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Pharmacokinetic and behavioral effects of allopregnanolone in healthy women
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
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2006 (English)In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 186, no 3, 414-424 p.Article in journal (Refereed) Published
Abstract [en]

Rationale  The behavioral effects of allopregnanolone (3α-hydroxy-5α-pregnan-20-one) in women are not known. Objective  Allopregnanolone, a neuroactive steroid secreted by the mammalian ovary, exerts its anesthetic, anxiolytic, and sedative/hypnotic effects through potentiation of GABAA receptors. The purpose of this study was to evaluate the behavioral effects of allopregnanolone in healthy women. Methods  Ten healthy women were given three increasing intravenous doses of allopregnanolone in the follicular phase of the menstrual cycle. Saccadic eye movement parameters and visual analogue scales of sedation were used to evaluate the behavioral response of allopregnanolone. Repeated blood samples for analyses of allopregnanolone were drawn throughout the study day. Results  Exogenously administered allopregnanolone decreases saccadic eye movement parameters and increases subjective ratings of sedation that correlate with increased serum concentrations of this neuroactive steroid. Conclusion  The behavioral effects of allopregnanolone are similar to that of its 5β-stereoisomer, pregnanolone (3α-hydroxy-5β-pregnan-20-one). Apart from fatigue and mild nausea, allopregnanolone given in a cumulative dose of 0.09 mg/kg did not have any adverse effects.

Place, publisher, year, edition, pages
2006. Vol. 186, no 3, 414-424 p.
Keyword [en]
Adult, Animals, Chickens, Egg Yolk/immunology, Female, Humans, Hypnotics and Sedatives/blood/pharmacokinetics/*pharmacology, Immune Sera/immunology, Immunoglobulins/immunology, Pregnanolone/blood/pharmacokinetics/*pharmacology, Saccades/*drug effects
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
URN: urn:nbn:se:umu:diva-16931DOI: 10.1007/s00213-005-0148-7PubMedID: 16177884OAI: oai:DiVA.org:umu-16931DiVA: diva2:156604
Available from: 2007-10-22 Created: 2007-10-22 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Allopregnanolone effects in women: clinical studies in relation to the menstrual cycle, premenstrual dysphoric disorder and oral contraceptive use
Open this publication in new window or tab >>Allopregnanolone effects in women: clinical studies in relation to the menstrual cycle, premenstrual dysphoric disorder and oral contraceptive use
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2011. 81 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1459
Keyword
Allopregnanolone, GABAA receptor, menstrual cycle, premenstrual dysphoric disorder, saccadic eye velocity, oral contraceptives, hypothalamic amenorrhea
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:umu:diva-50058 (URN)978-91-7459-316-7 (ISBN)
Public defence
2011-12-16, Bergasalen, Södra entrén, byggnad 27, Norrlands universitetssjukhus, Umeå, 09:00 (English)
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Available from: 2011-11-25 Created: 2011-11-24 Last updated: 2011-11-25Bibliographically approved

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