A Primal woman’s first reaction to the prospect of taking synthetic hormone replacements for menopause? Probably a healthy dose of skepticism. We in the ancestral health community, after all, tend to view pharmaceuticals as a last resort—interventions that are overprescribed by vested interests, create their own set of side effects, and may even do more harm than good. To suggest that we “need” this or that prescription raises our hackles.

Besides, it’s not like menopause is a product of modernity or an aberration our ancestors never experienced; it’s a physiological stage that evolution has protected and selected in humans. It’s perfectly natural. Rather than the debilitating, miserable experience many women report having, menopause should be easier. Graceful, even. But it often isn’t.

And nature unfortunately doesn’t care about that. Menopause is nature’s way of preventing undue discomfort and reducing genetic damage to the group. Your average 50-year-old woman has a lot to offer the tribe in terms of wisdom, child care, and general know-how, but natural selection has also determined that it’s better for everyone if middle-aged women don’t easily get pregnant. Menopause achieves this by down-regulating the hormones and weakening the tissues necessary for conception. The problem is that these same hormones and tissues also figure prominently in a woman’s enjoyment of life and overall health.

What can happen when Mother Nature decides to step in?

  • Anxiety
  • Irritability
  • Loss of libido, vaginal atrophy
  • Night sweats
  • Hot flashes
  • Weight gain
  • Forgetfulness

Longer-term, menopause increases the risk of serious diseases like osteoporosis, heart disease, and breast cancer.

Those aren’t mere inconveniences. They can mar the beauty of what should be an enjoyable part of a woman’s life, interfering with her relationships, her productivity, her cognitive function, her sleep, and her basic ability to enjoy living.

Mother Grok didn’t take pharmaceutical hormone replacements, you might counter. She didn’t hit up the shaman for a compound blend of hormones, so why should you?

First of all, maybe she did. Pre-scientific peoples have been known to develop folk cures that seem primitive but end up getting scientific validation. Think of the medieval garlic-based concoction that we just found out can eliminate medication-resistant staph infections. Or the indigenous Amazonian tribes who somehow figured out if you brewed a certain vine with a certain leaf and drank the finished product you’d visit the spirit world, all without knowing the vine contained DMT and the leaf contained an MAO-inhibitor that made the DMT orally active. Or, to bring it back to menopause, the yam, which cultures have used for hundreds of years for menopause treatment without actually knowing it contains an estrogen mimetic with clinical efficacy.

Second of all, the basic Primal stance on pharmaceutical interventions is that they are useful and suitable when correcting a deficiency, a genetic proclivity, or an evolutionary mismatch—particularly when dietary and lifestyle interventions aren’t cutting it. If they can help us treat a condition that seriously impedes our life or pursuit of health, we should avail ourselves of the fruits of modern science. Hormone replacement therapy may very well qualify.

Philosophical qualms aside—does hormone replacement therapy (HRT) work? What factors play into its effectiveness—and safety?

First, Is It Safe?

This might just be the most contentious topic in medicine.

For decades, HRT was the standard treatment for postmenopausal women. Not only was it given to treat the symptoms of menopause, it was billed as an antidote to many of the chronic diseases that increased in frequency after menopause like breast cancer, osteoporosis, and heart disease. Most of this was based on observational data and small pilot studies. That changed with the Women’s Health Initiative (WHI), a massive series of randomized controlled trials involving tens of thousands of postmenopausal women. Finally, the establishment would get the solid backing they needed to continue prescribing HRT to millions of women for prevention of chronic disease.

Except it didn’t turn out so well. Midway through, they stopped the trial because they weren’t getting the desired results.

There were two different HRT study groups. In one study, women without uteruses either got placebo or estrogen alone. In the other, women with uteruses got a combo of estrogen and progestin (a progesterone analogue) or placebo. The estrogen was Premarin, a conjugated estrogen. The progestin was Prempro, or medroxyprogesterone acetate.

The E/P combo increased the risk of heart disease, breast cancer, pulmonary embolism, and stroke, and reduced the risk of colorectal cancer and fractures (but not enough to offset the increased risks).

The estrogen alone had no effect on heart disease (contrary to their hypotheses), but it did appear to increase the risk of stroke while decreasing the risk of breast cancer and fractures.

Following the publication and wide dissemination of the WHI results, HRT use plummeted among women. Breast cancer cases subsequently dropped by 15-20,000 per year. Hormone replacement therapy developed a bad rap that it has yet to shake.

Is it deserved? Yes and no.

While the WHI results highlight some very real risks associated with HRT, they don’t tell the whole story. There are other variables to consider when deciding on HRT.

How Early You Start Taking HRT Matters

Most of the women in the WHI study began HRT when they were very post-menopause: older, in their 60s and upward. They got worse results.

A much smaller proportion of the women in the study were under 60 when they started HRT. They had better results. In fact, among those women who initiated HRT before age 60, total mortality actually dropped by 30%.

Another analysis of the Women’s Health Initiative data found that women who started taking HRT during early pre-menopause were less likely to see the negative effects, like increased breast cancer and heart disease.

Another study found that older post-menopausal women taking estrogen took hits to their working memory that remained after therapy cessation, while younger post-menopausal women had no such reaction.

Women who took oral estradiol 6 years after menopause saw their subclinical atherosclerosis slow down. Those who took it later (10 years after) did not.

A recent large Cochrane meta-analysis found that while in general postmenopausal women taking HRT had a moderately increased risk of heart disease, breast cancer, and other diseases, a subgroup of healthy, 50-59 year old (so, younger) HRT users only had a slightly increased risk of venous thromboembolism.

The longer you wait to initiate HRT after menopause, the more adverse effects occur. Start earlier, if you do start

How You Administer the HRT Matters

Oral hormones have different metabolic fates than transdermal hormones. When you swallow a hormone, it goes to the liver for processing. This creates various metabolites with different bioactivity. One example is oral estrogen. When you take estrogen orally, you raise CRP, a marker of inflammation. Transdermal estrogen has no effect on CRP.

Oral HRT has been shown across multiple studies to increase the risk of venous thromboembolism, while transdermal HRT does not. This is because oral HRT increases thrombin generation and clotting, while transdermal HRT does not.

In the Women’s Health Initiative that found negative effects, the HRT given to the subjects was oral. Perhaps this was the issue.

For local vaginal symptoms, local application is probably ideal, while oral application is suboptimal. In one study, vaginal estriol was far more bioactive than oral estriol, despite the latter resulting in higher serum levels of the hormone.

However, topical isn’t always best. In one study, sublingual users of bioidentical hormones saw relief from night sweats, irritability, hot flashes, anxiety, emotional lability, sleep, libido, fatigue, and memory loss, while topical users only saw relief from night sweats, emotional lability, and irritability.

The Type Of Hormone You Take Matters

Another factor the WHI failed to address was the composition of the medication itself. They used synthetic hormones—conjugated estradiol and medroxyprogesterone acetate. Could bioidentical hormones, exact replicas of endogenous hormones which exploded in popularity following the WHI, have a different effect?

The amount of research into conventional HRT dwarfs bioidentical hormone therapy (BHT) research, but what we have looks pretty compelling.

Breast cancer is a major concern for HRT users. Most breast cancers respond to estrogen, just over half respond to progesterone, and traditional HRT seems to increase their risk. Yet, at least in healthy postmenopausal women, a combination percutaneous estradiol gel (inserted into the skin) and oral micronized progesterone—both bioidentical to their endogenous counterparts—had no effect on epithelial proliferation of the breast tissue, while reducing activity of a protein that protects cancer from cell death. The conventional HRT had the opposite effect, increasing epithelial proliferation and breast volume (a risk factor for breast cancer). This wasn’t about cancer, but it’s suggestive.

In another study, postmenopausal women on BHT (which included estriol, estradiol, progesterone, testosterone, and DHEA) saw improvements across all measured cardiovascular, inflammatory, immune, and glucoregulatory biomarkers despite being exposed to high levels of life stress.

Then again, in a recent study, bioidentical hormones performed poorly compared to the pharmaceuticals equine estrogen and medroxyprogesterone acetate. The pharmaceutical hormones resulted in a lower risk of breast cancer, although the bioidentical hormones still reduced the risk compared to placebo.

Which Hormones You Take Matters

The vast majority of postmenopausal women take estrogen, progesterone, or some combination of the two. But there’s another hormone that, despite plummeting during menopause, gets ignored—testosterone.

Although testosterone is the “male hormone,” it also plays a vital role in female physiology, especially sexual function. Menopause reduces testosterone by about half, and studies indicate that topical testosterone replacement therapy can improve sexual function and desire (combined with estrogen) as well as musculoskeletal health and cognitive performance in postmenopausal women. More importantly, topical testosterone improves sexual function without causing any of the adverse effects commonly associated with testosterone usage in women, like hair loss, voice deepening, body hair growth, facial hair growth, breast pain or tenderness, or headaches.

Adding low-dose testosterone to a low-dose estrogen regimen may even be better at reducing somatic symptoms of menopause (sleep disturbances, hot flashes, and other physical symptoms) than a higher dose of estrogen alone.

Your Expectations Matter

Our big mistake was treating HRT as a panacea for the chronic conditions of aging. It’s not that smart hormone replacement can’t or won’t reduce the risk of certain diseases, like osteoporosis or heart disease. It’s that we’re still figuring it out.

A better, safer move is to focus on what we know HRT can treat: the symptoms of menopause.

Want to reduce hot flashes and get more sleep? HRT works.

Want to reduce anxiety? HRT works.

Want to improve cognitive function and your sense of smell? HRT works.

The use of bioidentical hormones may be safer or more effective against the bigger stuff. It remains to be seen. Until then, treat symptoms, not chronic disease—but keep in mind your overall risks and discern whether treating the symptoms is worth any additional risk for that bigger stuff.

Your Personal Context Matters

Women with a history of estrogen-responsive breast cancer (80% of breast cancers) should exhibit caution and check with their oncologist before taking any kind of HRT.

ApoE4 carriers should seriously look into taking HRT. In one recent study, postmenopausal ApoE4 carriers exhibited rapid cellular aging—except if they were taking HRT.

Whatever You Decide…

Don’t feel guilty if you decide to take some form of it. I myself take a small dose of testosterone to get my levels up to where they should be. My wife, Carrie, has taken bioidentical hormones in the past (a modest compound blend of estrogen, progesterone, and testosterone) to deal with the symptoms of menopause, including persistent brain fog that didn’t respond to any other herbal or alternative measure in her case. There’s no shame. This is restoration of what’s healthy and supportive of a good life. 

Heck, I know women who are both aware of the potential long term risks—heart disease, breast cancer, and the like—and enthusiastic about the shorter-term, more immediate quality-of-life benefits they currently enjoy. They prefer the definite benefits over the small and uncertain absolute risk increases. Some have even said that feeling better day-to-day gives them the energy to continue living a healthy life in other ways.

I also know women who do the opposite, who either are lucky enough to not experience any profound symptoms in their transition or who prefer to use other methods and interventions to deal with their symptoms in order to avoid any increased long-term complications. (I’ll delve more into this in the future if there’s interest.) Regardless, it’s all a choice.

Hopefully after today you feel better equipped to make an informed one.

What about you, folks? I know I have thousands of readers who are facing this very question—or who have already faced it. What did you choose? How did you handle the HRT question?

Thanks for reading. Take care!

References:

Wu WH, Liu LY, Chung CJ, Jou HJ, Wang TA. Estrogenic effect of yam ingestion in healthy postmenopausal women. J Am Coll Nutr. 2005;24(4):235-43.

Murkes D, Lalitkumar PG, Leifland K, Lundström E, Söderqvist G. Percutaneous estradiol/oral micronized progesterone has less-adverse effects and different gene regulations than oral conjugated equine estrogens/medroxyprogesterone acetate in the breasts of healthy women in vivo. Gynecol Endocrinol. 2012;28 Suppl 2:12-5.

Ruiz AD, Daniels KR. The effectiveness of sublingual and topical compounded bioidentical hormone replacement therapy in postmenopausal women: an observational cohort study. Int J Pharm Compd. 2014;18(1):70-7.

Stephenson K, Neuenschwander PF, Kurdowska AK. The effects of compounded bioidentical transdermal hormone therapy on hemostatic, inflammatory, immune factors; cardiovascular biomarkers; quality-of-life measures; and health outcomes in perimenopausal and postmenopausal women. Int J Pharm Compd. 2013;17(1):74-85.

Zeng Z, Jiang X, Li X, Wells A, Luo Y, Neapolitan R. Conjugated equine estrogen and medroxyprogesterone acetate are associated with decreased risk of breast cancer relative to bioidentical hormone therapy and controls. PLoS ONE. 2018;13(5):e0197064.

Schiff I, Tulchinsky D, Ryan KJ, Kadner S, Levitz M. Plasma estriol and its conjugates following oral and vaginal administration of estriol to postmenopausal women: correlations with gonadotropin levels. Am J Obstet Gynecol. 1980;138(8):1137-41.

Scarabin PY. Hormone therapy and venous thromboembolism among postmenopausal women. Front Horm Res. 2014;43:21-32.

Espeland MA, Rapp SR, Manson JE, et al. Long-term Effects on Cognitive Trajectories of Postmenopausal Hormone Therapy in Two Age Groups. J Gerontol A Biol Sci Med Sci. 2017;72(6):838-845.

Hodis HN, Mack WJ, Henderson VW, et al. Vascular Effects of Early versus Late Postmenopausal Treatment with Estradiol. N Engl J Med. 2016;374(13):1221-31.

Santoro N, Allshouse A, Neal-perry G, et al. Longitudinal changes in menopausal symptoms comparing women randomized to low-dose oral conjugated estrogens or transdermal estradiol plus micronized progesterone versus placebo: the Kronos Early Estrogen Prevention Study. Menopause. 2017;24(3):238-246.

Yazici K, Pata O, Yazici A, Akta? A, Tot S, Kanik A. [The effects of hormone replacement therapy in menopause on symptoms of anxiety and depression]. Turk Psikiyatri Derg. 2003;14(2):101-5.

Doty RL, Tourbier I, Ng V, et al. Influences of hormone replacement therapy on olfactory and cognitive function in postmenopausal women. Neurobiol Aging. 2015;36(6):2053-9.

Jacobs EG, Kroenke C, Lin J, et al. Accelerated cell aging in female APOE-?4 carriers: implications for hormone therapy use. PLoS ONE. 2013;8(2):e54713.

Kingsberg S. Testosterone treatment for hypoactive sexual desire disorder in postmenopausal women. J Sex Med. 2007;4 Suppl 3:227-34.

Davis SR, Wahlin-jacobsen S. Testosterone in women–the clinical significance. Lancet Diabetes Endocrinol. 2015;3(12):980-92.

Achilli C, Pundir J, Ramanathan P, Sabatini L, Hamoda H, Panay N. Efficacy and safety of transdermal testosterone in postmenopausal women with hypoactive sexual desire disorder: a systematic review and meta-analysis. Fertil Steril. 2017;107(2):475-482.e15.

Simon J, Klaiber E, Wiita B, Bowen A, Yang HM. Differential effects of estrogen-androgen and estrogen-only therapy on vasomotor symptoms, gonadotropin secretion, and endogenous androgen bioavailability in postmenopausal women. Menopause. 1999;6(2):138-46.

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