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Gonadal Steroids in the Treatment of Mood Disorders

From the Yale Behavioral Gynecology Program, Yale University School of Medicine, Department of Psychiatry, Connecticut Mental Health Center (C.N.E.), New Haven, CT; and the Mood Disorders Program, Department of Psychiatry and Reproductive Biology (K.L.W.), and Department of Psychiatry and Neuroscience (B.Y.), Case Western Reserve University School of Medicine, Cleveland, OH.

Address reprint requests to: C. Neill Epperson, MD, Director, Yale Behavioral Gynecology Program, Yale University School of Medicine, University Towers, 100 York Street, Suite 2H, New Haven, CT 06511.

	ABSTRACT

TOP ABSTRACT INTRODUCTION SEX-SPECIFIC DIFFERENCES IN... NEUROBIOLOGY OF GONADAL STEROIDS GONADAL STEROIDS AS... CONCLUSION REFERENCES

 
Increased interest in the complex interplay between gonadal steroids and neurotransmitter systems involved in mood has led investigators to question the role of gonadal steroids in the treatment of affective disorders, especially in women.

OBJECTIVES: The purpose of this article is to provide a rationale for using gonadal hormones in the treatment of depression in women.

METHODS: The literature is reviewed regarding 1) sex-specific phenomenologic and epidemiologic differences in the manifestation of psychiatric illness, 2) sex-specific differences in the therapeutic and adverse effects of psychotropic medications, 3) the complex interplay between gonadal steroids and neurotransmitter systems implicated in psychiatric disorders, and 4) the growing literature regarding the use of estrogen and progesterone in the treatment of mood disorders in women and androgens in the treatment of depression and sexual dysfunction in both men and women.

RESULTS: Findings from pharmacologic trials of estrogen and androgens are encouraging, albeit mixed, in the treatment of mood disorders and decreased libido in women, respectively. Controlled studies have failed to confirm early open-label reports of the effectiveness of progesterone in the treatment of premenstrual syndrome.

CONCLUSIONS: Pending replication, estrogen may become an important pharmacologic agent in the treatment of postnatal and perimenopausal depression, whereas androgens have been shown to improve libido in postmenopausal women and hypogonadal men. Progesterone cannot be recommended as a treatment for premenstrual sydrome or postnatal depression.

Key Words: Gonadal steroids • depression • treatment • libido

Abbreviations: AD = Alzheimer’s-type dementia; BDI = Beck DepressionInventory; cAMP = cyclic adenosine monophosphate; CEE =conjugated equine estrogen; CYP = cytochrome; DSM-III-R =Diagnostic and Statistical Manual of Mental Disorders,3rd edition, revised; DSM-IV = Diagnostic and StatisticalManual of Mental Disorders, 4th edition; EPDS = EdinburghPostnatal Depression Scale; ERT = estrogen replacement therapy; GABA = -aminobutyric acid; GHQ = General HealthQuestionnaire; HDRS = Hamilton Depression Rating Scale; m-CPP = meta-chlorophenylpiperazine; MDQ = Moos Menstrual Distress Questionnaire; OCP = oralcontraceptive pill; PDQ = Premenstrual Distress Questionnaire; PMDD = premenstrual dysphoric disorder; PMS = premenstrualsyndrome; PPD = postpartum depression; RDC = ResearchDiagnostic Criteria; SSRI = selective serotonin reuptakeinhibitor; TCA = tricyclic antidepressant; 5HT =serotonin.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION SEX-SPECIFIC DIFFERENCES IN... NEUROBIOLOGY OF GONADAL STEROIDS GONADAL STEROIDS AS... CONCLUSION REFERENCES

 
Several lines of evidence suggest that gonadal steroids may be important pharmacologic agents in the treatment of depression in women. Epidemiologic studies have consistently demonstrated a sex difference in lifetime prevalence of depression, with women experiencing major depression at twice the rate of men (1). Women have been shown to be particularly vulnerable to mood disturbances at key periods in their reproductive life cycle, ie, the premenstruum, puerperium, and perimenopause (2). The purpose of this article is to provide a rationale for using gonadal hormones in the treatment of depression in women by exploring the 1) sex-specific phenomenologic and epidemiologic differences in the manifestation of psychiatric illness with emphasis on reproductive-related mood disorders, 2) sex-specific differences in the therapeutic and adverse effects of psychotropic medications, 3) the complex interplay between gonadal steroids and neurotransmitter systems implicated in psychiatric disorders, and 4) the growing literature regarding the use of estrogen and progesterone in the treatment of mood disorders in women and androgens in the treatment of depression and sexual dysfunction in both men and women.

	SEX-SPECIFIC DIFFERENCES IN PSYCHIATRIC ILLNESS

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Epidemiology and Phenomenology
The distribution of illnesses in a population provides clues to the factors related to the occurrence of illness. Several characteristics of psychiatric illnesses are affected by the sex of the individual: prevalence, age of onset, treatment response, frequency of side effects, and production of increased or decreased risk for medical conditions. The relatively recent practice of including women in clinical trials will facilitate the acquisition of data regarding the effects of sex on these aspects of psychiatric illness. Assessment of the effects of the menstrual cycle on dependent variables in mood disorder research will enhance understanding of the neurobiology of mood disorders in general (3).

Although the prevalence of mood and anxiety disorders seems to be evenly distributed between prepubertal boys and girls (4), the onset of puberty heralds a female-specific increased risk for several mood disorders (major depressive disorder, dysthymic disorder, and rapid-cycling bipolar disorder) (5–7). Results from the National Comorbidity Survey have revealed that lifetime prevalence for major depression is 21.3% for women compared with 12.7% for men (1). Women are twice as likely as men to experience major depression during their lifetime and seem to be particularly vulnerable at transitions across the reproductive life cycle (ie, the premenstruum, puerperium, and perimenopause). These observations have led investigators to explore the relationship between hormonal cycling and the expression of psychiatric disorders in women (8). Although biological factors unique to women undoubtedly affect the occurrence of psychiatric illness, the most powerful explanatory models will likely include psychosocial variables as well (9).

With respect to female-specific mood disorders, about 5% of menstruating women develop PMDD (10); 10% of childbearing women experience postpartum onset of nonpsychotic major depressive disorder, commonly referred to as PPD (11); and 0.2% suffer a psychotic mood disorder (most often manic in type) (12). Findings from community-based surveys of menopausal women suggest that perimenopause (13, 14), but not postmenopause (15, 16), is frequently accompanied by depressive symptoms, but these studies offer little evidence of increased prevalence of major depressive disorder. Not surprisingly, however, studies of both peri- and postmenopausal women seeking gynecologic services have found a higher than expected prevalence of depressive symptoms (17, 18). In one such study, the severity of symptoms was consistent with major and/or minor depression (18). Interestingly, several community-based surveys of major depression in both men and women have found that women are three to four times more likely than men to develop major depression during midlife (45–55 years) compared with the 2:1 female to male ratio that exists from puberty to midlife (5, 19). In addition, there is growing evidence that vulnerability for psychiatric episodes at one point in the reproductive life cycle confers vulnerability for psychiatric episodes at other reproductive points (20, 21). "Kindling" has been proposed as an explanatory model for repeated episodes of major depression occurring in association with endocrine shifts across the female life cycle (20).

Symptoms that occur in women with PMDD are similar in clinical and community populations, with depressed mood, anxiety, sleep difficulties, fatigue, irritability, and physical symptoms prevalent in the luteal phase (21). By definition, PMDD is an episodic illness with symptoms isolated to the luteal phase and of sufficient severity to interfere with psychosocial functioning (22). Scientific advancement in elucidating the pathophysiology and treatment of PMDD has been thwarted by the heterogeneity inherent in the disorder, with some women experiencing a myriad of physical symptoms, others experiencing chiefly mood symptoms, and still others being plagued by a mix of both. It is noteworthy that women who meet criteria for severe PMS do not necessarily meet DSM-IV criteria for PMDD. The diagnosis of severe PMS, as well as that of PMDD, requires an impairment in function. However, for women with PMS to also meet criteria for PMDD, they must exhibit 5 of the 11 symptoms required for the PMDD diagnosis, with one of the five being a mood symptom characterized by depression, anxiety, irritability, or mood lability. In a recent treatment study, 79% of the women who met rigorous criteria for PMS also met criteria for PMDD (23). Interestingly, responses to medications (including the antidepressant nefazodone) in several treatment studies did not differ between the two groups (24).

Two categories of serious postpartum disorder have been described in the literature: PPD and postpartum psychosis. This dichotomy is the result of past differentiation of postpartum illness by the predominance of depressive or psychotic features. However, recent studies using RDC have demonstrated that the majority of serious illnesses that begin in the postpartum period are mood disorders (25–27). There has been a long-term debate about whether PPD, as an illness that occurs in the context of massive gonadal steroid withdrawal, is phenomenologically different than nonpuerperal major depression. Data collected by Wisner et al. (27) and Cooper et al. (28) provide little evidence of symptom differences in PPD compared with depression not temporally associated with childbirth. With respect to prevalence, Kumar and Robson (29) found a prevalence rate of depression (RDC minor or major) of 14% in the first 3 months postpartum compared with 4.2% during the 3 months before pregnancy. Cox et al. (30) found a three-fold increase in the relative risk of depression in the first 5 weeks postpartum. However, O’Hara et al. (31), in a prospective study, failed to find an increase in the prevalence of RDC minor or major depression within the first months after delivery. With respect to duration of illness and pattern of recurrence, the findings of Cooper and Murray (32) suggest that women who experience depression for the first time after pregnancy may have a shorter duration of illness and be more vulnerable to relapse with future pregnancies than postpartum depressed women with a pregravid history of depression.

Despite some inconsistencies in the data, psychotic and nonpsychotic puerperal mood disorders are not considered to be diagnostically distinct from their nonpuerperal counterparts by DSM-IV, although a fifth-digit onset specifier may be added when onset of the disorder is within 4 weeks of delivery (22). Although the terms postpartum depression and psychosis are not used in the language of the DSM-IV, they have been used in the literature for decades to describe postpartum onset of affective disorders and are used here as well.

With respect to menopause, the majority of postmenopausal women in community-based surveys do not experience prominent symptoms of depression (15, 16, 19). This is in contrast to the perimenopause, which has been characterized by higher rates of depressive symptoms in approximately 10% of perimenopausal women in longitudinal community-based studies (13–15, 33). As might be expected, estimates of major and minor depression are higher in surveys of women attending gynecologic clinics. In one study of 95 perimenopausal women presenting to a menopause clinic, 35% experienced their first episode of depression, as confirmed by the Lifetime version of the Schedule for Affective Disorders and Schizophrenia (34), during the perimenopausal period, whereas a total 45% met criteria for major or minor depression (18). Although postmenopausal women do not seem to be at increased risk for major depression, the postmenopausal status confers a vulnerability to AD (35). Several epidemiologic studies have confirmed that ERT decreases the risk of AD or the cognitive impairments associated with the disorder (36–38) in postmenopausal women.

Although there is no sex difference in the lifetime prevalence of schizophrenia, women develop the illness later, experience fewer and briefer hospitalizations (39, 40), and are less likely to abuse substances (41). Women with schizophrenia enjoy better psychosocial functioning and greater work competence than their male counterparts (40). In addition, women with schizophrenia perform better on neuropsychological tests (42). Women suffering from schizophrenia require lower doses of antipsychotic medication than men and respond better to both psychosocial and pharmacologic treatments (41).

Treatment Response
Although the literature on the gender specificity of antidepressant response is sparse, some studies have suggested differences in efficacy (43). Raskin (44) found that young women (<40 years old) responded less well to imipramine than did men and women aged 40 years and older, whereas Davidson et al. (45) found that depressed women with panic attacks had a more favorable response to monoamine oxidase inhibitors compared with men, who responded more favorably to TCAs.

Women with depression related to reproductive events may exhibit preferential responsivity to serotonergic antidepressants. Premenstrual dysphoric disorder responds more favorably to SSRIs than to other drugs (46–49). By virtue of their efficacy and tolerability, SSRIs have become the first-line pharmacologic agents used in the treatment of PMDD. In one study of women with chronic major depression or double depression, 26.8% experienced premenstrual exacerbation of symptoms, and more of these women responded to the SSRI sertraline than to imipramine (60% and 40%, respectively) (50). With respect to major depression occurring in the early puerperium, Dean and Kendell (12) observed that fewer women with PPD responded to TCAs than did nonpostpartum depressed women. These findings are in contrast to those from an open-label study of 35 women with postpartum-onset major depression who were treated with adequate doses of a TCA (nortriptyline, N = 19; desipramine, N = 1; imipramine, N = 1) or SSRI (sertraline, N = 8; fluoxetine, N = 5; paroxetine, N = 1) for 8 weeks (51). The response rate, as defined by a >50% decrease in scores on the Inventory to Diagnose Depression (52), for TCAs was 67%, whereas 79% of those receiving an SSRI were considered treatment responders. Although the difference did not achieve statistical significance secondary to the small sample size, the findings suggest that women with PPD do respond to treatment with TCAs at approximately the same rate as that reported by the National Institute of Mental Health Treatment of Depression Collaborative Research Project (53) and that postpartum depressed women may preferentially respond to SSRI treatment. Corroborating these findings regarding the efficacy of SSRIs are the results from an 8-week open-label study of sertraline (Zoloft), which showed that women with PPD were particularly responsive (54). Twenty of twenty-one (95%) women with PPD of moderate severity (25-item HDRS score (mean ± SD), 22 ± 3) had at least a 50% reduction in HDRS scores, and 14 (66%) experienced complete remission of their depression (HDRS score, <7).

Pharmacokinetics
The role of the liver’s CYP450 system in metabolizing gonadal steroids and psychotropic agents is being intensively investigated. Progesterone stimulates the hepatic microsomal mixed-function oxidase system, whereas estrogens are strong inhibitors (55). They are both substrates for isoenzymes, which are responsible for psychotropic drug metabolism, and the rate of drug metabolism may depend on the predominance of progesterone compared with estrogen. Interactions between gonadal steroids and psychotropic drugs at CYP450 become clinically relevant in the following situations: 1) during pregnancy, when steroid hormone levels are 100- to 1000-fold higher than before pregnancy; 2) with the use of estrogen or progesterone as a psychotropic agent, either alone or as an augmenting agent in the case of estrogen; and 3) with the use of hormone replacement therapy during menopause, when women may be taking medications from several classes.

CYP4503A3/4, quantitatively the most prevalent P450 isoenzyme, is responsible for 80% of estradiol hydroxylations as well as the metabolism of many clinically important medications and is more active in younger women than in men or postmenopausal women (56). Although the data are sparse and contradictory, estrogen may have modest inhibitory effects on CYP2D6 and CYP2C19 activity, as evidenced by greater activity in males and a decrease in activity in women receiving ERT. In contrast, CYP2D6 is induced during pregnancy, as evidenced by increased metabolism of the CYP2D6 substrate metoprolol during pregnancy (57). However, at constant serum levels, there is no evidence to suggest that the pharmacodynamic effect of nortriptyline, a substrate for CYP2D6, is altered during pregnancy or the puerperium. Wisner et al. (58) observed that similar drug concentrations were required to keep the symptoms of depression in remission during childbearing as in the nonchildbearing state and that a relative refractoriness in the ability to metabolize nortriptyline occurred only during the puerperium, when estrogen and progesterone levels were at their nadir (59). Fluctuations in the postpartum processing of nortriptyline may be particularly problematic for women who are at the extremes of genetically controlled CYP450 metabolic capacity (60). High-dose therapy during pregnancy is counterintuitive to most clinicians; however, women with rapid metabolism of CYP2D6 substrates require higher doses of nortriptyline than before pregnancy to maintain therapeutic blood levels and clinical efficacy. In the postpartum period, slow metabolizers will be at particularly high risk of toxicity.

	NEUROBIOLOGY OF GONADAL STEROIDS

TOP ABSTRACT INTRODUCTION SEX-SPECIFIC DIFFERENCES IN... NEUROBIOLOGY OF GONADAL STEROIDS GONADAL STEROIDS AS... CONCLUSION REFERENCES

 
There is a wealth of basic science and preclinical literature related to the biochemical underpinnings of gonadal hormones on brain neurochemistry. Steroid hormones act on their specific receptors in the brain and affect neuronal function and neurotransmission (61). Conversely, changes in neurotransmission evoke changes in the neuroendocrine systems (62). Moreover, there are sex differences in neurotransmitter receptor binding within specific brain nuclei that are dependent on the levels and types of steroid hormones that consequently affect behaviors classically associated with the function of those brain regions.

Monoamines Modulate Gonadal Steroid Function
In addition to the classic notion that neurotransmitters affect the neuroendocrine axis to control luteinizing hormone and prolactin secretion, there are several lines of evidence indicating that catecholamine neurotransmitters also increase the ligand-binding activity of estrogen receptors in the brain. Pharmacologic manipulations that reduce norepinephrine levels or block -adrenergic receptors can decrease the concentration of hypothalamic estrogen receptors or inhibit the ability of estrogen to induce progesterone receptor activity, the effect of which is reversed by -adrenergic agonists (63, 64). Several studies also have shown that dopamine agonists increase estrogen binding in several brain areas as well as in the anterior pituitary (63, 65). Furthermore, this effect of dopamine is exhibited to a greater extent in female than in male rats. These findings are supported by parallel biochemical studies illustrating that steroid receptors are innervated by norepinephrine and dopamine neurons and/or are colocalized with these neurotransmitters (66).

The mechanisms underlying the effects of dopamine on the modulation of estrogen or progesterone receptor binding are unknown but may occur through the D1 receptor subtype, cAMP, and cAMP-dependent protein kinase A to phosphorylate and activate the estrogen and progesterone receptors (67). In addition, dopamine D2 receptors affect ion conductance and protein kinase C. Protein kinase C activity has been shown to decrease estrogen receptors and estrogen receptor mRNA (68). Therefore, dopamine in particular may modulate estrogen receptor activity through phosphorylation via protein kinase A and protein kinase C or affect the binding and levels of estrogen receptors in the brain by some mechanism yet to be determined.

Gonadal Steroids Modulate Monoamine Neurotransmission
Relative to the number of studies examining the effect of neurotransmitters on steroid hormone function in the brain, the effects of gonadal steroid hormones on neurotransmission have received greater attention. Numerous studies have shown that estrogen or estradiol affects receptors for 5HT (69, 70) and dopamine (71, 72). Considerable evidence demonstrates that estrogen modulates neurotransmission at multiple points in the 5HT pathway. Estrogen may increase 5HT biosynthesis by inducing tryptophan hydroxylase gene expression in nonhuman primates (73), whereas estrogen has pronounced effects on 5HT uptake mediated by its action on the 5HT transporter (74). In addition, estrogen modulates the sensitivity of somatodendritic 5HT_1A autoreceptors and increases the density of the postsynaptic 5HT₂ receptors (70, 75), as evidenced by changes in 5HT receptor density during the estrous cycle of the rat (76) and after exogenous administration of sex steroids (70, 77).

Several studies conducted in healthy adults have demonstrated a greater prolactin response to the 5HT release of fenfluramine in women compared with men (78, 79) and during the luteal phase compared with the follicular phase of the menstrual cycle (80). Estrogen modulation of the postsynaptic 5HT receptor in humans is indirectly supported by findings from challenge studies using m-CPP. Several studies found higher peak change in prolactin response to intravenous m-CPP in healthy women compared with healthy men (81), whereas others found no sex-based differences in healthy subjects (82, 83) or depressed patients (82, 84). One study using the m-CPP paradigm demonstrated a deficit in postsynaptic 5HT function in postmenopausal women. Healthy postmenopausal women were found to have blunted prolactin response to m-CPP before estrogen replacement. After 4 weeks of estrogen administration, their prolactin response to the m-CPP challenge was not significantly different from that of premenopausal women (85).

Other indications of aberrant 5HT function have been demonstrated in relation to premenstrual and postpartum affective disorders. Women with PMS have been shown to have decreased peripheral platelet 5HT uptake, decreased whole-blood 5HT levels, blunted neuroendocrine response to the 5HT precursors L-tryptophan and 5-hydroxytryptophan (86), and worsening of premenstrual depressive symptoms after tryptophan depletion (87). Plasma tryptophan levels and platelet (³H) imipramine binding may be reduced in postnatal dysphoria (88). Thus, given the well-known involvement of 5HT in modulating affective state, estrogen-induced changes in 5HT neurotransmission and receptors during the menstrual cycle, pregnancy, and menopause may contribute to mood changes associated with mood disorders at these times.

In addition to the effects of estrogen on 5HT neurotransmission, ovarian steroid hormones can also affect dopaminergic function in the brain. Estrogen has been shown to increase dopamine neurotransmission and D2 dopamine receptor binding in the pituitary gland, hypothalamus, nigrostriatal system, and mesolimbic brain regions. The magnitude of the increases seems to be dependent on the hormonal status of the animal and the dose and duration of estrogen treatment (89). It is well recognized that there are sex differences in behavior mediated by the mesostriatal dopamine system. Estrogen enhances amphetamine-induced striatal dopamine release, which is associated with an enhanced frequency of stereotypic behaviors associated with amphetamine (90). Furthermore, there is a greater frequency of amphetamine-induced behaviors exhibited in estrus than in diestrus (91). Mesolimbic dopamine activity also fluctuates with alterations in endogenous steroid hormone levels and the estrous cycle, which is characterized by changes in both dopamine uptake and release, perhaps via the dopamine autoreceptor (92). The precise mechanisms mediating these effects are unknown. Nevertheless, because a dysfunction in mesolimbic dopamine activity is believed to underlie psychoses and affective disorders, changes in circulating estrogen that consequently alter dopamine function may play an important role in psychiatric disease states. In humans, estrogen modulation of dopaminergic function is suggested by the higher incidence of tardive dyskinesia in postmenopausal women exposed to chronic antipsychotic medications and the more pronounced growth hormone response to subcutaneous apomorphine (dopamine agonist) injections in postpartum women with a history of bipolar or schizoaffective psychosis compared with postpartum women with no such history (93).

Gonadal Steroids Modulate Amino Acid Neurotransmission
Gonadal steroids modulate glutamate and GABA neurotransmission in such a manner to profoundly modulate neuronal excitation and inhibition (94). Allopregnanolone, the 5-reduced metabolite of progesterone, is a potent barbiturate-like ligand of the GABA receptor–chloride ion channel complex, which has potent sedative and hypnotic effects (95). Progesterone, allopregnanolone, pregnenolone, and pregnenolone sulfate are considered neurosteroids because they can be produced in the brain (independent of peripheral sources) from cholesterol by glial cells (96). Plasma levels of allopregnanolone and progesterone have been shown to be highly correlated, with the former being more closely correlated with measures of fatigue, confusion, and immediate recall in a study of oral progesterone administration to healthy female volunteers (97). In contrast, pregnenolone sulfate, the sulfated neurosteroid precursor of progesterone, may have an opposite effect because it is an inverse agonist at the GABA_A receptor and a potentiator of the N-methyl-D-aspartate receptor (94). In addition, estrogen has been shown to facilitate neuronal growth by potentiating the N-methyl-D-aspartate glutamate receptor (98) and to regulate GABA_A receptor function by modulating mRNA expression in the medial preoptic nucleus and the bed nucleus of the stria terminalis.

Gonadal steroid modulation of GABAergic function is of interest when considering the pathophysiology of mood disorders in women because there is indirect evidence of aberrant GABAergic functioning in depression. Rodent studies have demonstrated changes in GABA levels (99), receptor sensitivity, and chloride influx with administration of antidepressants (100, 101), whereas human studies have revealed lower levels of plasma, cerebrospinal fluid (102), and cortical GABA (103) in depressed patients compared with healthy control subjects. Consistent with the evidence of lower plasma GABA levels in depression, Halbreich et al. (104) found significantly lower plasma GABA levels during both the follicular and luteal phases of the menstrual cycle in women with PMDD compared with healthy female control subjects. Women who also had a history of major depression had even lower luteal-phase plasma GABA levels, suggesting (according to the authors) that there may be a common biological link between subtypes of depressive and premenstrual dysphoric disorders.

Although most studies have not demonstrated a difference between women with PMS or PMDD and healthy control subjects with respect to plasma progesterone levels, Rapkin et al. (105) found that women with PMS had significantly lower luteal-phase plasma allopregnanolone levels despite no significant differences in plasma progesterone levels. Such a finding suggests that 5-reductase activity may be reduced in women with PMS, which results in slower conversion of progesterone to allopregnanolone and less GABAergic facilitation. In addition, findings from Wang et al. (106) imply that an imbalance between anxiolytic (allopregnanolone) and anxiogenic (pregnenolone sulfate) neurosteroids may be responsible for negative luteal-phase mood. In the 12 patients with PMS who experienced one symptomatic and one asymptomatic cycle during the course of the study, the symptomatic cycles were associated with higher pregnenolone sulfate and lower allopregnanolone levels, whereas the opposite was found during the asymptomatic cycles. Thus, reduced 5-reductase function in these women may result not only in decreases in allopregnanolone but also in a shunting of substrates toward production of the anxiogenic pregnenolone sulfate. When these women with PMS were compared with healthy subjects, no between-group differences were found in plasma allopregnanolone, pregnenolone, or pregnenolone sulfate levels. However, the women with PMS, when compared with control subjects, were found to have higher and lower luteal-phase estradiol and progesterone levels, respectively. These findings were not replicated by Schmidt et al. (107), who found no differences in late luteal-phase plasma progesterone, allopregnanolone, or pregnenolone levels between 15 women with PMS and 12 healthy subjects. The discrepancy may be secondary to the fact that Wang et al. measured steroid levels on days 1 to 4 of a given cycle and day 10 of that same cycle to day 4 of the next cycle, whereas Schmidt et al. limited steroid level measurements to one follicular and one late luteal-phase day.

Alternatively, preclinical evidence suggests that GABAergic function can be significantly modified by allopregnanolone in such a manner to support a neurosteroid withdrawal hypothesis for PMDD and PPD. Chronic administration of allopregnanolone to cultured rat cortical neurons produces downregulation of GABA and t-butylbicyclo-phosphothionate, a ligand that binds to the transmembrane portion of the GABA receptor, binding sites and a heterologous uncoupling of the GABA_A receptor complex (108). Therefore, it is conceivable that high levels of allopregnanolone during pregnancy and the luteal phase of the menstrual cycle may result in downregulation of the GABA_A receptor, which results in an increased vulnerability to mood disorders at times of rapid hormonal withdrawal.

Additional evidence that progesterone and allopregnanolone exert clinically relevant effects on GABAergic function comes from the finding that withdrawal of progesterone, and therefore allopregnanolone, leads to increased seizure susceptibility in women with seizure disorders (109) and decreased sensitivity to benzodiazepine sedatives (110) and pregnenolone (111) during the late luteal phase in women with PMS. Recent findings from Smith et al. (112) demonstrate that chronic administration of progesterone and allopregnanolone may decrease the sensitivity of the GABA_A receptor to GABA and cause cross-tolerance to benzodiazepines by increasing the production of a specific subunit of the GABA_A receptor, the 4 subunit. In addition, Smith et al. were able to block the allopregnanolone-induced cross-tolerance to benzodiazepines by blocking the metabolism of progesterone to allopregnanolone.

Effects of Estrogen on Neurotrophins
Estrogen enhances neurotrophins, which are proteins that affect the health and growth of neural axons and dendrites and the growth of new nerve cells. Hormonal modulation of neurotrophins increases the connections among neuronal branches and maintains a complex system of communication in the brain. After menopause, brain cells of women begin to degenerate at a faster pace than those of men. Additionally, estrogens also act as antioxidants, which protect against ß-amyloid, one of the proteins that accumulates in patients with AD to produce neuronal degeneration. Estrogens also modulate the secretion of acetylcholine in the hippocampus by their effect on choline acetyltransferase, an enzyme critical to the maintenance of memory functions (113).

Overall, there is substantial support from the preclinical and biochemical literature to indicate an intimate interaction between steroid hormones and neurotransmission in brain regions implicated in the mediation and manifestation of psychosis and affective mood states. Although the precise mechanisms are unknown, further investigation into the biochemical interactions between neurotransmitters and gonadal hormones could help to explain the sex differences present in psychiatric illnesses and help to guide the development of selective treatments using gonadal hormones as psychopharmacologic agents. That both estrogen and progesterone can increase binding of the antidepressant imipramine in the hypothalamus of rats (114) and that both seem to be required for expression of antidepressant activity in female rats (115) emphasizes the need to investigate the role of gonadal steroids in the pathophysiology and treatment of mood disorders in women.

	GONADAL STEROIDS AS PHARMACOLOGIC AGENTS

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Gonadal steroids, estrogen and progesterone, have been purported since the 1940s to be effective treatments for depression in women despite inconsistency in the data used to support such claims. This section is a review of studies examining the role of estrogen and progesterone in the treatment of major depression and depression associated with the menstrual cycle, puerperium, and menopause. In addition, the role of androgens as pharmacologic agents, recently reviewed by Rubinow and Schmidt (116), is discussed.

Estrogen
Major Depression.
In a frequently cited study, Klaiber et al. (117) demonstrated that estrogen, ie, CEE 5 to 25 mg/d, 5–20 times the usual postmenopausal replacement dose, was superior to placebo in the treatment of women with severe major depression that had been unresponsive to traditional antidepressants. Mean baseline HDRS scores in the group who received CEE and placebo were 31.2 and 30.6, respectively. The CEE group experienced a mean drop in HDRS of 9.2, whereas the mean drop in the placebo group was only 0.1. Six of the estrogen-treated patients had a drop of more than 15 points to achieve a posttreatment mean of 13.8, and two patients deteriorated on estrogen. None of the placebo-treated patients experienced a drop in HDRS of 10 or more points, and eight deteriorated on placebo. Menopausal status, defined as having amenorrhea for 6 months and a luteinizing hormone level above 500 ng/ml, was not associated with the degree of improvement. Length of illness was related to the degree of improvement in the expected direction. Although some women clearly experienced significant improvement with estrogen treatment, the majority of women treated with estrogen remained highly symptomatic. To date, there has been no published replication of these findings in women with major depression not specifically associated with a major endocrine shift. Oppenheim et al. (118) failed to demonstrate the superiority of estrogen over placebo as an augmentation to ongoing treatment with imipramine in depressed women with partial response to such treatment. However, in an interesting case report that demonstrates the ability of estrogen to precipitate mania, Oppenheim (119) described the course of a severely depressed 72-year-old woman with a history of recurrent major depression with onset before menopause. She had responded to various TCAs with previous episodes but now was being treated unsuccessfully with dibenzepin 480 mg/d at the time of CEE addition. With administration of CEE 0.625 mg/d, she developed rapid cycling (repeated cycles of depression, hypomania, and mania), which continued for 30 days despite an increase in CEE to 4.375 mg/d. Cycling ceased on withdrawal of CEE, and the patient returned to her pre-CEE depressed state. Despite the evidence that estrogen may be an effective antidepressant in the treatment of women with major depression not specifically related to reproductive function, all work with estrogen as a pharmacologic agent since that of Klaiber et al. has been in the treatment of mood disorders associated with the luteal phase of the menstrual cycle, puerperium, or menopause.

Premenstrual Syndrome.
The efficacy of estrogen in the treatment severe PMS has been demonstrated in several well-controlled studies (120–122), although not without inconsistency (123). Table 1 outlines the findings of these controlled studies and highlights the effects of estrogen on the mood symptoms of patients with PMS. The methodology used by the investigators varies in several ways. Multiple routes of estrogen administration, ie, implants (120), transdermal (121, 122), and oral (123), were used. The portion of the cycle treated varied, eg, follicular and luteal phases (118, 119, 120) or luteal phase only (123). Outcome measures also differed, eg, MDQ (120), PDQ (122), or a "daily rating scale" (123). However, findings from studies in which women were administered estrogen during both the follicular and luteal phases (at doses sufficient to suppress ovulation) consistently demonstrated the superiority of estrogen to placebo in the treatment of both the physical and psychological symptoms of prospectively diagnosed PMS. The suppression of ovulation seems to be a key factor in the efficacy of high-dose estrogen therapy. Other drugs, such as gonadotropin-releasing hormone agonists and danazol, which have been used in the treatment of severe PMS, also suppress ovulation (124). Unfortunately, each of these treatments are associated with significant side effects that limit their utility. Transdermal estrogen is more practical than estrogen implants with respect to administration and ability to discontinue treatment. Women using any route of administration of high-dose estrogen must be cycled with progesterone because of the proliferative effects of estrogen on the endometrium. About 30% of patients develop hyperplasia within 3 months of unopposed therapy (125). Addition of progesterone is associated with a partial return of symptoms in some cases. The need for sequential estrogen/progesterone therapy to reduce risk of uterine cancer along with the therapeutic effect of suppressed ovulation call into question the potential benefit of oral contraceptives in the treatment of PMDD. However, depressed mood is not an infrequent side effect of the combined oral contraceptive (126). A well-controlled study found a triphasic oral contraceptive to be more effective than placebo in reducing only premenstrual breast pain and bloating (127). The triphasic pill had no significant effect on any mood symptoms, as assessed using the Daily Rating Forms (128). Thus, treatments that suppress ovulation are less effective in reducing PMS symptoms if cyclic estrogen and progesterone are administered (129).

Antidepressants and psychotherapy are the mainstay of treatment for PPD as they are for nonpuerperal major depression. However, findings from a recent controlled study suggest that high-dose estrogen therapy (200 µg/d ß-estradiol) may be an effective treatment for PPD (133). In this study of 63 severely depressed women with onset of depression within 3 months after childbirth, 35 women underwent treatment with estrogen (N = 18) or placebo (N = 17) as a monotherapy, whereas 26 women who were depressed despite antidepressant treatment were randomly assigned to receive either estrogen (N = 16) or placebo (N = 10) as an augmentation strategy. Although estrogen was superior to placebo in reducing EPDS (134) and HDRS scores, the investigators rendered their findings difficult to interpret when they collapsed the two groups (monotherapy and augmentation) to analyze the data. Despite the differential effects of estrogen on norepinephrine and serotonin neurotransmission, the authors did not give the percentages of women taking TCAs and those taking SSRIs. However, it is noteworthy that the difference between the active treatment and placebo groups was significant after only 1 month of treatment, with 50% of the estrogen-treated women, compared with 26% in the placebo-treated group, rating themselves below the EPDS threshold (<14) for major depression. This response was sustained for the entire 6-month study. Replication of this study would be valuable to assess the rapidity of response, to determine the minimum dose and duration of estradiol required, and to determine the effectiveness of estrogen as a monotherapy and/or augmentative therapy in the treatment of PPD.

Consistent with Gregoire et al.’s (133) findings that estrogen may be an important pharmacologic agent in the treatment of PPD, Sichel et al. (135) demonstrated that estrogen may be effective as a prophylaxis against recurrent psychotic and nonpsychotic postpartum mood disorders. Eleven women with a history of severe PPD (N = 4) or puerperal psychosis (N = 7) were administered high-dose estrogen orally (N = 9) or intravenously (N = 2) immediately after delivery. The initial oral dosage, which was approximately 10 times that of the postmenopausal replacement dose, was slowly tapered over the first postpartum month. That administering a slow estrogen taper was associated with a reduction in relapse rate from the expected 35% to 60% down to 9% suggests that rapid withdrawal of estrogen may trigger such disorders. Enthusiasm for high-dose estrogen therapy as a prophylaxis against recurrent postpartum affective disorders is tempered by the need to coadminister anticoagulants and the interference of estrogen with production of breast milk. Therefore, estrogen cannot be considered a first-line agent for prophylaxis against recurrent postnatal mood disorders.

Menopausal Depression.
Estrogen has been used to treat the symptoms of menopause since the late 1800s. Well-controlled, large-scale investigations have consistently demonstrated the positive effects of estrogen on lipid profile (136), bone density (137), and cardiac health (78). However, studies touting the ameliorative effect of estrogen on mood during menopause have been less convincing. Most studies conducted in the past 58 years have only confirmed the original findings of Ripley et al. (138) that the milder depressive symptoms so common in menopause improve with ERT and that ERT has little effect on major depressive disorders. Table 2 highlights findings from controlled studies of ERT in peri- and postmenopausal women who have undergone natural or surgical menopause. Five studies found that ERT was more effective than placebo in improving psychological measures in a mixed group of peri- and postmenopausal women who had undergone natural menopause (139–143), and five found ERT to be as effective as placebo (144–148). Montgomery et al. (147) was the only group to analyze findings on the basis of menopausal status (ie, peri- or postmenopausal). They found that after 2 months, ERT was superior to placebo in reducing depressive symptoms in perimenopausal, but not postmenopausal, women. After 4 months of ERT, there were no significant differences between ERT and placebo regardless of menopausal status. It is noteworthy that of the five studies, which included a large percentage of women with clinical psychiatric illness (variably defined) (141, 143, 145, 147, 148), only two (141, 143) reported a greater improvement in mood with ERT compared with placebo. Findings from three (139, 140, 142) of the five studies using mainly nondepressed subjects (139, 140, 142, 144, 146) suggest that estrogen is effective in improving the well-being and "good spirits" of women undergoing natural menopause (139–142). Estrogen also seems to be effective in improving the psychological well-being of nondepressed women who have undergone surgical menopause (149).

In addition to the potential efficacy of estrogen as a monotherapy in the treatment of menopausal depression, there is growing evidence to suggest that estrogen may be useful as an augmentation strategy in menopausal depression. Post hoc analysis of 358 postmenopausal women participating in a 6-week, double-blind, placebo-controlled multicenter trial of fluoxetine (20 mg/d) in the treatment of elderly depressed female outpatients showed significant interaction between ERT status and treatment effect. Seventy-two women participating in the study received ERT, and 286 did not. The women receiving ERT who were randomly assigned to receive fluoxetine had greater improvement, as measured by mean HDRS percentage, than women receiving ERT who were assigned to receive placebo (40.1% vs. 17.0%, respectively). Conversely, of those women not receiving ERT, there was no significant difference in the degree of improvement between those assigned to fluoxetine and those assigned to placebo (150).

Progesterone
Premenstrual Syndrome.
Since the 1950s, when Katharina Dalton (151, 152) championed the use of progesterone in the treatment of PMS, seven double-blind, placebo-controlled studies have resoundingly failed to prove its efficacy (23, 153–158). Only three studies (159–161) have found any beneficial effect of progesterone above that of placebo. Table 3 describes the findings of Dalton’s early open-label reports and those of the 11 double-blind, placebo-controlled studies of progesterone in the treatment of PMS. Although the subjects included in the controlled studies were all prospectively screened over (in most cases) two menstrual cycles to confirm the PMS diagnosis, there are significant methodological differences among the studies that make them difficult to interpret as a group. All investigators claimed to exclude women with comorbid psychiatric disorders, which is necessary in the diagnosis of PMS; however, only Freeman et al. (23, 153) did so using structured clinical interviews, whereas five relied on unstructured clinical interviews (155, 156, 158–160) and three (154, 157, 161) did not describe the method used to exclude these women. A large percentage of women in three studies (23, 153, 158) reported a history of psychiatric illness, usually major depression. Each of these studies found progesterone to significantly reduce PMS symptoms, but not above those reductions achieved with placebo. Measurements used to assess both physical and psychological symptoms varied greatly, with some using validated daily rating instruments, such as the MDQ (162) and the Daily Symptom Report (163), and others using nonvalidated scales. These factors are important, because the degree to which women included in the studies meet criteria for PMDD as well as PMS depends on the number of mood symptoms that significantly interfere with a woman’s functioning during the luteal phase. Moreover, both diagnoses of PMDD and PMS depend on the absence of comorbid psychiatric disorders. Route of administration and dosage of progesterone used varied as well. However, Freeman et al. (153) found no difference between placebo and progesterone despite using doses as high as 800 mg/d.

Postpartum Depression.
Unlike the flurry of investigation regarding the potential efficacy of progesterone in the treatment of PMS, there has been only one report of progesterone in the treatment of postnatal depression. Dalton (164) investigated the use of progesterone in the prophylaxis of recurrent PPD by conducting a naturalistic study of 181 women who had suffered "idiopathic postnatal depression," defined as "the first psychiatric illness, severe enough to require medical help, occurring within 6 months of childbirth." The clinical status of women who requested information regarding progesterone prophylaxis was followed by mail. The 181 women who were treated with prophylactic progesterone for 2 months or until the return of menstruation had a recurrence rate of 7%, compared with a rate of 67% in the 21 women who did not receive progesterone treatment. According to Dalton, women suffered no adverse effects of postpartum progesterone administration, and breast-feeding was enhanced. These findings have not been confirmed by other open-label or controlled studies.

Does Exogenous Administration of Gonadal Steroids Cause Depression?.
Ten to forty percent of OCP users develop mild to moderate depressive "syndromes," with those who have had a previous depressive episode most at risk for this adverse side effect (165). According to clinical lore, progesterone is the offending agent when women become depressed and/or irritable while taking OCPs. However, one double-blind, placebo-controlled study demonstrated that, compared with placebo, 14% and 18% more women experienced mild depressive symptoms on a progestogen-dominated OCP and estrogen-dominated OCP, respectively (p = .05). Another study found that addition of medroxyprogesterone acetate 10 mg/d for 14 days to cyclic transdermal estrogen treatment produced no consistent adverse physical or psychological effects compared with placebo independent of a history of PMS (166). In a randomized, placebo-controlled study, Graham et al. (167) found that women from two centers (Edinburgh, Scotland, and Manila, Philippines) who were randomly assigned to receive a combined oral contraceptive reported more adverse affects on mood, whereas those receiving a progestogen-only pill reported some improvement in well-being. Although these finding do not implicate progesterone as the offending agent, there is a recent case report of two women who developed severe psychiatric disorders secondary to the use of Norplant (levonorgestrel). Each patient had onset of depressive symptoms with panic attacks within 2 months of Norplant insertion. Both met DSM-III-R criteria for major depression and panic disorder at the time of presentation. Neither had any previous psychiatric or substance abuse history, and both had complete resolution of symptoms within 1 month of Norplant removal. Additional evidence of the potential of progesterone to adversely affect mood comes from a study of 22 postmenopausal women who were given either estrogen for 21 days with a subsequent break of 7 days or estrogen throughout the cycle with progestogen given the last 11 days of the cycle. The women who were cycled with progestogen experienced substantial cyclicity in both mood and physical symptoms, with negative mood changes starting 1 to 3 days after progestogen was added (168). These findings were later confirmed by the same group (169) and are consistent with those of others (120, 170) but not with those of Kirkham et al. (166).

Anabolic-Androgenic Steroids
Anabolic-androgenic steroids are a group of steroids with both anabolic (ie, growth-promoting and anticatabolic) and androgenic (ie, masculinizing activity) activity. The prototypical androgenic steroid is testosterone, which is produced by the testes in men and the adrenal glands and ovaries in women. Dehydroepiandrosterone and androstenedione, other important androgenic steroids, are produced by the adrenal glands and ovaries in women (171). Men have both adrenal and testicular sources of androstenedione. Anabolic steroids possess significantly less androgenic potential and are best known as drugs of abuse by athletes, who may take up to 100 times the therapeutic dosage (116).

Androgens have been purported to possess invigorating effects on such functions as mental agility, stamina, energy, and muscular strength since the late 1880s, when the first injections of crushed animal testicles were given (172). Since the isolation of testosterone in 1935, there have been numerous case reports and open-label studies attesting to the antidepressant effects of testosterone in depressed and "climacteric" men (116). In a double-blind study in which 13 depressed men with a mean age of 39 years (range, 28–55 years) and baseline HDRS scores of 23.1 ± 8.9 (mean ± SD) received mesterolone (an oral androgen) 350 ± 64 mg/d for 7 weeks after 1 week of placebo, mesterolone was found to significantly lower the HDRS score by week 2 of active treatment. Final HDRS scores were 5.6 ± 3.9. Similarly, dehydroepiandrosterone was found in a recent double-blind, placebo-controlled trial to have mood-elevating effects in older men and women (173). Oophorectomized women may preferentially benefit from androgen replacement therapy because they have been shown to have significantly lower testosterone levels than similarly aged women who are less than 4 years postmenopausal and retain their ovaries (174). A study of 43 recently oophorectomized women who participated in a double-blind, placebo-controlled, crossover study in which they received estrogen alone (N = 11), estrogen plus testosterone (N = 12), testosterone alone (N = 10), or placebo (N = 10) showed that depression symptoms, as assessed with the Multiple Adjective Affect Checklist (175), were significantly lower when subjects received one of the three steroid treatment conditions, including testosterone alone (176).

In addition, androgens play an integral role in sexual behavior in rodents (177), and sexual desire, sexual thoughts, intensity of sexual feelings, and sexual activity seem to be, at least in part, androgen dependent in humans. Each of these aspects of sexuality is diminished in the hypogonadal male and is improved with testosterone treatment (178). Interestingly, testosterone administration in males with normal androgen levels does not effectively treat erectile dysfunction and disturbance of libido (179, 180). Similarly, women who are androgen deficient after surgical menopause experience an improvement in several aspects of sexual functioning with the administration of androgens. In the above-mentioned study of 43 oophorectomized women, sexual desire (defined as sexual awareness regardless of sexual activity), number of sexual fantasies and sexual arousal were significantly higher in both groups receiving testosterone than in the groups receiving placebo or estrogen alone (176). The findings from this study are consistent with those of Chakravarti et al. (181) and Burger et al. (182), who found that combined estradiol and testosterone implants resulted in an improvement in libido in postmenopausal women presenting with the specific complaint of decreased libido.

	CONCLUSION

TOP ABSTRACT INTRODUCTION SEX-SPECIFIC DIFFERENCES IN... NEUROBIOLOGY OF GONADAL STEROIDS GONADAL STEROIDS AS... CONCLUSION REFERENCES

 
There is now compelling evidence that sex may in large part dictate the natural history of many psychiatric disorders as well as the most effective and well-tolerated pharmacologic treatments. However, the extent to which the endocrine system vs. society’s differential treatment of men and women plays a role in the sex-specific manifestation of psychiatric illness has yet to be determined. Women are twice as likely as men to experience major depression as well as several other mood disturbances, such as dysthymia and rapid-cycling bipolar disorder. It is also quite clear that gonadal steroids have pronounced effect on areas of the brain that are responsible for mood and cognition in addition to reproductive behavior (183). However, neither the role of gonadal steroids in the treatment of depression in women nor the role of androgens in the treatment of depression in men has been clearly elucidated.

Despite the initial enthusiasm for progesterone in the treatment of PMS and postnatal depression, there is a resounding lack of evidence for its use in either condition. In fact, the addition of sequential progesterone to ERT in postmenopausal women is not infrequently accompanied by negative mood symptoms, particularly in women who suffered from PMS before menopause. Although progesterone has not been shown to be an effective treatment for female-specific mood disorders, several lines of evidence suggest that progesterone (via its effects on the GABA-benzodiazepine receptor complex) may play a role in the pathogenesis of depression. Chronic exposure of the GABA-benzodiazepine receptor complex by agonists such as alcohol and benzodiazepines results in alterations in cortical GABA content, as measured using nuclear magnetic resonance imaging (J. Krystal and A. Goddard, personal communication, 1998). Such alterations may also occur with chronic exposure to allopregnanolone and could explain the decreased sensitivity to benzodiazepines (110) and pregnanolone (111) found in women with PMS. These findings emphasize the importance of investigating the role of progesterone and the neurosteroids in the pathogenesis of PMS, PPD, and contraceptive-induced depression. Interventions targeted at specific points in the production of neurosteroids or at the receptors they modulate may have therapeutic potential.

The efficacy of estrogen (at doses sufficient to cause anovulation) has been demonstrated in controlled studies in the treatment of PMS. Findings from Gregoire et al.’s (133) controlled study and Sichel et al.’s (135) open-label investigation suggest that high-dose estrogen therapy may be effective in the treatment of postnatal depression and prophylaxis of postnatal psychotic and nonpsychotic mood disorders. However, methodological shortcomings of the treatment study and the open-label design of the prophylaxis investigation limit the interpretation and generalizability of the data. The encouraging findings of Gregoire et al. highlight the need to replicate their findings in another controlled study with estrogen as a monotherapy. Flexible dosing of estrogen would be necessary to determine the most effective dose and duration of treatment. A double-blind study of estrogen in the prophylaxis of recurrent severe postnatal mood disorder would be scientifically more rigorous, although fraught with ethical dilemmas because the relapse rate for puerperal psychosis in specific is greater than 50%. Moreover, estrogen can interfere with production of breast milk depending on length of time after delivery. Despite the difficulties with using estrogen in the postnatal period, further investigation is warranted to determine the role of estrogen in the pathogenesis of mood disorders occurring during this period.

Finally, ERT may be effective in the treatment of mild depressive symptoms in women who have undergone either natural or surgical menopause. Findings from Schmidt et al. (personal communication, 1998) are provocative because they suggest that rigorously diagnosed major and minor depression occurring during the perimenopausal period resolve with estrogen treatment regardless of the severity of depression. Both ERT and androgen replacement therapy have positive effects on measures of sexual functioning in oophorectomized women. The role of estrogen in the augmentation of antidepressant therapy in depressed women requires further elucidation through double-blind, placebo-controlled studies specifically designed to address this question.

In summary, women are twice as likely as men to experience major depression at some point in their lifetime and are particularly vulnerable to mood disturbances at predictable points in the reproductive life cycle. This observation emphasizes the richness of the human laboratory and the opportunity to investigate the endocrinologic component of psychiatric illness in a prospective fashion. It is vital that the knowledge gained through basic science research be translated into clinical research to develop innovative paradigms for investigating the interplay between gonadal steroids and the brain. It is likely that elucidating these complex relationships will define pathways to more effective therapies.

Received for publication June 3, 1998.

Revision received February 19, 1999.

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