is a need for the right amount of  all things, from water to air.  A bit too little or a bit too much food, insulin or cortisone will be seen and felt fairly soon; whereas with thyroid, vitamin D and the sex steroids it may take months to years before it becomes apparent – when it may be too late, with broken marriage, spirits, heart or bones, or cancer.  Optimal doses, blood levels and balance  are apparent throughout nature and  for all hormones – with balance between the hormones – between the strengthening androgens and the fattening estrogenics – being the most important to balance the bloodpressure and lipids, thrombosis and bruising, fat-mass and lean-mass,  concrete and intuitive skills,  hypo-and hyper-immunity,  apathy and drive.  

            Well-published clinical studies for 80 years since hormone measurements began (McLeod  & Banting; Albright; Dubois, Masters, Bulbring, Hayward, Stoll, Mackay,  Wang, Henderson, Greenblatt, Speroff, Vermeulen, Roitt & Delves, Nieschlag & Behre, Motohashi,  Studd, Whitehead, Maartens et al)  have  shown the importance of  titrating doses and measuring  bloodlevels of the superhormone family - estrogens and androgens, cortisone, insulin and thyroid -  in men and women,  on every system, the mind and body.

OPTIMAL SEXHORMONE LEVELS

Sue Davis et al from Monash University  have been eloquent advocates of normalizing female TT levels above the 1.5nmol/L level;  this has been done by eg  Schleyer-Saunders in London, Gelfand and Gambrell in Augusta,  Morrie Gelfand et al at McGill Quebec, and Davey’s group  in Cape Town for over 30 years. There seems to be wide consensus that E2 level should be between 0.1-0.25nmol/L – but bearing in mind that breast cancer increases in proportion to the estrogen dose, and that plasma E2 reflects the (free)  plasma estrogens and androgens only in the presence of normal SHBG and in the absence  of any other estrogenics.

The Healthy TT level in Young Men

      Most seem to take it for granted that, at any adult age, a plasma TT anywhere above the bottom of the population range (eg 10nmol/L) is normal and adequate. Pfizer claims  in it’s Viagra trials that only impotent men with TT below about 8nmol/L were excluded,  since  those with TT level less  than about 2sd or 20% below the lower range of “normal” were not classified as hypogonadal.

Yet this level is 1/4 of the vigorous youthful 35-40nmol/L which we sometimes find in dynamic men even  in their mid-fifties.  Aversa A ea in  Italy (in Clin Endoc 2000:53:517-22) show how Androgens and Erection correlate, that  older  impotent men have  TT  around 13-19, mean 16nmol/L  ie half the level of young men;  those with vascular impotence having 25% higher E2 & SHBG, and  40% lower free TT (only about 45pmol/L,  versus 75pmol/L) than in  the psychogenic group; thus fTT correlates with penile elasticity;  (cf  male TT “normal range” at all age  9-35 ie mean 22nmol/L- whereas eg Greek  recruits at  army intake: mean TT level about 32nmol/L-Mantzoros et al).

        Salmimies’ paper  (1982) already 20 years ago illustrated that there is no sharp cutoff point for impotence, for response to TT:  “15 diverse hypogonadic men received im TTEnanthate (25 to 250 mg TT) or placebo injections 2 weekly, each dose for 4 weeks. All patients with pre treatment plasma TT values below 2 ng/ml(ie <7nmol/L) reported impaired sexual function. In four patients with TT between 2 and 4.5 ng/ml who reported impairment, TTE 50 to 250mg successfully improved rated sexual behaviour. Four matched men with TT level in the same 2 - 4.5ng/ml range reported high erectile function that did not change with TT E inj. These data indicate that male sexual behaviour is impaired at an individual plasma TT below between 2.0 and 4.5 ng/ml “       ie : the range of erectile loss or response is at least between 7 and 16nmol/L on their assay.

But did they, does anyone,  give enough TT, achieve adequate blood levels for long enough in non-responders?

     Andy  Guay’s 2001 abstract  illustrates the same point, there is a (?semilog) linear response ; (as  is  seen eg in Gilbert Forbes’  1980’s elegant demonstration of the semilog linear response between total TT dose and lean body mass over years). In Guay’s 44 patients (apparently 50-70yrs old) studied in detail, altho 14.9pg/ml is in the lowest quintile of the “normal” fTT range, there was 100% response to Viagra. Drop the fTT 30% and the response fell 25%; drop the fTT 45% from 14.9 to 8.1 and the response drops 84%; drop the fTT 50% to 7.4 and the response drops by 91%.

      This predictable dose response curve correlates with the finding in wasting AIDS, (Rabkins’ and Wagner’s,  Bhasin’s, and Grinspoon’s groups), that some sick men with AIDS wasting do not become anabolic at 100mg TTenanthate/ week but, improve only when the dose is increased to 150 or even 200mg/week imi- ie to a mean TT level of 30 - 40nmol/L. Bhasin’s group in LA was the first to report, in 1995, that in HEALTHY men, modestly superphysiological doses of TT cypionate or enanthate  (eg 200mg/week) (which no more than double normal  TT blood levels to around 60nmol/L,  still below the danger level of 80nmol)  improve muscle mass and strength by 10-20%; and correspondingly in frail elderly – without adverse effect.

      Thus it is  obvious that there is no arbitrary TT bloodlevel cutoff point above which Viagra is justified de novo before trial of TT replacement. Since there are no absolute contraindications to physiological systemic human TT replacement [except untreated (prostate or breast) cancer]; and since there are no risks of such measured replacement except with untreated frank heart-failure, jaundice or untreated cancer, the phosphodiesterase inhibitors  PDI (with risk of sudden death) are never justified (at a local cost of about >US$130/month) until weekly subcutaneous gluteal selfinjection of depot TT has been tried for a few months at a cost of about US$3 to $5/month.

Our own search  a few years ago (Burman, Bornman ea)  traced over 73  published reports of studies which give TT levels in groups of  “normal” men  the past 40 years; of which about 64 reports measured TT levels in men below 39 years of age. Four  were longitudinal studies in such young men, amongst about 38 longitudinal and cross-sectional studies.  Bearing in mind Klee and Vermeulen’s recent conclusions (2000-2001) that laboratory method (RIA) has changed little the past 40 years and that all reliable measures (TT, fTT, bioavailable TT etc) correlate fairly well,  our plots confirm that  mean male TT level falls about 0.7% per year (range 0.2% to 2%pa) between youth and old age ie about 40% over 50years;  but that in healthy lean  young men under 39years, the mean TT level has remained about 24nmol/L(+-16%) for 40 years; in the 22 studies between 1958 & 1985, the range was 16-35nmol/L-mean 25; in the 42 studies since 1987, the range was 14-40nmol/L-mean 27nm; – Bornman’s Pretoria series(in young men admitted for voluntary sterilization) understandably  yielding the lowest testosterone means…

          But these figures belie that  while TT falls modestly, the TT/(E2XSHBG) product  falls drastically since both E2 and SHBG rise with aging, especially with disease: eg values may change  from  youthful (TT) 25X(SHBG norm) 20/(E2: 0.1X measured SHBG:20) = 250;  to  an aging man’s     15X20/(0.15X30)   = 66; ie the TT/E2 product has fallen by 75%.

Chapter 2 follows soon.

The Frisinas’ work (Univ Rochester) showing that estrogen protects but progestin worsens hearing is news, brought to our attention by Dr Joe Mercola’s email. Another nail in the coffin of the synthetic progestins.

The Frisinas stress that age-related hearing loss (presbycusis) is the number one communication disorder, and it is one of the top three chronic medical conditions of elderly persons.

Invariable simultaneous age-related hearing and sight loss associate with massive global impairment and early mortality.

Does human progesterone, and the aldosterone mimic Florinef have adverse or protective effect on hearing? Considering that all studies show largely opposite none-gyne effects of human vs synthetic progestins, androgens and estrogens, such discordance seems unlikely.

These questions have huge implications for the better-off, since tens of millions are using progestins/ progesterone (for both contraception and HT) without objective evidence of need or benefit: risk; and millions are using prednisone (or nonsteroidal anti-inflammatories) where androgen +- cortisone/ aldosterone might be much better.

Download the entire article here:

Preserving sight, sound and the senses.

If you are interested in the sources for this document, please contact me on doctor@healthspanlife.co.za.