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Women have a significantly higher risk for developing mood disorders than men. Although reasons for this gender difference are not fully understood, it is clear that changing levels of reproductive hormones throughout women's life cycles can have direct or indirect effects on mood. Fluctuations in reproductive hormones may interactively affect neuroendocrine, neurotransmitter, and circadian systems. Reproductive hormones also may affect response to some antidepressant drugs and alter the course of rapid-cycling mood disorders. Nonpharmacologic interventions, such as light therapy and sleep deprivation, may be beneficial for mood disorders linked to the reproductive cycle. These interventions may have fewer side effects and a greater potential for patient compliance than some antidepressant drugs. (The Journal of Gender-Specific Medicine 2000;3[5]:53-58)

Women have a greater lifetime risk for depression than men, with a ratio of approximately 2:1 for unipolar depression or recurrent episodes of depression.1,2 Men may be as likely as women to develop depression, but they are more likely to forget that they had a depressive episode.3 Although the prevalence of bipolar disorder in men and women is more equally distributed, the course of that illness may differ between the sexes. Men may be more prone to develop periods of mania, whereas women may be more likely to experience periods of depression.4

What are the contributing factors to the predominance of mood disturbance in women? Recent data suggest that the onset of puberty, rather than chronological age, is linked to the increase in rates of depression in women.5 Thus, changes in the reproductive hormonal milieu may precipitate or alleviate depression in women. This seems particularly likely in the case of rapid-cycling affective illness.

Cyclical Mood Disorders in Which Women Predominate

Rapid-cycling affective illness is a severe form of bipolar disorder in which individuals experience four or more cycles of mania and depression within a year.6 Approximately 92% of patients with rapid-cycling bipolar disorder are women.7 Thyroid impairment8 and treatment with a tricyclic or other antidepressant drug are risk factors for developing this form of manic-depressive illness. Women have 10 times the incidence of thyroid disease as men, and more than 90% of patients who develop lithium-induced hypothyroidism are women.9-11 Women are also more likely than men to develop rapid cycles induced by tricyclics or other antidepressants.12,13

Seasonal affective disorder (SAD), or recurrent winter depression, also predominates in females. Up to 80% of individuals diagnosed with SAD are women.14 The depressive symptoms in this disorder are inversely linked to the day length or photoperiod. The disorder can be treated successfully with bright light.15

Correlation With Estrogen

Reproductive hormones leads to higher risk for women in developing mood disorders and can affect response to some antidepressant drugs.Given that these risk factors are correlated with sex, it is likely that reproductive hormones play an important role in the pathogenesis of rapid mood cycles. Studies of estrogen treatment for mood disorders have shown that too much or too little estrogen can alter the course of mood cycles. For example, Oppenheim16 found that estrogen induced rapid mood cycles in a postmenopausal woman with depression refractory to treatment. When the estrogen was discontinued, the rapid mood cycles ceased. The postpartum period (including the time after an abortion), when there is a rapid decline of reproductive hormone levels and possibly an increased risk for developing hypothyroidism,17 can also be associated with the induction of rapid cycles of mood.

Connection With Thyroid Impairment

There may be a tighter connection between the reproductive system and the thyroid axis in women than in men. In hypogonadal women, the thyroid-stimulating hormone (TSH) response to thyrotropin-releasing hormone (TRH) is blunted.18 When a reproductive hormone such as human chorionic gonadotropin (hCG) is administered, women's response to TRH is enhanced, becoming comparable to that of control subjects. When the hCG is removed, the TSH response to TRH again becomes blunted. In contrast, hypogonadal men do not have a blunted TSH response to TRH, and adding reproductive hormones does not significantly enhance the effect. In healthy women, the TSH response to TRH also can be enhanced with the addition of oral contraceptives.19

Women may be vulnerable to thyroid impairment, predisposing them to rapid mood cycles; however, they are also more responsive to thyroid treatment. Stancer and Persad20 found that higher doses of thyroid hormone can improve rapid cycling in some women but not in men.

Effect of Oral Contraceptives

Parry and Rush21 found that oral contraceptives - particularly pills with a high progestin content - may induce depression. In fact, atypical depressive features are one of the most common reasons women stop taking birth control pills; up to 50% of women who discontinue oral contraceptives do so because of these side effects. The mediation of the depressive effect of estrogen is thought to be through tryptophan metabolism. Tryptophan is converted to kynurenine in the liver and to serotonin in the brain. Oral contraceptives enhance the kynurenine pathway in the liver and deter the serotonin pathway in the brain. A lower level of serotonin available in the brain is associated with depressive mood, suicidal symptoms, and impulsive behaviors. Oral contraceptives given with pyridoxine, or vitamin B6 (a competitive inhibitor of estrogen), can help mitigate some of the milder depressive symptoms.21,22