Introduction: Premenstrual Dysphoric Disorder (PMDD) is a condition that affects about 2-6% of women of reproductive age. The relation to ovarian steroids is apparent as symptoms are absent during anovulatory cycles. Neuroactive steroids like allopregnanolone have effect in the brain and on brain function and have been proposed to play an important role for the symptomatology of premenstrual symptoms and in the interaction between the GABAA receptor and alcohol. High doses of alcohol elevate allopregnanolone levels both in rats and humans. Allopregnanolone is a positive modulator of the GABAA receptor with sedative, anxiolytic and anticonvulsant effect in both human and animals. Aims: The aim was to investigate if a low dose (100μg) of GnRH agonist (buserelin) is effective for the treatment of PMDD and if allopregnanolone serum levels during treatment are associated to symptom severity. Furthermore, the studies aimed at investigating the effect of a low dose of alcohol upon saccadic eye movements in women with PMDD, and control subjects in different phases of the menstrual cycle, and to evaluate if there was a difference in response to alcohol between men and healthy women. We also wanted to see if this low dose of alcohol could have an effect on serum allopregnanolone levels in women with PMDD and control subjects in the follicular and luteal phases of the menstrual cycle. Methods: The effect of low dose (100μg) of GnRH agonist (buserelin) on premenstrual symptoms was evaluated in a randomized, placebo controlled, double-blinded cross-over trial. 27 PMDD patients were randomized to either GnRH agonist intranasally once a day or placebo for two months before the crossover. The main outcome measure was the daily symptom ratings for mood and physical symptoms made by the patients. In a subgroup of 12 women, grouped as buserelin responders and placebo responders, luteal phase serum progesterone, allopregnanolone, and pregnanolone was measured together with daily ratings for mood and physical symptoms. Alcohol responsiveness was measured in PMDD patients, female control subjects and men by comparing the effect of a low dose (0.2g/kg) of intravenous alcohol or placebo infusion upon saccadic eye movements. Blood samples for measurement of allopregnanolone and cortisol were taken throughout the alcohol/placebo challenges. Results: Low dose GnRH agonist was effective as treatment of premenstrual irritability and depression. Anovulatory cycles were confirmed in 56% of the subjects, particularly in older women. Buserelin as well as placebo responders displayed decreased allopregnanolone and progesterone levels in parallel with symptom improvement. PMDD patients displayed blunted saccadic eye movement response to alcohol infusion, especially in the luteal phase. Control subjects did not change their response to alcohol between cycle phases. We found no difference in saccadic eye movement sensitivity to alcohol between males and females. Allopregnanolone levels significantly decreased in the luteal phase following the alcohol infusion. Conclusions: Low dose GnRH agonist is effective in treatment of premenstrual depression and irritability but is likely to induce anovulation with increasing age. Independent of whether buserelin or placebo treatment was given decreased levels of allopregnanolone appear to be related to symptom improvement. Women with PMDD have altered saccadic eye movement sensitivity in response to alcohol, particularly in the luteal phase. The low dose of alcohol did not induce any difference in saccade measurements between males and females. Low dose of alcohol does not result in increased peripheral levels of allopregnanolone.

Background: Premenstrual dysphoric disorder (PMDD) affects 3–8% of women in fertile ages. Combined oral contraceptives (OCs) are widely used and some users experience adverse mood effects. The cyclicity of PMDD symptoms coincides with increased endogenous levels of allopregnanolone after ovulation. Allopregnanolone enhances the effect of γ-aminobutyric acid (GABA) on the GABAA receptor, the principal inhibitory transmitter system in the brain. The sensitivity to other GABAA receptor agonists than allopregnanolone (i.e. benzodiazepines, alcohol and the 5 β epimer to allopregnanolone, pregnanolone) has been reported to depend on menstrual cycle phase and/or PMDD diagnosis. Isoallopregnanolone, the 3 β epimer to allopregnanolone, has previously been used to verify specific allopregnanolone GABAA receptor effects. Saccadic eye velocity (SEV) is a sensitive and objective measurement of GABAA receptor function. Aims: To study the pharmacological effects, and any effect on gonadotropin release, of intravenous allopregnanolone in healthy women. A second aim was to explore whether allopregnanolone sensitivity differs over the menstrual cycle or during OC use in healthy women, and thirdly in PMDD patients. Methods: Ten women were challenged with a cumulative dose of intravenous allopregnanolone in the follicular phase of the menstrual cycle. The effect on FSH and LH was compared to women exposed to isoallopregnanolone. A single dose of allopregnanolone was administered once in the follicular phase and once in the luteal phase in another ten healthy women and in ten PMDD patients, and additionally in ten women using OCs. Repeated measurements of SEV, subjectively rated sedation and serum concentrations after allopregnanolone injections were performed in all studies. Results: Allopregnanolone dose-dependently reduced SEV and increased subjectively rated sedation. Healthy women had a decreased SEV response in the luteal phase compared to the follicular phase. By contrast, PMDD patients had a decreased SEV response and subjectively rated sedation response to allopregnanolone in the follicular phase compared to the luteal phase. There was no difference in the SEV response to allopregnanolone between women using oral contraceptives and healthy naturally cycling women. Allopregnanolone decreased serum levels of FSH and LH whereas isoallopregnanolone did not affect FSH and LH levels. Conclusion: Intravenous allopregnanolone was safely given and produced a sedative response in terms of SEV and subjectively rated sedation in women. The sensitivity to allopregnanolone was associated with menstrual cycle phase, but in the opposite direction in healthy women compared to PMDD patients. The results suggest mechanisms of physiological tolerance to allopregnanolone across the menstrual cycle in healthy women and support that PMDD patients have a disturbed GABAA receptor function. In addition, one of our studies suggests that allopregnanolone might be involved in the mechanism behind hypothalamic amenorrhea.

Background: Estrogen has been reported to enhance well-being and quality of life during the climacteric phase. In women with an intact uterus estrogen treatment is always combined with progestins in order to protect the endometrium from hyperplasia and malignancies. However, in certain women the addition of progestins causes cyclicity in negative mood symptoms and physical symptoms similar to those encountered during ovulatory cycles in women with premenstrual dysphoric disorder (PMDD). The ovarian hormones estradiol and progesterone have profound effects on a number of neurotransmitter systems in the brain, such as the gamma aminobutyric acid (GABA) system and the serotonergic system. Progesterone metabolites, such as allopregnanolone and pregnanolone (also referred to as neurosteroids) modify the GABAA receptor in the central nervous system (CNS) and enhance GABAergic inhibitory transmission. Neurosteroid sensitivity in human studies can be studied by saccadic eye movement measurements using pharmacodynamic challenges with pregnanolone. Altered neurosteroid sensitivity has been suggested as a possible contributory factor to the progesterone/progestin-induced adverse mood effects of hormone replacement therapy (HRT). There is also evidence of estrogen treatment affecting the serotonergic system in postmenopausal women, although progestin addition has been less well studied. Aims and method: The aim was to investigate whether the negative mood symptoms experienced during the progestin or progesterone phase of HRT were associated with changes in neurosteroid sensitivity, or changes in platelet serotonin uptake site (transporter) and serotonin2A (5-HT2A) receptor binding. The intention was also to investigate whether hormonal changes during the normal menstrual cycle affect these peripheral serotonergic parameters. Postmenopausal women with climacteric symptoms were given HRT in two randomized, double-blinded, placebo-controlled crossover studies. The women received 2 mg estradiol (E2) continuously during 28- day cycles. Synthetic progestins or natural progesterone were added sequentially during the last 14 days, and compared to a placebo addition. Before treatment, as well as during the last week of each treatment cycle the pharmacodynamic response to pregnanolone was assessed using saccadic eye movement measurements. Throughout the studies daily symptom ratings were made. In the study regarding synthetic progestins, platelet serotonin transporter and 5-HT2A receptor binding were assayed before entering the study, as well as during the last week of each treatment cycle. In the study on reproductive women, blood samples were collected for analysis of platelet serotonin transporter and 5-HT2A receptor binding at six different points in time during the menstrual cycle. Results and conclusion: The addition of synthetic progestins to estrogen treatment increased negative mood symptoms and physical symptoms, whereas positive symptoms decreased. The addition of progestins also increased the sensitivity to pregnanolone. The addition of natural progesterone to estrogen treatment increased the sensitivity to pregnanolone. However, in this study the pregnanolone sensitivity was enhanced also during estrogen treatment. Women expressing cyclicity in negative mood symptoms were more sensitive to pregnanolone than women without symptom cyclicity. Thus, it is evident that mood deterioration during HRT is associated with altered neurosteroid sensitivity. Platelet serotonin transporter and 5-HT2A receptor binding did not change during the different treatment conditions in HRT. Thus, we were unable to explain the negative mood changes of HRT by use of these peripheral serotonergic parameters. In the study on reproductive women however, it was clear that the serotonergic variables did change during the menstrual cycle. Binding to the serotonin transporter was higher in the late follicular phase than in the ovulatory, early luteal or mid-luteal phases. Binding to the 5-HT2A receptor was higher in the early follicular phase and the early luteal phase than in the mid-luteal phase. These findings may provide a link between the ovarian steroids, and the GABAergic and serotonergic neurotransmitter systems, which in turn, could explain part of the specific vulnerability that women have for the development of adverse mood effects during HRT, mood and anxiety disorders and for the deterioration of mood so frequently seen during the luteal phase.