9 Estrogens and Perinatal Disorders

Introduction

Pregnancy and childbirth are accompanied by important fluctuations in levels of circulating hormones including prolactin, cortisol, beta- endorphin, and human chorionic gonadotrophin. The most dramatic changes, however, probably occur in the levels of estrogens and progesterone that are produced by the placenta and rise steadily during pregnancy (Figs. 1, 2). Estriol levels increase by 100-fold and

Estrogens and Perinatal Disorders

Alain Gregoire

Fig. 1. Increase in maternal plasma estrogens during pregnancy

those of estradiol by 1,000-fold. Loss of the placenta at delivery leads to a sudden and rapid drop in these levels, the scale of which exceeds any other physiological event, prepregnancy levels being reached by day 5 postpartum. Estrogens freely cross the blood-brain barrier, and cerebrospinal fluid (CSF) levels appear to correlate well with puerperal circulating levels (Backström et al. 1976).

Because the perinatal period is also associated with a variety of changes in mental state, it provides a unique opportunity for studying the neuroendocrinology of such changes, both normal and patholog- ical, and for exploring potential clinical implications.

Changes in Mental State During Pregnancy and Postpartum

The postpartum period is associated with a well-documented in- creased incidence of mental disorders. The most dramatic of these is puerperal psychosis, which represents a 21-fold increase in risk of

Fig. 2. Increase in maternal plasma progesterone during pregnancy

psychotic illness, the highest at any time in a woman’s life (Kendell et al. 1987), resulting in up to one admission to a psychiatric hospital per 500 births. In most cases, puerperal psychosis is affective in nature: there is a pronounced disturbance of mood, which can be consistently low or high, or can fluctuate unpredictably between the two. Delusions and/or hallucinations may not always be congruent with mood or may be bizarre. Apparently organic features are also more commonly seen, such as visual or olfactory hallucinations.

Disorientation and cognitive disorganization are more common in puerperal than nonpuerperal women (Dean and Kendell 1981; Wisner et al. 1994). The prominence of cognitive disturbance is intriguing, as various aspects of cognitive function are increasingly associated with estradiol (see chapter 11). Abnormal beliefs and experiences generally involve issues relating to the child or the maternal role.

Functioning is invariably impaired, usually severely, and although the ability to care for the basic physical needs of the child may be preserved, more complex parenting functions are frequently compro- mised. Puerperal psychosis usually begins in the first few days after delivery; the incidence decreases sharply over the subsequent 1 or 2 weeks. The genetic characteristics appear to be those of bipolar disorder, probably with an additional familial predisposition to puerperal onset (Craddock and Jones 1999). There is recurrence in 50% of women in the first year and it is sometimes associated with the menstrual cycle (Brockington et al. 1988), which has been suggested as resulting from an association between falling estrogen levels and increased dopaminergic activity (Lovestone 1992).

Clinical services caring for this group of women are placing increasing emphasis on prediction and prevention in addition to assertive treatment programs.

In the first few days after childbirth, as many as 60%–70% of women experience a disturbance of mood and cognition known as

“the blues”. This is characterized by tearfulness, unpredictable mood

swings, anxiety, difficulty concentrating, a general feeling of con-

fusion, and lack of self-confidence (Kennerley and Gath 1989). The

peak incidence is on the fourth or fifth day, and generally these

feelings last for 2 or 3 days. Rates are increased in women with a

history of premenstrual syndrome, low mood in pregnancy, and poor

family or marital relationships, but social class and life events do not

seem to be related to the blues. Although clinicians and mothers

often attribute the symptoms to a difficult or exhausting delivery,

being in hospital, or suffering perineal pain, there is no evidence that these factors are more common in women who experience the blues than in those who do not. Although transient, they cause distress to the mother, which can be compounded by a lack of understanding and support from those around her. However, recognition of the problem, both by professionals and by women and their families, is growing.

Depressive illness is the most common major complication (physical or psychiatric) of the postnatal period. The prevalence of depressive illness in the postpartum period is 10%–15% and the incidence appears to be increased in the first 3 months (Cox et al.

1993; Cooper et al. 1988). Symptoms do not appear to differ signifi- cantly from nonpuerperal depressive disorders (O’Hara et al. 1990), although this finding is not consistent (Dean and Kendell 1981), which may reflect heterogeneity in the disorder. Social class, parity, and adverse obstetric factors appear to have little influence on the incidence of postnatal depression; contradictory results emerge from the association with stressful life events, but social and marital support appear to be important factors. However, the ability of all such factors to predict the occurrence of postnatal depression is limited (Cooper et al. 1996). Again, this may be due to the heteroge- neous etiology of depression, and at present there is evidence of a subgroup of women with specific vulnerability to postpartum depressive illness (Cooper and Murray 1995).

Although severe mental illnesses such as schizophrenia undoubt- edly have a significant impact on parenting function (Gregoire 2000), the effect of having a child during schizophrenia appears to be variable. One of the factors identified as predicting this differential effect is the nature of the schizophrenic illness, with less severe or typical illnesses being more associated with acute episodes of postnatal illness and more severe schizophrenic illnesses being unaffected by childbirth (Davies et al. 1995).

The Relationship between Estrogens and Mental State

The variations in the epidemiology of mood disorders and schizo- phrenia between the genders and over the life-cycle are strongly suggestive of a relationship with gonadal and reproductive function.

Numerous studies have demonstrated a higher lifetime prevalence

of depression in women compared to men, with a higher annual prevalence beginning after the age of 10 years (Weissman et al. 1988;

Kessler et al. 1993) but gradually disappearing after the age of 45 years. These differences apply to community samples as well as clinical populations and are therefore unlikely to be due to gender differences in presentation. The timing of the differences coincides almost precisely with the reproductive period in women’s lives and the fluctuations in gonadal steroids that characterize it.

The distribution of the onset of schizophrenia between genders and across age groups is also suggestive of an association with changes in reproductive hormones (Fig. 3; Häfner et al. 1993). Stevens (2002) postulated that this could be the result of the influence of estrogens and testosterone on anterior forebrain structures which might be associated with the development of schizophrenic symptoms.

Such influences on mental state are entirely compatible with what we know about the estrogenic effects on brain structures and neuro- transmitter systems involved in mood and cognition. Estrogen receptors are widely distributed in the brain, including the hippo- campus, amygdala, raphe nuclei, cingulate cortex, and nucleus accumbens (McEwen et al. 1997; Sumner and Fink 1995). They exert a modulating influence on a number of key neurotransmitter sys- tems, notably serotonergic, dopaminergic, noradrenergic, gamma- amino butyric, cholinergic, and glutamate systems (McEwen et al.

1997).

Estrogen binds to both membrane and intracellular receptors that exert a wide range of influences including modulation of other receptors and transcription of genes. Details of these effects are beginning to emerge from animal studies. Interspecies differences in neuroendocrinology demand caution in generalizing any such find- ings to humans, but they remain intriguing nevertheless. Estrogen increases the density of 5-hydroxytryptamine (5-HT) (Biegon and McEwen 1982) and 5-HT

(Sumner and Fink 1995; Fink and Sumner 1996) receptors in a tissue-specific manner. Furthermore, 5-HT

receptor changes that occur in response to antidepressants appear to be modulated by estrogen (Kendell et al. 1982). Thus, the seroton- ergic effects documented to date are consistent with an overall 5-HT agonist effect of estradiol which parallels the central effects of many antidepressants.

Despite these in vitro and animal findings, studies that have

Fig. 3. Sex-specific age distributions at first onset of schizophrenia of a broad definition (ICD-9: 295, 297, 298.3 and 298.4.) (a) At earliest sign of mental disorder

(–––, males, N = 117; ..., females, N = 131. (b) At first psychotic symptom (–––, males, N = 125; ..., females, N = 139) From Häfner et al. (1993)

(a)

(b)

attempted to identify abnormalities in sex steroid levels in relation to postpartum mood have all yielded negative results. For example, Nott et al. (1976), and Harris et al. (1989) found no difference in estradiol levels between women who developed postpartum de- pression and those who did not, a finding replicated by O’Hara et al.

(1989), who also measured free estriol.

As neither antenatal levels nor changes in levels predict de- pression, the remaining possibility is that the normal physiological changes lead to changes in mental state only in women rendered vulnerable by some other factor. Bloch et al. (2000) provide evidence for such a process in a small but elegant study. Eight women with a history of postnatal depression and eight women with no history of depression were given a gonadotrophin-releasing hormone (Gn-RH) agonist (leuprolide acetate) to induce hypogonadism, and supraphys- iological doses of estradiol and progesterone were then administered for 8 weeks to simulate late pregnancy levels. Following double-blind withdrawal of the estradiol and progesterone, five of the eight women with a history of postpartum depression developed significant mood symptoms as opposed to none of the women without such history.

Other, more naturalistic examples of observed changes in mental state associated with withdrawal of estrogens have been described.

For example, a psychotic episode X days after the removal of a hyda- tidiform mole (Hopker and Brockington 1991) and “puerperal psy- chosis” following estrogen withdrawal in a transsexual man who had been taking estradiol before gender reassignment surgery (Mallett et al. 1989). Further such cases are reviewed by Mahé and Dumaine (2001). These cases among men suggest that sensitivity to estrogen withdrawal is not exclusive to women, although obviously more rarely seen.

Therapeutic Effects of Estrogen Treatment

The first published randomized controlled trial of estrogen treatment for a psychiatric disorder was that of Klaiber et al. (1979), who randomly allocated a sample of 40 women with treatment-resistant depression to augmentation with high-dose estrogens (Premarin 15–25 mg) or placebo. Treatment-resistant depression was defined as

“at least 2 years of unsuccessful treatment by a variety of conven-

tional therapies.” They found a significant positive effect of estradiol

over placebo but, surprisingly, the study was never replicated.

Another randomized controlled trial examined the effects of the tricyclic antidepressant Imipramine combined with either Premarin or placebo in 11 women with resistant depression of at least 6 months’ duration (Shapira et al. 1985; Zohar et al. 1985). Although no overall statistically significant difference in symptomatic improve- ment emerged between the two groups, they noted that one subject in the estrogen group got dramatically better within 2 weeks and one became manic. This could be purely artifactual, but would also be compatible with the hypothesis that some women have a particular sensitivity to the antidepressant effects of estrogen. Oppenheim (1984) also described a case of rapid cycling which appears to have been induced by the addition of conjugated estrogen to antide- pressant treatment. A number of studies have also provided evidence that estrogens are effective in reducing symptoms in premenstrual syndrome, the perimenopause (Soares et al. 2001), and may augment the effect of antidepressants in postmenopausal women (Schneider et al. 1997; 2001).

Reports are also emerging of the potentially therapeutic effects of estrogens in schizophrenia. Hoff et al. (2001) found a strong positive correlation between estradiol levels and cognitive function, though not other symptoms, in women with schizophrenia. In a double-blind randomized controlled trial, Kulkarni et al. (2001; see chap. 5) found that women with schizophrenia receiving 50 µg/day or 100 µg/day of estradiol in addition to standard antipsychotic medication showed a significantly better response than women receiving placebo estradiol plus antipsychotics. Furthermore, Thompson et al. (2000) demons- trated that higher levels of estrogen are associated with lower extra- pyramidal side effects. The apparent contradiction of enhanced antip- sychotic effects and reduced extrapyramidal symptoms is consistent with the hypothesis advanced by Van Hartesvelt and Joyce (1986) of the differential effects of estrogen in mesolimbic and mesostriatal pathways. These findings obviously suggest an exciting therapeutic possibility which merits further exploration.

Similarly encouraging results emerge from studies of the impact

of estrogens on cognitive function in Alzheimer’s disease. For ex-

ample, Asthana et al. (2001) conducted a randomized controlled

trial of high-dose estradiol, which produced significant benefits in

cognitive function in postmenopausal women with Alzheimer’s

disease.

Estrogen Treatment for Postpartum Disorders

The only double-blind randomized controlled trial of estrogen treatment for postpartum psychiatric disorder was conducted by Gregoire et al. (1996), who studied the effects of six months’ treat- ment with estradiol skin patches (200 mg/day) on 63 women with moderate to severe depressive illness with postpartum onset [means for treatment and control groups, respectively: Edinburgh Postnatal Depression Scores (EPDS) 21.8 and 21.3; duration 31 and 36 weeks].

The estradiol was given without progesterone for the first 3 months after which cyclical dydrogesterone (10 mg for 12 days) was given.

Twenty-six of the women were also taking antidepressants at baseline but only women who had shown no improvement over the 6 weeks prior to recruitment and who had had no change in the antidepressant type or dosage during that time were included. Only women who had EPDS of 14 or more at the time of recruitment (scores indicative of moderate to severe depression) and 4 weeks later at baseline were included in the study. Considerable efforts were made to maintain blindness in scoring depression: stage of treatment, compliance, side effects, and physical health checks were recorded by a different researcher to the one scoring depressive symptoms, and participants were asked not to discuss these aspects of the trial with the psychiatric interviewer, a request which they observed well.

Psychopathology and functioning was rated by interview using the Schedule for Affective Disorders and Schizophrenia (SADS) and Global Assessment of Functioning (GAF), and participants com- pleted the EPDS.

Of the 63 women, two did not complete the trial: one woman was found to have hyperthyroidism and was excluded in the first month of the study and another participant committed suicide in the first month of treatment. She had been withdrawn from her trial medication by her local psychiatrist without consultation with the research team and had been started on progesterone. She was admitted to a psychiatric hospital and drowned herself while on leave. Of the remaining sample, 27 women were in the placebo group and 34 in the active treatment group.

As would be expected in any placebo-controlled trial of treatment

for depression, there was a significant improvement over time in both

the active and the placebo group. However, there was a significantly

greater improvement in the active group compared to the placebo

group at 1 month and this difference was maintained over the subse- quent 5-month treatment period and during the 3 months of fol- low-up (ANOVA means vs. means of recruitment minus 1 month and baseline scores, f = 12.36; p < 0.001). These findings, based on analysis of the EPDS results, also emerged when SADS depression and GAF scores were analyzed. The results of all three measurements were in fact very highly correlated (r = 0.61–0.87; p < 0.001). The treatment effect was also analyzed using a best-fit repeated measures analysis which yielded a treatment effect of p < 0.001. The mean difference in EPDS score between the active and placebo group was 4.38 (95% CI = 1.89–6.87). This suggests a clinically, as well as statis- tically, significant difference between the groups, which is further demonstrated by the finding that 69% of the women in the placebo group still had scores above 14 by 3 months compared to 20% of the women in the active group.

The above study has not yet been replicated using a randomized control design, but a number of small open-label trials and cases have been reported. Ahokas et al. (1998; 1999) reported four cases of women with moderate to severe postnatal depression lasting 2–5 months, all of whom were documented as having low estradiol levels.

One woman had a past history of postnatal depression and one was on treatment with Moclobemide but had shown no response to this drug. All four were treated with oral micronized 17β-estradiol 4 mg/day, and all four were described as improving within 1 week and being almost free of symptoms by 2 weeks.

The same group (Ahokas et al. 1999; 2000; 2001) has also reported the results of estradiol treatment for puerperal psychosis in a sample of ten women as well as case reports of one and two women, although it appears that these samples may overlap. All of these patients had low estradiol levels (13–90 pmol/l); all were better in 2 weeks. The authors also describe the relapse of florid psychotic symptoms within 1 week in one patient who discontinued the estradiol after 5 weeks.

Estrogen Prophylaxis for Postpartum Disorders

The possibility that the rapid drop in estrogen levels at delivery can

precipitate puerperal psychoses suggests that attenuation of this drop

by administration of estrogens after delivery might have a prophy-

lactic effect. Hamilton and Sichel (1992) describe a series of 50

women with a history of postpartum psychosis treated in this way.

The women were given a high dose of estrogen (10 mg by injection) immediately after delivery followed by oral Premarin for 14 days.

None of the women relapsed (as opposed to the expected rate of 30%–70% described above).

Sichel et al. (1995) describe 12 cases of estrogen used prophylac- tically immediately after delivery. Four of the women in their study had a history of postpartum depression and eight had a history of puerperal psychosis. A starting dose of 5 mg Premarin twice daily was administered from day 1 postpartum, gradually decreasing over a period of 28 days. Progress was evaluated daily for the first 5 days, then at 4 weeks and 3, 6, and 12 months. None of the four women with a history of postpartum depression showed any sign of relapse, and all but one of the women with a history of psychosis remained well. The one woman who did relapse was believed to have been noncompliant with the estrogen regime.

Kumar et al. (2002) carried out an open trial of three gradually reducing regimes of estradiol over 12 days in 29 women with a history of bipolar or schizoaffective disorder. Three different starting doses, administered within 48 h of delivery, were used: transdermal es- tradiol 200 mg, 400 mg, and 800 mg for 24 h. The dose was then halved every 4 days over 12 days. The study program began with the 200 µg starting dose, but as relapse rates appeared not to be reduced, this was increased to 400 µg and then 800 µg. No difference was found between the relapse rates in this study sample, or in subsamples, and the expected rates. However, among the women who did relapse, those who had received the higher-dose regime (starting at 800 µg/day) had significantly shorter hospital stays and possibly smaller (though not significantly) doses of antipsychotic medication.

No differences in estradiol levels were found between women who did and did not relapse. This is intriguing as it appears to contradict the findings of Ahokas et al., all of whose subjects had low estradiol levels. At least two factors may explain this apparent discrepancy.

Firstly, estradiol levels remain elevated soon after childbirth, 2–3 times the normal luteal phase levels. Secondly, it may be that there is a subgroup of women with these disorders who have low levels and who respond to estradiol treatment. It is not clear from the reports by Ahokas et al. whether their samples might have been selected on the basis of low levels and therefore constitute such a subgroup.

The apparent lack of a prophylactic effect of estrogen found by

Kumar et al. (2002), which is in stark contrast to the findings described by Hamilton and Sichel (1992) and those of Sichel et al.

(1995), also demands explanation. The authors do not attempt to address this issue. At present, the paucity of evidence in this area allows multiple hypotheses: (a) type-I or type-II errors in the studies (which are small and uncontrolled); (b) differences in dosages, prepa- rations, and regimes; and (c) possible sampling differences exposing important heterogeneity in the population.

Implications for Clinical Practice

Although the current state of knowledge is clearly still in its infancy, some tentative conclusions can be drawn that may be of relevance in the clinical setting. Firstly, the accumulated evidence and the findings of one randomized controlled trial support the efficacy of estradiol in the treatment of postpartum depression. Small, uncon- trolled case series also suggest that it may be effective for the treatment of puerperal psychosis and prevention of depression and psychosis. Trials so far have concentrated on moderate to severe and resistant cases of depression, and we therefore do not have evidence on effectiveness in mild to moderate depression. It seems that a response is usually seen within the first 4 weeks of treatment and, in some women, within a few days. It also appears that benefit from treatment is maintained following discontinuation of treatment after 6 months. There is no evidence of a disadvantage in combined treatment with antidepressants; however, it is not clear whether this confers any additional benefit, and so far there have been no compa- rative trials to tell us whether treatment with either one of these substances alone is superior to the other.

Given the very limited evidence at present, clinical use of

estradiol should most likely be restricted to moderate to severe and

resistant cases of postpartum depression, probably including those

with psychotic features. Estradiol treatment can also be appropriate

for women who have a particularly strong history of postpartum

depressive illness and those who tend to be well during pregnancy,

or have a history of premenstrual mood disorder or other history

suggestive of responsivity to estrogens. It may also be appropriate to

offer this treatment to women who refuse or will not engage with

any other form of treatment but are prepared to consider a hormonal

approach. Although one research group has provided data suggestive

of an association between response to treatment and low baseline estrogen levels, this may not be consistent with findings from other studies.

Research Implications

Research in this area is still in its infancy, but so far it does seem to suggest tantalizing opportunities for a better understanding of one of the elements of the complex processes underlying our mental state and may even offer effective new intervention strategies in a range of mental disorders. A few specific findings on neurotransmitter effects in animal studies need extending and of course, as much as possible, assumptions about generalization to humans need testing.

At present, the very best evidence of clinical applications comes from single, randomized, controlled studies with relatively small numbers that are unable to provide anything more than evidence on overall efficacy. We now need further preliminary randomized trials of this type across the range of disorders, but more importantly, larger trials, not only for replication but also to yield more detailed and clinically useful data. The questions which clinicians need answers to, in addition to efficacy in particular disorders, include:

• Are estrogens effective in prophylaxis?

• Which individual factors predict response?

• What are the long-term outcomes for mother and child?

• What are the dose–response relationships?

• What are the minimum and optimum durations of treatment?

• What are the undesirable effects in various patient populations?

• Are there short- or long-term effects on infants if used during breastfeeding?

Answers to some of these questions, hopefully available in the next few years, could reveal not only new insights into etiological processes but also open up a potentially exciting new area of treatment and prevention.

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