Catherine A. Roca

Estrogen–serotonin interactions: implications for affective regulation

A burgeoning literature documents the convergence of reproductive endocrine and central serotonergic systems in the regulation of a variety of behaviors. This review will focus on one element of this interaction, the modulation of serotonergic function by estrogen. After describing the manifold neuroregulatory effects of gonadal steroids, we summarize the effects of estrogen on central serotonin systems in animals and humans as inferred from studies demonstrating the impact of gender, estrus (or menstrual) cycle, or hormone manipulation. Finally, we summarize the putative roles of estrogen and serotonin in two reproductive-endocrine-related mood disorders: premenstrual syndrome and perimenopausal depression.

Risk for Premenstrual Dysphoric Disorder is Associated with Genetic Variation in ESR1, the Estrogen Receptor Alpha Gene

BACKGROUND Premenstrual dysphoric disorder (PMDD) is a heritable mood disorder that is triggered by gonadal steroids during the luteal phase in susceptible women. METHODS We performed haplotype analyses of estrogen receptors alpha and beta (ESR1 and ESR2) in 91 women with prospectively confirmed PMDD and 56 control subjects to investigate possible sources of the genetic susceptibility to affective dysregulation induced by normal levels of gonadal steroids. We also examined associations with the valine (Val)158methionine (Met) single nucleotide polymorphism (SNP) of the gene for catechol-O-methyltransferase (COMT), an enzyme involved in estrogen metabolism and prefrontal cortical activation. RESULTS Four SNPs in intron 4 of ESR1 showed significantly different genotype and allele distributions between patients and control subjects. Significant case-control differences were seen in sliding-window analyses of two-, three-, and four-marker haplotypes but only in those haplotypes containing SNPs in intron 4 that were positive in the single-locus analysis. No significant associations were observed with ESR2 or with the COMT Val158Met polymorphism, although the significant associations with ESR1 were observed only in those with the Val/Val genotype. CONCLUSIONS These are the first positive (albeit preliminary) genetic findings in this reproductive endocrine-related mood disorder and involve the receptor for a hormone that is pathogenically relevant.

Testosterone Suppression of CRH-Stimulated Cortisol in Men

Despite observations of age-dependent sexual dimorphisms in hypothalamic–pituitary–adrenal (HPA) axis activity, the role of androgens in the regulation of HPA axis activity in men has not been examined. We assessed this role by performing CRH stimulation tests in 10 men (ages 18–45 years) during gonadal suppression with leuprolide acetate and during testosterone addition to leuprolide. CRH-stimulated cortisol levels as well as peak cortisol and greatest cortisol excursion were significantly lower (p<0.05, 0.005, and 0.01, respectively) during testosterone replacement compared with the induced hypogonadal condition (leuprolide plus placebo); cortisol area under the curve was lower at a trend level (p<0.1). Paradoxically, CRH-stimulated corticotropin (ACTH) was increased significantly during testosterone replacement (p<0.05). The cortisol : ACTH ratio, a measure of adrenal sensitivity, was lower during testosterone replacement (p<0.1). A mixed effects regression model showed that testosterone but not estradiol or CBG significantly contributed to the variance of cortisol. These data demonstrate that testosterone regulates CRH-stimulated HPA axis activity in men, with the divergent effects on ACTH and cortisol suggesting a peripheral (adrenal) locus for the suppressive effects on cortisol. Our results further demonstrate that the enhanced stimulated HPA axis activity previously described in young men compared with young women cannot be ascribed to an activational upregulation of the axis by testosterone.

Estrogen receptor alpha (ESR-1) associations with psychological traits in women with PMDD and controls

Premenstrual Dysphoric Disorder (PMDD) is a mood disorder affecting about 5% of women and is associated with substantial morbidity. Albeit inconsistently, PMDD is described as being characterized by heritable personality traits. Although PMDD is a heritable disorder, it is unclear whether any of the heritable susceptibility to PMDD resides in heritable personality traits. In groups of carefully characterized women with PMDD (n=68) and controls (n=56), we attempted to determine whether diagnosis-related traits could be confirmed, as well as to determine whether such traits were associated with SNPs in estrogen receptor alpha (ESR-1) that we previously demonstrated were associated with PMDD. We observed 7/25 traits to be significantly different in patients and controls and further showed that 11/12 significant associations observed between these 7 traits and 16 ESR-1 SNPs involved the intron 4 SNPs previously shown to be the locus of the association with PMDD. While several interactions between genotype and diagnosis were observed, the effect of genotype in most instances was in the same direction in patients and controls. These data demonstrate affective state-independent personality traits that distinguish patients with PMDD from controls and further support the relevance of ESR-1 polymorphic variants in the regulation of non-reproductive behaviors.

Cerebrospinal fluid somatostatin, mood, and cognition in multiple sclerosis

BACKGROUND Cerebrospinal fluid (CSF) somatostatin (SS) levels have been shown to be decreased in multiple sclerosis (MS) during relapse as well as in disorders characterized by depression or cognitive impairment. Since MS is often associated with depression and cognitive impairment, we examined both the effect of course of illness on CSF SS as well as the variance in SS attributable to associated features (e.g., depression or cognitive impairment). METHODS Fifteen patients with chronic progressive MS participating in a 2-year cyclosporine trial underwent lumbar punctures for CSF SS at baseline and at 12 and 24 months. Additionally, patients were evaluated by neuropsychological testing, and physical disability and mood ratings. Baseline CSF SS levels were also obtained in a group of control subjects (n = 10). RESULTS At baseline, CSF SS levels were lower in MS patients than control subjects (p < .001). Decreased CSF SS at 24 months was correlated with decreased cognitive performance on several measures and was best and significantly predicted by cognitive deterioration at 24 months. CONCLUSIONS Our data support those from previous studies that found lower levels of CSF SS in MS during relapse and suggest that changes in CSF SS are related to the process responsible for diminished cognitive function in MS.

Review : Gonadal Steroids and Affective Illness

Gonadal steroids seem to regulate affective state in some people (but not all), despite the absence of abnormal steroid hormone levels or dysfunction of the reproductive endocrine axis. In this article, we attempt to explain this paradox 1) by describing the molecular mechanisms by which gonadal steroids can regulate neuronal function; 2) by describing the specific regulatory impact of gonadal steroids on two systems im plicated in the pathophysiology of mood disorders; and 3) by defining the role of gonadal steroids in several mood disorders linked to periods of reproductive change. We suggest that the context in which the neuro- regulatory actions of gonadal steroids occur determines the impact of steroid signaling on the regulation of affective state. NEUROSCIENTIST 5:227-237, 1999

Estrogens and Depression in Women

Publisher Summary Although the role of estrogen in the treatment of hot flushes has been consistently documented, the relationship between perimenopause-related changes in estrogen and depression remains to be established. In contrast, a considerable literature documents the widespread and important neuroregulatory effects of estrogen in animals, suggesting a neurobiologic basis for several recent reports of the salutary effects of estrogen on mood. This chapter reviews the effects of estrogen on the central nervous system (CNS) and mood; the relationship between perimenopause/postmenopause and depression; and the clinical evaluation and management of depression during the perimenopause. The majority of women do not develop depression during the menopausal transition, and the perimenopause is not uniformly associated with changes in a womans mood. Epidemiologic studies examining gender and age-related differences in the 6-month to 1-year prevalence of major depression report no increased prevalence of major depression in women at midlife. Nonetheless, although the postmenopause is not associated with an increased risk for developing depression in women, depressive symptoms are observed more frequently in perimenopausal women compared with postmenopausal women in several longitudinal, community-based studies as well as in women attending gynecology clinics. The timing of appearance of the depressions observed suggest an endocrine mechanism related to the perimenopause in the pathophysiology of perimenopausal depression.

14. Effects of gonadal steroids on the HPA axis response to stress

We evaluated the effects of hypogonadism and gonadal steroid replacement on measures of CNS physiology and behavior in women with perimenopause-related depression and in three groups of subjects with GnRH agonist (GnRH-A)-induced hypogonadism. Women with perimenopause-related depression participated in a double-blind, placebo-controlled trial of the antidepressant efficacy of estradiol (E2). GnRH-A induced hypogonadism was compared with testosterone (T) replacement in asymptomatic men and progesterone (P4) and E2 replacement in both asymptomatic (AS) women and those with menstrual-related mood disorder (MRMD). Compared to hypogonadism, gonadal steroid replacement was associated with the following: 1) Re-emergence of symptoms in MRMD but not AS controls (E2 or P4, but not placebo); 2) Remission of depressive symptoms in depressed perimenopausal women (E2); 3) Restoration of normal sexual function in men (T) but not women (E2, P4); 4) No effects on neuropsychological test scores in younger women (E2, P4), but decreased visual spatial performance in men (T) and improvement in verbal memory in depressed perimenopausal women (E2); 5) Normalization of cognition activated regional cerebral blood flow in the dorsolateral prefrontal cortex in younger women (E2, P4) and men (T); and 7) Increased m-CPP stimulated prolactin secretion and basal core temperature (P4 only). Our observations demonstrate that sex steroids regulate several measures of CNS function. However, the direction and patterns of effects vary with context including age and gender.