Obviously our skin (unless injured or diseased) – arguably our major organ of heat control, sweating, vitamin D activation and sexual enticement- serves as a major impenetrable barrier to absorption or leakage. Unlike amoebae- which live or die by their exterior- we feed and excrete via our digestive tract, using our skin mainly for attraction- or repulsion!.
It is common cause that, with intravenous injection ivi as the fastest alternative route (to swallowing), absorption is hardly better (than the skin) across aged dry vagina; better across moist ie mucous membranes eg of the eyes, nose, mouth and vagina/rectum; better by deep inhalation or subcutaneous s.c. placement (injection or pellet); and best by intramuscular injection imi – which is now rarely achieved with a standard 3/4 inch needle into the upper outer buttock in a fattening population . Such injections are mostly delivered s.c.
Which route is preferable depends obviously on the speed of action required eg high blood peak for an urgently needed antibiotic, analgesic, anaesthetic, antiasthma, acute insulin or resuscitation; as opposed to slow smooth delivery for maintenance eg hormone, antidepressant or analgesic delivery.
For depot injections, why use anything bigger than a 25g 10mm long needle? so that safe subcutaneous s.c.i. is ensured, guaranteeing avoidance of the many minor and major risks of intramuscular imi.
eg Meyer ea at Cornell Univ NY 1990 reported that subcutaneous administration of the gonadotropin releasing hormone agonist leuprolide took half the time to first response with double the amount absorbed compared to the same dose by the transdermal TD route.
Minto, Handelsman ea in 1997 showed that injection of an oil-based depot sex hormone into the fattier gluteal (ie upper outer buttock) region (as compared to the lean deltoid ie upper arm true imi) gave significantly slower smoother less peaked absorption and action of the hormone.
And obviously total delivery to the body is going to be less absorbed through the tightly layered skin than if 100% delivered under the skin by injection/implant. Fatty – steroidal- gonadal hormones are particularly altered by digestion and transhepatic absorption. But so will transdermal absorption fall with aging, drying of the skin.
Hence in postmenopausal women PMW the average dose equivalence for similar symptom- hot flash- relief has been found to be estradiol 1mg or CEE 0.625mg orally, but about 0.05mg E2 a day by modern TD designer patch (containing 4mg E2, changed twice a week) or cream; ie an effective oral: TD dose ratio of about 20:1. But oral estrogen eg 1mg E2 raises the E1 estrone (the hormone most associated with breast cancer) blood level 5-fold more than the E2 level, and increases urine estrogen excretion about 100fold; whereas the E2 patch 0.05mg/day raises serum E2 to a satisfactory ~120pmol/L but with little increase in E1 level or urine estrogen excretion. Thus TD but not oral ET restores the youthful healthy balance of blood E2>E1 aout 1.2 :1.
Conversely, in girls with delayed puberty and growth, physiological effect appears to be even higher with TD estradiol E2 than oral conjugated oral estrogen CEE Premarin. In a recent trial undeveloped girls with Turner’s syndrome were randomly assigned to receive initially CEE 0.3mg/d orally, or TD E2 0.025mg/d patch (17β-estradiol, Vivelle TD) for one year – doses chosen based on published E2 equivalence about 20:1. After 12 months the girls on TD ERT had better improvement in uterine, height, breast, and bone density growth than oral HT CEE. Hence they too (like postmenopausal PMW) needed far lower total dose estrogen exposure parenterally than orally. PMW certainly rarely if ever want bigger breasts or womb, so even lower transdermal microdoses are ideal for them.
Nachtigal ea 2009 show that oral but not TDE2 accelerate platelet reactivity ie thrombosis risk in some PMW.
Villa ea 2008 show that low dose 1mg/d micronized E2 lowers insulin resistance, whereas higher dose 2mg/d increases it.
Verhoeven ea 2006 showed that oral micronized E2, but not TD E2 treatment, significantly reduced arginine compared with placebo – and good arginine levels are crucial in maintenance of immunity; insulin sensitivity; growth hormone output; wound repair; fertility; and adequate nitric oxide levels for optimal muscle, heart and circulation..
And Shifren ea 2008 showed that compared with oral CEE, TD E2 exerts minimal effects on CRP and the other inflammation and hepatic parameters – more adverse hepatic first-pass effects of oral HT as regards both cancer and cardiovascular disease. .
Thus, given that the higher the rate of breast and uterus proliferation the greater the risks in later life, sex hormone therapy and replacement in women (let alone men) should always be parenteral- the lowest dose to achieve the desired goal- be it feminization in Turner’s Syndrome; contraception; or postgonadopausal HRT in men or women.
The ill-informed reaction to the poorly planned Womens’ Health Initiative led to a massive fall in all HRT use.
Yet abundant studies reviewed in this column the past two years show the incalculable benefits of appropriate balanced (E+P+T) in PMW. No-where is this better shown than in neuroprotection especially against Alzheimer’s disease AD, in which- in eg the Womens’ Health Initiative– introduction of oral xenohormones well after age 60years worsened the risk of AD, but CEE started soon after menopause greatly reduced AD risk.
University Beijing has shown that women who have taken lowdose oral E2 0.5-1mg plus progesterone 0.5-2mg for 4 to 33yrs have significantly less hippocampal atrophy; similarly at Univ S California, studies in AD-prone mice show that early oophorectomy worsens the AD pathology and behaviour changes, but this deterioration is better blocked by E2 + progesterone combined than by E2 alone.
Testosterone replacement is probably brain-protective in men; it remains to be seen whether it adds memory protection in women when combined with E+P. A 2006 British study of estrogen treatment in male to female transsexuals showed few and inconsistent changes in memory and cognition.
But a new Spanish study does show that when female-to-male transsexuals are treated with testosterone for 6 months, they show significant improvement in visual but not verbal memory. And a new Swedish study shows that “The most positive effects of estrogen plus progestogen therapy concerning memory and urinary tract and vaginal complaints were found in women with the highest and/or moderate testosterone levels (P < 0.05).”
A recent UK MRC study shows the critical importance of optimal thyroid function in memory, since excess of either thyrotropin or thyroid hormone can be adverse.
And it has long been known that the more hypoglycemic episodes diabetics experience, the worse long-term memory.
Thus balance of all three major sex hormones- estrogen, testosterone and progesterone, as well as insulin and the thyroid axis, is crucial in cognitive performance especially in women.
HORMONE CREAMS: for those who prefer creams to pills, implants or injections, a major advantage is that women can start low with all three main sex hormones as appropriate, and titrate them individually upwards to tolerance or designated ceilings. Once optimal intake and levels of each have been attained, they can then if wished be combined, compounded.
As this column discussed two weeks ago: mid- twentieth-century women now potentially live to double the age of those born in the early Victorian era; but increasing numbers undergo premature menopause and especially relative androgen deficiency due to elective sterilization, hysterectomy, survival from cancer and radiotherapy, or increasing cancer risk from smoking, alcohol, suppressed menstruation due to birth control hormones, cortisone use eg for autoimmune diseases and transplantation, nuclear fallout or the feminization of nature .
They thus spend the second half of their lives post menopause, with increasing premature mortality and morbidity from diseases of hormone deficiency: fattening and diabetes; heart and circulatory disease; muscle and bone frailty; arthritis; infections, incontinence; and worst of all, depression, cancer or loss of memory; and not least, loss of vital sexuality. These are all largely avoidable by appropriate early and permanent non-oral balanced HRT and a blend of the other three-score other natural supplements.
As Prof Robert Greenblatt from Augusta wrote in The Menopause Syndrome (Medcom Press) in 1974, ” the menopause is a physiological endocrine hormone deficiency state. It is good practice to offset endocrine deficiency states by hormone replacement therapy to restore hormone balance”- whether in a teenager or a grandmother.
And Prof Emanuel Schleyer-Saunders from London stressed in the same colloquium that even 35 years ago, half of all hospital beds were occupied by diseases of old age- obesity-diabetic-vascular, mental and malignant- which (as Masters and Grody had shown 20years earlier) are delayable by decades provided balanced parenteral permanent HRT is started early in menopause- which starts insidiously in the mid-forties if not earlier.
Whereas Masters and Grody in St Louis, and Gelfand in Quebec, established this by long term injections of testosterone TT and estradiol E2 esters (which for decades have been available as a 20:1 mixture lasting 2 to 3 weeks), Schleyer-Saunders and then Whitehead and Studd in London, and Gambrell in Augusta, maintained this long term by pellet implants every few months. Schleyer-Saunders showed with pellets that continuous balancing TT reduced the incidence of breakthrough bleeding from 20% on E2 alone , and 12% on E2 + progesterone P, to 8% on E2 + TT, but only 5% on all three ie E2 + P + TT – with reduction in cancers. He generally used a dose of 25mg of each hormone, but (at a time when women were far slimmer) 50mg E2 implant in women post oophorectomy.
Yet MacLennan ea from the International Menopause Society now report that in Australia, as a result of the hysteria generated by the wrong Womens’ Health Initiative and Million Women Study reports (in which most women used oral xenoHT), only 12% of postmenopausal use hormone replacement.
Convenience should be the last factor considered. Unless balanced lowdose mcronized estradiol, testosterone and progesterone are used orally – since micronized particles largely bypass transhepatic absorption- there is no longer excuse for the risks of oral CEE, progestins and similar hormone therapy with hepatic first pass adverse effects. “Convenience” is no defense against charge of negligence when the patient develops major complications from oral sex hormones. So the patient who insists on oral hormones should sign an informed consent form that she has been warned, but accepts the risks of the oral (as opposed to the physiological parenteral) regime.
All women (and men) – especially with chronic or serious acute ill health – should thus be ensured permanent youthful sex hormone levels with appropriate physiological HRT that avoids both hepatic first pass metabolism and hormone excess/ imbalance. Traditional American industrial hormone therapy ( dominant the past 50 years due to the connivance of the FDA with it’s supporting drug industry) with oral xenohormones eg CEE, progestins and anabolic steroids cannot provide the physiological replacement required, that is ensured with titrated human hormones in every other branch of endocrinology for the past generation.
It remains an indictment of American medicine and legislators that their Disease and Drug Industry- the FDA and mainstream physicians- put their commercial interests ahead of womens’ welfare in making postmenopausal women the exception to the rule of evidence-based medicine especially endocrinology. The most vulnerable group (after children)- the older women – are thus as always the main innocent victims of the FDA-led Disease Industry’s War on Humanity, the Black Mass of organized commercial Big-Pharma “medicine”- of which 13 USA firms in about 2006 had half the world’s gross “medicines” turnover of ~ $600billion. Based especially on womens’ ills and vulnerability- particularly cosmetics and cosmetic surgery, screening mammography and hysterectomy- the Beauty/Disease Industry is thus truly a multi-$trilliondollar moneyspinner, disaster capitalism targeting women.