My purpose in writing this educational, 2500 word, blog is to help women everywhere get the correct health care and improve their quality of life at menopause. I am trying to reverse an unfortunately bad trend that affected women’s health for the past decade. Please share this blog with your women friends and your doctors: This is an incredibly important women’s issue. Understanding the data on hormone replacement, when to give hormone replacement, who to give it to and why, and how to use hormone replacement correctly can make a huge difference for the quality of life and healthy ageing of all women.
Dr. JoAnn E. Manson, wrote an editorial piece, in the New England Journal of Medicine issue published March 3, 2016, with a plea to physicians to resume (and for some start) giving hormone replacement therapy to young menopausal women in their 40’s and 50’s with menopausal symptoms. JoAnn E. Manson was one of the principal authors of the now famous Women’s Health Initiative study (WHI). The WHI study put a significant halt to the practice of using hormone replacement therapy for symptomatic menopausal women in the United States after 2002. In fact, the use of hormone replacement therapy declined by 80% since then because physicians generalized the findings of the WHI study as if it applied to all women. Sadly, even very symptomatic young women in their 30’s and 40’s, who had early menopause due to autoimmune or surgical causes, were not offered hormone replacement.
So why did doctors become scared of prescribing hormone replacement therapy (HRT) after the publication of the WHI study in 2002? The study showed that some bad things can happen if you give by mouth (oral) non-bioidentical HRT (Premarin, an estogen made from pregnant mares, together with Provera, a synthetic progesterone) to older women (average age 63 years), many years after menopause, to prevent heart disease. Compared to older women who received no hormones, those receiving the treatment had a higher risk of stroke, deep vein thrombosis (blood clots), and a progressive increased risk of breast cancer. Moreover, there was no protective effect on heart disease. It was the 2.5 times increased risk of breast cancer over the 6-7 years of observation that caused the study to be halted before its conclusion. A subset of women with hysterectomies received estrogen alone (Premarin) because they did not need the synthetic progesterone to protect the uterus. They did not have an increase in breast cancer risk. Later on it was understood that it was the synthetic progesterone (Provera), unlike the natural progesterone, that was increasing the breast cancer risk. Natural progesterone does not cause breast cells to proliferate. This is also consistent with European studies on progesterone. Oral estrogens alone still increased the risk of stroke and blood clots. In the WHI study 12 additional strokes/ 10,000 person years were observed. The risk of blood clots was particularly present for obese women and women with clotting tendency or “thrombophilias” such as Factor 5 Leyden mutation and family history of stroke.
Dr. Manson states in her editorial, and I concur, that hormone replacement therapy continues to be the most effective treatment currently available to help women with hot flushes, impaired sleep, vaginal dryness and atrophy (leading to painful intercourse), and mood and cognitive changes. For more than a decade now, few women with menopausal symptoms are evaluated and treated with hormones, including by their gynecologists. The concern is not only that most doctors are not prescribing HRT, but that they are not teaching future doctors to be proficient in menopausal care of women. There is new data that says that hormone replacement therapy is beneficial to women, if given around the time of menopause. This new information is based on the The Keeps Study, a randomized controlled study, which focused on hormone replacement within 3 years of menopause. Dr. JoAnn Manson is also one of the principal investigators for this study. It showed that unlike giving hormones to older women, HRT in younger women was beneficial. In this study they used 0.45 mg oral conjugated estrogen (Premarin) daily with a bioidentical progesterone (Prometrium) 12 days a month and compared it transdermal (Vivelle) bioidentical estradiol 0.05 mg, and a placebo group. A most important finding that has been learned from the Keeps Study, other current studies, and studies in non-human female primates (who are biologically similar to women), is that The timing of when estrogen gets given to women makes a huge difference: Estrogen treatment, in young women or just after onset of menopause, decreases risk of heart disease by 40% and women treated with estrogen have less coronary artery calcifications, which is a sign of future heart disease. In contrast there is not protective effect of estrogen if it is initiated 10 years after menopause. There is actually an increase in cardiovascular risk.
The fact that doctors have not prescribed hormone therapy to symptomatic women for more than a decade has created significant changes in ways in which women address their menopausal symptoms and how they go about getting their therapies. The use of compounded non-FDA approved bioidentical hormones has increased since 2002 and now represents 40% of the total HRT market according to the North American Menopause Society (NAMS), as reported during the 2014 Annual Meeting. The Menopause Society had many concerns about compounded HRT including: 1) preparation of these is not regulated, 2) levels of these hormones are hard to measure by standard methods, 3) marketing for these preparations suggest that these compounded transdermal bioidentical preparations have less risks for women that those of transdermal bio-identical hormones which are currently available and approved by FDA. Further, many patients are not aware that these preparations are not FDA approved. Additionally, patients often pay for these compounded hormones out of pocket, since they are not covered by insurance.
So how do we select which estrogen preparation is best?
1) Both oral and transdermal estrogens improved the menopausal symptoms of hot flushes, night sweats, vaginal dryness and sleep disturbance. They also help maintain bone mass. Additional benefits include decrease hip fracture risk (oral estrogens, WHI), decrease colon cancer risk (oral estrogens, WHI). For women with just vaginal dryness and atrophy, low dose vaginal estradiol is safe and effective. (vagifem 10mcg twice a week inserted vaginally at bed time).
2) The transdermal estrogen/estradiol had the benefit of not causing a “first pass” effect in the liver. Oral estrogens are absorbed by the intestines, then they pass through the liver. These orally absorbed estrogens then induce the synthesis of hormone-binding proteins, which also tie-up hormones a woman’s own body makes. Unlike oral estrogens, transdermal hormones are absorbed by the skin and don’t pass directly through the liver. Because the liver isn’t binding up the patient’s own “endogenous” hormones, the testosterone a woman makes herself is more bioavailable. This is helpful for sexual arousal and libido. In addition, the transdermal route was helpful in improving insulin resistance and preventing diabetes. The patch was not more effective than placebo at improving cognitive complaints. Doses of the estradiol patch of 0.05 or less are not associated with increased risk of blood clot or stroke.
3) The oral estrogen was more effective at improving cholesterol profile and in improving cognitive complaints, but because it has the first pass effect (makes the liver produce more hormone binding proteins), you get the higher binding of free hormones, so it does not help with libido issues because your free testosterone gets bound up. It increases C-reactive protein (a marker of endogenous inflammation), and brings back the dreaded increased risks of stroke and DVT present at all ages.
What we do not know:
- How long women after menopause can be treated? I have patients that continue taking HRT into their 70’s and eighties, but this is no proof that they are safe for everyone. There may be a cumulative effect of long term estrogen use in increasing breast cancer risk. Observational studies suggest ovarian cancer risk is also increased with longer term estrogen use.
- Can lower doses of the hormones be used and still get the positive protective effects we get at these current doses?
- How risks on the breast and heart may be altered after long term therapy > 6 years using both a bio-identical estradiol and progesterone replacement?
- If compounded (non-FDA approved) bioidentical estradiol /progesterone creams have beneficial effects similar to what we know are achieved with FDA approved patches, particularly on breast, cognition, and bones? Will there ever be a good study on this?
- There is no data on what the risks are if you are age 65 or older and have been on HRT for years. We don’t know if starting estradiol as early as possible after menopause continues to have the same benefit if you stay on it for years, or forever? At a minimum, I might recommend an enteric coated baby aspirin daily to reduce clotting risk in older women and would not use estrogen products around the time I was having a hip or knee surgery!
What we know based on the evidence published to date.
- Estrogen is protective and decreases inflammation in women.
- Women in their 40’s and 50’s or women within 10 years of their menopause with menopausal symptoms and no risk for breast/uterine cancer should be offered hormone replacement therapy with FDA approved bio-identical hormones.
- Good products include the following biodentical estradiol preparations: 0.05 mg vivelle, minivelle, estradiol patches, or 1.25 mg divigel, or oral estradiol 0.625-0.45 mg.
- All women who have a uterus need to received bio-identical progesterone: 100 mg daily at bed time, or 200 mg a day for 12-14 days at monthly to trimonthly intervals to protect the uterus from unopposed proliferative effects of estradiol.
- Women in these categories who are obese, have metabolic syndrome, or have low physical activity should be treated with estradiol patches, and not with oral estrogen. These groups have a higher risk of blood clot formation, so oral estrogen should be avoided.
- Women who are thin and have no cardiovascular risk factors who have cognitive complaints as part of the menopause can try oral bioidentical estradiol. The oral route seems to be more helpful for cognitive complaints.
- Women 65 years of age or older should avoid initiating estrogen replacement if they are 10 years or more after the menopause. If estrogen is tried consider the Menostar, a low dose transdermal estradiol 14 mcg patch, and an enteric coated baby aspirin. There is no cardiovascular protective effect from use of oral estrogen above this age, and in fact there is a higher risk of blood clots, pulmonary embolus or stroke.
Breast Cancer Risk
- Women with breast cancer, high breast cancer risk, those with history of migraines, and those with thrombotic (forming clots) tendency should not use estradiol. Women with established or active coronary artery disease also need to avoid estrogen.
- All women have some risk of developing breast cancer. Even though the statistics show that 1 in 8 will develop breast cancer, the probability can vary between 4-23% depending on our genetics and environmental factors and lifestyle. Both estrogen and progesterone can and do promote cancer growth in breast cancers that have receptors for estrogen or progesterone. Women with faulty tumor suppressor genes, such as BRCA1 and BRCA2 have a five fold increased risk. The BRCA1 mutations have a lifetime risk of breast cancer of 87% and those with BRCA-2 also have ovarian cancer risk. For women with these mutations bilateral mastectomy with or without oophorectomy (ovary removal) has been the treatment of choice to prevent the cancers. However future therapy may involve blocking RANKL, a protein that promotes growth of these cancers, with therapy (denusomab or prolia) that we already use to prevent osteoporosis. These medications work by binding and blocking RANKL.
What can you do to prevent breast cancer
- Breast cancer risk is increased by 4 factors: obesity, cigarette smoke, drinking alcohol, and use of hormone replacement therapy. In fact a recent study notes that 29% of all breast cancer can be prevented by keeping healthy weight, not smoking or drinking alcohol and avoiding hormone replacement therapy.
- There are non-hormonal therapies available for most menopausal symptoms: seretonin reuptake inhibitors and gabapeptin for hot flushes, osphena for vaginal dryness (but higher risk of blood clot, so I add an enteric baby aspirin), lubricants such as astroglide, etc.
What Do I do with HRT and my menopausal patients?
- First I try to modify behaviors or factors that can affect breast cancer risk: Weight loss, daily exercise, limit or avoid non-organic and non-grass fed cow/dairy products, avoid smoking, avoid or limit drinking alcohol. Increase intake of dark leafy and cruciferous vegetable, and fruits in the diet. I encourage obtaining calcium through diet.
- I always start with bio-identical FDA approved preparations first. There is a lot more data on these. Having tried multiple preparations on my patients in the past 20 years as an integrative endocrinologist, I find these to be more reliable and rapidly effective. I can measure levels more reliably in regular laboratories, and I know the bone mass is protected. However if I need to add testosterone, I currently do not have an FDA approved preparation for women, so I have to use compounded testosterone or injections.
- Personally, I have taken courses on the use of bioidentical hormones and I do prescribe compounded bio-identical hormones in carefully selected patients who have strong desire for these preparations and do not tolerate available standard therapies. I now only use pharmacies that undergo Pharmacy Accreditation for Compounding Pharmacy Oversight. I use both the The Women’s International Pharmacy and University Compounding Pharmacies that have undergone such accreditation. Even with all my experience I feel significant uncertainty when using compounded preparations. There is NO data on efficacy, or long term outcomes. Then there is the problem of measuring resulting hormone levels with reliability, even though I use reputable labs, for example ZRT and Genova. I also explain my concern that we have no data showing that compounded HRT creams are as effective at protecting bone mass, an issue I deal with on a daily basis. My patients are aware of this, and do have to sign informed consents to use these compounded hormone therapies.
- I discuss with all my patients that I view all transdermal (patches, creams, gels) bioidentical hormones, whether FDA approved or not, as carrying the same potential risks for the breast and other hormone sensitive issues.
- See also my prior posts on FDA- approved HRT, and Compounded non FDA approved HRT on Beatrizolson.com or the Facebook group “Integrative Endocrinology with Dr. Beatriz Olson” on Set 19, 2014, and October 26, 2014.
- Check out free App Menopro which is a decision support tool that helps patients and doctors identify risk and guide potential options for hormone therapy for you. This app also gives access to Gail model breast cancer risk assessment app.
Manson JE & Kaunitz AM. Menopause management- Getting Clinical care back on track. N Engl J Med 374;9:803-805, 2016.
Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288(3):321-333.
Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA. 2004;291(14):1701-1712.
Manson JE. The Kronos Early Estrogen Prevention Study. Women’s Health, January 2013 ,Vol. 9, No. 1, Pages 9-11 , DOI 10.2217/whe.12.69 (doi:10.2217/whe.12.69)
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JoAnn E Manson The ‘timing hypothesis’ for estrogen therapy in menopausal symptom management. Women’s Health. July 2015 ,Vol. 11, No. 4, Pages 437-440 , DOI 10.2217/whe.15.24 (doi:10.2217/whe.15.24)
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Shifren, Jan L. MD1,2; Desindes, Sophie MD3 ; McIlwain, Marilyn BS4 ; Doros, Gheorghe PhD5; Mazer, Norman A. MD, PhD6 A randomized, open-label, crossover study comparing the effects of oral versus transdermal estrogen therapy on serum androgens, thyroid hormones, and adrenal hormones in naturally menopausal women Menopause: November/December 2007 – Volume 14 – Issue 6 – pp 985-994doi: 10.1097/gme.0b013e31803867a
Paige Maas, PhD; Myrto Barrdahl, PhD; Amit D. Joshi, PhD; et al. Breast Cancer Risk From Modifiable and Nonmodifiable Risk Factors Among White Women in the United States JAMA Oncol. Published online May 26, 2016. doi:10.1001/jamaoncol.2016.1025
Sigl, V., Owusu-Boaitey, K., Penninger, J., et al. 2016. RANKL/RANK control Brca1 mutation-driven mammary tumors. Cell Research.
Beatriz Olson. See also my prior posts on Set 19, 2014, and October 26, 2014 on FDA- approved HRT, and Compounded non FDA approved HRT on my web site Beatrizolson.com , or integrative endocrinology with Dr. Beatriz Olson .