From the Editor

Progestin-only systemic hormone therapy for menopausal hot flashes

OBG Manag. 2020 February;32(2):6-8

References

Hitchcock CL, Prior JC. Oral micronized progesterone for vasomotor symptoms—a placebo-controlled randomized trial in healthy postmenopausal women. Menopause. 2012;19:886-893.
Spark MJ, Willis J. Systematic review of progesterone use by midlife menopausal women. Maturitas 2012; 72: 192-202.
Manson JE, Ames JM, Shapiro M, et al. Algorithm and mobile app for menopausal symptom management and hormonal/nonhormonal therapy decision making: a clinical decision-suport tool from The North American Menopause Society. Menopause. 2015;22:247-253.
Herrington DM, Vittinghoff E, Howard TD, et al. Factor V Leiden, hormone replacement therapy, and risk of venous thromboembolic events in women with coronary disease. Arterioscler Thromb Vasc Biol. 2002;22:1012-1017.
Ensrud KE, Joffe H, Guthrie KA, et al. Effect of escitalopram on insomnia symptoms and subjective sleep quality in healthy perimenopausal and postmenopausal women with hot flashes: a randomized controlled trial. Menopause. 2012;19:848-855.
Schiff I, Tulchinsky D, Cramer D, et al. Oral medroxyprogesterone in the treatment of postmenopausal symptoms. JAMA. 1980;244:1443-1445.
Bullock JL, Massey FM, Gambrell RD Jr. Use of medroxyprogesterone acetate to prevent menopausal symptoms. Obstet Gynecol. 1975;46:165-168.
Loprinzi CL, Levitt R, Barton D, et al. Phase III comparison of depot medroxyprogesterone acetate to venlafaxine for managing hot flashes: North Central Cancer Treatment Group Trial N99C7. J Clin Oncol. 2006;24:1409-1414.
Prior JC, Nielsen JD, Hitchcock CL, et al. Medroxyprogesterone and conjugated oestrogen are equivalent for hot flushes: 1-year randomized double-blind trial following premenopausal ovariectomy. Clin Sci (Lond). 2007;112:517-525.
L’hermite M, Simoncini T, Fuller S, et al. Could transdermal estradiol + progesterone be a safer postmenopausal HRT? A review. Maturitas. 2008;60:185-201.
Simon JA. What if the Women’s Health Initiative had used transdermal estradiol and oral progesterone instead? Menopause. 2014;21:769-783.
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;107:103-111.
Hornstein MD, Surrey ES, Weisberg GW, et al. Leuprolide acetate depot and hormonal add-back in endometriosis: a 12-month study. Lupron Add-Back Study Group. Obstet Gynecol. 1998;91:16-24.
Barbieri RL, Canick JA, Ryan KJ. High-affinity steroid binding to rat testis 17 alpha-hydroxylase and human placental aromatase. J Steroid Biochem. 1981;14:387-393.
Chu MC, Zhang X, Gentzschein E, et al. Formation of ethinyl estradiol in women during treatment with norethindrone acetate. J Clin Endocrinol Metab. 2007;92:2205-2207.
Chwalisz K, Surrey E, Stanczyk FZ. The hormonal profile of norethindrone acetate: rationale for add-back therapy with gonadotropin-releasing hormone agonists in women with endometriosis. Reprod Sci. 2012;19:563-571.

Micronized progesterone vs medroxyprogesterone acetate

Experts in menopause medicine have suggested that in postmenopausal women micronized progesterone has a better pattern of benefits and fewer risks than medroxyprogesterone acetate.^10,11 For example, in the E3N observational study of hormones and breast cancer risk, among 80,377 French postmenopausal women followed for a mean of 8 years, the combination of transdermal estradiol plus oral micronized progesterone was associated with no significantly increased risk of breast cancer (relative risk [RR], 1.08, 95% confidence interval [CI], 0.89–1.31) compared with never users of postmenopausal hormone therapy.¹² By contrast, the combination of oral estrogen plus medroxyprogesterone acetate was associated with an increased risk of breast cancer (RR, 1.48; 95% CI, 1.02–2.16) compared with never users of postmenopausal hormone therapy. The E3N study indicates that micronized progesterone may have a more favorable breast health profile than medroxyprogesterone acetate.¹²

Norethindrone acetate

Norethindrone acetate monotherapy is not commonly prescribed for the treatment of menopausal hot flashes. However, a large clinical trial has demonstrated that norethindrone acetate effectively suppresses hot flashes in women with endometriosis treated with depot leuprolide acetate (LA). In one trial 201 women with endometriosis were randomly assigned to 12 months of treatment with¹³:

LA plus placebo pills
LA plus norethindrone acetate (NEA) 5 mg daily
LA plus NEA 5 mg daily plus conjugated equine estrogen (CEE) 0.625 mg daily, or
LA plus NEA 5 mg daily plus CEE 1.25 mg daily.

The median number of hot flashes in 24 hours was 6 in the LA plus placebo group and 0 in both the LA plus NEA 5 mg daily group and the LA plus NEA 5 mg plus CEE 1.25 mg daily group. This study demonstrates that NEA 5 mg daily is an effective treatment for hot flashes.

In the same study, LA plus placebo was associated with a significant decrease in lumbar spine bone mineral density. No significant decrease in bone mineral density was observed in the women who received LA plus NEA 5 mg daily. This finding indicates that NEA 5 mg reduces bone absorption caused by hypoestrogenism. In humans, norethindrone is a substrate for the aromatase enzyme system.¹⁴ Small quantities of ethinyl estradiol may be formed by aromatization of norethindrone in vivo,^15,16 contributing to the effectiveness of NEA in suppressing hot flashes and preserving bone density.

Progestin: The estrogen alternative to hot flashes

For postmenopausal women with moderate to severe hot flashes, estrogen treatment reliably suppresses hot flashes and often improves sleep quality and mood. For postmenopausal women with a contraindication to estrogen treatment, progestin-only treatment with micronized progesterone or norethindrone acetate may be an effective option.

References

Hitchcock CL, Prior JC. Oral micronized progesterone for vasomotor symptoms—a placebo-controlled randomized trial in healthy postmenopausal women. Menopause. 2012;19:886-893.
Spark MJ, Willis J. Systematic review of progesterone use by midlife menopausal women. Maturitas 2012; 72: 192-202.
Manson JE, Ames JM, Shapiro M, et al. Algorithm and mobile app for menopausal symptom management and hormonal/nonhormonal therapy decision making: a clinical decision-suport tool from The North American Menopause Society. Menopause. 2015;22:247-253.
Herrington DM, Vittinghoff E, Howard TD, et al. Factor V Leiden, hormone replacement therapy, and risk of venous thromboembolic events in women with coronary disease. Arterioscler Thromb Vasc Biol. 2002;22:1012-1017.
Ensrud KE, Joffe H, Guthrie KA, et al. Effect of escitalopram on insomnia symptoms and subjective sleep quality in healthy perimenopausal and postmenopausal women with hot flashes: a randomized controlled trial. Menopause. 2012;19:848-855.
Schiff I, Tulchinsky D, Cramer D, et al. Oral medroxyprogesterone in the treatment of postmenopausal symptoms. JAMA. 1980;244:1443-1445.
Bullock JL, Massey FM, Gambrell RD Jr. Use of medroxyprogesterone acetate to prevent menopausal symptoms. Obstet Gynecol. 1975;46:165-168.
Loprinzi CL, Levitt R, Barton D, et al. Phase III comparison of depot medroxyprogesterone acetate to venlafaxine for managing hot flashes: North Central Cancer Treatment Group Trial N99C7. J Clin Oncol. 2006;24:1409-1414.
Prior JC, Nielsen JD, Hitchcock CL, et al. Medroxyprogesterone and conjugated oestrogen are equivalent for hot flushes: 1-year randomized double-blind trial following premenopausal ovariectomy. Clin Sci (Lond). 2007;112:517-525.
L’hermite M, Simoncini T, Fuller S, et al. Could transdermal estradiol + progesterone be a safer postmenopausal HRT? A review. Maturitas. 2008;60:185-201.
Simon JA. What if the Women’s Health Initiative had used transdermal estradiol and oral progesterone instead? Menopause. 2014;21:769-783.
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;107:103-111.
Hornstein MD, Surrey ES, Weisberg GW, et al. Leuprolide acetate depot and hormonal add-back in endometriosis: a 12-month study. Lupron Add-Back Study Group. Obstet Gynecol. 1998;91:16-24.
Barbieri RL, Canick JA, Ryan KJ. High-affinity steroid binding to rat testis 17 alpha-hydroxylase and human placental aromatase. J Steroid Biochem. 1981;14:387-393.
Chu MC, Zhang X, Gentzschein E, et al. Formation of ethinyl estradiol in women during treatment with norethindrone acetate. J Clin Endocrinol Metab. 2007;92:2205-2207.
Chwalisz K, Surrey E, Stanczyk FZ. The hormonal profile of norethindrone acetate: rationale for add-back therapy with gonadotropin-releasing hormone agonists in women with endometriosis. Reprod Sci. 2012;19:563-571.

Progestin-only systemic hormone therapy for menopausal hot flashes

References

Micronized progesterone vs medroxyprogesterone acetate

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Norethindrone acetate

Progestin: The estrogen alternative to hot flashes

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