September 3, 2014

Estrogen for Depressed Menopausal Women

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Thalia Robakis, MD, PhD, and Natalie L. Rasgon, MD, PhD

Stanford School of Medicine, Stanford, California


The phases of a woman’s life are demarcated by points of transition in her reproductive cycle. Global shifts in the hormonal milieu accomplish the transitions from child to woman, woman to mother, and mother to elder.

The major hormones of the female reproductive cycle include estrogens (estrone, estradiol and estriol), progesterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH). The effects of these reproductive hormones on a woman’s mood are most prominent not at points of lowest or highest expression but rather at times of rapid change in serum concentration.1

The transition to menopause is accomplished over many years, beginning with gradual increases in the levels of FSH and LH while the woman maintains regular cycling. During perimenopause, menstrual cycles become intermittent, and, in the 6 months around the time of the final menstrual period, estrogen levels markedly decrease. A corresponding decline in FSH and LH quickly follows, ultimately resulting in stably low levels of all reproductive hormones in the postmenopausal period.2

An increase in risk for depressive symptoms occurs during the menopausal transition. Common symptoms of perimenopause like insomnia and vasomotor symptoms may be important contributors to low mood.3 The cessation of menstruation is not itself depressogenic, as depressive symptoms are reduced after the completion of menopause.4

Transdermal estradiol has been found effective for perimenopausal depression in randomized controlled trials.5 But, in accordance with the hypothesis that it is the rapid alteration in estrogen levels rather than low serum estrogen itself that predisposes perimenopausal women to depressive symptoms, treatment with estradiol alone appears less effective for depressed women who have completed menopause.6 However, estradiol treatment in postmenopausal women has been found to enhance7 or accelerate8 the effect of antidepressant treatment, resulting in improved global well-being and quality of life over and above that obtained with the antidepressant alone.9 Thus, combination of estrogen with an antidepressant can be an effective strategy that in some cases is greater than the sum of its parts.

Estrogen treatment has a positive effect on physiological symptoms associated with menopause.10 To some degree, the positive effect of estrogen on mood in perimenopausal women may be mediated by mitigation of physiological symptoms,3 but the extent of the interrelationship is not yet clear.

Potential adverse effects of estrogen replacement therapy in older women include increases in risk for the development of coronary heart disease, pulmonary embolism, and breast cancer.11 Combined treatment with estrogen and a progestin does not appear to mitigate these effects and may in fact increase breast cancer risk relative to use of estrogen alone.12

Thus, extended periods of hormone replacement therapy for postmenopausal women are not recommended and indeed are not indicated given the lack of effect of estrogen for depression after menopause. However, estrogen replacement therapy can be a reasonable short-term treatment for managing depressive as well as physiological symptoms associated with perimenopause. We suggest a treatment period of no longer than 6 months to cover the period of adjustment to the lower estrogen state while avoiding the multiple adverse effects associated with long-term use of hormone replacement therapy.

Financial disclosure:Dr Robakis has received grant/research support from NIMH. Dr Rasgon has received grant/research support and/or honoraria from and/or is a consultant for Magceutics, American Diabetes Association, Corcept, Shire, Sunovion, and Takeda.


1. Deecher D, Andree TH, Sloan D, et al. From menarche to menopause: exploring the underlying biology of depression in women experiencing hormonal changes. Psychoneuroendocrinology. 2008;33(1):3–17. PubMed

2. Rannevik G, Jeppsson S, Johnell O, et al. A longitudinal study of the perimenopausal transition: altered profiles of steroid and pituitary hormones, SHBG and bone mineral density. Maturitas. 1995;21(2):103–113. PubMed

3. Avis NE, Crawford S, Stellato R, et al. Longitudinal study of hormone levels and depression among women transitioning through menopause. Climacteric. 2001;4(3):243–249. PubMed

4. Freeman EW, Sammel MD, Liu L, et al. Hormones and menopausal status as predictors of depression in women in transition to menopause. Arch Gen Psychiatry, 2004;61(1):62–70. PubMed

5. Soares CN, Almeida OP, Joffe H, et al. Efficacy of estradiol for the treatment of depressive disorders in perimenopausal women: a double-blind, randomized, placebo-controlled trial. Arch Gen Psychiatry. 2001;58(6):529–534. PubMed

6. Morrison MF, Kallan MJ, Ten Have T, et al. Lack of efficacy of estradiol for depression in postmenopausal women: a randomized, controlled trial. Biol Psychiatry. 2004;55(4):406–412. PubMed

7. Schneider LS, Small GW, Hamilton SH, et al. Estrogen replacement and response to fluoxetine in a multicenter geriatric depression trial. Am J Geriatr Psychiatry. 1997;5(2):97–106. PubMed

8. Rasgon NL, Dunkin J, Fairbanks L, et al. Estrogen and response to sertraline in postmenopausal women with major depressive disorder: a pilot study. J Psychiatr Res. 2007;41(3–4):338–343. PubMed

9. Schneider LS, Small GW, Clary CM. Estrogen replacement therapy and antidepressant response to sertraline in older depressed women. Am J Geriatr Psychiatry. 2001;9(4):393–399. PubMed

10. Newton KM, Reed SD, LaCroix AZ, et al. Treatment of vasomotor symptoms of menopause with black cohosh, multibotanicals, soy, hormone therapy, or placebo: a randomized trial. Ann Internal Med. 2006;145(12):869–879. PubMed

11. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288(3):321–333. PubMed

12. Bakken K, Fournier A, Lund E, et al. Menopausal hormone therapy and breast cancer risk: impact of different treatments. The European Prospective Investigation into Cancer and Nutrition. Int J Cancer. 2011;128(1):144–156. PubMed

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  1. It would be helpful if you reviewed the studies using conjugated estrogens (that contain no estradiol) vs transdermal estradiol for efficacy studies. The biological estrogen is estradiol and it should not be administered orally due to high first-pass liver metabolism. Most of the national recommendations are mixing all estrogen products into one heading and these need to be separated based on the biological products (ie. 17-beta estradiol) vs other non-estradiol products (ie, conjugated estrogens that are primarily estrones and not active in the brain).

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