Mood and well-being are believed to be regulated by mechanisms of estrogen and progesterone. How effective are they in the treatment of major and minor depression?
Estrogen and progesterone are believed to play a role in the regulation of mood and well-being. Several mechanisms have been proposed for this effect, including the hormones' influence on monoamine oxidase (MAO) metabolism. Estrogen inhibits MAO, thereby diminishing the degradation of norepinephrine and serotonin and thus increasing their activity, while progesterone has the reverse impact on MAO (Chakravorty and Halbreich, 1997; Luine and Rhodes, 1983). Allopregnanolone, a metabolite of progesterone, is a potent neuroactive steroid that modulates g-aminobutyric acid (GABA) receptors and may be anxiolytic (Majewska et al., 1986).
Estrogen's influence on mood has been studied significantly more than that of progesterone. While estrogen's mood-elevating effect is generally acknowledged, the clinical magnitude of this effect remains unclear. Unfortunately, many studies examining this question have been uncontrolled or retrospective or have used populations with only mild levels of depression. A meta-analysis of research done between 1970 and 1995 (mostly involving conjugated equine estrogen [Premarin]) reported moderate-to-large mood-elevating effects from estrogen administration, which diminished following addition of a progestogen (Zweifel and O'Brien, 1997). Interestingly, in this meta-analysis, perimenopausal women appeared more likely to benefit than postmenopausal women. The authors, however, cautioned that methodological shortcomings limited the generalizability of several of the studies.
Three controlled studies evaluated the use of estrogen for perimenopausal and postmenopausal women with major and minor depression. The first, which evaluated the effect of transdermal estrogen (17-ß estradiol) in a group of 31 women and used the Hamilton Rating Scale for Depression (HAM-D) and Center for Epidemiologic Studies, Depression Scale (CES-D), reported that 80% of subjects experienced a response to estradiol compared to 22% of the placebo group (Schmidt et al., 2000). The second study, which comprised 50 perimenopausal depressed women on transdermal estrogen, reported a 68% remission rate among the estradiol group compared to 20% in the placebo group as measured with the Montgomery-Asberg Depression Rating Scale (MADRS) (Soares et al., 2001). A third study, also using transdermal estrogen, reported remission of depression in six of nine (66.7%) perimenopausal women but only two of 11 (18%) postmenopausal women, as defined by ratings on the MADRS, Beck Depression Inventory (BDI) and Clinical Global Impression (CGI) scale (Cohen et al., 2003). In all three studies, the mood effect was independent of estrogen's relief of vasomotor symptoms. Most recently, the Women's Health Initiative evaluated 16,609 postmenopausal women with a brief rating scale composed of items from the CES-D and Diagnostic Interview Schedule (DIS) and reported no improvement of depressive symptoms from equine estrogen. These inconsistent findings may result from different formulations of estrogen (Table 1), different menopausal status (perimenopausal versus postmenopausal), different methods of assessment of mood and/or different levels of depression among the subjects (major versus minor depression).
Unopposed estrogen produces substantial health risks, such as endometrial hyperplasia. Therefore, a progestogen must be added (except in women who have undergone a hysterectomy). Progestogen is an umbrella term for progesterone (which is natural) and progestins (which are synthetic). Progestogens, of which the most widely prescribed in the United States is medroxyprogesterone acetate (Provera), are administered either continuously (every day of the month) or cyclically (at a higher dose, 10 to 14 days of each month). Many studies have reported a worsening of mood following addition of a progestogen to the estrogen (Zweifel and O'Brien, 1997). One study did not find an adverse effect of medroxyprogesterone on mood; however, the study followed women on this regimen for only one week (Schmidt et al., 2000). The impact of progestogens on mood needs to be further examined using longer follow-up times and different formulations of progestogens (e.g., comparing progestins to natural progesterone).
A concern about the use of estrogen plus progestogen emerged last year following early results from the Women's Health Initiative, a randomized, controlled trial of the benefits and risks of hormone replacement therapy (HRT) (Rossouw et al., 2002). The study's duration had originally been planned for 8.5 years, but in 2002 the study's estrogen (Premarin) plus medroxyprogesterone acetate arm was abruptly discontinued after 5.2 years because preliminary findings showed that this hormone combination appeared to increase rather than decrease the risk of coronary heart disease. In addition, this hormone combination was associated with an elevated risk of invasive breast cancer compared to placebo. The estrogen alone arm continues as it remains uncertain whether the benefits outweigh the risks. The Women's Health Initiative has involved postmenopausal women aged 50 to 79, and its generalizability to younger, perimenopausal women remains unclear.
A number of studies have demonstrated a positive effect of testosterone administration on mood in men (Margolese, 2000). Few studies, however, have examined the effect of testosterone on mood in women (Davis and Tran, 2001). Testosterone is prescribed to enhance libido in perimenopausal and postmenopausal women, and it also helps relieve vasomotor symptoms, thereby reducing the amount of estrogen necessary. In the United States, testosterone is available to women as methyltestosterone (Estratest) and is prescribed in conjunction with HRT at 1.25 mg to 2.5 mg daily. Its use among perimenopausal and postmenopausal women is increasing and data on its psychological effects are therefore likely to expand. The sparse data currently available show that co-administration of testosterone with estrogen produces greater enhancement of well-being and energy than estrogen alone in perimenopausal and postmenopausal women (Brincat et al., 1984; Montgomery et al., 1987; Sherwin, 1988; Zweifel and O'Brien, 1997). Testosterone's use is limited by its androgenizing effects and its potentially negative influence on cardiolipids (Table 2).
In sum, the data show that estrogen administration appears to benefit mood primarily in perimenopausal women with mild or moderate levels of depression. Further research is necessary to examine the benefit of estrogen for severe or recurrent depression in this population of women. Also, future studies should examine the use of estrogen as an augmentation agent for antidepressant medications, as no controlled studies exist to date on this treatment approach. Testosterone's role in improving mood in perimenopausal and postmenopausal women merits study in controlled trials. Particular attention should be given to possible adverse cardiovascular effects in aging women who may already be at risk for cardiovascular disease. There are additional questions that remain to be addressed. Do hormone formulations differ in their mood effects? Do certain women respond more favorably than others (e.g., women with histories of reproductive-related depressions)? What are the optimal hormone doses and durations of treatment that benefit mood while producing minimal health risks?
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