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Allopregnanolone, a GABA-A receptor agonist, decreases gonadotropin levels in women: a preliminary 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.
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2011 (English)In: Gynecological Endocrinology, ISSN 0951-3590, E-ISSN 1473-0766, Vol. 27, no 12, 1087-1093 p.Article in journal (Refereed) Published
Abstract [en]

Animal studies suggest regulatory effects on the hypothalamic-pituitary-gonad axis by allopregnanolone, an endogenous gamma-aminobutyric acid A (GABAA) receptor agonist. Elevated levels of allopregnanolone in women with hypothalamic amenorrhea have been seen. Isoallopregnanolone is an isomer to allopregnanolone, but without GABAA 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 GABAA 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.

Place, publisher, year, edition, pages
Informa Healthcare, 2011. Vol. 27, no 12, 1087-1093 p.
Keyword [en]
FSH, LH, GABA, allopregnanolone, isoallopregnanolone
National Category
Obstetrics, Gynecology and Reproductive Medicine Endocrinology and Diabetes
Identifiers
URN: urn:nbn:se:umu:diva-49369DOI: 10.3109/09513590.2010.540603ISI: 000296777700026OAI: oai:DiVA.org:umu-49369DiVA: diva2:455428
Note

Fulltext publiceras 2012-12-01

Available from: 2011-11-14 Created: 2011-11-10 Last updated: 2017-12-08Bibliographically approved
In thesis
1. GABA-steroid effects in healthy subjects and women with polycystic ovary syndrome
Open this publication in new window or tab >>GABA-steroid effects in healthy subjects and women with polycystic ovary syndrome
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[en]
GABA-steroid effects : in healthy subjects and women with polycystic ovary syndrome
Abstract [en]

Background: The progesterone metabolite allopregnanolone is involved in several clinical conditions in women, e.g. premenstrual dysphoric disorder. It is a very potent GABA-steroid with GABA-A receptor effects similar to other GABA-agonists, e.g. benzodiazepines, and it causes sedation. An objective way to examine effects on the GABA-A receptor in humans is to measure saccadic eye velocity (SEV), which is reduced by GABA-agonists, e.g. allopregnanolone. Animal studies suggest that allopregnanolone is involved in the regulation of gonadotropin secretion via the GABA-A receptor, but this has not been studied in humans. Polycystic ovary syndrome (PCOS) is the most common endocrine disturbance among women of fertile age (5–10%), characterized by polycystic ovaries, menstrual dysfunction, hyperandrogenity, and 50% have obesity. Studies have shown higher allopregnanolone levels in overweight people. PCOS women have increased levels of androstanediol, an androgen metabolite which is an GABA-A receptor agonist. Tolerance often occurs when persons are exposed to high levels of GABAergic modulators. It has not been studied whether GABA-A receptor sensitivity in PCOS women is changed. Another progesterone metabolite, isoallopregnanolone, is the stereoisomere of allopregnanolone but has not been shown to have any GABA-A receptor effect of its own. Instead it has often been used to control steroid specificity to allopregnanolone.

Aims: To compare the effects of allopregnanolone and isoallopregnanolone on gonadotropin secretion. To compare allopregnanolone levels, GABA-A receptor sensitivity to allopregnanolone and effects on gonadotropin secretion in both cycle phases and PCOS conditions. To examine pharmacokinetics and pharmacodynamic properties for isoallopregnanolone.

Method: In the follicular phase healthy women were examined for the effect of allopregnanolone or isoallopregnanolone on gonadotropin secretion. PCOS women and healthy women in both cycle phases were given allopregnanolone and the differences in effects on SEV were examined, as well as changes in serum levels of gonadotropins and allopregnanolone at baseline and during the test day. Pharmacokinetics and GABA-A receptor sensitivity using SEV were explored for isoallopregnanolone in healthy women.

Results: Allopregnanolone decreases gonadotropin serum levels in healthy controls in both cycle phases, but has no effect on gonadotropin secretion in women with PCOS. PCOS women have higher baseline serum levels of allopregnanolone than follicular phase controls, but lower levels than luteal phase controls. PCOS women show greater reduction in SEV to allopregnanolone than controls. Isoallopregnanolone has no effect on gonadotropin secretion. There is an effect of isoallopregnanolone on SEV, explained by a metabolism of isoallopregnanolone into allopregnanolone.

Conclusion: There are significant differences in the GABA-A receptor response to a GABA-steroid in different endocrine conditions in women of fertile age examined with saccadic eye velocity. The GABA-steroid allopregnanolone decreases gonadotropin serum levels in healthy women but not in PCOS women. The lack of effect on gonadotropins by isoallopregnanolone suggests an involvement of the GABA-A receptor.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2011. 70 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1455
Keyword
Allopregnanolone, isoallopregnanolone, gonadotropins, GABA-A receptor, women, polycystic ovary syndrome, saccade
National Category
Obstetrics, Gynecology and Reproductive Medicine
Research subject
Obstetrics and Gynaecology
Identifiers
urn:nbn:se:umu:diva-49375 (URN)978-91-7459-309-9 (ISBN)
Public defence
2011-12-02, Bergasalen, byggnad 27, Norrlands Universitets sjukhus, Umeå, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2011-11-11 Created: 2011-11-10 Last updated: 2011-11-22Bibliographically approved
2. 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)
Opponent
Supervisors
Available from: 2011-11-25 Created: 2011-11-24 Last updated: 2011-11-25Bibliographically approved

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