Victoria Hendrick, MD

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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 Cohen LS, Soares CN, Poitras JR et al. (2003), Short-term use of estradiol for depression in perimenopausal and postmenopausal women: a preliminary report. Am J Psychiatry 160(8):1519-1522.
 

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Articles

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?

Hormones for Perimenopausal and Postmenopausal Depression

Following delivery, approximately 13% of new mothers experience a major depressive episode (Wisner et al., 2002). This rate translates to hundreds of thousands of women in the United States each year. This widespread condition affects not only the mother but also the child; numerous studies have documented an adverse effect on children's cognitive and social development from exposure to maternal depression in the first year of life (Hay et al., 2001). Women with a previous history of depression are at a particularly high risk for depression (Wisner et al., 2002). Additional risk factors include conflict with the baby's father, stressful life events and child care stresses. Many women benefit from individual or group psychotherapy (Appleby et al., 1997; O'Hara et al., 2000). Attending weekly therapy sessions, however, is frequently difficult for women who are looking after one or more small children at home. Further, many patients are unable to afford ongoing psychotherapy.

Antidepressants are an additional treatment option for postpartum depression, and several appear to be safe when used during breast-feeding (Burt et al., 2001; Hendrick et al., 2001; Stowe et al., 2000). Nevertheless, many new mothers are reluctant to take medications while nursing because they are concerned about the potential adverse effects on their infant. Further, antidepressants are not universally effective and often produce unacceptable side effects such as reduced libido. Many women look forward to a renewed intimacy with their partners after the pregnancy and prefer not to take medications with such a side effect. Therefore, alternative treatment approaches for postpartum depression merit consideration.

The use of alternative treatments, including acupuncture, homeopathy, herbs, dietary supplements, massage and relaxation techniques, for depression is becoming increasingly widespread (Figure) (Eisenberg et al., 1998; Gallagher et al., 2001; Habek et al., 2002). However, few studies have examined these alternative treatments for depression occurring in the postpartum period.

A recent case report described successful treatment of major depression during pregnancy and following delivery with omega-3 polyunsaturated fatty acids (4 g/day ethyl eicosapentaenoic acid and 2 g/day docosahexaenoic acid). Inadequate levels of omega-3 fatty acids have been associated with depression, including postpartum depression (Hibbeln, 1998; Horrobin and Bennett, 1999; Peet and Horrobin, 2002; Peet et al., 1998), and these fatty acids (e.g., 1 g/day to 4 g/day ethyl eicosapentaenoate) have been used to potentiate the effects of antidepressant medications (Nemets et al., 2002; Peet and Horrobin, 2002).

Omega-3 polyunsaturated fatty acids offer significant health benefits to pregnant and nursing women and their infants. An adequate supply of maternal docosahexanoic acid during pregnancy and nursing is necessary to support the optimal neurological development of the fetus and infant (Birch et al., 2000; Willatts and Forsyth, 2000). Underscoring the importance of maternal dietary supplementation of omega-3 fatty acids, the high fetal demand for these fatty acids can lead to a 50% reduction of the maternal levels (Hornstra, 2000). Research has demonstrated that the risk of preterm labor is reducedin women who consume omega-3 fatty acids during pregnancy (Olsen and Secher, 2002).

The health benefits of these fatty acids continue following delivery. For example, when supplied in infant formula at adequate doses, omega-3 fatty acids improve infant cognitive development and visual acuity (Birch et al., 2000; Willatts and Forsyth, 2000). If the preliminary data on omega-3 fatty acids' positive mood effects are corroborated in larger studies, they will become a safe and healthful treatment option for depression occurring during pregnancy and the postpartum period.

Herbal supplements offer an alternative treatment for depression. Nationwide, the most widely used herbal compound for depression is St. John's wort (

) (Bilia et al., 2002). The hypericin in this herb is believed to produce its therapeutic effects. Meta-analyses and systematic reviews of clinical trials support the efficacy of St. John's wort in the treatment of depression (Bilia et al., 2002; Gaster and Holroyd, 2000; Kim et al., 1999; Linde et al., 1996). St. John's wort is generally well-tolerated, relatively inexpensive and widely accessible. It is important to keep in mind, however, that the purity and potency of commercially available preparations of St. John's wort may not be what the labels purport. As a result of the Dietary Supplement Health and Education Act of 1994, the U.S. Food and Drug Administration minimally regulates most herbal products sold in the United States.

Nursing women may mistakenly assume that since St. John's wort and other herbs are "natural," they are safe. While case reports have described no adverse effects on pregnancy (Grush et al., 1998) or on infants exposed to St. John's wort through breast milk (Klier et al., 2002), data are too limited to recommend these herbs for use by pregnant or nursing women. An additional consideration among women of reproductive age is that St. John's wort induces the 3A4 isoenzyme of the cytochrome P450 system (Markowitz and DeVane, 2001). This enzyme metabolizes reproductive steroids and its induction can result in substantially lower efficacy of hormonal contraception. Women using hormonal contraceptives should be informed of this possibility and advised to use an alternative form of birth control.

Estrogen has been used to treat postpartum depression in two studies. In a double-blind study of 61 women with major depression that began three months postpartum, transdermal estrogen (as 17 Ã-estradiol 200 µg/day) led to a rapid improvement in mood (Gregoire et al., 1996). The mean score on the depression rating scale (Edinburgh Postnatal Depression Scale) remained elevated among the women on estrogen, however, suggesting that the antidepressant effect was not robust.

In a second study, 23 women with major depression that occurred in the six months following delivery took sublingual estrogen (as micronized 17 Ã-estradiol, mean dose=4.8 mg/day after the first week) (Ahokas et al., 2001). After two weeks of treatment, 19 of the women experienced a clinical recovery as defined by a score <7 on the Montgomery-Asberg Depression Rating Scale (MADRS).

Estrogen may appeal to patients because it is a naturally occurring substance. Also, since estrogen levels precipitously decline following delivery, some women may believe that estrogen deficiency underlies postpartum depression. However, postpartum depression has not been conclusively linked to low levels of estrogen or any other hormone (Hendrick et al., 1998). Patients should be warned that the use of estrogen is associated with several risks, including endometrial hyperplasia and thromboembolism. It also diminishes the production of breast milk in nursing mothers. Given these considerations, estrogen does not appear to have a primary role in the treatment of postpartum depression at this time.

The treatment of postpartum depression with natural progesterone has yet to be evaluated in a clinical trial. Natural progesterone is metabolized into allopregnanolone, a neuroactive steroid that enhances 

-aminobutyric acid (GABA) in the central nervous system, producing anxiolytic and hypnotic effects (Rupprecht and Holsboer, 1999). Natural progesterone may therefore have a role in the treatment of postpartum depression with comorbid anxiety. This possibility should be explored in future treatment studies of postpartum depression.

Synthetic progestogens do not help postpartum depression and may, on the contrary, exacerbate the symptoms (Lawrie et al., 2000). Unlike natural progesterone, synthetic progestogens (e.g., medroxyprogesterone) are not metabolized into GABA-ergic neuroactive steroids.

Sleep deprivation improves depressive symptoms in approximately 40% to 60% of patients suffering from depression and has the advantage of very quick onset (Giedke and Schwarzler, 2002; Riemann et al., 2001). It may present a quick, easy and free treatment intervention for women with postpartum depression. On the other hand, sleep deprivation has been reported to exacerbate mood in new mothers, and improvement of children's disrupted sleep is associated with significant improvement in maternal mood (Armstrong et al., 1998). Sleep deprivation resulting from multiple, erratic awakenings may produce a very different effect compared to controlled and predictable sleep deprivation. Further research on sleep deprivation would be useful, including strategies to prolong its benefits. Sleep deprivation is probably not a reasonable intervention for new mothers who are generally trying to sleep whenever the baby sleeps, but it may benefit mothers of older infants who are able to sleep through the night.

Bright light therapy produced antidepressant effects in a small study of 16 pregnant patients with major depression (Oren et al., 2002) and in two women with postpartum-onset major depression (Corral et al., 2000). Since it is well-tolerated and does not produce medication exposure to the nursing infant, it may become a promising treatment for postpartum depression.

Massage therapy and relaxation training for mothers who are depressed have been reported to improve mood and produce more positive mother-infant interactions and better growth and health in the infants (Field et al., 2000). Infant massage classes also appear to improve mood in new mothers with depression and contribute to more rewarding mother-infant interactions (Onozawa et al., 2001).

In summary, women suffering from postpartum depression may benefit from several interventions other than medications and psychotherapy. More research is necessary to determine the efficacy of alternative treatments. Many alternative treatments have the advantages of being inexpensive, accessible, and generally safe and well-tolerated, thereby presenting attractive options to traditional treatments for postpartum depression.

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The use of alternative treatments--like acupuncture, homeopathy, herbs, dietary supplements--for postpartum depression is becoming widespread. Dr. Hendrick discusses the benefits and risks of these alternative treatments and research that is being done to ensure their safety for new mothers

Victoria Hendrick, MD

Articles

Hormones for Perimenopausal and Postmenopausal Depression

Alternative Treatments for Postpartum Depression