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Best Practice Estrogen and Progesterone Treatment in Women - Summary of The Evidence 2022

Doreen Saltiel, MD, JD, has practiced medicine for almost 40 years. She completed a cardiology fellowship and board certification and practiced interventional cardiology for more than 25 years. She currently practices functional medicine with an emphasis on hormone health in both men and women as well as preventive cardiology. Dr. Saltiel completed advanced fellowship training in Metabolic and Nutritional Medicine from MMI and is a Diplomate of the American Board of Anti-Aging and Regenerative Medicine. She also completed MMI’s advanced certification in Endocrinology and Cardiovascular Health. Dr. Saltiel has co-authored multiple peer-reviewed papers and recently joined the Founder of Precision Analytical, Mark Newman, to present hormone testing research at the North American Menopause Society’s Annual Meeting.

Here is her summary of the highlights from key peer-reviewed human intervention trials:

Endometrial Hyperplasia and Endometrial Cancer Unopposed estrogen (o-E), even TD E2, increases endometrial hyperplasia and endometrial cancer risk. Pg is necessary to balance TD E2’s proliferative endometrial effects.25-28 TD E2 dose is one determinant to consider when deciding on the appropriate Pg dose and delivery.26-33 Another is a woman’s baseline E2 serum level. Women with a baseline E2 ≥ 10pg/mL are significantly more likely to have a baseline proliferative endometrium than women with a baseline E2 < 5pg/mL or in the 5 to < 10pg/mL range. Together, the TD E2 dose and serum E2 level may necessitate a higher Pg dose than originally thought. Further, in women with baseline E2 levels ≥ 10pg/mL, you may consider additional testing, i.e. transvaginal ultrasound (TVUS). OMP 200mg is what guidelines suggest and evidence supports for endometrial protection.1,26-28, Vaginal micronized progesterone (VMP), because of its first-pass uterine effects, also protects the endometrium by achieving high endometrial levels.32 With either a low-dose (0.025mg/d) or an ultralow-dose (0.014mg/d) TD E2 patch, or a low-dose TD E2 gel (DIVIGEL 0.25mg/d), an argument can be made for prescribing either continuous lower-dose OMP or VMP. However, there is a paucity of short-term and/or long-term studies, especially in younger PMP women, using these lower-dose combined regimens.26 If one chooses to use lower Pg doses, diligent follow-up and surveillance is necessary. Non-vaginal TD Pg (applied to the skin) does not provide adequate endometrial protection in women with a uterus. Currently, there is one small study documenting endometrial protection with estrogen + non-vaginal TD Pg. Leonetti et al., using endometrial histology, found that when TD Pg 20mg BID was added to 0.625mg CEE/d there was no endometrial hyperplasia. Read the study and you will see that Leonetti concludes there is not enough data to recommend TD Pg as an alternative until larger and longer studies are conducted. To date there are no larger and longer studies. Keys to preventing endometrial hyperplasia and endometrial cancer are: ensure treatment compliance and balance the TD E2 proliferative dose with a protective OMP/VMP dose. It should never be a one size fits all approach!

Breast Cancer Neither o-CEE (in the typical hormone naïve PMP woman),35 o-E2, or TD E2 patches and gels increase breast cancer. In fact, these E/E2 preparations when prescribed alone decrease breast cancer.36,37 Five studies are commonly cited: the WHI-CEE,36 WHI-CEE + MPA,36 FINNISH-OS,36,37 Million Women’s Study, and E3N. The landmark WHI’s results were re-analyzed in 2018, finding in the typical, hormone naïve, hysterectomized, PMP woman, a decreased breast cancer mortality (45%) when CEE-alone (0.625mg/d) was continued for 7.1 years with 18 years of cumulative follow-up (included the treatment phase). Interestingly, when MPA (2.5mg) was added to CEE, in naturally menopausal, hormone naïve women, the decreased risks seen with CEE-alone were neutralized. In the latter group, there was no increased or decreased breast cancer risk.36 The FINNISH observational trial, which evaluated o-E2, TD E2 patches, and TD E2 gels, found that the longer a PMP woman was prescribed and taking E2 the greater the mortality benefit (up to 54% mortality reduction). FINNISH documented that TD E2 can be continued safely, even in older PMP women, for > 10 years. In addition, time since menopause probably has no impact on either breast cancer risk or breast cancer mortality.37 The Million Women’s Study38 and E3N39 both found increased “relative” breast cancer risks. Both have been criticized, i.e. design flaws, and relying on low relative risks for their conclusions which, when < 2-3 in observational studies, are subject to bias, interpretation difficulties, etc.36 What about when OMP is added to TD E2? OMP, when added to TD E2, is not associated with any increase in breast cancer risk, even when treatment is continued for ≥ 10 years. The data on VMP and breast cancer is scarce and long-term data on TD Pg is non-existent. Two studies are commonly cited to justify TD Pg’s use to prevent breast cancer: Change and Foidart. These studies are not applicable because in both the E2 and Pg gels were placed directly on the breast. Yes, in both studies, when TD Pg gel, either alone or in combination with TD E2 gel, was applied directly to the breast, Pg significantly decreased the E2-induced epithelial breast cell proliferation.41,44,45 These results do not apply to current practice patterns. Non-vaginal TD Pg is typically placed on the thigh, buttocks, etc., not on the breast. Other than Leonetti,34,35 there are no studies that document that when TD Pg is placed on the skin, not the breast, and not vaginally, that the endometrium and/or the breast are protected. In summary, TD E2 alone decreases breast cancer, adding OMP does not increase the risk, VMP data is scarce, and non-vaginal TD Pg data is nonexistent. TD E2 + OMP may be continued safely in women ≥ 10 years PMP. Ongoing follow-up with diligent surveillance is a must.

Cardiovascular disease (CVD) For most women, TD E2 provides cardiovascular protection. At present, there are no studies indicating a time limit on the administration of properly monitored MHT, including TD E2. TD E2 patch doses as low as 0.025mg/d, E2 gel doses of 1-2mg/d, and o-E2 doses of 1-2mg/d are effective in decreasing CVD mortality risk in women, and this mortality reduction is positively related to hormone exposure time. The literature documents that OMP is safe for the cardiovascular system and does not increase venous thromboembolic risk.46,48 All commonly used OMP doses (100mg, 200mg, and 300mg) are safe and do not negatively affect the coronary arteries. These commonly used OMP doses do not increase DVT or PE risk. ELITE used VMP 45mg in women with a uterus, which was also safe. Five studies are commonly cited: WHI-CEE,56 KEEPS,50 ELITE,54 DOPS, and FINNISH-OS.47 The WHI-CEE56 trial evaluated CEE 0.625mg/d. WHI concluded that in the typical PMP women, ages 50-59 there was a 40% decreased MI risk and all-cause mortality when compared to placebo. With increasing age, the benefits decreased. In women 60-70 years old CEE had a neutral effect, and in women > 70 there was a trend towards an increased CVD risk.46 This data is reassuring, but should not be used as a roadmap for decision making. TD E2 is safer; CEE should not be used.57 KEEPS, using PREMARIN 0.45mg/d and CLIMARA 0.05mg/d, both with PROMETRIUM 200mg/d x 12 days, assessed CIMT and CAC, finding no change in CIMT rate of progression after 4 years in healthy, recently PMP women. OMP 200mg did not cause any adverse events.50 ELITE, using o-E2 1mg/d and VMP gel 45mg/d x 10d (in women with a uterus), found significantly slower CIMT progression only among women who initiated E2 therapy < 6 years after menopause, and only at the 5-year follow-up. In women > 10 years post menopause the results were similar to placebo.54 DOPS studied o-E2 in recently PMP women. Two follow-up points were noted, 10 and 16 years. DOPS found that o-E2-treated PMP women had a significantly lower coronary heart disease risk at both the 10- and 16-year follow-ups. At 10 years, o-E2 treated PMP women had significantly less heart attacks and heart failure.55 FINNISH patients were primarily prescribed TD E2 products. In E2 users, CAD-related death risk was reduced by up to 54% in a time-dependent manner. The longer a woman was prescribed and used an E2-based MHT, the greater the risk reduction. All risk reductions were comparable in PMP women initiating E2 < age 60 years and in women initiating therapy ≥ 60 years.47


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