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Hedström, Helena
Publications (8 of 8) Show all publications
Turkmen, S., Bixo, M., Hedström, H., Gideonsson, I., Nyberg, S., Wang, M. & Bäckström, T. (2016). The author's reply: Blood allopregnanolone levels in women with polycystic ovary syndrome [Letter to the editor]. Clinical Endocrinology, 85(1), 152-154
Open this publication in new window or tab >>The author's reply: Blood allopregnanolone levels in women with polycystic ovary syndrome
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2016 (English)In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 85, no 1, p. 152-154Article in journal, Letter (Refereed) Published
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:umu:diva-124215 (URN)10.1111/cen.13079 (DOI)000378512100023 ()27061597 (PubMedID)
Available from: 2016-08-01 Created: 2016-07-28 Last updated: 2018-06-07Bibliographically approved
Bengtsson, S. K. S., Nyberg, S., Hedström, H., Zingmark, E., Jonsson, B., Bäckström, T. & Bixo, M. (2015). Isoallopregnanolone antagonize allopregnanolone-induced effects on saccadic eye velocity and self-reported sedation in humans. Psychoneuroendocrinology, 52, 22-31
Open this publication in new window or tab >>Isoallopregnanolone antagonize allopregnanolone-induced effects on saccadic eye velocity and self-reported sedation in humans
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2015 (English)In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 52, p. 22-31Article in journal (Refereed) Published
Abstract [en]

Allopregnanolone (AP) is an endogenous neurosteroid. It modulates the effect of gamma-amino-butyric acid (GABA) on the GABA type A (GABA(A)) receptor, which leads to increased receptor activity. Since the GABA-system is mainly inhibitory, increased AP activity leads to modulation of neuronal activity. In vitro studies of GABA(A) receptor activity and in vivo animal studies of sedation have shown that AP-induced effects can be inhibited by another endogenous steroid, namely isoallopregnanolone (ISO). In this study we investigated if ISO can antagonize AP-induced effects in healthy female volunteers, via measurements of saccadic eye velocity (SEV) and self-rated sedation. With a single-blind cross-over design, 12 women were studied on three separate occasions; given AP alone or AP in combination with one of two ISO doses. Congruent with previous reports, AP administration decreased SEV and induced sedation and these effects were diminished by simultaneous ISO administration. Also, the ISO effect modulation was seemingly stronger for SEV than for sedation. These effects were observed already at an ISO dose exposure that was approximately half of that of AP. In conclusion, ISO antagonized AP-induced decrease in SEV and self-reported sedation, probably in a non-competitive manner.

Keywords
Allopregnanolone, Isoallopregnanolone, Saccadic eye velocity, GABA(A) receptor, Sedation, Premenstrual dysphoric disorder
National Category
Endocrinology and Diabetes Neurosciences
Identifiers
urn:nbn:se:umu:diva-100765 (URN)10.1016/j.psyneuen.2014.10.025 (DOI)000349271000004 ()25459890 (PubMedID)
Available from: 2015-04-26 Created: 2015-03-09 Last updated: 2018-06-07Bibliographically approved
Hedström, H., Bäckström, T., Bixo, M., Nyberg, S., Wang, M., Gideonsson, I. & Turkmen, S. (2015). Women with polycystic ovary syndrome have elevated serum concentrations of and altered GABA A receptor sensitivity to allopregnanolone. Clinical Endocrinology, 83(5), 643-650
Open this publication in new window or tab >>Women with polycystic ovary syndrome have elevated serum concentrations of and altered GABA A receptor sensitivity to allopregnanolone
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2015 (English)In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 83, no 5, p. 643-650Article in journal (Refereed) Published
Abstract [en]

ObjectiveSeveral studies have reported that -aminobutyric acid (GABA) ergic circuits are involved in the pathophysiology of polycystic ovary syndrome (PCOS). The progesterone metabolite allopregnanolone is a potent GABA(A)-receptor-modulating steroid, and patients may have increased concentrations of allopregnanolone or altered GABA(A) receptor sensitivity. We investigated both of these possibilities in this study. PatientsWe enrolled 9 women with PCOS and 24 age-matched eumenorrhoeic controls, who were divided into two groups by body mass index (BMI) (16 normal weight and 8 overweight). MeasurementsWe investigated the effects of allopregnanolone injection on GABA(A) receptor sensitivity in both groups of women. All women received a single intravenous dose of allopregnanolone (0050mg/kg). GABA(A) receptor sensitivity was assessed with the saccadic eye velocity (SEV) over 30 degrees (SEV30 degrees), the SEV30 degrees/allopregnanolone concentration ([Allo]) ratio, and sedation, which were measured together with serum allopregnanolone at intervals for 180min after injection. The controls were tested in the follicular phase of the menstrual cycle. ResultsBaseline allopregnanolone concentrations were higher in the PCOS women than in the normal-weight (P=0034) and overweight controls (P=0004). The allopregnanolone concentrations after injection were higher in the PCOS women (P=0006) and overweight controls (P=0037) than in the normal-weight controls. All groups showed a decline in the SEV30 degrees/[Allo] ratio after injection. Allopregnanolone had a smaller effect on the SEV30 degrees/[Allo] ratio in the overweight women (PCOS, P=0032; controls, P=0007) than in the normal-weight controls. The sedation score after allopregnanolone injection was lower in the PCOS patients than in the controls, but was not different between the two control groups. ConclusionsPCOS women had elevated baseline allopregnanolone concentrations compared with follicular-phase controls. All overweight women (PCOS and controls) were less sensitive to allopregnanolone than normal-weight controls.

Place, publisher, year, edition, pages
John Wiley & Sons, 2015
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:umu:diva-111462 (URN)10.1111/cen.12809 (DOI)000363267400008 ()25929428 (PubMedID)
Available from: 2015-12-01 Created: 2015-11-13 Last updated: 2018-06-07Bibliographically approved
Timby, E., Hedström, H., Bäckström, T., Sundström-Poromaa, I., Nyberg, S. & Bixo, M. (2011). Allopregnanolone, a GABA-A receptor agonist, decreases gonadotropin levels in women: a preliminary study. Gynecological Endocrinology, 27(12), 1087-1093
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, p. 1087-1093Article 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
Keywords
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: 2018-06-08Bibliographically approved
Hedström, H. (2011). GABA-steroid effects in healthy subjects and women with polycystic ovary syndrome. (Doctoral dissertation). Umeå: Umeå University
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. p. 70
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1455
Keywords
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: 2018-06-08Bibliographically approved
Hedström, H., Bixo, M., Nyberg, S., Spigset, O., Zingmark, E. & Bäckström, T. (2009). Studies of pharmacokinetic and pharmacodynamic properties of isoallopregnanolone in healthy women. Psychopharmacology, 203(1), 85-98
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, p. 85-98Article 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.

Keywords
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: 2018-06-08Bibliographically approved
Hedström, H., Bäckström, T., Wang, M., Nyberg, S. & Bixo, M.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: 2018-06-08Bibliographically approved
Hedström, H., Bäckström, T., Bixo, M., Nyberg, S., Turkmen, S. & Wang, M.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: 2018-06-08Bibliographically approved
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