Women with premenstrual dysphoric disorder have altered sensitivity to allopregnanolone over the menstrual cycle compared to controls-a pilot study.

RATIONALE: In premenstrual dysphoric disorder (PMDD), a condition that afflicts 3-8 % of women in fertile ages, the cyclic recurrence of debilitating mood symptoms is restricted to the luteal phase of the menstrual cycle. The progesterone metabolite allopregnanolone is produced by the corpus luteum, and circulating levels are reflected in the brain. Allopregnanolone is a modulator of the GABAA receptor, enhancing the effect of γ-aminobutyric acid (GABA). Previous studies have demonstrated different sensitivity to other GABAA receptor agonists, i.e., benzodiazepines, alcohol, and pregnanolone, in PMDD patients compared to controls. OBJECTIVES: This study aimed to investigate the sensitivity to intravenous allopregnanolone over the menstrual cycle in PMDD patients. METHODS: Allopregnanolone, 0.05 mg/kg, was administered intravenously once in the mid-follicular and once in the luteal phase of the menstrual cycle to 10 PMDD patients and 10 control subjects. The saccadic eye velocity (SEV) was recorded by electrooculography as a measurement of functional GABAA receptor activity, at baseline and repeatedly after the injection. A mixed model was used to analyze data. RESULTS: There was a highly significant group × phase interaction in the SEV response to allopregnanolone (F(1,327.489) = 12.747, p < 0.001). In the PMDD group, the SEV response was decreased in the follicular phase compared to the luteal phase (F(1,168) = 7.776, p = 0.006), whereas in the control group, the difference was opposite during the menstrual cycle (F(1,158.45) = 5.70, p = 0.018). CONCLUSIONS: The effect of exogenous allopregnanolone is associated with menstrual cycle phase in PMDD patients and in controls. The results suggest an altered sensitivity to allopregnanolone in PMDD patients.

Women with PTSD have a changed sensitivity to GABA-A receptor active substances.

RATIONALE: The use of benzodiazepines in treating anxiety symptoms in patients with posttraumatic stress disorder (PTSD) has been debated. Studies on other anxiety disorders have indicated changed sensitivity to GABA-A receptor active substances. OBJECTIVE: In the present study, we investigated the GABA receptor sensitivity in PTSD patients. METHODS: Injections of allopreganolone, diazepam, and flumazenil were carried out, each on separate occasions, in 10 drug naïve patients with PTSD compared to 10 healthy controls. Effects were measured in saccadic eye velocity (SEV) and in subjective ratings of sedation. RESULTS: The PTSD patients were less sensitive to allopregnanolone compared with healthy controls. This was seen as a significant difference in SEV between the groups (p = 0.047). Further, the patients were less sensitive to diazepam, with a significant less increase in sedation compared to controls (p = 0.027). After flumazenil injection, both patients and controls had a significant agonistic effect on SEV, leading to decreased SEV after injection. The patients also responded with an increase in sedation after flumazenil injection, while this was not seen in the controls. CONCLUSIONS: Patients with PTSD have a changed sensitivity to GABA-A receptor active substances. As a consequence of this, benzodiazepines and other GABA-A receptor active compounds such as sleeping pills will be less useful for this group of patients.

Women with polycystic ovary syndrome have elevated serum concentrations of and altered GABA(A) receptor sensitivity to allopregnanolone.

OBJECTIVE: Several studies have reported that γ-aminobutyric acid (GABA) ergic circuits are involved in the pathophysiology of polycystic ovary syndrome (PCOS). The progesterone metabolite allopregnanolone is a potent GABA(A) -receptor-modulating steroid, and patients may have increased concentrations of allopregnanolone or altered GABAA receptor sensitivity. We investigated both of these possibilities in this study. PATIENTS: We enrolled 9 women with PCOS and 24 age-matched eumenorrhoeic controls, who were divided into two groups by body mass index (BMI) (16 normal weight and 8 overweight). MEASUREMENTS: We investigated the effects of allopregnanolone injection on GABA(A) receptor sensitivity in both groups of women. All women received a single intravenous dose of allopregnanolone (0·050 mg/kg). GABA(A) receptor sensitivity was assessed with the saccadic eye velocity (SEV) over 30° (SEV30°), the SEV30°/allopregnanolone concentration ([Allo]) ratio, and sedation, which were measured together with serum allopregnanolone at intervals for 180 min after injection. The controls were tested in the follicular phase of the menstrual cycle. RESULTS: Baseline allopregnanolone concentrations were higher in the PCOS women than in the normal-weight (P = 0·034) and overweight controls (P = 0·004). The allopregnanolone concentrations after injection were higher in the PCOS women (P = 0·006) and overweight controls (P = 0·037) than in the normal-weight controls. All groups showed a decline in the SEV30°/[Allo] ratio after injection. Allopregnanolone had a smaller effect on the SEV30°/[Allo] ratio in the overweight women (PCOS, P = 0·032; controls, P = 0·007) than in the normal-weight controls. The sedation score after allopregnanolone injection was lower in the PCOS patients than in the controls, but was not different between the two control groups. CONCLUSIONS: PCOS women had elevated baseline allopregnanolone concentrations compared with follicular-phase controls. All overweight women (PCOS and controls) were less sensitive to allopregnanolone than normal-weight controls.

Isoallopregnanolone antagonize allopregnanolone-induced effects on saccadic eye velocity and self-reported sedation in humans.

Allopregnanolone (AP) is an endogenous neurosteroid. It modulates the effect of γ-amino-butyric acid (GABA) on the GABA type A (GABAA) receptor, which leads to increased receptor activity. Since the GABA-system is mainly inhibitory, increased AP activity leads to modulation of neuronal activity. In vitro studies of GABAA receptor activity and in vivo animal studies of sedation have shown that AP-induced effects can be inhibited by another endogenous steroid, namely isoallopregnanolone (ISO). In this study we investigated if ISO can antagonize AP-induced effects in healthy female volunteers, via measurements of saccadic eye velocity (SEV) and self-rated sedation. With a single-blind cross-over design, 12 women were studied on three separate occasions; given AP alone or AP in combination with one of two ISO doses. Congruent with previous reports, AP administration decreased SEV and induced sedation and these effects were diminished by simultaneous ISO administration. Also, the ISO effect modulation was seemingly stronger for SEV than for sedation. These effects were observed already at an ISO dose exposure that was approximately half of that of AP. In conclusion, ISO antagonized AP-induced decrease in SEV and self-reported sedation, probably in a non-competitive manner.

Erratum to: Women with PTSD have a changed sensitivity to GABA-A receptor active substances.

Erratum to: Pyschopharmacology, DOI 10.1007/s00213-014-3776-y . In the original publication of this paper the name of the first author was incorrectly rendered as "Möller AT." In fact, her name is Anna Tiihonen Möller and her family name is Tiihonen Möller. Thus her name should be rendered as "Tiihonen Möller A."

Posttraumatic stress among women after induced abortion: a Swedish multi-centre cohort study.

BACKGROUND: Induced abortion is a common medical intervention. Whether psychological sequelae might follow induced abortion has long been a subject of concern among researchers and little is known about the relationship between posttraumatic stress disorder (PTSD) and induced abortion. Thus, the aim of the study was to assess the prevalence of PTSD and posttraumatic stress symptoms (PTSS) before and at three and six months after induced abortion, and to describe the characteristics of the women who developed PTSD or PTSS after the abortion. METHODS: This multi-centre cohort study included six departments of Obstetrics and Gynaecology in Sweden. The study included 1457 women who requested an induced abortion, among whom 742 women responded at the three-month follow-up and 641 women at the six-month follow-up. The Screen Questionnaire-Posttraumatic Stress Disorder (SQ-PTSD) was used for research diagnoses of PTSD and PTSS, and anxiety and depressive symptoms were evaluated by the Hospital Anxiety and Depression Scale (HADS). Measurements were made at the first visit and at three and six months after the abortion. The 95% confidence intervals for the prevalence of lifetime or ongoing PTSD and PTSS were calculated using the normal approximation. The chi-square test and the Student's t-test were used to compare data between groups. RESULTS: The prevalence of ongoing PTSD and PTSS before the abortion was 4.3% and 23.5%, respectively, concomitant with high levels of anxiety and depression. At three months the corresponding rates were 2.0% and 4.6%, at six months 1.9% and 6.1%, respectively. Dropouts had higher rates of PTSD and PTSS. Fifty-one women developed PTSD or PTSS during the observation period. They were young, less well educated, needed counselling, and had high levels of anxiety and depressive symptoms. During the observation period 57 women had trauma experiences, among whom 11 developed PTSD or PTSS and reported a traumatic experience in relation to the abortion. CONCLUSION: Few women developed PTSD or PTSS after the abortion. The majority did so because of trauma experiences unrelated to the induced abortion. Concomitant symptoms of depression and anxiety call for clinical alertness and support.

The prevalence of posttraumatic stress among women requesting induced abortion.

OBJECTIVES: To describe the prevalence and pattern of traumatic experiences, to assess the prevalence of posttraumatic stress disorder (PTSD) and posttraumatic stress symptoms (PTSS), to identify risk factors for PTSD and PTSS, and to analyse the association of PTSD and PTSS with concomitant anxiety and depressive symptoms in women requesting induced abortion. METHODS: A Swedish multi-centre study of women requesting an induced abortion. The Screen Questionnaire - Posttraumatic Stress Disorder was used for research diagnoses of PTSD and PTSS. Anxiety and depressive symptoms were evaluated by the Hospital Anxiety and Depression Scale (HADS). RESULTS: Of the 1514 respondents, almost half reported traumatic experiences. Lifetime- and point prevalence of PTSD were 7% (95% confidence interval [CI]: 5.8-8.5) and 4% (95% CI: 3.1-5.2), respectively. The prevalence of PTSS was 23% (95% CI: 21.1-25.4). Women who reported symptoms of anxiety or depression when requesting abortion were more likely to have ongoing PTSD or PTSS. Also single-living women and smokers displayed higher rates of ongoing PTSD. CONCLUSIONS: Although PTSD is rare among women who request an induced abortion, a relatively high proportion suffers from PTSS. Abortion seeking women with trauma experiences and existing or preexisting mental disorders need more consideration and alertness when counselled for termination.

Allopregnanolone serum concentrations and diurnal cortisol secretion in women with premenstrual dysphoric disorder.

Most prior studies in patients with premenstrual dysphoric disorder (PMDD) indicate a blunted hypothalamus-pituitary-adrenal axis function. However, the relationship between neuroactive progesterone metabolites, such as allopregnanolone, and hypothalamus-pituitary-adrenal (HPA) axis function in PMDD patients is relatively sparsely studied. The primary aims of this study were to assess diurnal variation in circulating cortisol and low-dose dexamethasone suppression in PMDD patients and healthy controls, and the relationship between these two HPA axis indices and allopregnanolone serum concentrations. Twenty-six women with prospectively defined PMDD and 30 healthy controls were recruited. Participants underwent diurnal sampling for cortisol serum concentrations and a low-dose dexamethasone suppression test. In addition, morning allopregnanolone serum concentrations were determined. There was no difference in diurnal secretion of cortisol and degree of dexamethasone suppression of cortisol between PMDD patients and healthy controls. However, PMDD patients with high allopregnanolone levels displayed blunted nocturnal cortisol levels in comparison with healthy controls who had low allopregnanolone serum concentrations. In women with PMDD, diurnal secretion of cortisol may be influenced by allopregnanolone levels of the luteal phase. This finding may be attributed to timing of blood sampling in the late luteal phase as well as the individual level of allopregnanolone but could potentially explain the discrepancies in results between studies examining HPA axis function in women with PMDD.

Mood and physical symptoms improve in women with severe cyclical changes by taking an oral contraceptive containing 250-mcg norgestimate and 35-mcg ethinyl estradiol.

BACKGROUND: The purpose of this study was to investigate how women without and with different severity of premenstrual symptoms react to treatment with a combined oral contraceptive containing 250-mcg norgestimate/35-mcg ethinyl estradiol (EE). Focus was placed on mood and physical symptoms. STUDY DESIGN: This open, prospective study evaluated 24 women using norgestimate/EE for three cycles in a 21/7 regimen. Symptoms and bleeding pattern were captured by daily ratings on the Cyclicity Diagnoser scale. RESULTS: Women with severe premenstrual mood symptoms improved in summarized negative mood (p<.001) and summarized positive mood (p<.05), as well as in swelling (p<.05) and effect on daily life (p<.05). Women with no or mild or moderate symptoms did not show any significant improvement or deterioration in any symptom after 3 months of treatment. CONCLUSIONS: Norgestimate 250 mcg/EE 35 mcg significantly improved premenstrual summarized negative mood symptoms during 3 treatment months compared to pretreatment in women with severe premenstrual symptoms, together with improvement in positive symptoms, swelling and effect on daily life.

Increased neurosteroid sensitivity--an explanation to symptoms associated with chronic work related stress in women?

Work related psychosocial stress can be accompanied by so called burnout syndrome with symptoms of mental exhaustion, physical fatigue, and cognitive dysfunction. Underlying mechanisms for acquiring burnout syndrome are not clear. Animal studies show that chronic stress is associated with altered release of GABA-A receptor modulating steroids (GAMS), altered composition of the GABA-A receptor and altered sensitivity to GAMS. In the present study we investigated if such changes occur in women with burnout syndrome. We further asked whether flumazenil (a benzodiazepine antagonist, but with positive modulating effects on GABA-A receptors with altered subunit composition) can block the effect of the GAMS allopregnanolone. Ten women with occupational psychosocial stress and burnout syndrome were compared with twelve healthy controls in an experimental setting. Saccadic eye velocity (SEV) was measured after an injection of allopregnanolone, followed by an injection of flumazenil and a second injection of allopregnanolone. The sensitivity to allopregnanolone was significantly higher in the patients compared to controls after the first injection (p=0.04) and the difference increased when the response per allopregnanolone concentration unit was compared (p=0.006). Following the flumazenil injection the burnout patients (p=0.016), but not controls, showed a decrease in SEV and flumazenil acted like a positive modulator that is agonistic. There was no significant difference between the groups after second allopregnanolone injection. In conclusion, patients with work related psychosocial stress and burnout syndrome show a different response to GABA-A receptor modulators than controls suggesting a changed GABA-A receptor function in these patients. More precisely we hypothesize that the α4 and delta subunits are up-regulated elevating the responsiveness to allopregnanolone and change the effect of flumazenil, which provides a potential explanation to the burnout syndrome. Flumazenil does not block the effect of allopregnanolone.

How to determine symptom severity in premenstrual syndrome: a combination of daily symptom ratings and interviews.

OBJECTIVE: To investigate how premenstrual symptoms are experienced and affect daily life, and to see if there is an agreement in reported symptom severity based on interviews compared to ratings on a symptom rating scale. STUDY DESIGN: Twenty-two women with different degree of premenstrual symptoms were interviewed about their symptoms. Based on the luteal-phase interviews, they were categorized in four different severity groups: severe (n=5), moderate (n=3), mild (n=8), and no symptoms/cyclicity (n=6). The interviews were then compared with rated symptom scores, number of expressed symptoms per day, number of days with symptoms, and daily life impairment. MAIN OUTCOME MEASURES: Agreement between rated symptom scores and reported symptoms in the interviews. RESULTS: Comparing seven days in luteal phase scorings with interview data the group with no symptoms/cyclicity showed high agreement between severities reported in the interviews and daily rated scores. Among women who reported severe symptoms, an agreement was seen in three out of five. In the mild/moderate group, the agreement was less conclusive. The day of interview there was a high agreement between data from the reported symptom ratings and symptoms reported in the interview. CONCLUSION: Rated symptom scores the day of interview reflects well symptoms reported in the interviews. Mean symptom scores for seven luteal phase days showed an agreement between symptom ratings and symptoms expressed in interviews among women with severe symptoms and no symptoms/cyclicity. In the group with mild/moderate symptoms, data was less conclusive.

Prevalence of violence exposure in women with premenstrual dysphoric disorder in comparison with other gynecological patients and asymptomatic controls.

OBJECTIVE: The aim of the present study was to estimate prevalence rates of physical, emotional and sexual abuse in women with premenstrual dysphoric disorder (PMDD) in comparison with gynecological outpatients and asymptomatic healthy control subjects. DESIGN: Cross-sectional study. SETTINGS: Departments of obstetrics and gynecology in three different Swedish hospitals. POPULATION: Fifty-eight women meeting strict criteria for PMDD, a control group of 102 women seeking care at the gynecological outpatient clinic (ObGyn controls) and 47 asymptomatic healthy control subjects were included in this study. METHODS: The Swedish version of the Abuse Assessment Screen was used to collect information on physical and sexual abuse, and the screening instrument was administered as a face-to-face interview. MAIN OUTCOME MEASURES: Previous and ongoing physical and sexual abuse. RESULTS: Any lifetime abuse (physical, emotional or sexual) was reported by 31.0% of PMDD patients, by 39.2% of ObGyn controls and by 21.3% of healthy controls. The ObGyn controls reported physical and/or emotional abuse significantly more often than PMDD patients as well as healthy controls (p<0.05). Lifetime sexual abuse was reported significantly more often by ObGyn controls than by healthy controls (p<0.05). CONCLUSIONS: Patients with PMDD appear not to have suffered physical, emotional or sexual abuse to a greater extent than other gynecological patients or healthy control subjects. However, exposure to violence was common in all groups of interviewed women, and for the individual patient these experiences may contribute to their experience of symptoms.

Allopregnanolone, a GABAA receptor agonist, decreases gonadotropin levels in women. A preliminary study.

Animal studies suggest regulatory effects on the hypothalamic-pituitary-gonad axis by allopregnanolone, an endogenous gamma-aminobutyric acid A (GABA(A)) receptor agonist. Elevated levels of allopregnanolone in women with hypothalamic amenorrhea have been seen. Isoallopregnanolone is an isomer to allopregnanolone, but without GABA(A) receptor effects. The purpose of this study was to investigate effects of allopregnanolone and isoallopregnanolone on gonadotropin levels in healthy women of fertile age. Ten women were given allopregnanolone and five women isoallopregnanolone intravenously in follicular phase. Repeated blood samples were drawn during the test day. Main outcomes were changes in serum levels of follicle-stimulating hormone (FSH), luteinising hormone (LH), oestradiol, and progesterone. Serum-FSH decreased between 5 and 105 min after the allopregnanolone injection (F(16,144)=2.18, p=0.008). Serum-LH was reduced between 5 and 35 min following the allopregnanolone injection (F(16,144)=2.63, p=0.001). Serum-oestradiol and -progesterone were not significantly changed after allopregnanolone injections. No effect on gonadotropin levels were seen after administration of isoallopregnanolone. Allopregnanolone reduces FSH and LH levels in women and the effect might be mediated via a specific GABA(A) receptor activation since isoallopregnanolone lacked this effect. Although the number of women was small, the results suggest a regulatory mechanism on the hypothalamic-pituitary-gonadal axis by allopregnanolon.

Evaluation of different add-back estradiol and progesterone treatments to gonadotropin-releasing hormone agonist treatment in patients with premenstrual dysphoric disorder.

OBJECTIVE: The aim of this study was to investigate which add-back hormone replacement therapy would be most beneficial in terms of mood effects for patients with premenstrual dysphoric disorder who are receiving gonadotropin-releasing hormone agonist therapy. STUDY DESIGN: Three different add-back hormone replacement treatments were evaluated in a randomized, double-blinded, cross-over clinical trial in 27 patients premenstrual dysphoric disorder. The add-back treatments consisted of 1.5 mg estradiol and 400 mg progesterone, 1.5 mg estradiol and placebo, and 0.5 mg estradiol and 400 mg progesterone. The primary outcome measure was daily symptom ratings for mood and physical symptoms. RESULTS: The highest dose of estradiol in combination with progesterone was associated with the most pronounced symptom recurrence, both in comparison with a lower dose of estradiol together with progesterone and estradiol-only treatment. CONCLUSION: Based on the findings of the present study, long-cycle add-back treatment to avoid frequent progestagen use appears to be most beneficial for patients with premenstrual dysphoric disorder.

Sex steroid induced negative mood may be explained by the paradoxical effect mediated by GABAA modulators.

UNLABELLED: Certain women experience negative mood symptoms as a result of progesterone during the luteal phase of the menstrual cycle, progestagens in hormonal contraceptives, or the addition of progesterone or progestagens in sequential hormone therapy (HT). This phenomenon is believed to be mediated via the action of the progesterone metabolites on the GABA(A) system, which is the major inhibitory system in the mammalian CNS. The positive modulators of the GABA(A) receptor include allopregnanolone and pregnanolone, both neuroactive metabolites of progesterone, as well as benzodiazepines, barbiturates, and alcohol. Studies on the effect of GABA(A) receptor modulators have shown contradictory results; although human and animal studies have revealed beneficial properties such as anaesthesia, sedation, anticonvulsant effects, and anxiolytic effects, recent reports have also indicated adverse effects such as anxiety, irritability, and aggression. It has actually been suggested that several GABA(A) receptor modulators, including allopregnanolone, have biphasic effects, in that low concentrations increase an adverse, anxiogenic effect whereas higher concentrations decrease this effect and show beneficial, calming properties. The allopregnanolone increase during the luteal phase in fertile women, as well as during the addition of progesterone in HT, has been shown to induce adverse mood in women. The severity of these mood symptoms is related to the allopregnanolone serum concentrations in a manner similar to an inverted U-shaped curve. Negative mood symptoms occur when the serum concentration of allopregnanolone is similar to endogenous luteal phase levels, while low and high concentrations have less effect on mood. It has also been shown that progesterone/allopregnanolone treatment in women increases the activity in the amygdala (as measured with functional magnetic resonance imaging) in a similar way to the changes seen during anxiety reactions. However, it is evident that only certain women experience adverse mood during progesterone or GABA(A) receptor modulator treatments. Women with premenstrual dysphoric disorder (PMDD) have severe luteal phase related symptoms; in this phase, they show changes in GABA(A) receptor sensitivity and GABA concentrations that are related to the severity of the condition. These findings suggest that negative mood symptoms in women with PMDD are caused by the paradoxical effect of allopregnanolone mediated via the GABA(A) receptor. CONCLUSION: Progesterone and progestagens induce negative mood, most probably via their GABA(A) receptor active metabolites. In postmenopausal women treated with progesterone and animals treated with allopregnanolone, there is a bimodal association between serum allopregnanolone concentration and adverse mood, resembling an inverted U-shaped curve. In humans, the maximal effective concentration of allopregnanolone for producing negative mood is within the range of physiological luteal phase serum concentrations.

Studies of pharmacokinetic and pharmacodynamic properties of isoallopregnanolone in healthy women.

RATIONALE: The pharmacokinetics and behavioral effects of isoallopregnanolone (3beta-hydoxy-5alpha-pregnan-20-one) in women are not known. OBJECTIVES: Allopregnanolone (3alpha-hydoxy-5alpha-pregnan-20-one) is a well-known neurosteroid, acting via the GABA(A) receptor in the human brain. The naturally occurring progesterone metabolite isoallopregnanolone is the 3beta-stereoisomer of allopregnanolone. Prior studies have concluded that isoallopregnanolone has no effect on the GABA(A) receptor. However, an antagonistic effect of isoallopregnanolone to allopregnanolone on the GABA(A) receptor has been shown in animal and in vitro studies. The purpose of this study was to evaluate the pharmacokinetics and behavioral effects of isoallopregnanolone in humans. MATERIALS AND METHODS: Six healthy women were given three increasing doses of isoallopregnanolone intravenously in the follicular phase. Repeated blood samples for analyses of isoallopregnanolone and allopregnanolone concentrations were drawn. Saccadic eye movement variables, self-rated sedation, and mood rating scales were used during the test day. A Likert scale for prospective symptoms was used to measure daily fluctuations during the ongoing menstrual cycle. RESULTS: Exogenously administered isoallopregnanolone produced a dose-dependent increase in the serum concentration of isoallopregnanolone. In parallel, there was also a rise in the allopregnanolone concentration. There was a decrease in saccadic eye movement variables, but no effect was found on self-rated sedation or mood and no changes were seen in prospective symptoms during the menstrual cycle. CONCLUSIONS: After administration of isoallopregnanolone at a cumulative dose of 0.20 mg/kg, no adverse effects were observed. There is a metabolism of isoallopregnanolone to allopregnanolone, most likely explaining the effects on the saccadic eye movements.

Allopregnanolone serum concentrations and neurosteroid sensitivity during withdrawal from postmenopausal hormone therapy.

BACKGROUND: We have previously compared the pharmacodynamic response to a neuroactive steroid, pregnanolone, before and during sequential treatment with estradiol-only (E2-only) and estradiol together with progesterone (E2 + P) in postmenopausal women. The aim of the present study was to evaluate the pharmacodynamic response to pregnanolone during withdrawal from E2-only treatment and during withdrawal from treatment with E2 + P. METHOD: Twenty-six postmenopausal women were administered hormone therapy (HT) in a randomized, double blinded, placebo-controlled, crossover study. The women received 2 mg oral estradiol continuously during two 28-day cycles and 800 mg vaginal progesterone or placebo sequentially for the last 14 days of each treatment cycle. The pharmacodynamic response to pregnanolone was assessed during the last week of the last treatment cycle and 48 h after termination of the last treatment cycle (withdrawal) by comparing the effects of intravenous pregnanolone (3alpha-hydroxy-5beta-pregnan-20-one) on saccadic eye movements. RESULTS: During E2-only withdrawal the pregnanolone sensitivity was reduced compared with E2-only treatment. Pregnanolone sensitivity remained unaltered between the combined E2 + P treatment regimen and the withdrawal from these steroids. CONCLUSION: The study indicates that withdrawal from E2-only treatment might change neurosteroid sensitivity, whereas the immediate withdrawal from E2 + P results in unchanged neurosteroid sensitivity.

Allopregnanolone decrease with symptom improvement during placebo and gonadotropin-releasing hormone agonist treatment in women with severe premenstrual syndrome.

BACKGROUND: Neurosteroids such as allopregnanolone and pregnanolone are suggested to be of importance for the pathophysiology of premenstrual dysphoric disorder. The aim of this study was to investigate whether the luteal-phase serum concentrations of these neurosteroids are associated with improvement of premenstrual symptoms in 12 women with severe premenstrual syndrome after treatment with low-dose gonadotropin-releasing hormone agonist and placebo. METHODS: Daily ratings for mood and physical symptoms were made prior to treatment and throughout the study. Serum progesterone, allopregnanolone and pregnanolone were assessed in the luteal phase (cycle day -9 to cycle day -1). Based on their symptom ratings, subjects were grouped as either buserelin responders (n = 6) or placebo responders (n = 6). RESULTS: Buserelin responders displayed decreased levels of allopregnanolone (p < 0.05) and progesterone (p < 0.05) in parallel with improvement of symptoms. During the placebo treatment, the placebo responders had lower serum allopregnanolone concentrations than buserelin responders (p < 0.05). This was associated with improvement in symptoms compared with pre-treatment ratings. CONCLUSION: Treatment response, whether induced by buserelin or placebo, appears to be associated with a decrease in allopregnanolone concentration.

Increased cortisol responsivity to adrenocorticotropic hormone and low plasma levels of interleukin-1 receptor antagonist in women with functional hypothalamic amenorrhea.

OBJECTIVE: To assess the hypothalamic-pituitary-adrenal (HPA) axis at all levels, to determine the origin of the previously reported hypercortisolism in patients with functional hypothalamic amenorrhea. A secondary aim was to evaluate factors outside the central nervous system which are known to affect the HPA axis, i.e., circulating levels of interleukin-6 (IL-6), interleukin-1 receptor antagonist (IL-1Ra), and fat mass-adjusted leptin levels, in patients with functional hypothalamic amenorrhea and healthy controls. DESIGN: Cross-sectional study. SETTING: Umeå University Hospital, Umeå, Sweden. PATIENTS: Fifteen subjects with hypothalamic amenorrhea, and 14 age- and weight-matched controls. INTERVENTIONS: None. MAIN OUTCOME MEASURES: We collected blood samples four times during a 24-hour interval for analysis of cortisol, leptin, IL-1Ra, and IL-6 levels. We performed a low-dose oral dexamethasone test and a low-dose ACTH test. We measured body-fat percentage using a dual-energy X-ray absorptiometer. RESULTS: Patients with hypothalamic amenorrhea had increased diurnal cortisol levels (P<.001). The cortisol response to intravenous low-dose ACTH was increased in functional hypothalamic amenorrhea patients compared to control subjects (P<.01), but they had similar rates of dexamethasone suppression. Patients with hypothalamic amenorrhea also had decreased diurnal leptin (P<.05), and decreased diurnal IL-1Ra levels (P<.05), compared to controls. Body-fat percentage was the main predictor of leptin levels. CONCLUSION: The present study suggests novel links for the development of functional hypothalamic amenorrhea, including increased adrenal responsiveness and impairments in proinflammatory cytokine pathways.