TESTOSTERONE REPLACEMENT IN WOMEN FOR SEX, LEAKY BLADDERS?

 This topic has regularly been reviewed in this column.

This update reviews relevant peer-reviewed papers on Pubmed the past two year.

 

1. TESTOSTERONE REVERSES PATHOGENESIS OF URINARY STRESS URINARY INCONTINENCE  SUI IN RATS:

The Turkish trial (Cayan  Aug-2008) confirms in rats  that “bladder functions may deteriorate post menopause ” and “in addition to estrogen replacement therapy ERT, testosterone TRT  has a significant role to increase bladder smooth muscle, leading to improvement in bladder functions”  “In castrated rats  on HT for 60 days, smooth muscle/collagen ratio of the bladders was significantly higher on  testosterone and testosterone + estradiol treatment groups.” .

The Turkish rat trial confirms the rat trial in Brazil (Madeiro 2002) where “the group receiving  androgen/estrogen retained a higher number of vessels, epithelial thickness and quantity of muscular fibers (p < 0.05) than those on  isolated conjugated estrogen” .

Laura Owens  claims recently  that testosterone has been shown to reduce SUI  in women, but there are no peer-reviewed studies on Pubmed that claim this, only in rats so far.

 This is in stark contrast  to estrogen therapy ET  alone in women- which (like the SERMS) double the already majority incidence of leaky bladder by the midsixties, with rapid loss of bladder collagen; which worse SUI on estrogen  is only partly mitigated by addition of progestin, which may also worsent SUI.

             Since  low  testosterone  (as opposed to vigorous youthful level) also associates with worse prostate cancer, and prostatism in men, restoring youthful testosterone levels may also be relevant to men for the above urinary reasons.

 

2. TESTOSTERONE REPLACEMENT AND SEXUAL WELLBEING:

2.1The Lund (Sweden- Gotmar,  Aug 2008) study of 6900 women aged 60-70yrs confirmed the obvious, that   “women on HT(oral estrogen ± progestin)  had lower testosterone and FTI and were less satisfied with mood and energy (p < 0.05)”;

YET “sexual well-being was not correlated to testosterone or FTI (p > 0.05)”

In  perimenopausal women  Lower testosterone concentrations were associated with lower quality of life.   but counter-intuitively found     Lower testosterone concentrations were  not related to sexual well-being”.

 

2.2 Finally, the report this week by Sue Davis, John Studd ea NEJM 2008: Nov 6  from Australia, UK, Sweden, France, USA and Canada on Testosterone for Low Libido in Postmenopausal Women Not Taking Estrogen:   a 52-week strict  RCT  in 814 women with hypoactive sexual desire disorder  randomly assigned to receive a patch delivering 150 or 300 µg of testosterone TRT per day or placebo; with a subgroup of participants followed for an additional year. As compared with placebo, the higher dose  of TRT was associated with more significant increases in desire and decrease in distress p<0.001. They dont say how many continued their usual vaginal estrogen or phytoestrogen..   The vigorous physiological TT level that the TRT achieved  produced plausible symptom relief, and some androgen overdose symptoms easily controlled by dose titration.

 But  the women in this RCT  were already mostly overweight if not obese; and thus surely with  implausibly low basal E2 levels – 17.5pmol/L  both off and on TRT  at +- 54.4 years?  despite more than half not having had hysterectomy;  and no data were given about previous HT use (which omission  was massively  criticised in WHI reports) – and no mention of how many of the women trialists did continue   vaginal estrogen or phytoestrogens, or how ths was factored into mulltifactorial analysis of outcomes. 

 

And unlike healthy young women who have testosterone:estradiol ratios of about 4:1 eg 1000pmol:250pmol/L , these women had mean T:E2 ratios of 150:5pg/m/L ie  30:1 at baseline, which rose to 660:5 pg/ml or  130:1 on the higher dose of TRT.  In addition, their DHT levels doubled  from about 70 to 170 pg/mlL.  So their effective androgen (TT+DHT) :E2 ratio rose from about 220:5 ie 44:1 to 830:5 ie the ratio almost quadrupled to 166:1 – ie 40 times the ratio in healthy young women.

       So apart from  the one woman who (perhaps deliberately out of fear both of refusal, and fear of breast surgery) failed to report her bleeding breast cancer before starting on TRT, there were 2 women who developed BRCA out of well over 500 women-years on TRT,  after 4 and 12mo respectively. But breast cancer takes decades to grow to become clinically detectable. – ie they must obviously already  have had longstanding   small BRCA which (in these buxom women) was obviously missed on the baseline mammogram.  And since  the women of widely different ethnic (albeit mostly “European”)  origins were recruited to 65 centres accross 3 continents, there could have been low chance of uniform rigorous screening mammography standardization.

          2.3 ROUTE OF TESTOSTERONE REPLACEMENT: as discussed in previous comments, the important issue is appropriate parenteral HRT. Whether HRT including  testosterone is better delivered by patch, vaginally or by subcut injection is a separate issue not addressed by Davis and Studd  – since so much metabolism occurs during transcutaneous passage (eg to DHT) , but surely less during faster transmucosal absortion, and less still during subcutaneous absorption.

          But all of endocrinology depends on correcting hormone imbalance  to physiological levels and balance. However, unlike hypogonadal men who have always been prescribed physiological levels of testosterone replacement by the physiological parenteral route, the HT industry treats postmenopusal women like they do livestock, expecting commercial industrial doses of nonhuman hormones (eg premarin, progestins) by the known higher-risk oral route –OHT. It is incomprehensible that qualified medical doctors still comply with this heresy despite the hazards of industrial OHT being well known and publicised the past 30years. Is it just to let women take even “appropriate” OHT up to the age of 60 years (which did well in the young WHI and Oulu cohorts for up to 8 to 10years) for the sake of William Masters’ “convenience” (1957) , given the risks long term of such high doses, including longterm increase in breast cancer (Henderson ea 1980)      

       The same argument applies to any prescribed hormone imbalance- why induce even worse androgen excess in such sexually dysfunctionl postmenopausal women than these trialists already showed at baseline? When all they required was measurement also of their progesterone levels, and appropriate supplement  with appropriate estrogen-progesterone cream eg on the face (to counteract testosterone virilism) – as is routine in good practice    which has been long known to do nothing but good?

 

 

 

3. DISCREDITED REPORTS ON HT:

3.1  Margo  & Winnin a comprehensive 2006  review Testosterone Treatments: Why, When, and How?  detailed  well all the benefits of parenteral TRT including augmenting and balancing estrogen replacement ERT against hot flashes; fractures depression, and loss of memory, drive/energy and sexual responsiveness; with no evidence of harm provided  TRT dose is titrated to maintain bloodlevels within the range and overall sexhormone balance of healthy young women

 But they made one crucially  misleading assertion – that  “traditional hormone therapy using estrogen and progesterone can increase the dose of CVD and uterine/ breast cancer”   for which they quote the WHI (2002 Rossouw) paper.   But Rossouw’s paper did not say that.   And “traditional” HT has never used oral progesterone HT,  in USA largely  the far more potent and adverse synthetic medroxyprogesterone – which is hardly used in Europe.

 As the Nurses’ Study suggested, and the International Menopause Society, and the WHI itself,  and numerous other expert papers have pointed out since, appropriate hormone therapy using ±1mg/d  oral estrogen equivalent (± appropriate progestin) ie in otherwise well women from menopause produces about 1/3 reduction in all major common aging diseases and mortality- with only slight increase in the rare complications- deep vein thrombosis and gallstones.   

       To any clinician who bothered to read the original  1998 WHI  design paper  and the key 2002 and 2004 WHI papers, it was and has always been  obvious that only the WHI women allocated oral HT soon after menopause ie well below 60yrs were appropriately allocated oral HT as is always done in clinical practice – and these women (as in both WHI 2002 and  the Oulu trial) have always done very well up to about 10 years.

       But no sensible clinician ever put on “conventional” oral estrogen- progestin  elderly overweight  women, as in the majority in WHI -well over 60yrs, smoking, hypertensive and predictably with latent vascular disease and preclinical breast cancer- which has been well known since the 1970s to increase risk when started or long continued is such at-risk women. Rossouw ea carefully specified in 2002 that the global results of the first report should not be extrapolated to other agegroups, other forms or routes or ethnicities of women.

But Margo & Winn’s paper  made it clear that they were respectively academics in family practice and community medicine, not in specialist menopause medicine, gynaecology or endocrinology. Their review was and is (like eg the anecdotal  Million-Women Study , and the hysterical analogy in 2002-2003  of HT with  “thalidomide disaster” from European  and German medicines Regulators ) thus understandably superficial,  of limited relevance, and not to be quoted. It was the Million Women Study report which infamously confused the natural prime human  hormone estradiol  with the vastly potent synthetic  ethinyestradiol –  which has never been recommended for HT (except by bureaucrats- not menopause specialists- also infamously on the  EU  core drug list for HT at  the time).   

 

3.2 As about so many misguided  condemnatory pronouncements on appropriate HRT for men and women from “authorities” in USA UK and Europe the past 6 years since the first WHI report, one  can only echo  international experts like Traish A, Guay AT  ea from Boston University  a year ago:  Are the Endocrine Society’s Clinical Practice Guidelines on Androgen Therapy in Women misguided? the Guidelines _  do not necessarily represent the opinion held by the many health-care professionals and clinicians who are specialized in the evaluation, diagnosis, and treatment of women’s health in androgen insufficiency states… The recommendations provided in the published Guidelines are neither accurate nor complete… In their own disclaimer, they stated that the Guidelines do not establish a standard of care… It is our goal to elevate this debate in order to provide women who are afflicted with androgen insufficiency and sexual disorders with the highest quality health care and to relieve their distress and suffering, as well as to improve their quality of life.”

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