ARE SYNTHETIC HORMONES THAT WERE DESIGNED FOR CONTRACEPTION IN HEALTHY YOUNG WOMEN SUITABLE FOR POSTMENOPAUSAL PREVENTION?

It is at least 70years  since modern science suggested hormone contraception with prolactin or progesterone or estrogen; and since estrogen therapy of menopause was first described (by Prof Joe Meigs himself) on Pubmed – with presentation of endometrial cancer after 8 years on estrogenics .

In general, after 50 years of hormone contraception since we were students, with more than a hundred million women now on low-dose hormone contraception, such synthetics – a progestin with or without ethinylestradiol EE2 – are considered pretty safe in current low dose compared to unplanned pregnancy or physical contraceptive methods, provided contra-indications are respected; with almost 50% reduction in future endometrial and ovarian cancer; and no change in mortality from breast cancer.

But in A Short History of Oral Contraception (2006), Prof Wolfgang Oelkers notes that Ethinylestradiol EE2 was only discovered in 1938 and the first highly active progestin in 1954, leading to the registration of the first oral contraceptive OC pill in USA in 1961-  and within 10years the occurrence of malignant hypertension on such OC pill, with acute and often irreversible renal failure due to the EE2 activating both the renin-angiotensin syndrome and thrombosis. (I had the misfortune to have to put on chronic dialysis a beautiful young university student who presented on such OC pill in 1974 with thrombotic thrombocytopenic purpura with irreversible renal failure, while I was working at the Leeds General Infirmary under the dialysis pioneer Dr Frank M Parsons).

Oelkers notes that even ultralow dose combinations of EE2 and 3rd-generation progestins can still cause thrombosis; and The thromboembolic risk associated with the recently introduced transdermal combined  contraceptive Evra®does not seem to be any better than modern oral contraceptives, since it also uses EE. This, unlike natural oestradiol, seems to affect hepatic protein synthesis  independent of its route of application.    In postmenopausal hormone replacement therapy, the transdermal route of oestradiol application seems to be devoid of a prothrombotic risk.  Development of a transdermal combined hormonal contraceptive with oestradiol instead of EE would provide a great next  chapter in this endocrine story.

Wiki reports that The Ortho Evra contraceptive patch and the Evra contraceptive patch are both intended to gradually release into the systemic circulation approximately 20 µg/day of ethinyl estradiol and 150 µg/day of norelgestromin. Since such hormones bypass hepatic metabolism, no wonder the doses delivered still have thrombotic risks. 

Does that make such massively profitable contraceptive hormones that were designed in fierce competition for fertility (and ovarian) suppression in healthy young women both safe and effective for the ageing no-longer-healthy fattening (post)menopausal women? Parenteral physiological balanced HRT does not cause the fattening and muscle loss that OHT does.

Now young Janey asks an important question: “I am 56 yrs old and very happy with Yaz (ethinyl estradiol EE2 plus drospirenone). I do menstruate while on the placebo. I would like to find a doctor who will let me stay on Yaz, which I like a lot, or if absolutely necessary try the Testosterone, Bi-estrogen, Progesterone combo. I worry about weight gain that occurs in almost all cases of oral HRT. I need the bone protection and hair, skin and vagina health benefits that have been wonderful on Yaz. “

CANCER RISK OF ORAL XENOHORMONE THERAPY:

In July this column last visited ovarian cancer as a relatively rare disease but with high (70%) mortality due to its late presentation, hence feared more  than other womens’ cancers eg breast, endometrial or cervix.

So it is worth revisiting the major Danish observational study spanning 10 years published last July ; which documented almost a million women for   8 years. The crude primary ovarian cancer OvCa incidence rate in never-users (5 million women-years) was only 0.04%, vs 0.052% in current  HT users (1.4million women-years) ie overall, hormone therapy HT increased the risk by 1.3, or 30%. That study concluded: “Combined therapy with norethisterone was associated with an increased risk of epithelial ovarian cancer (RR, 1.55; 95% CI, 1.36-1.76), which was not significantly different from the RRs associated with medroxyprogesterone, levo- norgestrel, or cyproterone acetate CPA”.

The only regime in that series which was not statistically significantly associated with increase in OvCa was in the 23 women who developed OvCa on solo transdermal E2TD ie hormone replacement HRT (out of a total of 64000 women-years on E2TD), where OvCa relative risk increased by 13% but the 95% confidence interval spanned unity (0.74 – 1.71) ie not significant . By contrast, oral estrogen HT for some 287 000women years increased OvCa risk significantly by 34%; and any progestin added to estrogen ie in some 847 000 women years increased OvCa risk above no HT by 47% to 68%.

This neutral effect on OvCa only of unopposed E2TD is most reassuring for women. All the synthetic progestins they compared – including the antiandrogen CPA- were associated with significantly more OvCa (let alone BRCA).

The nub of the matter is that gynecological cancers generally do not apparently proliferate without the influence of female cyclical hormone levels- FSH, LH, estrogen – and especially oral estrogens and progestins. In the main study of cancer with Turner syndrome, in 3425 women in UK followed for some 17years ie 58000 patient-years, breast cancer was 70% less common than average women, while the only gynecolological cancers that appeared to increase were endometrial cancer 8fold at age 15-44years, and gonadoblastoma of the ovary by 8% by age 25years- and gonadoblastoma is over 90% associated with the ‘male’ chromosome Y . These statistics are reassuring considering that most such women were treated with oral estrogen therapy, and that uterine cancer is avoidable if estrogen therapy is appropriately opposed with some progestin, with periodic withdrawal bleeding allowed.

Unbalanced anabolics eg vitamins or sex hormones merely promote dormant malignant cells already present, they do not cause cancer de novo; and adult cancers take an average of 20 years to present clinically.

There is no report on Pubmed of testicular cancer developing on testosterone TT replacement let alone abuse; nor of increased ovarian or breast or uterine or colonic cancer in long term female testosterone users – if anything long term testosterone replacement in women appears to diminish breast proliferation in rodents, monkeys and humans, as this column has regularly reviewed..

It is common cause from clinical menopause practice and trials that pharmacological ie unphysiological oral estrogen – progestin therapy – while improving bone density- increases body fat and if anything decreases lean ie muscle mass and collagen -hence the increasing postmenopausal fatness frailty and urinary incontinence of elderly women on oral HT.

DROSPIRENONE

The new combinations with  drospirenone for contraception ( Yaz/Yasmin- drospirenone DSP -ethinylestradiol EE2 in fertile women), and post menopause (Angeliq – DSP -estradiol E2) certainly seems to reduce fluid retention and thus weight and hypertension problems, and to have anti-androgenic benefits when required. There is apparently no published longterm data on DSP to judge it’s influence on cancer and mortality.

This column has regularly detailed reasons for postmenopausal women PMW to avoid oral transhepatic sexhormone therapy with the high doses of oral estrogen needed to control menopause symptoms, and the multiple adverse effects of transhepatic xenohormones like EE2, premarin and progestins. But 50 years of experience including the under 60’s cohort of the WHI, and the Oulu trial (Heikkinen ea ) certainly showed overwhelming benefit of oral estradiol/conjugated estrogen-progestin combination when started appropriately in well young PMW for up to 10 years. It has been well known for three decades that continuing such OHT well beyond 10 years gradually increases the incidence of BRCA above non-users.

However, as we have repeatedly discussed, why should Kitty subject herself to the longterm risks of eg breast cancer from such oral use of any designer hormones like orohepatic estrogens and progestins? when evidence is that physiological human HRT with non-oral, or oral micronized (see Dr Lee Vliet’s books) sexhormones, has no risks, only benefits – especially when human E2+- estriol E3 are balanced by progesterone P4 and testosterone TT as by creams, or implants, or tiny subcutaneous self-injection, all easily available by prescription in US.

And when oral EE2 ethinylestradiol for contraception is associated with low but real thrombosis and biliary risks; and when it is enormously potent compared to human estradiol; and when it’s successor competitor diethylstilbestrol DES is still causing horrendous problems in women and their children and grandchildren after it was recklessly prescribed from the 1940s to the 1970 without there ever being evidence of benefit let alone safety.

Lowdose EE2 has certainly proved it’s relative safety when used as birth control in young healthy non-overweight women. But just as oral prempro has proved that it causes problems and little benefit when started after the age of 60years in overweight women ie those already with atheromatous disease, why take potent synthetic oral EE2 post menopause? Using a potent synthetic is neither prudent, physiological nor replacement.

Recently a Brazilian trial confirms equal benefit of “nonoral HRT (nasal spray- estradiol -micronized vaginal progesterone) ; or oral HT (low-dose estradiol-drospirenone ) for 2 years on metabolic, vascular and body fat risks in early postmenopause; but once again that Triglycerides and von Willebrand factor levels decreased significantly only with nonoral treatment”– ie the nonoral- parenteral- route is better protection against atheroma and thrombogenesis.

DSP combined with oral E2 is certainly theoretically advantageous HT for those PMW with hypertension and fluid retention. But since no longterm trials or studies of DSP use are available yet, it is too early to judge if DSP+E2 is as safe as physiological HRT with appropriate combination of E2/ estriol E3/ P4/ TT.

But as we have repeatedly pointed out, the evidence from both evolution, and 60 years of experience, and trials, is that physiological parenteral human hormones ie not by the orohepatic route have distinct safety and physiological benefits, as comprehensively detailed by l’Hermite, Genazzani ea on behalf of the International Menopause Society recently , as well as all the data this column has previously reviewed on the importance of balance non-oral testosterone as part of the HRT regime.

So the answer for Janey is: be a volunteer guinea-pig if you like, but dont use Yaz (ie EE2)  but rather use  the natural  E2 -containing Angeliq – in low dose. Since all other synthetic progestins increase ovarian cancer in women, rather use natural progesterone parenterally until Schering publishes a controlled trial showing that drospirenone does not increase ovarian cancer when fed to reproductive age female rodents (let alone women) for the human equivalent of a decade or more. There are no human studies reporting drospirenone use for a decade or more.

But  preferably enroll yourself in a longterm randomized comparative trial of the new (eg Angeliq)  versus the old. – balanced appropriate estradiol-estriol-progesterone-testosterone, whether as a cream or depot injection-  titrated to what suits you.  Why risk the new but long-term unproven when the evidence for the old (as long as human evolution with balanced non-oral human estrogen +P4+TT) is so strong.

And while you may find out the best for you  by your trial and error without longterm adverse effect, none of us may  learn better by your self-experimentation?

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