The steroid metabolome in women with premenstrual dysphoric disorder during GnRH agonist-induced ovarian suppression: effects of estradiol and progesterone addback.

Clinical evidence suggests that symptoms in premenstrual dysphoric disorder (PMDD) reflect abnormal responsivity to ovarian steroids. This differential steroid sensitivity could be underpinned by abnormal processing of the steroid signal. We used a pharmacometabolomics approach in women with prospectively confirmed PMDD (n=15) and controls without menstrual cycle-related affective symptoms (n=15). All were medication-free with normal menstrual cycle lengths. Notably, women with PMDD were required to show hormone sensitivity in an ovarian suppression protocol. Ovarian suppression was induced for 6 months with gonadotropin-releasing hormone (GnRH)-agonist (Lupron); after 3 months all were randomized to 4 weeks of estradiol (E2) or progesterone (P4). After a 2-week washout, a crossover was performed. Liquid chromatography/tandem mass spectrometry measured 49 steroid metabolites in serum. Values were excluded if >40% were below the limit of detectability (n=21). Analyses were performed with Wilcoxon rank-sum tests using false-discovery rate (q<0.2) for multiple comparisons. PMDD and controls had similar basal levels of metabolites during Lupron and P4-derived neurosteroids during Lupron or E2/P4 conditions. Both groups had significant increases in several steroid metabolites compared with the Lupron alone condition after treatment with E2 (that is, estrone-SO4 (q=0.039 and q=0.002, respectively) and estradiol-3-SO4 (q=0.166 and q=0.001, respectively)) and after treatment with P4 (that is, allopregnanolone (q=0.001 for both PMDD and controls), pregnanediol (q=0.077 and q=0.030, respectively) and cortexone (q=0.118 and q=0.157, respectively). Only sulfated steroid metabolites showed significant diagnosis-related differences. During Lupron plus E2 treatment, women with PMDD had a significantly attenuated increase in E2-3-sulfate (q=0.035) compared with control women, and during Lupron plus P4 treatment a decrease in DHEA-sulfate (q=0.07) compared with an increase in controls. Significant effects of E2 addback compared with Lupron were observed in women with PMDD who had significant decreases in DHEA-sulfate (q=0.065) and pregnenolone sulfate (q=0.076), whereas controls had nonsignificant increases (however, these differences did not meet statistical significance for a between diagnosis effect). Alterations of sulfotransferase activity could contribute to the differential steroid sensitivity in PMDD. Importantly, no differences in the formation of P4-derived neurosteroids were observed in this otherwise highly selected sample of women studied under controlled hormone exposures.

Binge eating and purging in young women with IDDM.

Case reports and empirical studies suggest that young women with insulin-dependent diabetes mellitus (IDDM) may be at high risk for developing eating disorders. In this study, self-reports of binge eating and purging from 59 IDDM women (aged 18-30 yr) were obtained. Most participants (58%) reported that they went on eating binges, and 12% met the DSM-III criteria for a diagnosis of bulimia. Nearly 40% admitted to controlling their weight by insulin purging, and 13.5% reported purging by other means. A group of bulimic participants had mean scores on an eating disorder questionnaire in the pathological range. Bulimic symptoms were positively related to reports of hospitalizations, episodes of ketoacidosis, and psychological symptoms. Implications of these results on the medical management of young women with IDDM are discussed.

Sexually dimorphic behavioral and brain asymmetries in neonatal rats: effects of prenatal alcohol exposure.

Behavioral and neuroanatomical asymmetries were assessed in 3-day-old male and female rat pups chosen from litters whose dams had received one of 3 prenatal treatments: 35% ethanol-derived calories, pair-fed control, or lab chow control. Behavioral laterality was assessed by observing the preferred tail bias on postnatal (PN) day 1. On PN day 3, brains were sectioned and morphometric analyses conducted for total brain volume, left and right neocortical volumes, and left and right hippocampal volumes. Prenatal alcohol exposure altered the population proportions of left, right and neutral tail biases in male pups on PN day 1. Female pups were affected by both prenatal alcohol exposure and maternal undernutrition/stress of pair-feeding. Prenatal alcohol exposure decreased body weight and total brain volume, but increased the brain volume/body weight ratio compared to both control groups. Prenatal alcohol exposure also reduced the volumes of the hippocampus and neocortex, with the greatest proportional reduction found in the volume of the anterior neocortex. A left-right anterior neocortical asymmetry was observed, with tail bias, prenatal treatment and sex all significant factors. Alcohol-exposed males showed a 'feminized' asymmetry. These results demonstrate that a sexually dimorphic cerebral asymmetry can be detected at birth in rats; this asymmetry appears to be related to a postural position bias. The reversal of normal interhemispheric relations by prenatal alcohol exposure in male offspring suggested that the in utero hormonal milieu modulates the development of cerebral lateralization.