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Neuroactive Steroid±Serotonergic Interaction European Journal of Endocrinology (2001) 145 25±33 ISSN 0804-4643 CLINICAL STUDY Neuroactive steroid±serotonergic interaction: responses to an intravenous L-tryptophan challenge in women with premenstrual syndrome Natalie Rasgon, Mariangela Serra2, Giovanni Biggio2, Maria Giuseppina Pisu2, Lynn Fairbanks, Sahrab Tanavoli and Andrea Rapkin1 Departments of Psychiatry and Biobehavioral Sciences, Neuropsychiatric Institute and 1Obstetrics and Gynecology, UCLA School of Medicine, Los Angeles, California 90095, USA and 2Department of Experimental Biology, University of Cagliari, Italy (Correspondence should be addressed to A Rapkin, Department of Obstetrics and Gynecology, UCLA School of Medicine, Los Angeles, Calfornia 90095-1740, USA; Email: [email protected]) Abstract Objective: To evaluate the circulating concentrations of the neuroactive steroids in response to an i.v. L-tryptophan (L-TP) challenge across the menstrual cycle in women with premenstrual syndrome (PMS) and in controls. Method: An i.v. L-TP challenge was administered eight times during 1 month to five women with prospectively documented PMS and five age- and body mass-matched controls. Progesterone, allopregnanolone pregnenolone and 3a-5a-tetrahydrocorticosterone were assessed 15 and 0 min before, and at 30, 60 and 90 min after the challenge, across the menstrual cycle. Results: In response to L-TP challenge, only allopregnanolone concentrations were significantly increased across the cycle and this increase was of a greater magnitude in women with PMS. Pregnenolone and 3a-5a-tetrahydrocorticosterone concentrations were not affected in women with PMS or controls after L-TP challenge. Conclusions: The data provide evidence for possible interaction between the serotonergic system and the neuroactive steroid, allopregnanolone. Women with PMS demonstrated a more significant increase in allopregnanolone concentrations in response to L-TP challenge, which could be due to an initial low basal serotonergic tone in the luteal phase in the PMS group. European Journal of Endocrinology 145 25±33 Introduction the irritability, anxiety and tension associated with the syndrome (6, 7). In both animal and clinical studies it Serotonergic dysfunction as a potential cause of has been demonstrated that neuroactive steroids dis- premenstrual syndrome (PMS) has been postulated on play anxiolytic, anticonvulsant and mood stabilizing the basis of decreased concentrations of whole-blood effects (8±12). Behavioral effects of neuroactive ster- serotonin and diminished platelet uptake of serotonin oids are mainly determined by their modulation of the (1, 2). This concept has been supported by studies g-aminobutyric acid (GABAA) receptor complex. demonstrating the effectiveness of selective serotonin Progesterone, the progesterone metabolite 3a-5a- reuptake inhibitors (SSRIs) in the treatment of pre- tetrahydroprogesterone (allopregnanolone), and the menstrual dysphoric disorder (PMDD), a severe form of 11-deoxycorticosterone metabolite 3a-5a-tetrahydro- PMS (3, 4). It has been speculated that SSRIs corticosterone (THDOC) are positive allosteric modu- ameliorate PMS symptoms by increasing the central lators of the GABAA receptor, whereas pregnenolone serotonergic tone. However, the exact mechanism is sulfate is a negative allosteric GABAA receptor still not known, as the anxiolytic effect of SSRIs in modulator (9). These neuroactive steroids are produced premenstrual syndrome cannot be fully explained on in the periphery (ovary, adrenals) and de novo in the the basis of augmented serotonergic transmission alone brain (neurosteroids) either from cholesterol or (5). As the symptoms of PMS are maximal in the late through metabolism of blood-borne precursors (10). luteal phase, it has been postulated that allopregnano- It has been suggested that some of the effects of SSRIs lone, a neuroactive anxiolytic metabolite of progester- on mood and seizure threshold could result from one, may be decreased in women with PMS and might increased allopregnanolone production. Recent studies account for some of the symptoms of PMS, in particular have suggested that the administration of SSRIs q 2001 Society of the European Journal of Endocrinology Online version via http://www.eje.org Downloaded from Bioscientifica.com at 09/25/2021 01:51:16PM via free access 26 N Rasgon and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2001) 145 increase allopregnanolone concentrations most prob- (BMI) for all participants was calculated as the weight ably as a result of a direct effect on the enzyme in kilograms divided by the square of the height in 3a-hydroxysteroid oxidoreductase, one of the two meters. Women with a BMI exceeding 25 were enzymes involved in the conversion of progesterone excluded. to allopregnanolone (13, 14). All the women were administered a comprehensive The present study was therefore undertaken to assess psychiatric evaluation, the Structured Clinical Inter- whether alterations in central serotonergic tone view for DSM-IV (19), in the follicular phase of the modulate, by some mechanism, the circulating con- menstrual cycle to confirm the absence of significant centration of allopregnanolone in addition to the current or recent (past 2 years) major psychiatric progesterone precursor pregnenolone in women with illness including substance and alcohol abuse. Those PMS. This was indirectly assessed by evaluating the with PMS who failed to demonstrate moderate to severe plasma allopregnanolone and pregnenolone concen- symptom scores on the daily dairy with at least a 50% trations before and after the administration of increase in a minimum of five symptoms including one L-tryptophan (L-TP), a precursor of serotonin that psychological symptom between the follicular and readily crosses the blood±brain barrier. luteal phases were excluded. Women accepted for We evaluated allopregnanolone and pregnenolone study were required to meet the DSM-IV criteria for concentration before and after L-TP challenge, twice premenstrual dysphoric disorder. None of the women per week for 1 month in women with prospectively recruited into the study was receiving psychoactive documented PMS, and in controls. THDOC is predomi- medications, hormonal preparations (including oral nantly an adrenal-derived metabolite of progesterone contraceptives and thyroid replacement), mineral and corticosterone which has been shown to increase supplements or vitamins within the 3 months before in the brain and plasma after stress (15±17). The pre- or during the study. Eligibility criteria for controls were and post-challenge concentrations of THDOC were the same, except that premenstrual symptoms were therefore also assessed in order to determine whether absent. Once accepted into the study, all the women the changes, if any, in neuroactive steroids were were required to complete the symptom diary for the specifically modulated by L-TP or were due to an ensuing 1 month of the study. increased response caused by stress. Procedure Methods The duration of the challenge study was 1 month. All women were required to abstain from alcohol and to Selection of participants follow a tyramine-free diet for 2 weeks before the Women were recruited through advertisements in challenge phase and throughout the study. All were local newspapers. The study was approved by the required to abstain from food intake for the 12 h Human Subject Protection Committee at the Univer- preceding the test. sity of California, Los Angeles. All gave informed Participants were required to present to the Clinical consent their participation. All prospective partici- Research Center (CRC) at the UCLA Medical Center pants were evaluated for 2 months before acceptance twice a week for four consecutive weeks. They began into the study. During evaluation, the women were the month-long study within a few days of signing a required to complete a daily symptom diary (18). This consent form, irrespective of the day of their last premenstrual diary consists of 11 of the more menstrual period and were encouraged to keep their commonly experienced symptoms of PMS, including visits on the same day of the week (e.g. Thursday± depression, anxiety, mood swings, irritability or anger, Sunday, Tuesday±Friday etc.), to eliminate fluctuations headaches, breast pain, low energy, edema, food in the schedule. cravings, avoidance of social activity, impaired rela- Because actual visits to the CRC were not timed to tionships, and diminished work performance. Each the particular phase of the menstrual cycle data were symptom was rated on a scale of 1 (not at all) to 6 transformed according to the idealized 28-day men- (extreme). strual cycle. The day of luteinizing hormone (LH) surge Eligibility criteria for the PMS group included: age as determined by urinary LH detection test was 18±40 years, history of regular menses with moderate considered as day 0. The follicular phase (inclusive of to severe premenstrual symptoms lasting for at least 1 mid-to-late follicular phases) was considered as ovula- week before menses occurring for at least the previous tion days 212 to 25, the ovulatory phase was 6 months, negative medical history and no use of calculated as ovulation days 24 to +3, and the luteal hormonal preparations including oral contraceptives phase (inclusive of mid-to-late luteal phases) was for at least 6 months before enrollment into the study. calculated as ovulation days +7 to +14. The phase of All women were screened for the absence of significant the menstrual cycle in which blood was
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