Clinical Review

2022 Update on menopause

OBG Manag. 2022 July;34(7):16-19, 24-25, 32, 49-50 | doi: 10.12788/obgm.0210

A review of new evidence on risks of synthetic progestins in menopausal women at average risk for breast cancer, advantages of avoiding oophorectomy in women at average risk for ovarian cancer undergoing benign hysterectomy, and trends in estrogen therapy use in surgically menopausal women

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References

Chlebowski RT, Hendrix SL, Langer RD, et al; WHI Investigators. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women’s Health Initiative randomized trial. JAMA. 2003;289:3243-3253. doi: 10.1001/jama.289.24.3243.
Anderson GL, Limacher M, Assaf AR, et al; Women’s Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA. 2004;291:1701-1712. doi: 10.1001/jama.291.14.1701.
Opatrny L, Dell’Aniello S, Assouline S, et al. Hormone replacement therapy use and variations in the risk of breast cancer. BJOG. 2008;115:169-175. doi: 10.1111/j.14710528.2007.01520.x.
Fournier A, Berrino F, Riboli E, et al. Breast cancer risk in relation to different types of hormone replacement therapy in the E3N-EPIC cohort. Int J Cancer. 2005;114:448-454. doi: 10.1002/ijc.20710.
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. doi: 10.1007/s10549-007-9523-x.
Beral V; Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the million women study. Lancet. 2003;362:419–27. doi: 10.1016/s01406736(03)14065-2.
Yang Z, Hu Y, Zhang J, et al. Estradiol therapy and breast cancer risk in perimenopausal and postmenopausal women: a systematic review and meta-analysis. Gynecol Endocrinol. 2017;33:87-92. doi: 10.1080/09513590.2016.1248932.
Asi N, Mohammed K, Haydour Q, et al. Progesterone vs synthetic progestins and the risk of breast cancer: a systematic review and meta-analysis. Syst Rev. 2016;5:121. doi: 10.1186/ s13643-016-0294-5.
Abenhaim HA, Suissa S, Azoulay L, et al. Menopausal hormone therapy formulation and breast cancer risk. Obstet Gynecol. 2022;139:1103-1110. doi: 10.1097/AOG.0000000000004723.
Chlebowski RT, Rohan TE, Manson JE, et al. Breast cancer after use of estrogen plus progestin and estrogen alone: analyses of data from 2 Women’s Health Initiative randomized clinical trials. JAMA Oncol. 2015;1:296-305. doi: 10.1001/ jamaoncol.2015.0494.
Chlebowski RT, Anderson GL, Aragaki A, et al. Association of menopausal hormone therapy with breast cancer incidence and mortality during long-term follow-up of the Women’s Health Initiative randomized clinical trials. JAMA. 2020;324:369-380. doi: 10.1001/jama.2020.9482.
Cordina-Duverger E, Truong T, Anger A, et al. Risk of breast cancer by type of menopausal hormone therapy: a case-control study among postmenopausal women in France. PLoS One. 2013;8:e78016. doi: 10.1371/journal.pone.0078016.
Simin J, Tamimi R, Lagergren J, et al. Menopausal hormone therapy and cancer risk: an overestimated risk? Eur J Cancer. 2017;84:60–8. doi: 10.1016/j.ejca. 2017.07.012.
Stanczyk FZ, Hapgood JP, Winer S, et al. Progestogens used in postmenopausal hormone therapy: differences in their pharmacological properties, intracellular actions, and clinical effects. Endocr Rev. 2013;34:171-208. doi: 10.1210/er.20121008.
Stute P, Wildt L, Neulen J. The impact of micronized progesterone on breast cancer risk: a systematic review. Climacteric. 2018;21:111-122. doi: 10.1080/13697137.2017.1421925.
Anderson GL, Chlebowski RT, Aragaki A, et al. Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women’s Health Initiative randomised placebo-controlled trial. Lancet Oncol. 2012;13:476-486. doi: 10.1016/S1470-2045(12)70075-X.
Chlebowski RT, Barrington W, Aragaki AK, et al. Estrogen alone and health outcomes in black women by African ancestry: a secondary analyses of a randomized controlled trial. Menopause. 2017;24:133-141. doi: 10.1097/ GME.0000000000000733.
The NAMS 2017 Hormone Therapy Position Statement Advisory Panel. The 2017 hormone therapy position statement of The North American Menopause Society. Menopause. 2017;24:728-753. doi: 10.1097/GME.0000000000000921.
Pinkerton JV. Hormone therapy for postmenopausal women. N Engl J Med. 2020;382(5):446-455. doi: 10.1056/ NEJMcp1714787.
Marchetti C, De Felice F, Boccia S, et al. Hormone replacement therapy after prophylactic risk-reducing salpingooophorectomy and breast cancer risk in BRCA1 and BRCA2 mutation carriers: a meta-analysis. Crit Rev Oncol Hematol. 2018;132:111-115. doi: 10.1016/j.critrevonc.2018.09.018.
Vinogradova Y, Coupland C, Hippisley-Cox J. Use of hormone replacement therapy and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases. BMJ. 2019;364:k4810. doi: 10.1136/bmj.k4810.
Pinkerton JV. Hormone therapy: key points from NAMS 2017 Position Statement. Clin Obstet Gynecol. 2018;61:447453. doi: 10.1097/GRF.0000000000000383.
Parker WH, Broder MS, Liu Z, et al. Ovarian conservation at the time of hysterectomy for benign disease. Obstet Gynecol. 2005;106:219-226. doi: 10.1097/01. AOG.0000167394.38215.56.
Parker WH, Broder MS, Chang E, et al. Ovarian conservation at the time of hysterectomy and long-term health outcomes in the Nurses’ Health Study. Obstet Gynecol. 2009;113:10271037. doi: 10.1097/AOG.0b013e3181a11c64.
Rocca WA, Bower JH, Maraganore DM, et al. Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause. Neurology. 2007;69:10741083. doi: 10.1212/01.wnl.0000276984.19542.e6.
Rocca WA, Gazzuola Rocca L, Smith CY, et al Loss of ovarian hormones and accelerated somatic and mental aging. Physiology (Bethesda). 2018;33:374-383. doi: 10.1152/ physiol.00024.2018.
Mytton J, Evison F, Chilton PJ, et al. Removal of all ovarian tissue versus conserving ovarian tissue at time of hysterectomy in premenopausal patients with benign disease: study using routine data and data linkage. BMJ. 2017;356:j372. doi: 10.1136/bmj.j372.
Erickson Z, Rocca WA, Smith CY, et al. Time trends in unilateral and bilateral oophorectomy in a geographically defined American population. Obstet Gynecol. 2022;139:724-734. doi: 10.1097/AOG.0000000000004728.
Choi YH, Terry MB, Daly MB, et al. Association of risk-reducing salpingo-oophorectomy with breast cancer risk in women with BRCA1 and BRCA2 pathogenic variants. JAMA Oncol. 2021;7:585-592. doi: 10.1001/jamaoncol.2020 .7995.
Suzuki Y, Huang Y, Melamed A, et al. Use of estrogen therapy after surgical menopause in women who are premenopausal. Obstet Gynecol. 2022;139:756-763. doi: 10.1097/ AOG.0000000000004762.
Faubion S, Kaunitz AM, Kapoor E. HT for women who have had BSO before the age of natural menopause: discerning the nuances. OBG Manag. 2022;34(2):20-27, 45. doi: 10.12788/ obgm.0174.
Kaunitz AM, Kapoor E, Faubion S. Treatment of women after bilateral salpingo-oophorectomy performed prior to natural menopause. JAMA. 2021;326:1429-1430. doi: 10.1001/ jama.2021.3305.

This year’s Menopause Update focuses on 2 menopause-related issues relevant to ObGyns and our menopausal patients:

choosing the safest regimens, particularly with respect to risk of breast cancer, when prescribing hormone therapy (HT) to menopausal women
reviewing the risks and benefits of premenopausal bilateral salpingo-oophorectomy and the pros and cons of replacement HT in surgically menopausal patients.

We hope that you find this updated information useful as you care for menopausal women.

Revisiting menopausal HT and the risk of breast cancer: What we know now

Abenhaim HA, Suissa S, Azoulay L, et al. Menopausal hormone therapy formulation and breast cancer risk. Obstet Gynecol. 2022;139:1103-1110. doi: 10.1097/AOG.0000000000004723.

Reevaluation of the Women’s Health Initiative randomized controlled trials (WHI RCTs), long-term (median follow-up more than 20 years) cumulative follow-up data, and results from additional studies have suggested that estrogen therapy (ET) alone in menopausal women with prior hysterectomy does not increase the risk of breast cancer. By contrast, estrogen with progestin (synthetic progestogens that include medroxyprogesterone acetate [MPA] and norethindrone acetate) slightly increases the risk of breast cancer. In the past 10 years, several publications have shed light on whether the type of progestogen affects the risk of breast cancer and can help provide evidence-based information to guide clinicians.

Breast cancer risk with combined HT and synthetic progestin

In the first part of the WHI RCT, women were randomly assigned to receive either conjugated equine estrogen (CEE) plus synthetic progestin (MPA) or a placebo. Combined estrogen-progestin therapy (EPT) was associated with a modestly elevated risk of breast cancer.¹ In the second part of the WHI trial, CEE only (estrogen alone, ET) was compared with placebo among women with prior hysterectomy, with no effect found on breast cancer incidence.²

Most older observational studies published in 2003 to 2005 found that neither CEE nor estradiol appeared to increase the risk of breast cancer when used alone.^3-5 However, estrogen use in combination with synthetic progestins (MPA, norethindrone, levonorgestrel, and norgestrel) has been associated with an increased risk of breast cancer,^4,6 while the elevated risk of breast cancer with micronized progesterone has been less substantial.^7,8

Continue to: Newer data suggest the type of progestogen used affects risk...

References

Chlebowski RT, Hendrix SL, Langer RD, et al; WHI Investigators. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women’s Health Initiative randomized trial. JAMA. 2003;289:3243-3253. doi: 10.1001/jama.289.24.3243.
Anderson GL, Limacher M, Assaf AR, et al; Women’s Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA. 2004;291:1701-1712. doi: 10.1001/jama.291.14.1701.
Opatrny L, Dell’Aniello S, Assouline S, et al. Hormone replacement therapy use and variations in the risk of breast cancer. BJOG. 2008;115:169-175. doi: 10.1111/j.14710528.2007.01520.x.
Fournier A, Berrino F, Riboli E, et al. Breast cancer risk in relation to different types of hormone replacement therapy in the E3N-EPIC cohort. Int J Cancer. 2005;114:448-454. doi: 10.1002/ijc.20710.
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. doi: 10.1007/s10549-007-9523-x.
Beral V; Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the million women study. Lancet. 2003;362:419–27. doi: 10.1016/s01406736(03)14065-2.
Yang Z, Hu Y, Zhang J, et al. Estradiol therapy and breast cancer risk in perimenopausal and postmenopausal women: a systematic review and meta-analysis. Gynecol Endocrinol. 2017;33:87-92. doi: 10.1080/09513590.2016.1248932.
Asi N, Mohammed K, Haydour Q, et al. Progesterone vs synthetic progestins and the risk of breast cancer: a systematic review and meta-analysis. Syst Rev. 2016;5:121. doi: 10.1186/ s13643-016-0294-5.
Abenhaim HA, Suissa S, Azoulay L, et al. Menopausal hormone therapy formulation and breast cancer risk. Obstet Gynecol. 2022;139:1103-1110. doi: 10.1097/AOG.0000000000004723.
Chlebowski RT, Rohan TE, Manson JE, et al. Breast cancer after use of estrogen plus progestin and estrogen alone: analyses of data from 2 Women’s Health Initiative randomized clinical trials. JAMA Oncol. 2015;1:296-305. doi: 10.1001/ jamaoncol.2015.0494.
Chlebowski RT, Anderson GL, Aragaki A, et al. Association of menopausal hormone therapy with breast cancer incidence and mortality during long-term follow-up of the Women’s Health Initiative randomized clinical trials. JAMA. 2020;324:369-380. doi: 10.1001/jama.2020.9482.
Cordina-Duverger E, Truong T, Anger A, et al. Risk of breast cancer by type of menopausal hormone therapy: a case-control study among postmenopausal women in France. PLoS One. 2013;8:e78016. doi: 10.1371/journal.pone.0078016.
Simin J, Tamimi R, Lagergren J, et al. Menopausal hormone therapy and cancer risk: an overestimated risk? Eur J Cancer. 2017;84:60–8. doi: 10.1016/j.ejca. 2017.07.012.
Stanczyk FZ, Hapgood JP, Winer S, et al. Progestogens used in postmenopausal hormone therapy: differences in their pharmacological properties, intracellular actions, and clinical effects. Endocr Rev. 2013;34:171-208. doi: 10.1210/er.20121008.
Stute P, Wildt L, Neulen J. The impact of micronized progesterone on breast cancer risk: a systematic review. Climacteric. 2018;21:111-122. doi: 10.1080/13697137.2017.1421925.
Anderson GL, Chlebowski RT, Aragaki A, et al. Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women’s Health Initiative randomised placebo-controlled trial. Lancet Oncol. 2012;13:476-486. doi: 10.1016/S1470-2045(12)70075-X.
Chlebowski RT, Barrington W, Aragaki AK, et al. Estrogen alone and health outcomes in black women by African ancestry: a secondary analyses of a randomized controlled trial. Menopause. 2017;24:133-141. doi: 10.1097/ GME.0000000000000733.
The NAMS 2017 Hormone Therapy Position Statement Advisory Panel. The 2017 hormone therapy position statement of The North American Menopause Society. Menopause. 2017;24:728-753. doi: 10.1097/GME.0000000000000921.
Pinkerton JV. Hormone therapy for postmenopausal women. N Engl J Med. 2020;382(5):446-455. doi: 10.1056/ NEJMcp1714787.
Marchetti C, De Felice F, Boccia S, et al. Hormone replacement therapy after prophylactic risk-reducing salpingooophorectomy and breast cancer risk in BRCA1 and BRCA2 mutation carriers: a meta-analysis. Crit Rev Oncol Hematol. 2018;132:111-115. doi: 10.1016/j.critrevonc.2018.09.018.
Vinogradova Y, Coupland C, Hippisley-Cox J. Use of hormone replacement therapy and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases. BMJ. 2019;364:k4810. doi: 10.1136/bmj.k4810.
Pinkerton JV. Hormone therapy: key points from NAMS 2017 Position Statement. Clin Obstet Gynecol. 2018;61:447453. doi: 10.1097/GRF.0000000000000383.
Parker WH, Broder MS, Liu Z, et al. Ovarian conservation at the time of hysterectomy for benign disease. Obstet Gynecol. 2005;106:219-226. doi: 10.1097/01. AOG.0000167394.38215.56.
Parker WH, Broder MS, Chang E, et al. Ovarian conservation at the time of hysterectomy and long-term health outcomes in the Nurses’ Health Study. Obstet Gynecol. 2009;113:10271037. doi: 10.1097/AOG.0b013e3181a11c64.
Rocca WA, Bower JH, Maraganore DM, et al. Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause. Neurology. 2007;69:10741083. doi: 10.1212/01.wnl.0000276984.19542.e6.
Rocca WA, Gazzuola Rocca L, Smith CY, et al Loss of ovarian hormones and accelerated somatic and mental aging. Physiology (Bethesda). 2018;33:374-383. doi: 10.1152/ physiol.00024.2018.
Mytton J, Evison F, Chilton PJ, et al. Removal of all ovarian tissue versus conserving ovarian tissue at time of hysterectomy in premenopausal patients with benign disease: study using routine data and data linkage. BMJ. 2017;356:j372. doi: 10.1136/bmj.j372.
Erickson Z, Rocca WA, Smith CY, et al. Time trends in unilateral and bilateral oophorectomy in a geographically defined American population. Obstet Gynecol. 2022;139:724-734. doi: 10.1097/AOG.0000000000004728.
Choi YH, Terry MB, Daly MB, et al. Association of risk-reducing salpingo-oophorectomy with breast cancer risk in women with BRCA1 and BRCA2 pathogenic variants. JAMA Oncol. 2021;7:585-592. doi: 10.1001/jamaoncol.2020 .7995.
Suzuki Y, Huang Y, Melamed A, et al. Use of estrogen therapy after surgical menopause in women who are premenopausal. Obstet Gynecol. 2022;139:756-763. doi: 10.1097/ AOG.0000000000004762.
Faubion S, Kaunitz AM, Kapoor E. HT for women who have had BSO before the age of natural menopause: discerning the nuances. OBG Manag. 2022;34(2):20-27, 45. doi: 10.12788/ obgm.0174.
Kaunitz AM, Kapoor E, Faubion S. Treatment of women after bilateral salpingo-oophorectomy performed prior to natural menopause. JAMA. 2021;326:1429-1430. doi: 10.1001/ jama.2021.3305.

Hormone therapy and breast cancer: An overview

2022 Update on menopause

References

Revisiting menopausal HT and the risk of breast cancer: What we know now

Breast cancer risk with combined HT and synthetic progestin

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