Introduction
One of the most widely documented findings in psychiatric epide- miology is that women have higher rates of major depressive episodes than men. This has been found all around the world using a variety of diagnostic schemes and interview methods (Bland et al. 1988;
Cheng 1989; Weissman and Myers 1978; Nolen-Hoeksema 1987;
Weissman and Klerman 1992). The prevalence of depression among women in these studies has been reported to be between one and a half and three times that of men. It can be argued that societal norms and sex role socialization experiences make it easier for women than for men to admit depression in epidemiological surveys (Phillips and Segal 1969; Young et al. 1990). However, a number of methodological studies have been carried out on this type of response bias in community surveys of nonspecific psychological distress using standard psychometric methods to assess potential biasing factors (Clancy and Gove 1972; Gove and Geerken 1977; Gove 1978). No evidence was found in any of these studies that the significantly higher levels of self-reported distress found among women than among men was due to these biasing factors.
Female sex steroids profoundly influence the brain. Apart from the symptoms characterizing female-specific mood disorders such as irritability, dysphoria, affect lability, and changes in appetite, other aspects of brain function, such as sexual activity (Sanders et al. 1983), cognitive capabilities, sensorimotor function, and seizure suscepti- bility (Bäckström 1976) are also related to serum levels of estrogens, progesterone, and various progesterone metabolites. Moreover, sex steroids play a major role in the etiology and treatment of premen- strual syndrome (PMS), premenstrual dysphoric disorder (PMDD), postnatal depression (PND), and menopausal related complaints.
These roles will be discussed in more details later in this chapter.
Estrogen Therapy: Interface Between Gynecology and Psychiatry
Khaled M. K. Ismail, G. V. Sunanda and P. M. Shaughn O’Brien
Estrogens in the Different Stages of the Life Cycle The major circulating estrogen in women of reproductive age is 17β- estradiol. The other significant estrogen is estrone, which is produced from both direct ovarian secretion and peripheral aromatization of ovarian and adrenal-derived androstenedione in the adipose tissue.
Estrogen circulates while bound to sex hormone-binding globulin (SHBG), which is produced by the liver; the quantity produced is under partial control of estrogen.
The event of childbirth is a time of drastic endocrinological and neurobiological alterations in a woman’s body. During pregnancy, there is a gradual rise in estrogen with a peak occurring at the time of delivery (Williams et al. 1985). There is precipitous drop in estrogen levels just after delivery. Within 48 h of delivery, there is a 400–1000-fold drop in estrogen, bringing it down to follicular phase levels (Sichel et al. 1995). This has been called “estrogen with- drawal.”
After the menopause, estradiol and estrone production by the ovaries dramatically declines. Estradiol levels decrease to less than 40 pg/ml, while testosterone production declines by only 25% at the time of the natural menopause. Although adrenal steroid production is gradually reduced with age, there is still substantial androstene- dione production for peripheral conversion. Therefore, estrone is the major circulating estrogen in the menopause. Due to an increased androgen-to-estrogen ratio, SHBG declines (Yonkers et al. 2000).
Estrogen and Brain Function
Behavioral studies in animals and humans have shown that the estrogen-dominated follicular phase is related to increased activity and wakefulness (Asso and Braier 1982). A higher rapidity of fine motor skills in both the hands and the legs has been noted during the follicular phase, when compared with the luteal phase. Animal experiments and clinical studies suggest that increased estradiol concentrations are related to increased two-points discrimination ability, touch sensitivity, visual function, hearing, and olfactory function (Hampson and Kimura 1988). In addition, an improvement in postural balance has been reported in postmenopausal women on estrogen replacement therapy when compared with women without treatment (Hammar et al. 1996).
Estrogen is important in neuronal development and health (Henderson 1997). Subsets of neurons within the brain possess intra- cellular estrogen receptors. The classic mechanism of action of a steroid is to act (in conjunction with a steroid receptor) as a genomic transcription factor, hence influencing protein synthesis; such effects are relatively slow (McEwen 1994; Joels 1997). Estrogens also affect brain function through interactions with membrane receptors that do not require genomic activation or ion channels (Joels 1997).
In responsive neurons, estrogen promotes cell differentiation, the growth of nerve processes, and the formation of new synapses between nerve cells.
Estrogen has clear effects on several neurotransmitter systems, including those using acetylcholine, noradrenaline, serotonin, and dopamine. This can explain many of the functional effects of estrogen. The epileptogenic effects of estrogens may be related to an effect on glutamate. The influence of sex steroids on symptoms such as irritability and depressed mode may be related to their effect on serotonergic transmission and the effect of estrogen on motor control could be dopamine-mediated.
The relationship between estrogen and the serotonergic [5-hy- droxytryptamine (5-HT)] system is of particular interest. In rat brain, estrogen treatment decreases 5-HT1 receptor density and increases 5-HT2 receptor density in the frontal cortex (Biegon et al. 1983;
Summer and Fink 1995; Jarrett 1995; Fiscette et al. 1983) as well as the nucleus accumbens, cingulated cortex, and olfactory cortex (Sumner and Fink 1995; Jarrett 1995; Fink et al. 1996). In raphe cells, estrogen increases serotonin content via stimulation of tryptophan hydroxylase mRNA (Pecins-Thompson et al. 1996). In humans, estrogen increases platelet 5-HT2 binding and is associated with increased binding in the platelet serotonin transporter (Rojansky et al. 1991). Finally, both endogenous and exogenous estrogens increase the prolactin response to serotonin agonists (Halbreich et al.
1995; O’Keane et al. 1991).
Estrogen also increases locomotor activity and enhances the activity of excitatory amino acids in the central nervous system of rodents (Smith 1994). It is suggested that the latter property is respon- sible for the cognition-enhancing effects, but may also relate to mood effects (Sherwin 1994; Phillips and Sherwin 1992; Kampen and Sherwin 1992). These various properties in humans and animals are similar to those found with antidepressant agents, and thus
strengthen the position that estrogens may have mood-elevating properties.
Premenstrual Syndrome and Premenstrual Dysphoric Disorder
Premenstrual syndrome (PMS) is a psychological and somatic disorder of unknown etiology. However, hormonal and other, possibly neuroendocrine, factors probably contribute (O’Brien 1993;
Rapkin et al. 1997). Most menstruating women exhibit some pre- menstrual symptomatology, but hormonal differences do not appear to account for the extreme severity of the symptoms seen in some women. There has been a reluctance, until relatively recently, to accept PMS as a serious condition. This has arisen because of a failure to distinguish true PMS from the milder physiological premenstrual symptoms occurring in the normal menstrual cycle of the majority of women.
There is now a trend, especially with psychiatrically trained clini- cians, to define PMS in terms of the American Psychiatric Asso- ciation Diagnostic and Statistical Manual of Mental Disorders (DSM-IV; American Psychiatric Association 1994). PMS was defined
Table 1. DSM-IV PMDD diagnostic symptoms
1* Markedly depressed mood, feelings of hopelessness, or self-depreciating thoughts
2* Marked anxiety, tension, feelings of being ‘keyed up’, or ‘on edge’
3* Marked affective lability
4* Persistent and marked anger, irritability, or increased interpersonal conflicts 5 Decreased interest in usual activities
6 Subjective sense of difficulty in concentrating 7 Lethargy, easy fatigability or lack of energy 8 Marked change in appetite
9 Hypersomnia or insomnia
10 Subjective sense of being overwhelmed or out of control 11 Other physical symptoms
* Symptoms required for the diagnosis of premenstrual dysphoric disorder (PMDD) under the Diagnostic Statistical Manual IV; the symptoms marked with an asterisk are defining symptoms and at least one of these must be present for a diagnosis of PMDD
as late luteal phase dysphoric disorder (LLPDD) in DSM-III, and is now premenstrual dysphoric disorder (PMDD) under DSM-IV. Table 1 shows the criteria for a DSM-IV PMDD diagnosis. It is important to clarify what is meant by the terms PMDD and PMS, as current literature often uses them interchangeably. PMDD is the extreme, predominantly psychological end of the PMS spectrum.
Some patients may additionally have an underlying psychological disorder that coexists with PMS; others self-diagnose PMS but actually have depression unrelated to their cycle. These patients are characterized by the fact that their symptoms fail to resolve after menstruation.
Definition
A woman has PMS if she complains of recurrent psychological or somatic symptoms (often both), occurring specifically during the luteal phase of the menstrual cycle and resolving by the end of menstruation. These symptoms are so severe that they disrupt the patient’s normal functioning, quality of life and interpersonal rela- tionships. Symptoms must have occurred in at least four of the previous six cycles.
PMDD is defined according to DSM-IV as five or more of the diagnostic symptoms listed in Table 1 being present for most of the last week of the luteal phase and remitting within a few days after the onset of the follicular phase. At least one of the symptoms must be from the cluster of PMDD defining symptoms. The disturbance caused by the symptoms must interfere markedly with work, school, or usual social activities and relationships. The disturbance must not be an exacerbation of another psychiatric disorder such as major depression disorder, panic disorder, dysthymic disorder, or person- ality disorder.
It has long been suggested that fluctuation in mood may be related to ovarian hormone imbalance (Dalton 1977). Research has produced data, which could support theories of estrogen excess, progesterone deficiency, estrogen/progesterone imbalance, and progesterone ex- cess. None of these has been confirmed, and thus, factors other than differences in the levels of individual hormones must be important.
Interactions with other endocrine or biochemical systems could be present or differences in receptor status may be relevant.
Investigations of the metabolites of progesterone have shown that women with PMS had lower levels of the progesterone metabolite allopregnanolone in the luteal phase (Rapkin et al. 1997). This provides a plausible theory because allopregnanolone has γ-amino- butyric acid (GABA)-ergic activity, which could be lost in allopreg- nanolone deficiency, thus giving rise to PMS.
A link with ovarian hormone changes, particularly progesterone, seems likely however, since the temporal relationship between progesterone secretion and symptoms is so close. Ablation of the ovarian endocrine cycle by oophorectomy or more conveniently by the administration of analogs of gonadotropin-releasing hormone (Gn-RH) is associated with the parallel elimination of PMS symptoms (Hussain et al. 1992). Furthermore, in women whose ovarian cycles have ceased (due to the menopause or bilateral oopho- rectomy) and who subsequently receive hormone replacement therapy (HRT), a significant percentage redevelop PMS symptoms during the progesterone phase of therapy (Hammarbäck et al. 1985).
In a pilot study, women with severe PMS who had undergone hysterectomy and bilateral salpingo-oophorectomy were recruited to assess the effects of hormone replacement on their PMS symptoms (Henshaw et al. 1993). During estrogen-only replacement therapy they remained asymptomatic; when progesterone was administered, PMS symptoms recurred, demonstrating fairly clearly that patients remained sensitive to the effects of progesterone.
The knowledge of serotonin involvement in depression has been extended into PMS research. Low serotonin levels in red cells and platelets (Rapkin 1992) have been demonstrated in PMS patients.
This serotonin deficiency has been proposed to enhance sensitivity to progesterone (Rapkin et al. 1997). Selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine and sertraline, have been shown to be an extremely efficacious treatment for severe PMS/PMDD (Dimmock et al. 2000). This gives further indirect support to the involvement of serotonin in PMS etiology. Vitamin B6 (pyridoxine) is a cofactor in the final step of the synthesis of serotonin and dopamine from tryptophan. However, no data have yet demonstrated consistent abnormalities either of brain amine synthesis or de- ficiency of vitamin B6.
Other neurotransmitters may have relevance to PMS, for example GABA, dopamine, and acetylcholine, although research data are less convincing for these in comparison to β-endorphin and serotonin.
If these theories are true, it would seem that PMS is not caused by an endocrine imbalance. However, it appears that there is increased sensitivity to normal circulating level of ovarian hor- mones, particularly progesterone, secondary to a neuroendocrine disturbance, probably serotonin deficiency. Accordingly, approaches to treatment fall into two broad strategies: (a) correction of the neuroendocrine anomaly and (b) suppression of ovulation.
Estrogen for the Treatment of PMS/PMDD
There are studies to suggest that estrogenic ovarian suppression may eliminate PMS (Watson et al. 1989; de Lignieres 1986). Estradiol has been used in the form of patches (100–200 µg), subcutaneous implants (50–100 mg), or gel. The last was shown in one study to reduce premenstrual migraine (de Lignieres 1986). Progestogens are necessarily prescribed with estrogen in order to protect the endome- trium from the untoward effects (hyperplasia and adenocarcinoma) of unopposed estrogen. However, progestogens may reintroduce PMS-like symptoms. To avoid this systemic effect, progestogen can be used locally [i.e., levonorgestrel intrauterine system (LNG-IUS), when systemic levels remain low and restimulation is not seen].
Research on the use of estrogen plus the LNG-IUS has not yet been published, although there is evidence to demonstrate that suppression of ovulation by estrogen treats PMS symptoms, and there is good evidence to demonstrate that the LNG-IUS successfully protects the endometrium from, or even reverses, hyperplasia. This combination has the potential to eliminate PMS, treat flushes, reduce heavy periods, give endometrial protection, and provide contraception. It is well known that these disorders frequently coexist in the same patient.
Most gynecologists would reserve estradiol implants for severe cases and in those patients for whom the menopause is imminent.
Testosterone implants have also been given empirically when diminished libido is a significant symptom.
Therefore, although estrogen does not seem to be directly related to the etiology of PMS, it can be considered as one of the broadways of controlling the condition, through ovarian suppression or possibly its direct effect on the serotonergic system in the brain.
Postpartum Psychiatric Disorders
Postpartum psychiatric illnesses have a long-lasting effect on the woman, the marital relationship, and the child’s emotional, social, and cognitive development (Weinberg and Tronick 1998). The likeli- hood of a woman experiencing a depressive episode in the postpartum period is higher in women with a family history and/or personal history of depressive disturbance. Obstetric difficulties appear to be irrelevant in both puerperal psychosis and postnatal depression.
There is clear evidence of an increased susceptibility to depression postnatally in comparison with nonchildbearing women. There is a threefold increase in the relative risk of depression in the first 5 weeks after delivery (Cox 1993).
Postpartum psychiatric illnesses can be classified into five groups (Sichel 2000) (Table 2). The first group is the maternity blues. This condition is relatively common, affecting 50%–80% of women postpartum. It begins on the second or third postpartum day and should start to remit by the second week (Kendell 1981). Symptoms are mild, transient, and require no treatment other than support and reassurance.
The second group of patients are those suffering from “pure”
postpartum depression. Postnatal depression is seen in 10%–12% of women, often within the first 4 weeks after delivery (Kumar and Robson 1984; O’Hara et al. 1984; Kendell et al. 1987). The onset of depression is early, rapid, and often severe enough to require therapy.
Relapse rates have been estimated at 24%–40% (Davidson and Robertson 1985). The third group comprises postpartum psychiatric illnesses affecting women with a previous history of major or minor depression. These women often have a family history of depression and premenstrual dysphoria.
Table 2. Incidence of postpartum psychiatric illnesses
Group Illness Incidence
1 Maternity blues 50–80%
2 “Pure” postpartum depression 10–12%
3 Women with a previous history of major and minor
depression –
4 Postpartum psychosis 0.05–0.1%
5 Comorbid emergence of postpartum depression –
The fourth group of postpartum psychiatric illness is postpartum psychosis. It occurs following 0.05%–0.1% of births (Brockington 1996). The psychosis presents acutely in the first 2–4 weeks post- partum with symptoms resembling mania with delusions, hal- lucinations, agitation, and confusion. It requires hospital admission and aggressive pharmacological management. Relapse rates greater than 90% are reported if the index episode of puerperal psychosis occurred during the 24 months prior to delivery (Kendell 1987).
The last group comprises the comorbid emergence of postpartum depression. Panic attacks, generalized anxiety, and obsessive-com- pulsive disorder (OCD) are evident from a history in the pregravid state, but worsen in the postpartum period followed by depression.
Etiology of Postpartum Psychiatric Illnesses
The etiology of postpartum psychiatric disorders is likely to be heterogeneous and the interaction between biological, psychological, and social factors is extremely complex.
Consistent endocrine differences have not been found between women who develop postpartum depression and those who do not (Willcox 1985). However, failure to demonstrate systemic evidence of hormone deficiencies does not exclude sex hormones as etiological factors (O’Brien 1994). Peripheral hormone levels need not corre- spond with brain levels, nor are they necessarily an index of brain receptor numbers and affinity. It is possible that a susceptible subpo- pulation of women experiences mental disorders as a result of the
“estrogen withdrawal” (Sichel 2000).
Role of Estrogen in Postpartum Psychiatric Disorders
Gregoire et al (1996) conducted a randomized, controlled trial evalu- ating transdermal estrogen therapy for the treatment of severe postnatal depression. Sixty-one British women with major post- partum depression were recruited. They were assessed using the Research Diagnostic Criteria (RDC), the Schedule for Affective Disorders and Schizophrenia (SADS), and the Edinburgh Postnatal Depression Scale (EPDS); a score of more than 13 on the EPDS on two occasions was required for enrollment. Participants were randomized
to receive transdermal 17β-estradiol 200 µg/day or placebo for 6 months. After 3 months, dydrogesterone 10 mg/day was added for 12 days per month. More women in the treatment group required concurrent conventional antidepressant medication (16/34 vs. 10/27) and more women in the placebo group missed their follow-up visits (10/27 vs. 6/34). Estrogen therapy was associated with a greater improvement in depression scores than placebo, but the treatment and placebo groups may not have been sufficiently comparable (Lawrie et al. 2000). The results of Gregoire et al. (1996) suggest that high-dose estrogen therapy could be a useful adjunct after conven- tional antidepressant therapy alone has failed. However, because of the practical and theoretical disadvantages, which include deep vein thrombosis, endometrial hyperplasia, and inhibition of lactation, it is unlikely to be investigated further (Lawrie et al. 2000).
High-dose estrogen was also used prophylactically in 11 post- partum women, seven of whom had a history of puerperal psychoses and four a history of puerperal major depression. (Sichel et al. 1995).
Although 10 of these 11 women did not suffer from a postpartum psychiatric illness, the authors caution that this particular treatment regimen might be specific for a small subgroup of women who do not experience depressive disorder outside the context of their pregnancy. Moreover, high-dose estrogen could add to the risk of thromboembolism at a time when the chances of this complication are at their highest. Antidepressants and mood stabilizers are not only effective but are also safer.
Although estrogen was shown to help some women with severe postnatal depression, its effectiveness has not been adequately shown and the side effects of this treatment have not been widely studied. Postnatal depression is treated by supportive therapy and conventional antidepressant medication. Finally, hormones will not be the only factors precipitating depression; rather it is a combination of fluctuating hormone levels and the impending social and psycho- logical changes that go along with the birth of a child.
Menopause
The World Health Organization (WHO) defines the menopause as
“the permanent cessation of menstruation resulting from loss of ovarian follicular activity”. The average age in Western women is 51 years, range 48–58. The perimenopause is defined as the time period
immediately before menopause when endocrinological, biological, and clinical features of approaching menopause commence, and lasts until the first year after the menopause. The postmenopause is defined as dating from the time of menopause, although the meno- pause cannot be determined until after a period of 12 months of spontaneous amenorrhea has been observed (WHO 1981). Surgical menopause occurs as a result of bilateral oophorectomy, mostly, at the time of hysterectomy.
It is estimated that approximately 35% of women will seek medical treatment for symptoms associated with the menopause (Bäckström 1995). The complaints most commonly noted by women include hot flushes, muscle and joint pain, headaches, weight gain, decreased libido, fatigue, insomnia, low mood, and irritability (Stuen- kel 1989). Estrogen preparations are used to treat menopausal symp- toms, including mood symptoms, which commonly accompany physical symptoms. While estrogen is effective in treatment of hot flushes, evidence for its therapeutic efficacy in ameliorating mood symptoms is less concrete. A possible antidepressant effect of es- trogen has been evaluated in menopausal women suffering from depression. Several randomized controlled studies showed no antide- pressant effect of estrogen in the doses used for HRT (Coope 1981;
Campbell 1976; Thomson and Oswald 1977), whereas other studies suggested that estrogen may improve mood in mildly depressed, menopausal women and in high doses may even be useful for the treatment of severely depressed patients (Ditkoff et al. 1991; Klaiber et al. 1979).
Investigation of the relationship between the timing of the menopause and depressed mood has been beset by methodological problems. Longitudinal studies have failed to demonstrate an increase in the frequency of major depression or severe mood changes in relation to the transition (Hällstrom and Samuelsson 1985; Kaufert et al. 1992; Avis et al. 1994). Some studies, however, suggest that milder mood changes, expressed as decreased well-being, are more common after the menopause than before; data in this field are not unanimous (Graham and Sherwin 1987; Kaufert et al. 1992; Hunter 1992; Holte 1992; Ballinger 1990; Dennerstein et al. 1993; McKinlay et al. 1992; Collins and Landgren 1994).
Women attending menopause clinics may not be typical. High levels of depressive disorder have been reported in women attending gynecology clinics (Ballinger 1977; Ballinger et al. 1987). Pearce et al.
(1995) point out the importance of assessing and controlling for environmental factors and stresses. In a study of women with HRT given by estradiol implants, it was found that vasomotor symptoms were related to falling estradiol levels, but psychological symptoms were more closely related to minor stresses or hassles (Alder 1992).
The contribution of estrogens to psychological health is contro- versial. A meta-analysis of the effect of HRT on depressed mood found that estrogen treatment of menopausal women had a moderate to large benefit on mood, compared to control or placebo conditions (Zweifel and O’Brien 1997). The review found a greater effect among perimenopausal than among postmenopausal women. According to this meta-analysis, women who were treated for longer than 8 months exhibited the greatest improvement. In addition, the effect was greater for naturally versus surgically induced menopause.
However, in another qualitative review, the benefits of estrogen treatment appeared to be more consistent in surgically menopausal women (Yonkers et al. 2000).
While studies did not generally compare one estrogen preparation to another, the trials, which were most reliably able to detect a drug- placebo difference, employed parenteral or transdermal estradiol as a treatment. In a qualitative review, only one of six studies using parenteral or transdermal estradiol was negative, whereas negative findings occurred in 9 of 12 studies using an estrogen compound that predominantly yielded estrone. 17β-Estradiol is the more biological- ly active estrogen, whereas estrone has one-tenth of the biological activity. This suggests that 17β-estradiol is possibly more effective at ameliorating mood symptoms associated with the menopause (Yonkers et al. 2000).
There is a possibility that psychological benefits of HRT may occur because they are secondary to the relief of vasomotor symp- toms and a reduction in vaginal dryness. In an American study of 426 pre- and perimenopausal American women, depression was signifi- cantly associated with hot flushes but not hormonal levels (Avis et al. 1994). In another study of hormones, sexuality and well-being in 140 women aged 40–60 years, it was found that tiredness was the only significant predictor of depression (Zuckerman et al. 1983).
These findings suggest that mood enhancement in symptomatic women treated with HRT is more likely due to a “domino effect”
rather than a direct psychotropic or placebo effect.
Role of the Obstetrician/Gynecologist and Psychiatrist Nearly all the psychological disorders associated with reproduction are amenable to treatment with either hormonal therapy or psychotropic drugs. Even though the patient might be seen by either specialist, it is apparent that psychiatrists will not usually prescribe hormones and obstetricians/gynecologists will rarely prescribe anti- depressants even for the same patient. Such patients have histori- cally fallen between the two specialists since neither has taken responsibility for the disorder.
Most of these women present with a mixture of symptoms. For example, a patient presenting with PMS/PMDD might have asso- ciated gynecological disorders like heavy, painful periods, or she might be requesting contraception. Treatments (particularly hor- monal) may have effects on the menstrual cycle and can cause irregular uterine bleeding. One cannot expect the psychiatrist to undertake the management of such side effects.
Postnatal depression and PMS/PMDD may be associated with coexisting psychiatric problems. The psychiatrist will be the most appropriate specialist to identify and manage these cases.
Appropriate training of obstetricians/gynecologists and psychia- trists might be the key factor in improving the service offered by either specialty to these patients. There is also a strong case for the development of combined clinics for treating women’s mental health when the expertise can be combined and shared. These clinics do exist in the USA and in continental Europe but are rarely seen in the UK.
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