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Women with premenstrual dysphoric disorder have altered sensitivity to allopregnanolone over the menstrual cycle compared to controls — a pilot study
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
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2016 (English)In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 233, no 11, 2109-2117 p.Article in journal (Refereed) Published
Abstract [en]

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 GABA(A) receptor, enhancing the effect of gamma-aminobutyric acid (GABA). Previous studies have demonstrated different sensitivity to other GABA(A) receptor agonists, i.e., benzodiazepines, alcohol, and pregnanolone, in PMDD patients compared to controls.

This study aimed to investigate the sensitivity to intravenous allopregnanolone over the menstrual cycle in PMDD patients.

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 GABA(A) receptor activity, at baseline and repeatedly after the injection. A mixed model was used to analyze data.

There was a highly significant group x 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).

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.

Place, publisher, year, edition, pages
2016. Vol. 233, no 11, 2109-2117 p.
Keyword [en]
Neurosteroid, GABA, Premenstrual dysphoric disorder, Saccadic eye velocity, Menstrual cycle
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
URN: urn:nbn:se:umu:diva-50057DOI: 10.1007/s00213-016-4258-1ISI: 000376102100009OAI: oai:DiVA.org:umu-50057DiVA: diva2:458834
Note

Originally included in thesis in manuscript form

Available from: 2011-11-24 Created: 2011-11-24 Last updated: 2017-12-08Bibliographically 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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