email@example.com Oct 6th , 2012 UPDATE: THE KRONOS EARLY ESTROGEN STUDY KEEPS TRIAL PRELIMINARY RESULT just announced (3 Oct) by Mitch Harman ea at the current Florida North American Society Florida Congress.
It supercedes as the most important RCT in 50 years and confirms in early postmenopausal women the results we summed up below in 2009 in pubertal Turner’s Syndrome girls in the Indiana University study, which used the same dose of premarin but almost half the dose of estradiol patch- but found better results with the E2 patch than premarin orally.
see global KEEPS results at http://www.heraldonline.com/2012/10/03/4311575/hormone-therapy-has-many-favorable.html
April 10, 2009: THE MOST IMPORTANT HRT STUDY IN HALF A CENTURY: Nabhan ea at Indiana University have just published perhaps the most important randomized controlled trial RCT in half a century on physiological benefits and pitfalls of Estrogen replacement ERT in women.
Pubmed search under menopause or HRT trials yields reports only from 1975, simply because that is when Medline was established.
But in fact William Masters ea in 1953 in St Louis published the first traceable- and most important ever- sex hormone SHRT RCT, giving balanced testosterone plus estradiol (in a ratio that they found was optimally 20:1) or placebo parenterally for 13 months apparently blind to already institutionalized old women at a mean age of 73years; showing that while 1/3 were not unsurprisingly too far gone to benefit, 2/3 of them recovered sufficiently over 6 weeks that the nursing care on the ward could be halved for the next year of followup- without any significant reported adverse effects, and with uniform atrophy of the endometrium at 6months on curettage. This trial may not have been double blind, but Masters and Grody detailed the randomization to hormone or control injection.
Albeit using perhaps half the dose of hormones as far longer- acting esters (than Masters used), Gelfand in Montreal (1987-2004) confirmed the long-term safety and benefits of combined depot injection. As Gelfand wrote in 1999, “The objectives for the management of a menopausal patient are ( I ) to increase longevity, (2) to prevent age-related deterioration, (3) to maintain a quality of life, (4) to prevent induced risks, and (5) to maintain a physiologic hormone balance.” We should regard longevity as the lowest priority, Gelfand’s other four objectives are equally paramount- and the bedrock of medicine especially endocrinology is to mintain physiological balance. Why should women be treated otherwise?
As this column has regularly described, most women find that the dose of about 0.5 to 1 mg testosterone and 25 to 50mcg of estradiol daily as a pro rata +- fortnightly tiny subcutaneous depot (self) injection) via a 25g needle is optimal, providing reasonably physiological mean blood levels, and once dose titration has found the right recipe, some (like most men) prefer it to the bother of patches or creams.
And many groups world wide have for decades done so with human E+T hormone combination long term as implants, albeit in a much lower ratio. Now this combination has become the physiological gold standard as creams and patches, which allows the patient more promptly and safely to determine her optimal dose and route of each sex hormone. Three monthly depot injection of Nebido testosterone undecanoate has become the gold standard in men, as it will in due course in women at 5% to 10% of the male dose.
For over 30 years scientific studies have broadcast the many adverse effects of oral CEE with progestins, especially on the risk of breast cancer long term. But, led by drug companies and their well-paid researchers and lobbyists promoting patented equine and other designer hormones so as to suppress the sale of cheap human sex hormones, women and gynecologists duped themselves into following Wyeth’s saturation marketing and, especially in the English-speaking countries, continued to use mostly oral conjugated equine estrogen and synthetic progestins.
Barbara Seamen, who died last year, was a prophet of sex hormone benefits and risks as Margaret Sanger was of proven safe barrier contraception. But the climate against advocacy for women was still so hostile in USA that even in 1978 Barbara and her psychiatrist husband Gideon Seamen published their book Women and the Crisis in Sex Hormones in UK (as Sanger had had to do with her book My Fight for Birth Control in 1934). A decade before the Seamens’ book, Dr Robert Wilson’s hysterical Feminine Forever had been published in 1966 in USA – marketing premarin CEE 1.25mg a day – leading up to the flood of endometrial cancer by the mid-1970s, and increasing breast cancer (Henderson ea 1980)..
But many doctors and patients were convinced about the dangers of progestin when the first badly analyzed results of the WHI- with oral OCEE premarin + MPA provera- were published in 2002; although the CEE- only arm of the WHI was allowed to continue another 2 years until it too was wrongly stopped because of overestimated accruing adverse events in all-age EXCEPT when started well under 60yrs.
But the hardest skeptics had to concede that oral CEE at the then-standard dose of 0.625mg/d (equivalent to estradiol 1mg/d) in women post hysterectomy reduces all common major aging events (fractures, breast & colon cancer, cardiovascular, memory problems and all-cause mortality) when started appropriately soon after menopause and used for up to 9 years- with the only adverse effects being increase in adiposity, urinary incontinence, venous thromboses and gallstones. .
The Womens’ Health Initiative WHI 2007 showed plainly that OHT started (as is conventional practice) soon after menopause ie near age 50yrs with OCEE alone (ie after hysterectomy) or with CEE+MPA, for up to 8 years, reduced all-cause mortality by 30%; BUT whereas CEE alone in this young cohort reduced both (breast cancer and CVD and fracture) events AND (breast cancer and CVD and fracture ) mortality by about 30% , CEE+MPA increased CHD and stroke events by 49%.
Thus in the young WHI cohort, given that all-cause mortality also fell by 30%, CEE +MPA must have reduced breast cancer mortality by even more to offset increased mortality from CVD in the young CEE+MPA cohort. . This improvement in survival after breast cancer with “appropriate” early and long term OHT has been long recognized.
Earlier studies eg the open prospective StaTur ( Soriano-Gullen ea 2005) in France in girls with Turner Syndrome had already suggested ” that growth hormone and estrogen (from about age 12yrs) attain optimal adult height; and the use of percutaneous vs. oral estrogens was associated with greater height (_2.1 cm; 95% confidence interval, 1.00–3.25).”
Now the 12month Indiana trial highlights the physiological benefit for teenagers of human transdermal TD E2 (HERT 25 then 37.5mcg/day) versus +- 20 times the estradiol equivalent dose as conjugated equine oral xenoestrogen (0.3mg then 0.46mg CEE/day) in obese short prepubertal girls age +- 14 (range 11-17) yrs with Turner Syndrome TS (half 45XO karyotype; mean height 1.427m , weight 49.6kg, BMI 25.3kg/sqm). At a CEE dose per kg body weight similar to that used in PMW postmenopausal women (mean weight +- 73kg, BMI 28.5kg in the WHI), the TDHRT dose had far superior effect over oral hormone therapy OCEE in promoting better height, bone density, and uterine and breast growth catch-up .
According to CDC tables 2000, the average height of USA 14yr old girls was 1.6m and BMI 19.3kg/sqm; but girls at 1.45m height had mean BMI 17.7kg/sqm; thus the TS girls in the Indiana study at baseline were 17cm shorter than average normal 46XX girls, but (like postmenopausal women) 43% over average weight for height. They report that there was no difference between the estrogen routes in change in body composition.
Although the Indiana study for economic reasons omits blood sex hormone levels, the results highlight some stark facts about unopposed parenteral HERT versus OCEE in women without functioning ovaries:
* lowdose TD ERT had far more effect than OCEE in promoting progressive height and bone density accrual; but
*TD ERT is far more potent than the perceived “equivalent” dose of OCEE in promoting both myometrium, and glandular proliferation (breast and and endometrial) .
This observation obviously cannot simply be extrapolated from sex-hormone-naive girls to PMW; but it reinforces that
*in PMW, human estrogen (rather than breast-cancer-promoting OCEE) should be given parenterally in small enough dose to replicate low average monthly physiological (free) estrogen levels in young women, and
*should never be given without ensuring that physiological androgen (and progesterone) levels as (in healthy young women) are available (naturally or by parenteral androgen replacement ART and parenteral progesterone replacement PRT) to offset the proliferative effect of even lowdose estrogen on both breast and uterus, let alone on dissolution of muscle collagen as witnessed by the doubling of postmenopausal stress incontinence on OET.
The Karolinska institute showed in 2007 that lowdose testosterone patch reversed the increase in breast proliferation caused by OE+P; and in 2008 that endogenous free TT levels have antiproliferative effect on breast tissue, perhaps mediated via the progesterone receptor; this confirms the observations of Masters, Greenblatt, Schleyer-Saunders, Gelfand, Gambrell, Vliet, Buster, Clarkson, Whitehead, Studd, Burger, Davis, Dimitrikakis Zhou and Bondi, and Davies’ Cape Town group, that the preservation of youthful female testosterone balance protects both breast and womb of primates from the proliferative effect of estrogen and progestin.
And in 2006 the Karolinska also reported in a retrospective observational study that previous HT (mostly OHT) use was associated with a 70% increase in meningioma.
Last year l’hermite, Genazzani ea reviewed the sixty-year -known benefits of parenteral over oral estrogen and progestins.
Shufelt and Braunstein last month sum up the accumulating safety data on female testosterone replacement TRT the past sixty years: that “replacement of serum plasma testosterone levels to or slightly above the reference range for young women does not increase the risk of hepatotoxicity, endometrial hyperplasia, behavioral, cardiovascular, cancer or haematolological adversity. Models of superphysiologic testosterone levels, such as polycystic ovarian disease, have not shown an increased risk of breast cancer. As with all hormone therapy, testosterone therapy should be individualized to optimize benefits without risks”.
ie all SHT- ERT, TRT and PRT- should be parenteral and titrated to physiological SH balance so as to give maximal well-being without causing significant proliferation in acne, hirsutism, adiposity, breast or uterus.
Hence it is unwise to give even TD estrogen unopposed even after hysterectomy.
Even unopposed progesterone- as is now so popular as “natural” over-the-counter cream- has proliferative effects on the uterus and breast, so should not be used post menopause without monitoring these organs and ensuring adequate blood levels of balancing androgen. While progesterone itself has many physiological benefits, both natural progesterone and synthetic progestins may activate dormant breast cancer (Horwitz 2008), accelerate aging hearing loss (Sellars 1971; Dubno 2008; Horner 2008; Price 2009); and overall, RCTs do not show that they reduce fracture risk. And of course liberal use of progesterone will suppress what endogenous estrogen and testosterone remains post menopause, as oral and depot synthetic hormones do in contraceptive use.
As always in human physiology, it is unpredictable to what extent progesterone may convert to testosterone and estradiol. Despite Dr John Lee’s enthusiastic advocacy (backed by no RCTs), the absence of proven benefit of progesterone on bone density and fracture risk long term discredits progesterone as a significant source of estrogen and testosterone- but does not negate it’s indisputable role in longterm balanced HRT as an immunomodulating neuropsychoprotective.
The comprehensive recent review of HRT by Santiago Palacios points out that progesterone has a different function profile from all synthetics, being anti-aldosteronergic ie not fluid-retaining, and weakly anti-androgenic. He stresses the target of ultralowdose estrogen to maximize the benefit:risk ratio, with consensus that appropriate HT started soon after menopause almost halve both CHD and fracture risk.
The KEEPS RCT now well under way (Harman, Naftolin ea – with roughly similar CEE and TDERT dose to the Indiana trial, and oral micronized progesterone) will no doubt again confirm the better safety profile of TD ERT over premarin, with no risk from the cyclical progesterone- but that trial is only to run for 5 years ie to finish in 2012, so it will not negate Henderson’s strong 30year-old data that oral CEE +- progestin taken for more than about a dozen years increases the incidence of breast cancer, although it lowers mortality. So far KEEPS is running smoothly without concerns arising (Mitch Harman personal communication).
Prescribing appropriate OHT extends healthspan and lifespan. But should it ever be preferred if it increases the risk of thrombosis, and from the 2nd decade of use breast cancer? whereas this risk is minimized with addition of appropriate testosterone, especially if all SHRT is parenteral.
In contrast to Victorian times when only a minority of women survived to menopause, the average age of menopause is now around woman’s midlife, and there is never contra-indication to the healthspan-lengthening benefits of balanced SHRT for the second half-century of life.
The Indiana study in hormone-deficient teens is a signpost that both young and old need the youthful balance of physiological levels estradiol, testosterone and progesterone – for far more than reproduction, sexuality and femininity- but, crucially, at physiological parenteral dose that will not expose her to breast cancer activation, ie avoiding oral HT.
Crucial as all three prime hormones are in the young, sexuality and femininity are sadly not essential for reproduction- but once experienced, cherished while the heart and eyelashes still flutter… For obvious reasons well known to sexually active adults, like PMW at all ages, girls with Turner’s syndrome should also be entitled to the benefits of appropriate triple hormone replacement from mid-teens so they too can experience appropriate mature adult sensuality and bonding.
The estrogen-progestin treatment of Turner’s Syndrome and PMW is also a paradigm of the increasingly common problem of flattened sexuality in young women- from birth-control xeno-hormones; cortisone and psychotrope use; AIDs and ARV use; metabolic syndrome and diabetes; and after pelvic cancer therapy or sterilization. All these women should be considered for appropriate parenteral sex hormone therapy (if necessary with all three hormones) based on both their clinical picture and full hormone profile.