Introduction: Gender Differences in Prevalence of Depression and Responses to Psychotropic Medication Women suffer disproportionately from several major psychiatric disorders. According to worldwide epidemiological studies, the prevalence of major depressive disorder (MDD) among women is 1.5–3 times higher than that of men (Kessler 2000; Weissman et al.
1996). According to The World Health Organization (WHO), unipolar MDD is the number one cause of disease burden for reproductive- aged women (18–44 years old) in both developed and developing countries, followed by schizophrenia (Murray and Lopez 1996). In developing regions, suicide is the fourth leading cause of disease burden for women (Murray and Lopez 1996) – which suggests that serious mental disorders such as depression are not adequately diagnosed and treated.
In the USA, the National Comorbidity Survey (NCS) reports that the lifetime prevalence of MDD is 21% for women, compared to 13%
for men (Kessler et al. 1994). For dysthymia (a chronic low-grade form of depression), the lifetime prevalence is 8% for women, and 4.8%
for men (Kessler et al. 1994). In the USA, the lifetime prevalence for any affective disorder among women is reported to be 24% for women and 15% for men (Kessler et al. 1994). These reports confirm earlier studies (Weissman et al. 1991) reporting gender differences in preva- lence of unipolar MDD of 7% in women as compared to 2.8% in men and a prevalence of dysthymia of 4.1% in women and 2.2% in men.
Women are also more vulnerable to developing other types of affective disorders, including anxious depression (van Valkingburg 1984), seasonal affective disorders (Parry 1989), and phobias (Kessler 1995), compared to men. The gender disparity in affective disorders is most evidenced between menarche and 55 years of age, suggesting that gonadal hormones play a major role in the onset and course of depressions in women (Archer 1999; Burvill 1995).
The Effect of Estrogens on Depression
Linda S. Kahn and Uriel Halbreich
The first onset of mood symptoms or exacerbations of pre-existing affective disorders may be triggered by specific hormonal and life- cycle conditions (e.g., menarche, postpartum, peri-menstrual, peri- menopause) (Stewart and Boydell 1993; Halbreich 1996, 1997;
Appleby et al. 1994; Kumar and Robson 1984; O’Hara and Swain 1996). Evidence exists suggesting a significant association between certain reproductive-related depressions (RRDs), particularly pre- menstrual dysphoric disorder (PMDD), and other affective disorders, including postpartum depression (PPD) and MDD (Halbreich and Endicott 1985).
The consumption of psychotropic medications, particularly anxiolytics and antidepressants (Halbreich 1997), is higher among women than men, with a ratio of greater than 2:1 (Ohayon and Caulet 1995; Rawson and D’Arcy 1991; Skegg et al. 1977). Compared to men, women taking psychotropic drugs experience more frequent side effects (about twice as often than men), and they also experience more adverse responses to psychotropic drugs (Hamilton and Yonkers 1996; Halbreich 1997). It has been suggested that women are more frequently given questionable and high-risk prescriptions than men, particularly for psychotropic drugs (Jensvold and Hamilton 1996). Drug consumption, including psychotropic drugs, increases with age and is higher among women (Halbreich 1997; Jensvold and Hamilton 1996). Among adults over 65 years of age, 16.7% of women, compared to 10.1% of men, take psychotropic drugs (Jensvold and Hamilton 1996). Because it is more common for women to be taking multiple medications (e.g., hormone replacement therapy, HRT, oral contraceptives, OCs, anti-inflammatories, thyroid hormones, etc.), they may also be at higher risk of adverse drug-drug reactions (Seeman 2000).
Women differ from men in their pharmacokinetic and pharmaco- dynamic responses to psychotropic medications. Gender differences exist in key pharmacokinetic variables, including absorption, distri- bution and bioavailability, hepatic function and changes in hepatic enzymes, metabolism, and clearance and elimination (Jensvold 1996;
Yonkers et al.; Halbreich 2000). Because women’s bodies contain proportionately more adipose tissue than men’s, and because psy- chotropic drugs (especially antipsychotics, antidepressants, and anxiolytics) are lipophilic, these drugs remain longer in women’s bodies after discontinuance and may cause side effects during periods of rapid weight loss (Seeman 2000). In addition, liver pathways and
renal clearance are slower in younger women than in men and further contribute to higher psychotropic blood levels for longer periods (Halbreich 1997). Other important gender-related pharmacokinetic factors include gonadal hormones, ovulation-related cyclicity, and exogenous hormones such as OCs or HRT – all of which may signif- icantly alter protein binding (Yonkers et al. 2000; Hamilton and Yonkers 1996).
Central nervous system (CNS) distribution of medications may be accelerated during periods of more rapid blood flow to the CNS (Yonkers et al. 2000). In general, women of reproductive age and postmenopausal women on estrogen replacement therapy have greater cerebral blood flow (CBF) than men, contributing to improved site delivery of psychotropic medications (Halbreich 1997).
It is likely that also pharmacodynamic properties contribute to a gender difference in drug-response. Pharmacodynamic processes include receptor distribution and action, neural structure/plasticity, enzymes, and messenger systems (Jensvold and Hamilton 1996).
Pharmacodynamics may also include drug-drug interactions and the behavioral impact of drug administration. Although less is known about sex differences in the pharmacodynamic effects of medications, these differences may be as significant as pharmacoki- netic aspects, especially if therapeutic compounds interact with testosterone, estrogen, or progesterone (Yonkers et al. 2000).
Role of Estrogen in Symptom Formulation
The brain and gonadal hormones interact in a bi-directional manner.
Peripheral gonadal hormones exert both organizational/genomic and activational/nongenomic actions on the CNS (McEwen 1991). The organizational/genomic effects are trophic and permanent and control neural architecture and future activity. They occur during the brain’s early development, and their influences, or their absence, are responsible for gender differences in brain and behavior. Activa- tional/nongenomic effects of gonadal hormones occur mostly during postnatal life and continue throughout the life cycle, adding to and supporting gender-differentiated brain functions. They are reversible and entail alterations of normal electrical and biochemical functions and structure, as well as many functions implicated in the con- tinuous regulation of mood and behavior that are believed to be
impaired in mental disorders and to be influenced by psychotropic medications. These activities include receptor potentiation by direct or modulatory effects, enzyme induction or inhibition, potentiation of intracellular second-messenger processes, and other transitory effects. Due to their selective distribution in the brain, the effects of receptors, binding sites, and other targeted sites for actions of gonadal hormones cannot be generalized. In addition, different metabolic or synthetic analogues might cause opposing behavioral effects. For example, several progesterone metabolites and progestins are anxio- lytic while some others are anxiogenic. Timing is also a key factor – and cyclic administration might cause different effects than contin- uous use (Halbreich 2000). In addition, priming with estrogen might alter the effects of progesterone.
Estrogen Cyclicity and the Course of Pre-existing Mood Disorders
The role of gonadal steroids in the precipitation and course of mood disorders in women has been well documented (Archer 1999;
Rubinow et al. 1998a, b; Yonkers 1998). The cyclicity of hormonal fluctuations throughout reproductive life is one of the dominant characteristics of women’s biology. This is especially evidenced by the significant hormonal changes during pregnancy, followed by the abrupt postpartum withdrawal of estrogen. During the last trimester of pregnancy, hormonal rates are relatively stable, and depression is rare – but the rates jump to 20% postpartum, corresponding to the sharp drop in estrogen (Archer 1999; Studd and Smith 1994). The inherent cyclical hormonal instability, combined with the multifac- eted interactions between hormones, neurotransmitters, and other CNS processes, as well as the influences of behavior and mood, might explain why women appear more vulnerable to affective disorders than men (Halbreich 2000).
Menstrually related processes (presumably hormonal) have been linked to exacerbation of a variety of related disorders, including late luteal phase exacerbation of MDD, bulimia nervosa or epilepsy, panic attacks, agoraphobia, alcoholism, puerperal psychosis-like episodes, periodic psychosis, violent criminal acts, and various other condi- tions (Abramowitzet al. 1982; Backstrom et al. 1984; Brockington et al. 1988a, b; Endicott and Halbreich 1988; Friedman et al. 1982;
Gladis and Walsh 1987; Hatotani et al.1979; d’Orban and Dalton 1980; Luggin et al. 1984; Price et al. 1987). That such a broad spectrum of diagnostic conditions and symptom clusters may be expressed or exacerbated during the late luteal phase of the menstrual cycle suggests that they may be activated by a similar trigger or con- ditions, depending upon the individual’s specific vulnerability (Halbreich 1997).
The Relevant Influences of Estrogen on Mood-related CNS Processes
Estrogen has multiple effects on neural functions putatively impli- cated in multiple processes involving the regulation of mood, behavior, and cognition (Halbreich and Lumley 1993). It enhances monoamine activity and increases serotonergic (5-HT) postsynaptic responsivity (Halbreich et al. 1995), increasing both the number of serotonergic receptors as well as neurotransmitter transport and uptake (McEwen et al. 1997; Matsumoto et al. 1985). Estrogen also increases 5-HT synthesis and 5-HTIAA levels (Dickinson and Curzon 1986). It upregulates 5-HT1 receptors and downregulates 5-HT2 receptors and decreases MAO activity (Chakravorty and Halbreich 1997). The cumulative effect of estrogen on serotonergic function is as a 5-HT agonist (Halbreich 1997). In selective brain regions estrogen acts as a cholinergic agonist. It accelerates the activity of acetylcholine transferase in the preoptic area, amygdala, horizontal diagonal nucleus, frontal cortex, and area CA1 of the hippocampus (McEwen et al. 1997; 1998; Wolley and McEwen 1992).
It increases the number of muscarinic receptors in the medial, lateral, and ventromedial hypothalamus, but decreases their number in the medial preoptic area. Estrogen also increases electrical firing of neurons in the hypothalamus in response to acetylcholine. Estrogen selectively increases norepinephrine (NE) activity in the brain. Its effect on the enzyme tyrosine hydroxylase is mixed. Some investi- gators have reported increased activity in some areas, whereas others have reported decreased activity in other areas. Estrogen increases NE turnover, while its effects on plasma levels of the NE metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) are mixed. Increased NE activity may be caused by decreased NE reuptake and decreased NE metabolism due to inhibition of monoamine oxidase and decreased
catechol-o-methyl transferase (COMT) activity (Luine 1985). Estro- gen’s effect on α2-andrenoceptor binding is mixed, and it increases β-adrenoceptor binding. It decreases the binding of the partially related imidazoline receptors (Piletz and Halbreich 2000). Estrogen decreases D2 receptor sensitivity and probably other dopaminergic receptors as well. Estrogen’s influence is not limited to monoamines.
It acts as a γ-aminobutyric acid (GABA) adjunct agonist by increasing binding of GABA agonists and their upregulation of GABA receptors and also decreases activity of glutamic acid decarboxylase in the hypothalamus. Its effects on endorphins is mixed: it increases overall endorphic activity but decreases their levels in the mesolimbic hypothalamus (see review by McEwen et al. 1997)
Estrogen’s neurostructural effects point to a broad and extensive impact on the CNS, with significant implications for human cognitive abilities (McEwen et al. 1997). Estrogen induces dendritic spines, creating new synapses in the ventromedial hypothalamus. It also increases dendritic spinal density on pyramidal neurons in the hippocampus (McEwen et al. 1997; 1998; McEwen and Woolley 1994). Estrogen stimulates expression of neurotrophic factors (NGF, BDNF) (Singh et al. 1994; Singh et al. 1995) and stimulates axonal regeneration and synaptogenesis (Matsumoto et al. 1985). It de- creases cAMP while increasing PCK. It maintains the viability of neurons and inhibits β-amyloid toxicity (Simpkins et al. 1994).
Estrogen also increases cerebral blood flow and glucose transport (McEwen et al. 1998; McEwen and Woolley 1994; Ohkura et al. 1994;
Birge 1997).
The overall neurostructural and neurophysiological effects of estrogen can be summarized as preventative of neurodegeneration (neuroprotective), probably neuroregenerative, and selectively stimulating of neurotransmission. Some of its inhibitory effects might also be viewed as contributing to mental well-being, and thus pertinent to current hypotheses of the pathophysiology of depres- sions and their treatment (Archer 1999; Halbreich 1997; Garlow et al. 1999; Young and Korszun 1998; Young et al. 2000).
The Role of Estrogen in the Symptoms, Mechanisms, and Treatment of MDD and Reproductive-Related
Disorders in Women Major Depressive Disorder
There is growing evidence of differences between women and men in the clinical manifestations of MDD (Kornstein and Schatzberg 2000). Depressed women present more frequently with atypical symptoms: increased appetite, weight gain, as well as anxiety and somatic symptoms (Kornstein 1997). A recent large clinical study reported that women with chronic major depressive disorder are more severely depressed and experience greater functional im- pairment than men (Kornstein and Schatzberg 2000; Kornstein 1997;
Kornstein et al. 1995). Women were also more likely to report a younger age at onset and a family history of clinical depression (Kornstein and Schatzberg 2000; Kornstein and McEnany 2000).
A study of a female twin population found a high concordance in the subphenotypes of depression, especially for monozygotic (MZ) twins (Kendler et al. 1996), with differences in comorbidity of depression. Women with atypical depression had high rates of bulimia and increased obesity, compared to those with severe
“typical” depression who had comorbid anxiety and panic as well as longer episodes and impairment. This suggests a partial overlap between vulnerability to atypical depression and to obesity and overeating under stress (Stunkard et al. 1990). The propensity of women to “atypical depression”, characterized by increased sleep and appetite, motor retardation, increased lethargy, anxiety, hyper- activity to external events, mood lability and interpersonal sensi- tivity (Stewart and Boydell 1993; West and Dally 1959), resembles the more prevalent dysphoric subtypes of premenstrual syndromes (PMS) (Halbreichet al. 1982; Wikander et al. 1998).
Compared with men, women are more likely to have reported a stressful life event in the 6 months leading up to an episode of MDD (Kornstein 1997). Women’s depressions are also more frequently triggered by seasonal influences (Leibenluft and Hardin 1995) – and the female-to-male ratio for seasonal affective disorder is greater than 3:1 (Kornstein 1997; Leibenluft and Hardin 1995). Episodes of MDD among women may also be produced by reproductive-related (RRD) hormonal changes occurring during pre-menstruation, pregnancy, postpartum, and perimenopause, as well as those brought on by HRT,
particularly when it is administered sequentially (Parry 1989; Korn- stein 1997).
Research on the pathophysiology of RRDs suggests that several systems and processes may be abnormal among depressed women, including hypothyroidism (Brayshaw and Brayshaw 1986; Roy-Byrne et al. 1987; Casper et al. 1989; Halbreich et al. 1988), abnormal, mostly decreased serotonegic functions (extensive reviews: Halb- reich and Tworek 1993; Lepage et al. 1991) dysregulation of NE systems and related processes (Halbreich et al. 1993; Gurguiset al.
1998a, b), anxiety symptoms in response to lactate infusions (Sand- berg et al.1993), CO2 inhalation (Harrison et al. 1989) and cholecy- stokinin (CCK4) injections (LeMeledo et al. 1995) as well as a dysre- gulated dopaminegic system (Halbreich et al. 1976), which is recently drawing renewed interest. That some of these abnormalities also occur during nonsymptomatic periods suggest the existence of a trait or an indication of vulnerability. Whether these abnormalities are distinguishable from each other and represent different biological subtypes that might be associated with different phenotypes remains unclear. The consistent increased variance of biological values in women as compared to men (Halbreich and Lumley 1993) combined with the diversified symptoms of some RRDs, especially during the late luteal phase (Halbreich 1997), might support the notion of diver- sified biological traits that might be related to diversified genetic factors.
Treatment
Several studies have documented that women may respond better to serotonergic agonists, especially SSRIs, than to NE agonists, to which men respond somewhat better (Hamilton and Yonkers 1996; Korn- stein and McEnany 2000; Kornstein and Schatzberg 2000; Steiner et al.1993; Yonkers et al. 1992, 1998). One explanation for this differ- ence in treatment response is that female gonadal steroids may enhance serotonin activity, thus augmenting SSRI efficacy (Korn- stein and McEnany 2000). Therefore, based on side-effect profile and patient compliance, the SSRIs are a first choice for treatment, especially for women.
Estrogen has been tested both as monotherapy (Klaiber et al. 1979;
Michael et al. 1970) and adjunct therapy (Prange 1972; Shapira et al.1985; Schneider et al. 1997) for treatment of MDD in repro- ductive-age women.
Klaiber et al. (1979) tested conjugated estrogen as monotherapy for severe MDD in 40 female inpatients. Although the 23 women in the estrogen group showed significantly greater improvement than those in the placebo group, post-treatment depression scores in the estrogen group were still moderate to severe – raising doubts as to whether estrogen as monotherapy is efficacious. The dosages admini- stered in the study were significantly higher than the usual ERT dosage (up to 25 mg), suggesting that estrogen might entail a signif- icant benefit only when administered in high dosages (Klaiber et al.
1979). However, at least four studies reported no improvement in depression in response to treatment with estrogen (Prange 1972;
Shapira et al. 1985; Schneider et al. 1977; Coope and Poller 1975;
Coope 1981). Other studies have suggested that estrogen might improve overall sense of well-being among nondepressed women (a “mental tonic effect”), but it does not appear to be an efficacious treatment for MDD (Archer 1999).
Estrogen has also been evaluated as an adjunct therapy for MDD.
Prange et al. (1972) added estrogen to a tricyclic antidepressant (TCA) and noted that improvement in the TCA plus high-dose estrogen group was initially greater than in the low-dose estrogen and TCA or a TCA alone group. Two weeks later, this benefit was lost, and the high-dose estrogen plus TCA patients did not experience the same improvement in mood, compared to the low-dose estrogen plus TCA group or the TCA alone group. Cholinergic adverse effects were very high. A small study of 11 women treated with imipramine and then randomized to conjugated estrogen (in doses up to 3.75 mg per day) or placebo as an adjunct treatment reported similar results (Shapira et al. 1985). Compared to placebo augmentation, estrogen augmen- tation yielded no benefit. In a placebo-controlled trial of older women on fluoxetine for MDD, those who were also taking estrogen (ERT) showed slightly greater improvement than those on fluoxetine alone (Schneider et al. 1997). However, women on ERT without fluoxetine did less well than women not on ERT. Similar results were reported by Schneider’s group (Schneider et al. 1998) in a post hoc analysis of sertraline with or without HRT. Even though estrogen as mono- therapy probably does not improve mood of depressed women, it might be a potent adjunct to SSRI for postmenopausal women diagnosed with depression (Schneider et al. 1997; Schneider et al.
1998).
Depression and the Menarche
Before puberty, the prevalence of mood disorders is evenly distributed between boys and girls (Epperson et al. 1999). Beginning at menarche, however, the prevalence of depressions and dysphorias becomes significantly higher among girls (Epperson et al. 1999; Steiner et al.
2000). Among 14- to 18-year-olds, females are twice as likely to be depressed as males (Lewinsohn et al. 1998). In the USA, the preva- lence of MDD is 20.6% among females between 15 and 24 years of age, compared to 10.5% among males in the same age group (Kessler and Walters 1998).
Much remains unknown regarding the etiology and mechanisms underlying the apparent female-specific increased risk for depres- sions emerging during menarche. Angold et al. (1998) tried to pin- point the age at which the gender disparity in depression prevalence emerges, and whether pubertal timing affects unipolar depression rates among girls. In their study of 4,509 11- to 13-year-olds, they noted that girls experienced consistently higher rates of unipolar depression than boys beginning around age 13. Using Tanner staging, they determined that this gender disparity develops during mid- puberty in girls, as demarcated by Tanner stage III.
More recently, Angold et al. (1999) tried to determine whether an association exists between depression among adolescent girls and pubertal morphological status, as measured by Tanner stages, or hormonal levels. They measured testosterone, estrogen, FSH and LH levels, and rates of depression among 465 girls. Their results point to a direct link between pubertal increases in testosterone, and estrogen in particular, and the prevalence of depression in females. Increases in gonadal steroid levels alone do not cause depression in adolescent girls; but may render some girls more vulnerable to depression, depending upon specific environmental or psychosocial cognitive variables.
Other hypotheses on the emergence of mood disorders during menarche have focused on the serotonergic system. Because gonadal hormones influence the production and function of 5-HT receptors during menarche, alterations may result, leading to an increased vulnerability to mood disorders (Steiner et al. 2000). Disturbed sleep patterns or menstrual cycles, or other disruptions of biological rhythms, combined with psychosocial stresses, might trigger depres- sion in vulnerable individuals (Steiner et al. 2000).
There is much that is still unknown regarding why depressions emerge during menarche, and their pathophysiology. Once these questions are answered, knowledge about the mechanisms of gender differences in depressions will be significantly furthered. For female adolescents, no accepted specific pharmacological therapy exists – especially involving possible hormonal interventions for depression.
Premenstrual Dysphoric Syndrome (Dysphoric PMS or PMDD) Approximately 50%–80% of women will experience at least a few premenstrual symptoms that may vary from mild to severe (Woods, Most, and Dery 1982), while the prevalence of severe dysphoric premenstrual symptoms (or PMDD) ranges from 3% to 9% (Woods et al. 1982; Rivera-Tovar and Frank 1990; Johnson 1987; Merikangas et al. 1993; Ramcharan et al. 1992).
Patients with PMS have reported up to 300 different premenstrual complaints (Halbreich et al. 1982), with depressed mood, mood swings, anxiety/tension, anger/irritability, low interest, decreased concentration, poor energy and changes – mostly increase – in sleep and appetite, and physical symptoms most commonly attributed to PMS (Hurt et al. 1992).
Since the 1930s and the seminal work of Frank (Frank 1931), gonadal steroids have been considered a major causal factor in PMS.
Hypotheses included lack of estrogen, lack of progesterone, and dif- ferences in their ratios. At one time, progesterone suppository treatment was given much publicity, based on the hypothesis that PMS was caused by insufficient progesterone (Dalton 1964). Proges- terone suppository treatment, however, remains controversial. It is most likely that many women with PMS have increased and not decreased levels of progesterone (Halbreich et al. 1986; Freeman et al. 1985; 1990). Absolute plasma levels of gonadal hormones are probably comparable between women with and without PMS – although there might be differences in cyclicity or rate of fluctua- tions as well as an increased sensitivity to “normal” fluctuations (Halbreich et al. 1986; 1988; Schmidt et al. 1998). Hormonal changes during the early luteal phase might be equally important as those that occur during the symptomatic period. The pivotal role of gonadal hormone fluctuations in the pathophysiology of PMS is further underscored by reports that women with PMS are asymptomatic during anovulatory cycles and that ovulation suppression alleviates
PMS symptoms (Halbreich et al. 1991). It is probable that the inter- actions between gonadal hormones, neurotransmitters, and other processes putatively involved in regulation of mood and behavior, combined with individual vulnerability, distinguishes women with PMS from those without PMS. Differences between these two groups in a variety of variables, including personality, cognition, seroton- ergic processes, thyroid functions and NE-related receptors (even among women with PMS when they do not have any symptoms) have been widely documented (for review see Halbreich 1995).
This strongly suggests that the pathophysiology of PMS involves a kindling effect caused by the multifaceted interactions and accumulated impacts of vulnerability, hormonal changes, and brain processes, combined with environmental and psychosocial factors.
Treatment
There are a number of efficacious treatments currently used for PMS.
Antidepressant medications, primarily SSRIs, are a treatment of choice for women with severe dysphoric PMS (Steiner et al. 1995;
Yonkers et al. 1996). The administration of SSRIs can be limited to the luteal phase (Halbreich and Smoller 1997). With continuous or intermittent SSRI treatment, the reported success rate approaches 60%–70%.
Suppression of ovulation, mostly with GnRH analogues (Muse et al. 1984), but also with danazole is widely considered the most effective treatment for a broad spectrum of physical and dysphoric PMS symptoms. Because it induces “pharmacological menopause,”
however, it is not a treatment of choice for most women. Adding cyclic estrogen-progesterone replacement may undermine the effec- tiveness of GnRH analogues by simulating the physiological hor- monal fluctuation.
Estrogen has been used as a treatment modality for PMS mood symptoms or premenstrual dysphoric disorder (PMDD). Studies that have examined the effectiveness of treatment with transdermal β-estradiol followed by 7 days of norethisterone, as compared to placebo (Magos et al. 1986; Watson et al. 1989), found 17β-estradiol more effective than placebo. However an often-cited study of PMS treatment with conjugated estrogens (Dahr and Murphy 1990) reported no difference between estrogen and placebo. Because the sample size for this study was quite small (11 women), the lack of significant difference may be due to a lack of power.
We have found that estradiol transdermal patches can be effica- cious if administered in dosages high enough to suppress ovulation and in a continual, cyclic fashion to promote withdrawal and endometrial shedding (Halbreich 1999). We have had good experience with transdermal 17β-estradiol (0.2 mg) for women with PMS. This treatment suppresses ovulation, eliminates hormonally related fluctuations, and offers the CNS benefits of estrogen – without the bothersome side effects of pharmacological menopause.
Postpartum Depressions
Within the first 6-months postpartum, between 10% and 22% of adult women will experience an episode of major or minor depression (Appleby et al. 1994; Kumar and Robson 1984; O’Hara and Swain 1996; Cooper et al. 1996; Troutman and Cutrona 1990; O’Hara et al.
1990; Reighard and Evans 1995; Roy et al. 1993; Whiffen 1988;
Demyttenaere et al. 1995; Terry et al. 1996; Cox et al. 1982); and this rate is even higher (26%) among adolescent mothers (Troutmann and Cutrona 1990). Data suggest that the risk of MDD during the puerperium may be higher than in non-postpartum periods (Whiffen 1992). One large study (n = 6,000) estimated that the 2-month preva- lence for postpartum MDD was 15% (Cooper et al. 1996) – surpassing the 12-month prevalence rate for MDD found in a US epidemiolog- ical survey (Kessler et al. 1994). The onset of PPD usually occurs within the first 4 weeks after delivery (Kumar and Robson 1984;
O’Hara et al. 1990; Carothers and Murray 1990; Zelkowitz and Milet 1995).
Most women experience postpartum blues, the most mild of postpartum dysphorias, and this is considered normal. Postpartum blues, characterized by dysphoria, mood lability, irritability, crying, anxiety, insomnia, and poor appetite, occur in most women, begin during the first week postpartum, peak on the fifth day, and resolve shortly thereafter. Unlike postpartum blues, PPD symptoms last beyond the second week postpartum and mirror those of MDD, except for the unique timing and context.
Although the most widely accepted pathobiological explanation for PPD focuses on the abrupt and substantial hormonal withdrawal immediately following delivery, this hypothesis has not yet been fully proven. A recent report that simulation of this hormonal process causes symptoms in vulnerable women (Bloch et al. 2000)
strongly suggests its validity. Postpartum changes in gonadal hor- mones are also linked to dysfunction of the thyroid system, “posi- tive” or “negative” changes in the hypothalamo-pituitary-adrenal (HPA) system, rapid postpartum withdrawal of endorphins, and a gonadal hormones-associated decrease in serotonergic activity, and probably also in some other neurotransmitters systems. As with other mental disorders, the pathobiology of postpartum disorders may also involve vulnerability to affective disorders and to disrupted homeostasis. It is likely that the abrupt withdrawal of gonadal hormones and their influence on a broad spectrum of other biological systems involved in the regulation of mood and behavior results in disrupted homeostasis. Almost all women have “blues” short- ly following delivery, but there is probably a strong stabilizing mechanism that restores the euthymic state. In some women, that mechanism may be deficient; they continue to be dysphoric with increased severity for longer periods. In these cases, treatment is warranted. Estrogen may be an effective treatment for postpartum MDD. Gregoire et al. (1996) treated 64 women with MDD with either transdermal 17β-estradiol or with placebo. The 17β-estradiol-treated women had a significantly greater response, both statistically and clinically, than the placebo group. However, because 32 women in this trial were also being treated with antidepressants, the effec- tiveness of 17β-estradiol as monotherapy for PPD cannot be assessed.
It is likely that estrogen can act as a potent adjunct for women with PPD also undergoing a treatment with antidepressant drugs. Whether it modulates the effects of abrupt estrogen withdrawal postpartum remains unknown, as does its long-term effects.
Perimenopausal Depressions
The perimenopause is the transitional period leading up to the menopause. During perimenopause, FSH levels increase while estro- gen and progesterone levels decrease – until menopause, when folli- cules no longer mature, ovulation is absent, menstrual cycles cease, along with their associated estradiol and progesterone secretion, and LH and FSH levels are continuously high due to the lack of gonadal feed-back mechanism.
Most women usually experience perimenopause during their late 1940 to early 1950. It is marked by irregular menstrual cycles and may also include symptoms such as hot flashes, night sweats, insomnia
and other sleep disturbances, vaginal dryness, as well as possible mental sluggishness, irritability, and decreased libido.
At one time, the menopause, and especially the perimenopause, were associated with severe depression. This belief was furthered by Kraepelin, who described “Involutional melancholia” (1907) as a very severe depression with hypochondrial delusions among women with no prior history of depression. This was later classified as a form of manic-depressive illness. Epidemiological studies during the 1970s questioned and then dismissed the prevalence of new-onset depres- sions during the perimenopause and menopause (Weissman and Klerman 1977; Weissman 1979).
Based on recent epidemiological studies, roughly 10% of women experience mood symptoms or changes which can be directly linked to perimenopause (Schmidt et al. 1997). Mood symptoms tend to be more commonly reported among perimenopausal women than menopausal women and the ratio of affective disorders is higher (from 2:1 to 3–4 : 1) among women than men during midlife. This suggests a strong relationship between the perimenopause and the onset of mood symptoms. Further support for this suggestion is provided by Angst et al. (1980), who reported a second peak of onset of bipolar affective disorder in women aged 45–55 but not in men of the same age. It is conceivable that a relationship exists between the hormonal instability or substantial hormonal changes during perimenopause and exacerbations of bipolar disorder and other affective disorders (Halbreich 1997).
Treatment with Estrogen
There have been few studies of female depressions during midlife that have focused only on perimenopausal women (Thompson and Oswald 1977; Schmidt et al. 2000). Most studies of female depres- sions at midlife have included both depressed perimenopausal and postmenopausal women (Coope and Poller 1975; Coope 1981;
Aylward et al. 1974; Montgomery et al. 1987; Strickler et al. 1977).
Several researchers have documented beneficial effects from estrogen administration (Schmidt et al. 2000; Aylward et al. 1974; Mont- gomery et al. 1987). Aylard et al. (1974) found that estrone sulfate improved mood, and that this correlated with an increase in free tryptophan levels. Montgomery’s group (Montgomery et al. 1987) compared 17β-estradiol alone or 17β-estradiol in conjunction with
testosterone, to placebo, and noted improvement in both the peri- and postmenopausal women in all treatment groups, with signifi- cantly greater improvement in the active treatment groups. In both peri- and postmenopausal women, the benefit from hormonal treatment was lost by 4 months – perhaps because either hormonal levels were diminished at this point or because placebo-treated patients continued to improve.
Schmidt et al. (2000) administered transdermal 17β-estradiol (Estraderm 0.05 mg/d) to 34 women in a recent randomized, double- blind trial. After 3 weeks, a positive response was noted among women undergoing estradiol treatment. After 6 weeks, a full or par- tial therapeutic response was reported by 80% of subjects receiving estradiol, compared to 22% of those on placebo.
Those trials not showing benefit of estrogen over placebo were using conjugated equine estrogen (Coope 1981; Montgomery et al.
1987; Strickler et al. 1977; Coope 1981) and estrone sulfate (Thomson and Oswald 1977). Several, but not all, of these trials included women with comorbid psychiatric illnesses (Strickler et al. 1977; Coope 1981) who were permitted to continue psychotropic medication throughout the trials. Thus, the results are difficult to interpret due to the possibility that the underlying psychopathology among these women played a greater role in precipitating and exacerbating mood symptoms that did the hormonal changes brought on by menopause.
Several other studies also reported a high nonspecific response rate with significant improvement over baseline in both the estrogen and placebo conditions (Coope 1981; Thompson and Oswald 1977).
Menopausal Depressions
Natural menopause is generally defined as starting 1 year after a woman’s last menstrual period and usually occurs by 55 years of age (the mean age is 51) in industrial societies. Surgical menopause occurs after a bilateral oophorectomy.
During menopause, sex hormones’ feedback inhibition ceases, resulting in decreased gonadal estrogen and progesterone secretions and gonadotropin (LH and FSH) levels. Postmenopause estrogen levels drop to less than 20 ng/l (compared to between 50–250 ng/l in normally menstruating women). Generally, the main indication of menopausal state occurs when levels of follicle-stimulating hormone (FSH) increase to over 20 ng during the perimenopausal period and over 40 ng during menopause (Kouri and Halbreich 1998).
After menopause, estrone becomes the most active form of estrogen. It is derived from the peripheral conversion of adrenal androstanedione (Kouri and Halbreich 1998), while estradiol is produced mainly in the ovaries.
A number of multisystemic changes accompany the decrease in circulating estrogen during menopause. These occur not only in the reproductive system, but also in bone mineral density, in the cardio- vascular system, as well as in the CNS (Kouri and Halbreich 1998).
Although hormonal decrease is associated with decreases in selected cognitive functions, depression is not necessarily increased.
Estrogen for Treating Dysphorias Among Perimenopausal and Menopausal Women
Although estrogen is most often prescribed for alleviation of the vasomotor and physical symptoms of perimenopause, evidence for its therapeutic efficacy in ameliorating dysphoric symptoms during menopause is not clear. Over 20 placebo-controlled studies have evaluated the therapeutic efficacy of estrogen for depressive symp- toms or depressive disorders during the menopause.
Estrogen for Treating Dysphorias Among Surgically Menopausal Women
Estrogen may be more beneficial than placebo for improving mood in women who have undergone surgical menopause (Ditkoff et al.
1991; Sherwin and Gelfand 1985; Dennerstein and Burrows 1979).
The estrogen preparations used in these positive studies included conjugated estrogens (Ditkoff et al.; Lobo 1991), ethinyl estradiol and estradiol valerate (Sherwin and Gelfand 1985), while two negative trials with smaller sample sizes employed either estrogen sulfate (Coppen et al. 1977) or conjugated estrogen (George et al. 1973).
Sherwin et al. (1985) compared placebo, estradiol valerate, testos- terone enanthate, or a combination of the two preparations in oophorectomized women who had mood baseline levels equivalent to a hysterectomized but nonoophorectomized control group – the placebo group reported a deterioration in mood whereas the three hormonal treatment groups reported improved mood. Although the testosterone-only group experienced the most significant decrease in mood symptoms, they also reported increased hostility scores.
Ditkoff et al. (1991) undertook a trial which excluded women
suffering from either substantial mood or physical symptoms. The researchers found that women taking conjugated estrogens still showed a more improved mood than the placebo group.
It is suggested that estrogen is superior to placebo in alleviating depressed mood among women who have undergone surgical menopause. Estrogen appears to effectively lift mood and improve well-being. Testosterone probably amplifies this effect.
Estrogen for Treating Dysphorias Among women with Naturally Occurring Postmenopause
Most reports (Brincat et al. 1984; Deerman et al. 1995; Fedor-Frey- bergh 1977; Furuhjelm et al. 1984; Wiklund et al. 1993) have demon- strated that estrogen (mostly parenteral and oral estradiol) is more effective than placebo in alleviating physical and emotional symp- toms of menopause. 17β-estradiol administered parenterally with testosterone was significantly better than placebo for all menopausal symptoms evaluated (somatic as well as psychological), with the exception of aches and pains (Brincat et al. 1984).
Results of a large study (n = 223) support these findings. Wiklund et al. (1993) compared transdermal estradiol to placebo in a group of mildly symptomatic women. A dose of 50 µg 17β-estradiol proved more efficacious than placebo for psychological well-being, anxiety, and depressive symptoms, as well as vasomotor symptoms.
Another study raised questions regarding estrogen’s relative benefits over placebo. Patterson (1982) compared placebo to admini- stration of a synthetic estrogen, mestranol, followed by addition of norethisterone. Active treatment was superior to placebo only for night sweats and flushing but not for mood symptoms.
A high nonspecific response rate (placebo response) was found among postmenopausal women with MDD (Saletu et al. 1995), who were given either 50 µg of transdermal 17β-estradiol or placebo and in minimally symptomatic women receiving either conjugated estrogen or placebo (Campbell 1976; Campbell and Whitehead 1977).
Gerdes et al. (1979) administered HRT with conjugated estrogen daily and 14 days of medroxyprogesterone was compared with clonidine, and a no treatment group, and showed improvement of the HRT group on a variety of personality measures and on a self-report mood measure.
Long-term estrogen therapy may provide greater mood-enhancing effects than short-term administration. In one longitudinal study,
women continuing on estrogen for 1 year reported greater improve- ment in mood and sexual functioning, compared to those who dis- continued treatment (Maoz and Durst 1980). Palinkas and Barrett- Connor (1992) conducted a cross-sectional epidemiological study of nearly 1200 women and reported more frequent depressive symp- toms in the 50-60 group than in the over 60 group. The authors suggest that symptomatic women sought treatment and thus showed higher initial rates in the 50- to 60-year-old hormone replacement group. Over time and with treatment, these women felt better and sought treatment less.
Summary
Although much is known about the multiple actions and interac- tions of estrogens, less is known about its specific role in each dysphoric state. Several compelling facts suggest that estrogen or its absence play a major role in the onset and course of depressions in women. (1) From menarche through perimenopause, a significant gender difference exists in the prevalence of depressions. This dis- tinction does not exist among prepubescent children, nor between postmenopausal women and older men. (2) The gender difference in prevalence of depressions is especially apparent during periods when estrogen levels are high but unstable. This is caused by cyclicity during the menstrual cycle and increases in estrogen levels during pregnancy, and sharp withdrawals in the postpartum period. (3) During periods of estrogen change (premenstrual, postpartum, and perimenopause), depressive symptoms are also more prevalent – although the direct effects of estrogen cannot be clearly distinguished from other factors, such as environmental influences, etc. (4) During menopause, when estrogen is almost absent, there is no increase in the prevalence of first-episode depression.
It is plausible that hormonal fluctuations or lack of estrogen increase the risk of depression among vulnerable women. Based on current knowledge, treatment of depression with estrogen may:
(1) stabilize and restore disrupted homeostasis – as during post- partum, premenstrual, or perimenopausal conditions; (2) act as a psy- chomodulator to offset vulnerability to dysphoric mood when estro- gen levels are significantly decreased, as in the case of postmen- opausal women.
There is evidence demonstrating estrogen’s beneficial effects in alleviating mood symptoms during the menopause and improving well-being and sexual drive. Based on reports from placebo-controlled studies, the most consistent effects of estrogen were found in surg- ically menopausal women or those with mild symptoms. Trans- dermal β-estradiol is the preparation most highly associated with positive mood changes, even though conjugated estrogen remains the most widely prescribed.
Surgically menopausal women appear to benefit most from estrogen therapy for prevention and treatment of mood disturbances.
Among these women, the type of estrogen preparation administered appears to matter less and the addition of testosterone or other androgens might be beneficial. However, there are situations that might warrant changing to a preparation that delivers 17β-estradiol:
(1) If a woman fails to respond to conjugated estrogens or to other preparations that predominantly deliver estrone, and (2) if there are no contraindications to parenteral or transdermal estrogen.
At present no definitive support exists for the use of estrogen as monotherapy for severe depression in menopausal women.
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