Remedy Pharmacist + Founder
Estrogen and progesterone are the cornerstones of hormone replacement therapy. During our reproductive years, these hormones predictably fluctuate throughout our cycle (for most women). During perimenopause, which can last for up to 10 years before menopause, our ovaries production of LH and FSH start to decline we first see a lower level of progesterone and sporadic levels of both estrogen and then finally in menopause they settle to a lower but consistent level (figure 1, below).
Estrogen is involved in many vital systems and has effects on many tissue types. As estrogen declines, women can notice vaginal atrophy (which is related to pain with sex, increased risk of UTI/vaginal infections and symptoms of overactive bladder), hot flashes, thin or sagging skin, brain fog and/or depressed mood. Estrogen helps regulate cholesterol and helps maintain bone density. Estrogen can have stimulating effects on different tissues, including our uterus.
Progesterone balances mood, stress, sleep, and irritability. Progesterone calms the brain and nervous system by converting to the neurosteroid allopregnanolone (ALLO) which acts on GABA receptors. Physically it improves the good cholesterol HDL and increases bone density.
Most women will be put on BOTH estrogen and progesterone therapy for the benefits, but also because when used together they help balance each other’s effects and minimize side effects. When used alone, estrogen causes uterine tissue to grow which can increase the risk of endometrial cancer. Adding the progesterone helps counteract that negative side effect (and the bioidentical form has a ton of great benefits itself!). If you have had a hysterectomy (and no longer have a uterus) you no longer are at risk for endometrial cancer, and you have the option to use estrogen-alone, without progesterone combination.
In Part 1 of this series, we explained the differences between the conventional or first-generation estrogen and progesterone molecules and the bioidentical or second-generation estrogen and progesterone molecules. These differences are important when talking about how to apply what we know about HRT using conventional hormones to that using bioidentical. It is incorrect to use information from studies using conventional hormones like the WHI Study, to guide the use of bioidentical hormones.
So what do we know about the safety of Bioidentical Hormone Therapy (BHT)?
Breaking Down The Risks:
Most women who are nervous about using HRT are concerned with the risk of breast cancer. And most women have a major misconception that the estrogen in HRT is what increases the risk of breast cancer. This is not true. In fact, in the WHI study, women on estrogen-only therapy actually had a DECREASE risk of breast cancer. The increased risk of breast cancer seen in the WHI was for women who were receiving the synthetic progesterone, medroxyprogesterone (1).
Well, then why not skip the progesterone component altogether you ask? The answer is because without it, the tissue stimulating effect of estrogen goes unchecked and that is what causes the increased risk of uterine cancer. Therefore, some sort of progesterone is needed to balance this stimulatory effect. What we do know now though is that the type of progesterone used is important. We know from the WHI study that the synthetic progesterone caused an increase in breast cancer, cardiovascular disease (aka stroke, heart attack, blood clots) and diabetes (1).
The good news?
Studies suggest BIOIDENTICAL progesterone may carry less risk with respect to breast cancer incidence (2-4) and does NOT have an increased risk of blood clots (5-6) or a negative effect on LDL (7) like synthetic progestins do.
Studies have revealed that perhaps the dosage form of estrogen might have an impact on reducing the risks of estrogen therapy. Oral estrogen therapy which was used in the WHI Study may exert a prothrombotic effect through hepatic induction (8,9). This induction can be avoided by using different routes of administration such as topical or sublingual.
In addition, transdermal estrogen has been shown to have beneficial effects on pro-inflammatory markers (such as C-reactive protein and prothrombin activation peptide) as well as antithrombin activity. It may have a suppressive effect on tissue plasminogen activator antigen and plasminogen activator inhibitor activity in contrast to oral estrogen as well, which would also be beneficial in many cases (10-14).
In addition to having a better safety profile compared to the synthetic version, bioidentical progesterone also does wonder to relieve symptoms of progesterone-deficiency such as depressed mood and insomnia (15). This is in stark difference to the synthetic version which on top of the increased risk of breast cancer, did not provide any therapeutic benefit.
So what does all of this mean?
In summary, bioidentical estrogen and progesterone are natural to our bodies. They produce a cascade of effects on tissues in many parts of our bodies (vaginal, brain, uterine, breast, vasculature). When balanced together they work best to provide us with more of the benefits and less of the risks. Since the WHI Study in 2002, we are learning more about the ways to reduce some of the risks that were associated with older first-generation forms of estrogen and progesterone. This includes the use of bioidentical hormones and also adjusting the dosage forms used.
In addition to understanding the differences between BHT hormones and non-BHT hormones, another consideration is whether you will use a compounded or non-compounded (ie commercially made) product). In our final section of this 3 Part Series, we will describe the difference between compounded BHRT versus commercially made BHRT.
Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials. JAMA. 2013;310(13):1353–1368. doi:10.1001/jama.2013.278040
Fournier A, Mesrine S, Dossus L, Boutron-Ruault MC, Clavel-Chapelon F, Chabbert-Buffet N. Risk of breast cancer after stopping menopausal hormone therapy in the E3N cohort. Breast Cancer Res Treat 2014;145:535–43
Fournier A, Berrino F, Riboli E, Avenel V, Clavel-Chapelon F. Breast cancer risk in relation to different types of hormone replacement therapy in the E3N-EPIC cohort. Int J Cancer 2005;114:448–54
Fournier A, Berrino F, Clavel-Chapelon F. Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res Treat 2008;107:103–11
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Canonico M, Oger E, Plu-Bureau G, et al. Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: the ESTHER study. Circulation 2007;115:840–5
Writing Group for the PEPI Trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) trial. JAMA 1995;273:199–208
Nabulsi, A. A., Folsom, A. R., White, A., Patsch, W., Heiss, G., Wu, K. K., & Szklo, M. (1993). Association of hormone-replacement therapy with various cardiovascular risk factors in postmenopausal women. The New England Journal of Medicine, 328(15), 1069–1075. https://doi.org/10.1056/NEJM199304153281501
Lowe, G. D., Upton, M. N., Rumley, A., McConnachie, A., O’Reilly, D. S., & Watt, G. C. (2001). Different effects of oral and transdermal hormone replacement therapies on factor IX, APC resistance, t-PA, PAI and C-reactive protein — A cross-sectional population survey. Thrombosis and Haemostasis, 86(2), 550–556.
Folsom, A. R., Lutsey, P. L., Astor, B. C., & Cushman, M. (2009). C-reactive protein and venous thromboembolism. A prospective investigation in the ARIC cohort. Thrombosis and Haemostasis, 102(4), 615–619. https://doi.org/10.1160/TH09-04-0274
Post, M. S., Christella, M., Thomassen, L. G., van der Mooren, M. J., van Baal, W. M., Rosing, J., … Stehouwer, C. D. (2003). Effect of oral and transdermal estrogen replacement therapy on hemostatic variables associated with venous thrombosis: A randomized, placebo-controlled study in postmenopausal women. Arteriosclerosis, Thrombosis, Vascular Biology, 23(6), 1116–1121.
Margarido, P. F., Bagnoli, V. R., Maggio da Fonseca, A., Maciel, G. A., Soares, J. M., Jr., D’Amico, E. A., & Baracat, E. C. (2011). Transdermal estrogen therapy effects on fibrinogen levels in women with a past history of venous thromboembolism: A pilot study. Clinical and Experimental Obstetrics & Gynecology, 38(3), 232–235.
Oger, E., Alhenc-Gelas, M., Lacut, K. Blouch, M. T., Roudaut, N., Kerlan, V., … Mottier, D. (2003). Differential effects of oral and transdermal estrogen/progesterone regimens on sensitivity to activated protein C among postmenopausal women: A randomized trial. Arteriosclerosis, Thrombosis, and Vascular Biology, 23(9), 1671–1676. https://doi.org/10.1161/01.ATV.0000087141.05044.1F