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GABA-steroid effects in healthy subjects and women with polycystic ovary syndrome
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
2011 (English)Doctoral thesis, comprehensive summary (Other academic)Alternative title
GABA-steroid effects : in healthy subjects and women with polycystic ovary syndrome (English)
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 [en]
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: urn:nbn:se:umu:diva-49375ISBN: 978-91-7459-309-9 (print)OAI: oai:DiVA.org:umu-49375DiVA: diva2:455484
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
List of papers
1. Studies of pharmacokinetic and pharmacodynamic properties of isoallopregnanolone in healthy women
Open this publication in new window or tab >>Studies of pharmacokinetic and pharmacodynamic properties of isoallopregnanolone in healthy women
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2009 (English)In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 203, no 1, 85-98 p.Article in journal (Refereed) Published
Abstract [en]

Rationale  The pharmacokinetics and behavioral effects of isoallopregnanolone (3β-hydoxy-5α-pregnan-20-one) in women are not known. Objectives  Allopregnanolone (3α-hydoxy-5α-pregnan-20-one) is a well-known neurosteroid, acting via the GABAA receptor in the human brain. The naturally occurring progesterone metabolite isoallopregnanolone is the 3β-stereoisomer of allopregnanolone. Prior studies have concluded that isoallopregnanolone has no effect on the GABAA receptor. However, an antagonistic effect of isoallopregnanolone to allopregnanolone on the GABAA receptor has been shown in animal and in vitro studies. The purpose of this study was to evaluate the pharmacokinetics and behavioral effects of isoallopregnanolone in humans.

Materials and methods  Six healthy women were given three increasing doses of isoallopregnanolone intravenously in the follicular phase. Repeated blood samples for analyses of isoallopregnanolone and allopregnanolone concentrations were drawn. Saccadic eye movement variables, self-rated sedation, and mood rating scales were used during the test day. A Likert scale for prospective symptoms was used to measure daily fluctuations during the ongoing menstrual cycle.

Results  Exogenously administered isoallopregnanolone produced a dose-dependent increase in the serum concentration of isoallopregnanolone. In parallel, there was also a rise in the allopregnanolone concentration. There was a decrease in saccadic eye movement variables, but no effect was found on self-rated sedation or mood and no changes were seen in prospective symptoms during the menstrual cycle.

Conclusions  After administration of isoallopregnanolone at a cumulative dose of 0.20 mg/kg, no adverse effects were observed. There is a metabolism of isoallopregnanolone to allopregnanolone, most likely explaining the effects on the saccadic eye movements.

Keyword
Isoallopregnanolone, Neurosteroids, Pharmacokinetics, Pharmacodynamics, Women
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:umu:diva-49365 (URN)10.1007/s00213-008-1372-8 (DOI)
Available from: 2011-11-10 Created: 2011-11-10 Last updated: 2017-12-08Bibliographically approved
2. Allopregnanolone, a GABA-A receptor agonist, decreases gonadotropin levels in women: a preliminary study
Open this publication in new window or tab >>Allopregnanolone, a GABA-A receptor agonist, decreases gonadotropin levels in women: a preliminary study
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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
Keyword
FSH, LH, GABA, allopregnanolone, isoallopregnanolone
National Category
Obstetrics, Gynecology and Reproductive Medicine Endocrinology and Diabetes
Identifiers
urn:nbn:se:umu:diva-49369 (URN)10.3109/09513590.2010.540603 (DOI)000296777700026 ()
Note

Fulltext publiceras 2012-12-01

Available from: 2011-11-14 Created: 2011-11-10 Last updated: 2017-12-08Bibliographically approved
3. Does chronic endogenous exposure to neuroactive steroids change receptor sensitivity to allopregnanolone in humans?
Open this publication in new window or tab >>Does chronic endogenous exposure to neuroactive steroids change receptor sensitivity to allopregnanolone in humans?
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(English)Manuscript (preprint) (Other academic)
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:umu:diva-49374 (URN)
Available from: 2011-11-10 Created: 2011-11-10 Last updated: 2011-11-11Bibliographically approved
4. Allopregnanolone, a GABA-A receptor agonist, decreases gonadotropin levels in healthy fertile women but not in women with polycystic ovary syndrome
Open this publication in new window or tab >>Allopregnanolone, a GABA-A receptor agonist, decreases gonadotropin levels in healthy fertile women but not in women with polycystic ovary syndrome
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(English)Manuscript (preprint) (Other academic)
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:umu:diva-49373 (URN)
Available from: 2011-11-10 Created: 2011-11-10 Last updated: 2011-11-11Bibliographically approved

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