Science Matters October 31, 2023
Bio-identical hormones
BACKGROUND
Menopause & Hormone Replacement Therapy (HRT)
Menopause is experienced by every older woman throughout history but has never been considered a “disease” requiring treatment. But in 1942, Ayerst Laboratory marketed an oral estrogen called Premarin which became one of the best selling drugs in the world. They marketed this drug to physicians and patients for a “non-disease” for every woman in the world to “need” at one point. Not only was the drug marketed for “hot flashes” and irritability during menopause; but later it was advocated for osteopo-rosis turning it into a lifelong drug for every older women in the world!
The first bombshell went off in 1998 which was the very first randomized con-trolled trial (N=3,000) which showed no improved cardiovascular risk with increased risk of blood clots(1) Any benefits were outweighed by harms. Another bombshell ex-ploded in 2002 which was the randomized controlled trial called the Women’s Health Initiative (N=30,000) which showed no improved survival with increased risk of heart attack, stroke, and breast cancer.(2) Any benefit appeared to be offset by harm, espe-cially in the older woman. This is a classic example of the medical community making a rush to judgement based upon observational trials before randomized controlled trials were done. The question becomes what forces were there that made it take 20 plus years to do a RCT?
Male Menopause & Testosterone Treatment
In April 2000, the Endocrine Society convened its “First Annual Andropause Consensus Conference” held in Beverly Hills. It set out to define “andropause” (male menopause) and how to treat it. A 13 member panel acknowledged that a benefit of tes-tosterone treatment has not been established; and then proceeded to recommend that all men over the age of 50 be screened for testosterone deficiency. What used to be pre-scribed only for rare conditions called Klinefelter’s syndrome and pituitary dysfunction in males was now potentially being advocated for any male in the world over 50 years old! They did qualify that you had to have a low level of tester one defined as a level less than 300, you were given a questionnaire to see if you had “symptoms of low T”. The broad range of symptoms included fatigue, decreased sex drive, decreased enjoyment, decreased strength, grumpy, falling asleep after dinner etc.
This conference occurred 6 weeks before ANDROGEL came on the market. The conference was sponsored by the makers of ANDROGEL; and 9 of the 13 panel members, including the co-chair, had significant financial conflicts of interest.(3) Fur-thermore, the FDA never approved ANDROGEL for “male menopause” - neither was it concluded that such an entity exists. The NIH also organized a panel without conflicts of interest and also came to the conclusion that the “andropause hypothesis” is un-proven.(4)
What we know about testosterone levels is that they vary by age, time of day, exercise, illness, and other variables. We also know that there are many different assays of variable accuracy and quality. Together, these have been studied and found that 50% of normal healthy asymptomatic men had intermittent testosterone levels that fell below 300. Furthermore, testosterone supplementation may worsen indolent prostate cancer and can cause an increase in heart attacks. (5)
In 2018, the Endocrine Society reversed its position stating “recent surveys indicate that men are prescribed testosterone treatment who do not have adequately documented hypogonadism.” “Testosterone therapy is reserved for well-documented cases of hypogonadism.” “The Society recommends against routinely prescribing tes-tosterone to men older than 65 with low testosterone levels.” (6) Even stronger state-ments have been made such as “A prescription of testosterone supplementation for “low T” for cardiovascular health, sexual function, physical function, mood or cogni-tive function is without support from a randomized controlled trial.”(7)
In spite of this, physicians gave out 2.3 million prescriptions for testosterone in 2013, with annual sales over 2 Billion!
BIO-IDENTICAL HORMONES
The background on Premarin and testosterone for female menopause & “male meno-pause” is essential to understand before discussing “bio-identical hormones. These bil-lion dollar drugs which one is prescribed for many people most of their older years dropped off dramatically with the published reports of increased risk of cardiovascular disease for both.
The bio-identical hormone industry began when the natural foods industry started sell-ing soy and yam-derived hormones as “natural” alternatives to prescription estrogens and progestins. The claim, still unsubstantiated, is that because they are “natural”; they do not carry the risks of synthetically produced estrogen and testosterone.
Here is a litany of conclusions by several endocrine & scientific authorities:
In our current climate, compounding pharmacies prepare, assemble and package cus-tom-compounded bioidentical hormone products as gels, creams, lotions, sublingual tablets, subnormal implants, suppositories, and troches according to a provider’s pre-scription. The contents, concentration,
tory oversight. There are no large, long-term, randomized, double-blind, placebo-con-trolled studies that determine the effectiveness, safety or adverse effects of custom-compounded bioidentical hormones.” (8)
“Custom compounded hormones are 80% lower potency than synthetic hormones…De-spite the lack of data to support the use of custom compounded hormone therapy, the past decade has witnessed a tremendous growth of the bioidentical hormone industry.” (9)
“There is a general lack of standardization and quality control regarding the practice
of baseline hormone measurements to replace “abnormal” hormone deficiencies has no basis in medical practice. Finally, there is no evidence that monitoring compounded hormone therapy with serial salivary or blood testing is effective…Finally, there is no evidence to support the popularized notion that custom-compounded bioidentical hor-mones have fewer risks compared with FDA approved hormone treatments.” (10)
“The most recent version of the American Association of Clinical Endocrinologists menopause guidelines cautioned against the use of bioidentical hormone replacement noting that there is no evidence to support superior safety with these products and that there is a lack of consistency in the content of compound products leading to either less or greater amounts of biologically active hormone received.” (11)
“The FDA is also not aware of sound evidence showing the superiority of compounded bioidenyical hormone replacement therapy (BHRT)products over FDA -approved drugs. Likewise, the FDA has no information indicating that the side effects and risks of compounded bioidentical hormone replacement therapies are dissimilar to those FDA-approved drugs. Thus claims regarding the safety , efficacy, and superiority of compounded bioidentical hormone replacement therapies have not been substantiated by the FDA and may mislead patients and practitioners.”
references
1. Hulley, S. et al “Randomized Trial of Estrogen and progestin for secondary prevention of coronary heart disease in post-menopausal women-HERS” JAMA Aug. 19, 1998;280(7):605-613.
2. Writing group for the women’s health initiative investigators, “Risks and benefits of es-trogen plus progestin in healthy post-menopausal women.” JAMA 2002;288:321-333.
3. On the Take: How Medicine’s Complicity with big business can endanger your health by jerome kassirer MD (2005)
4. Pines, A. “Male menopause: is it a real clinical syndrome?” climacteric 2011, Feb. 14(1):15-17.
5. McBride, Ja et al. “Testosterone deficiency in the aging male” Ther Adv Urol 2016 Feb. 8(1): 47-60.
6. Endocrine society “experts issue recommendations to improve testosterone prescribing practices” March 17, 2018.
7. Bhasin, s et al. “Testosterone therapy in men with hypogonadism: an endocrine society clinical practice guideline” journal of clinical endocrinology (JCEM) May 2018; 103(5): 1715-1744.
8. Bhavnani, BR et al. “Misconception and concerns about bioidentical hormones used for custom-compounded hormone therapy” J Clin Endocrinol Metab 2012.
9. Sood, r. et al. “Bioidentical compounded hormones: a pharmacokinetic evaluation in a randomized controlled trial.” Maturitas 2013;74:375-382.
10. Santoro, N. et al. “Compounded bioidentical hormone in endocrinology practice- an endocrine society scientific statement” JCEM April 26, 2016; 101(4):1318-43.
11. “compounded bioidentical hormone therapy-an endocrine society position state-ment” Endocrine Society ;oct. 2, 2019.