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- Hedström, Helena
(author)
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GABA-steroid effects in healthy subjects and women with polycystic ovary syndrome
- 2011
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Doctoral thesis (other academic/artistic)abstract
- 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.
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| 2. |
- Franzén, Karin, 1958-
(author)
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Interventions for urinary incontinence in women : survey and effects on population and patient level
- 2011
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Doctoral thesis (other academic/artistic)abstract
- Urinary Incontinence is a common health problem that can cause both severe medical and social problems, resulting in negative impact on different aspects of Quality of Life. In 2000, the Swedish Council on Health Technology Assessment (SBU) published a systematic review, “Treatment of Urinary Incontinence” where multiple knowledge gaps in the field of UI, all of considerable clinical importance, were pointed out.Several of these knowledge gaps have been the starting points for the projects in this thesis. The overall aim has been to study the impact of different interventions for urinary incontinence in women on the population level but also on the patient group level, for assessessing the significance of UI on general living conditions and to validate instruments to measure quality of life to be used as part of the evaluation of treatment effectiveness.Paper I: A population-based study where UI amongst women was found to be commonly associated with different psychosocial problems and an expressed feeling of vulnerability.Paper II: A population-based study where informative material on UI to the general public in order to increase knowledge and encourage self management was found promising for meeting increasing demands and optimizing healthcare resources.Paper III: A randomized controlled trial where both electrical stimulation and drug therapy reduced the number of micturitions and improved QoL in women with urge or urge incontinence, but electrical stimulation was not found to be superior to drug therapy.Paper IV: A prospective cohort study where the international questionnaires UDI-6 and IIQ-7 after translation and validation, showed good responsiveness and were easy to administer and to fill out. The UDI-6 scale did not accomplish the same solid result in the psychometrical analysis as the IIQ-7 scale but both scales showed good responsiveness and can thereby be recommended for clinical use.
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