In Pursuit of Best Practice: Menopausal Hormone Therapy (MHT)
by Clinical Consulting Team
Doreen Saltiel, MD, JD, FACC is board certified in Internal Medicine and an Advanced Fellow in Anti-Aging and Regenerative Medicine. Recently, she served as the Vice-President, Medical Affairs and Chief Medical Officer for Genova Diagnostics and is currently the Medical Director of Peak Health and Wellness in Asheville, NC. and a consultant for clinical materials at Precision Analytical Inc.
This post originally appeared on the Dr. Kara Fitzgerald Functional Medicine blog on May 1, 2020, and has been reposted with permission.
I have practiced medicine for more than 30 years. Throughout, I, like most of you, always wished I had more time to read. My wish came true! This past year, I had the opportunity to roll up my sleeves, dig in, and really understand the literature. Literature on what? In addition to being a cardiovascular disease (CVD) expert, I wanted to continue my growth and development as a hormone expert.
I wanted to know everything I could about hormones, hormones in health and disease, hormones in both men and women, hormone dosing, delivery systems, and monitoring, such that I could educate myself, fellow clinicians, and patients. And that is exactly what I have done.
I would like to share some of what I’ve learned, what I thought I knew and later found out I was wrong about, while at the same time replacing “long-held beliefs” with facts, such that you can use the evidence to support your clinical decision making. This brief review will focus on menopausal hormone therapy (MHT), transdermal estradiol (TD E2), and micronized progesterone (Pg) in both natural and surgical postmenopausal (PMP) women. Testosterone in women requires an entirely separate writing.
I chose MHT because it has been hotly debated since the Women’s Health Initiative’s (WHI) publications. Often there are misconceptions overshadowing the facts. We know that MHT improves vasomotor (VMS)1,2,3,4,5,6,7 and vulvovaginal atrophy (VVA) symptoms,8,9,10,11,12,13,14 while improving bone mineral density (BMD).15,16,17,18,19,20,21,22,23,24 FDA-approved patch doses as low as 0.014mg/d and gel doses as low as 0.25mg/d (DIVIGEL), and 0.375mg/d (ESTROGEL) improve VMS and VVA symptoms.3,4,10-14 Additionally, all FDA-approved patches improve BMD and are approved for osteoporosis prevention.15,17-20 FDA-approved TD E2 gels require higher doses and take longer to be effective21 therefore, they are not FDA approved for improving BMD and/or osteoporosis prevention.
Despite MHT’s benefits, two concerns are often raised: is there an increased cancer risk (breast and endometrial) and/or is MHT going to increase CVD risk. These will be addressed below.
My hope is that this writing will encourage more conversation and research about MHT, primarily compounded MHT, because there are no studies using compounded products. This doesn’t mean they aren’t effective; it’s just that there are no outcome studies documenting their effectiveness. Going forward, question the absolutes and ask for the evidence, such that you and your patients can make well-informed, evidence-based, treatment decisions. Here are 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.25,26,27,28 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.29
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.1,26-28,30,31,32 Vaginal micronized progesterone (VMP), because of its first-pass uterine effects, also protects the endometrium by achieving high endometrial levels.32,33
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.34,35 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!
Neither o-CEE (in the typical hormone naïve PMP woman),36 o-E2, or TD E2 patches and gels increase breast cancer.37 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,38 and E3N.39
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
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: Chang44 and Foidart.45 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.46,47,48
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.49,50,51,52,53,54
Five studies are commonly cited: WHI-CEE,56 KEEPS,50 ELITE,54 DOPS,55 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.46,56 This data is reassuring, but should not be used as a roadmap for decision making. TD E2 is safer;57,58,59 CEE should not be used.57,60
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
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
If the lowest effective TD E2 dose can be determined, along with the most effective OMP/VMP dose that balances E2’s proliferative endometrial effects, MHT may be continued safely in women who are ≥ 60 years old and/or ≥ 10 years since menopause onset. Time since menopause and age ≥ 60 should cause pause, but not prevent MHT initiation or continuation.
In all women, ongoing cardiovascular, endometrial, and breast surveillance is a must. Treatment dose and duration, along with a risk assessment, should be individualized and monitored on a regular basis. A hormone practice is never “one size fits all.”
 Pinkerton JAV, et al. The 2017 hormone therapy position statement of the North American Menopause Society. Menopause. 2017; 24(7): 728-753.
 Stuenkel CA. Vasomotor and Related Menopausal Symptoms. Clin Obstet Gynecol. 2018; 61(3): 433-446.
 Bachmann GA, et al. Lowest Effective Transdermal 17b-Estradiol Dose for Relief of Hot Flashes in Postmenopausal Women: A Randomized Controlled Trial. Obstet Gynecol. 2007; 110(4): 771-779.
 Corbelli J, et al. Low-dose transdermal estradiol for vasomotor symptoms: a systematic review. Menopause. 2015; 22(1): 114-121.
 Hitchcock CL, Prior JC. Oral micronized progesterone for vasomotor symptoms – a placebo-controlled randomized trial in healthy postmenopausal women. Menopause. 2012; 19(8): 1-8.
 Prior JC. Progesterone for treatment of symptomatic menopausal women. Climacteric. 2018; 21(4): 358-365.
 Prior JC, Hitchcock CL. Progesterone for hot flush and night sweat treatment – effectiveness for severe vasomotor symptoms and lack of withdrawal rebound. Gynecol Endocrinol. 2012; 28(Suppl 2): 7-11.
 Faubion SS, et al. Genitourinary Syndrome of Menopause: Management Strategies for the Clinician. Mayo Clin Proc. 2017; 92(12): 1842-1849.
 Crandall CJ. Treatment of Vulvovaginal Atrophy. JAMA. Published online September 26, 2019. doi:10.1001/jama.2019.15100.
 Bachmann GA, et al. Microdose transdermal estrogen therapy for relief of vulvovaginal symptoms in postmenopausal women. Menopause. 2009; 16(5): 877-882.
 Simon JA, et al. Low Dose of Transdermal Estradiol Gel for Treatment of Symptomatic Postmenopausal Women. A Randomized Controlled Trial. Obstet Gynecol. 2007; 109(3): 588-596.
 Archer DF, et al. Transdermal estradiol gel for the treatment of symptomatic postmenopausal women. Menopause. 2012; 19(6): 622-629.
 Archer DF, for the EstroGel Study Group. Percutaneous 17b-estradiol gel for the treatment of vasomotor symptoms in postmenopausal women. Menopause. 2003; 10(6): 516-521.
 Gupta P, et al. The effect of transdermal and vaginal estrogen therapy on markers of postmenopausal estrogen status. Menopause. 2008; 15(1): 94-97.
 Bertonazzi A, et al. The smallest available estradiol transdermal patch: a new treatment option for the prevention of postmenopausal osteoporosis. Womens Health. 2015; 11(6): 815–824.
 von Mach-Szczypiński J. New aspects of postmenopausal osteoporosis treatment with micronized estradiol and progesterone. Ginekol Pol. 2016; 87(11): 739–744.
 Levin VA, et al. Estrogen therapy for osteoporosis in the modern era. Osteoporos Int. 2018; 29(5):1049-1055.
 Weiss SR, et al. A Randomized Controlled Trial of Four Doses of Transdermal Estradiol for Preventing Postmenopausal Bone Loss. Obstet Gynecol. 1999; 94(3): 330-336.
 Notelovitz M, et al. Effectiveness of ALORA estradiol matrix transdermal delivery system in improving lumbar bone mineral density in healthy, postmenopausal women. Menopause. 2002; 9(5): 343-353.
 Ettinger B, et al. Effects of Ultralow-Dose Transdermal Estradiol on Bone Mineral Density: A Randomized Clinical Trial. Obstet Gynecol. 2004; 104(3): 443-451.
 Yang TS, et al. A Clinical Trial of 3 Doses of Transdermal 17b-estradiol for Preventing Postmenopausal Bone Loss: A Preliminary Study. J Chin Med Assoc. 2007; 70(5): 200-206.
 Li D, et al. Negative Spinal Bone Mineral Density Changes and Subclinical Ovulatory Disturbances – Prospective Data in Healthy Premenopausal Women with Regular Menstrual Cycles. Epidemiol Rev. 2014; 36: 137-147.
 Prior JC, et al. Ovulation Prevalence in Women with Spontaneous Normal-Length Menstrual Cycles – A Population-Based Cohort from HUNT3, Norway. PloS One. 2015; 10(8): e0134473.
 Prior JC. Progesterone for the prevention and treatment of osteoporosis in women. Climacteric. 2018; 21(4), 366-374.
 Allen NE, et al. Menopausal Hormone Therapy and Risk of Endometrial Carcinoma Among Postmenopausal Women in the European Prospective Investigation into Cancer and Nutrition. Am J Epidemiol. 2010; 172(12): 1394-1403.
 Stute P, et al. The impact of micronized progesterone on the endometrium: A systematic review. Climacteric. 2016; 19(4); 316-328.
 The PEPI Writing Group. Effects of Hormone Replacement Therapy on Endometrial Histology in Postmenopausal Women. The Postmenopausal Estrogen/Progestin Intervention Trial (PEPI). JAMA. 1996; 275(5): 370-375.
 Gompel A. Progesterone, progestins and the endometrium in perimenopause and in menopausal hormone therapy. Climacteric. 2018; 21(4): 321-325.
 Mirkin S, et al. Endometrial safety and bleeding profile of a 17b-estradiol/progesterone oral softgel capsule (TX-001HR). Menopause. 2020; 27(4): 000-000.
 Moyer DL, et al. Prevention of endometrial hyperplasia by progesterone during long-term estradiol replacement: influence of bleeding pattern and secretory changes. Fertil Steril. 1993; 59(5): 992-997.
 Gillet JY, et al. Induction of amenorrhea during hormone replacement therapy: optimal micronized progesterone dose. A multicenter study. Maturitas.1994; 19(2): 103-115.
 Di Carlo C, et al. Transdermal Estradiol and Oral or Vaginal Natural Progesterone: Bleeding Patterns. Climacteric. 2010; 13(5): 442-446.
 Fernandez-Murga L, et al. Endometrial response to concurrent treatment with vaginal progesterone and transdermal estradiol. Climacteric. 2012; 15(5): 455-459.
 Leonetti HB, et al. Topical progesterone cream has an antiproliferative effect on estrogen-stimulated endometrium. Fertil Steril. 2003; 79(1): 221-222.
 Leonetti HB, et al. Transdermal progesterone cream as an alternative progestin in hormone therapy. Altern Ther Health Med. 2005; 11(6):36-38.
 Hodis HN, Sarrel PM. Menopausal hormone therapy and breast cancer: what is the evidence from randomized trials? Climacteric. 2018; 21(6): 521-528.
 Mikkola TS, et al. Reduced risk of breast cancer mortality in women using postmenopausal hormone therapy: a Finnish nationwide comparative study. Menopause. 2016; 23(11): 1199-1203.
 Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet. 2003; 362(9382): 419-427.
 Fournier A, et al. Unequal risk for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res Treat. 2008; 107(1): 103-111.
 Stute P, et al. The impact of micronized progesterone on breast cancer risk: A systematic review. Climacteric. 2017; 21(2): 111-122.
 Gompel A, Plu-Bureau G. Progesterone, progestins and the breast in menopause treatment. Climacteric. 2018; 21(4): 326-332.
 de Lignières B, et al. Combined hormone replacement therapy and risk of breast cancer in a French cohort study of 3175 women. Climacteric. 2002; 5(4): 332-340.
 Espie M, et al. Breast cancer incidence and hormone replacement therapy: Results from the MISSION study, prospective phase. Gynecol Endocrinol. 2007; 23(7): 391-397.
 Chang KJ, et al. Influences of percutaneous administration of estradiol and progesterone on human breast epithelial cell cycle in vivo. Fertil Steril. 1995; 63(4): 785-791.
 Foidart JM, et al. Estradiol and progesterone regulate the proliferation of human breast epithelial cells. Fertil Steril. 1998; 69(5): 963-969.
 Naftolin F, et al. Cardiovascular health and the menopausal woman: the role of estrogen and when to begin and end hormone treatment [version 1; peer review: 3 approved]. F1000Research. 2019; 8 (F1000 Faculty Rev): 1576.
 Mikkola TS, et al. Estradiol-based postmenopausal hormone therapy and risk of cardiovascular and all-cause mortality. Menopause. 2015; 22(9): 976-983.
 Mikkola TS, et al. New evidence for cardiac benefits of postmenopausal hormone therapy. Climacteric. 2017; 20(1): 5-10.
 Miller VM, et al. The Kronos Early Estrogen Prevention Study (KEEPS): what have we learned? Menopause. 2019; 26(9): 000-000. DOI: 10.1097/GME.0000000000001326.
 Prior JC, et al. Progesterone Therapy, Endothelial Function and Cardiovascular Risk Factors: A 3-Month Randomized, Placebo-Controlled Trial in Healthy Early Postmenopausal Women. PLoS One. 2014; 9(1): e84698.
 Canonico M, 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(7): 840-845.
 Canonico M, et al. Progestogens and venous thromboembolism among postmenopausal women using hormone therapy. Maturitas. 2011; 70(4): 354-360.
 Hodis HN, et al. Vascular Effects of Early versus Late Postmenopausal Treatment with Estradiol. N Engl J Med. 2016; 374(13): 1221-1231.
 Schierbeck LL, et al. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial. BMJ. 2012; 345: e6409: 1-11.
 Manson JE, 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): 1353-1358.
 Goodman MP. Are all estrogens created equal? A review of oral vs transdermal therapy. J Womens Health (Larchmt). 2012; 21(2): 161-169.
 L’Hermite M, et al. Could transdermal estradiol + progesterone be a safer postmenopausal MHT? A review. Maturitas. 2008; 60(3-4): 185-201.
 L’Hermite M. Bioidentical menopausal hormone therapy: registered hormones (non-oral estradiol ± progesterone) are optimal. Climacteric. 2017; 20(4): 331-338.
 Beck KL, et al. Transdermal estrogens in the changing landscape of hormone replacement therapy. Postgrad Med. 2017; 129(6): 632-636.