EDITORIAL
Progestin-only systemic hormone therapy for menopausal hot flashes Clinicians treating postmenopausal hot flashes often recommend “systemic estrogen treatment.” However, progestin-only therapy also can effectively treat hot flashes and is an option for women with a contraindication to estrogen therapy.
Robert L. Barbieri, MD Editor in Chief, OBG Management Chair, Obstetrics and Gynecology Brigham and Women’s Hospital Boston, Massachusetts Kate Macy Ladd Professor of Obstetrics, Gynecology and Reproductive Biology Harvard Medical School
he field of menopause medi- women. In one study, 133 postmeno- in postmenopausal women with cine is dominated by studies pausal women with an average age an American Heart Association risk T documenting the effective- of 55 years and approximately 3 years score greater than 10% over 10 years.3 ness of systemic estrogen or estro- from their last menstrual period were Additional contraindications to sys- gen-progestin hormone therapy for randomly assigned to 12 weeks of temic estrogen include women with the treatment of hot flashes caused treatment with placebo or micronized cardiac disease who have a throm- by hypoestrogenism. The effective- progesterone 300 mg daily taken at bophilia, such as the Factor V Leiden ness of progestin-only systemic bedtime.1 Mean serum progesterone mutation.4 hormone therapy for the treatment levels were 0.28 ng/mL (0.89 nM) and For women who are at high risk of hot flashes is much less studied 27 ng/mL (86 nM) in the women taking for estrogen-induced cardiovascu- and seldom is utilized in clinical placebo and micronized progesterone, lar events, micronized progesterone practice. A small number of stud- respectively. Compared with placebo, may be a better option than systemic ies have reported that progestins, micronized progesterone reduced day- estrogen for treating hot flashes. including micronized progesterone, time and nighttime hot flash frequency Alternatively, in these women at risk medroxyprogesterone acetate, and and severity. In addition, compared of cardiovascular disease a selective norethindrone acetate, are effective with placebo, micronized progester- serotonin reuptake inhibitor, such as treatment for hot flashes. Proges- one improved the quality of sleep.1 escitalopram, 10 mg to 20 mg daily, tin-only systemic hormone therapy Most reviews conclude that may be a good option for treating might be especially helpful for post- micronized progesterone has mini- postmenopausal hot flashes.5 menopausal women with moderate mal cardiovascular risk.2 Micronized to severe hot flashes who have a con- progesterone therapy might be espe- traindication to estrogen treatment. cially helpful for postmenopausal Medroxyprogesterone women with moderate to severe hot acetate flashes who have a contraindication Medroxyprogesterone acetate, at a Micronized progesterone to estrogen treatment such as those at dosage of 20 mg daily, is an effective Micronized progesterone (Prome- increased risk for cardiovascular dis- treatment for hot flashes. In a ran- trium) 300 mg daily taken at bed- ease or women with a thrombophilia. domized clinical trial 27 postmeno- time has been reported to effectively Many experts believe that systemic pausal women with hot flashes were treat hot flashes in postmenopausal estrogen therapy is contraindicated randomly assigned to treatment with
6 OBG Management | February 2020 | Vol. 32 No. 2 mdedge.com/obgyn placebo or medroxyprogesterone group and 0 in both the LA plus NEA acetate 20 mg daily for 4 weeks. Vaso- 5 mg daily group and the LA plus NEA motor flushes were decreased by 26% 5 mg plus CEE 1.25 mg daily group. and 74% in the placebo and medroxy- This study demonstrates that NEA progesterone groups, respectively.6 5 mg daily is an effective treatment Depot medroxyprogesterone for hot flashes. acetate injections at dosages from In the same study, LA plus 150 mg to 400 mg also have been placebo was associated with a sig- reported to effectively treat hot nificant decrease in lumbar spine flashes.7,8 In a trial comparing the bone mineral density. No significant effectiveness of estrogen monother- decrease in bone mineral density was apy (conjugated equine estrogen 0.6 observed in the women who received mg daily) with progestin monotherapy LA plus NEA 5 mg daily. This finding (medroxyprogesterone acetate 10 mg indicates that NEA 5 mg reduces bone daily), both treatments were equally 2.16) compared with never users of absorption caused by hypoestrogen- effective in reducing hot flashes.9 postmenopausal hormone therapy. ism. In humans, norethindrone is a The E3N study indicates that micron- substrate for the aromatase enzyme ized progesterone may have a more system.14 Small quantities of ethinyl Micronized progesterone favorable breast health profile than estradiol may be formed by aroma- vs medroxyprogesterone medroxyprogesterone acetate.12 tization of norethindrone in vivo,15,16 acetate contributing to the effectiveness of Experts in menopause medicine NEA in suppressing hot flashes and have suggested that in postmeno Norethindrone acetate preserving bone density. pausal women micronized pro- Norethindrone acetate monotherapy gesterone has a better pattern of is not commonly prescribed for the benefits and fewer risks than med- treatment of menopausal hot flashes. Progestin: The estrogen roxyprogesterone acetate.10,11 For However, a large clinical trial has dem- alternative to hot flashes example, in the E3N observational onstrated that norethindrone acetate For postmenopausal women with study of hormones and breast can- effectively suppresses hot flashes in moderate to severe hot flashes, estro- cer risk, among 80,377 French post- women with endometriosis treated gen treatment reliably suppresses hot menopausal women followed for with depot leuprolide acetate (LA). flashes and often improves sleep qual- a mean of 8 years, the combina- In one trial 201 women with endome- ity and mood. For postmenopausal tion of transdermal estradiol plus triosis were randomly assigned to 12 women with a contraindication to oral micronized progesterone was months of treatment with13: estrogen treatment, progestin-only associated with no significantly • LA plus placebo pills treatment with micronized progester- increased risk of breast cancer (rela- • LA plus norethindrone acetate one or norethindrone acetate may be tive risk [RR], 1.08, 95% confidence (NEA) 5 mg daily an effective option. interval [CI], 0.89–1.31) compared • LA plus NEA 5 mg daily plus conju- with never users of postmenopausal gated equine estrogen (CEE) 0.625 hormone therapy.12 By contrast, the mg daily, or
combination of oral estrogen plus • LA plus NEA 5 mg daily plus CEE [email protected] medroxyprogesterone acetate was 1.25 mg daily. associated with an increased risk of The median number of hot flashes in Dr. Barbieri reports no financial rela- breast cancer (RR, 1.48; 95% CI, 1.02– 24 hours was 6 in the LA plus placebo tionships relevant to this article.
References 1. Hitchcock CL, Prior JC. Oral micronized proges- one use by midlife menopausal women. Maturitas decision making: a clinical decision-suport tool terone for vasomotor symptoms—a placebo- 2012; 72: 192-202. from The North American Menopause Society. controlled randomized trial in healthy postmeno- 3. Manson JE, Ames JM, Shapiro M, et al. Algorithm Menopause. 2015;22:247-253. pausal women. Menopause. 2012;19:886-893. and mobile app for menopausal symptom man- 4. Herrington DM, Vittinghoff E, Howard TD, et al.
DIGITAL ILLUSTRATION: JOHN J. DENAPOLI IMAGES: © ANA BLAZIC PAVLOVIC/VADYM NECHYPORENKO/SHUTTERSTOCK JOHN J. DENAPOLI IMAGES: © ANA BLAZIC PAVLOVIC/VADYM ILLUSTRATION: DIGITAL 2. Spark MJ, Willis J. Systematic review of progester- agement and hormonal/nonhormonal therapy Factor V Leiden, hormone replacement therapy,
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and risk of venous thromboembolic events North Central Cancer Treatment Group Trial 13. Hornstein MD, Surrey ES, Weisberg GW, et in women with coronary disease. Arterioscler N99C7. J Clin Oncol. 2006;24:1409-1414. al. Leuprolide acetate depot and hormonal Thromb Vasc Biol. 2002;22:1012-1017. 9. Prior JC, Nielsen JD, Hitchcock CL, et al. Med- add-back in endometriosis: a 12-month study. 5. Ensrud KE, Joffe H, Guthrie KA, et al. Effect of roxyprogesterone and conjugated oestrogen are Lupron Add-Back Study Group. Obstet Gynecol. escitalopram on insomnia symptoms and sub- equivalent for hot flushes: 1-year randomized 1998;91:16-24. jective sleep quality in healthy perimenopausal double-blind trial following premenopausal ova- 14. Barbieri RL, Canick JA, Ryan KJ. High-affinity ste- and postmenopausal women with hot flashes: riectomy. Clin Sci (Lond). 2007;112:517-525. roid binding to rat testis 17 alpha-hydroxylase and a randomized controlled trial. Menopause. 10. L’hermite M, Simoncini T, Fuller S, et al. Could trans- human placental aromatase. J Steroid Biochem. 2012;19:848-855. dermal estradiol + progesterone be a safer postmen- 1981;14:387-393. 6. Schiff I, Tulchinsky D, Cramer D, et al. Oral medroxy- opausal HRT? A review. Maturitas. 2008;60:185-201. 15. Chu MC, Zhang X, Gentzschein E, et al. Forma- progesterone in the treatment of postmenopausal 11. Simon JA. What if the Women’s Health Initiative tion of ethinyl estradiol in women during treat- symptoms. JAMA. 1980;244:1443-1445. had used transdermal estradiol and oral proge- ment with norethindrone acetate. J Clin Endocri- 7. Bullock JL, Massey FM, Gambrell RD Jr. Use of sterone instead? Menopause. 2014;21:769-783. nol Metab. 2007;92:2205-2207. medroxyprogesterone acetate to prevent meno- 12. Fournier A, Berrino F, Clavel-Chapelon F. Unequal 16. Chwalisz K, Surrey E, Stanczyk FZ. The hormonal pausal symptoms. Obstet Gynecol. 1975;46:165-168. risks for breast cancer associated with different profile of norethindrone acetate: rationale for 8. Loprinzi CL, Levitt R, Barton D, et al. Phase III hormone replacement therapies: results from add-back therapy with gonadotropin-releasing comparison of depot medroxyprogesterone the E3N cohort study. Breast Cancer Res Treat. hormone agonists in women with endometriosis. acetate to venlafaxine for managing hot flashes: 2008;107:103-111. Reprod Sci. 2012;19:563-571.
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