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- Andréen, Lotta, et al.
(författare)
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Sex steroid induced negative mood may be explained by the paradoxical effect mediated by GABAA modulators
- 2009
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Ingår i: Psychoneuroendocrinology. - : Elsevier BV. - 0306-4530 .- 1873-3360. ; 34:8, s. 1121-1132
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Tidskriftsartikel (refereegranskat)abstract
- Certain women experience negative mood symptoms as a result of progesterone during the luteal phase of the menstrual cycle, progestagens in hormonal contraceptives, or the addition of progesterone or progestagens in sequential hormone therapy (HT). This phenomenon is believed to be mediated via the action of the progesterone metabolites on the GABA(A) system, which is the major inhibitory system in the mammalian CNS. The positive modulators of the GABA(A) receptor include allopregnanolone and pregnanolone, both neuroactive metabolites of progesterone, as well as benzodiazepines, barbiturates, and alcohol. Studies on the effect of GABA(A) receptor modulators have shown contradictory results; although human and animal studies have revealed beneficial properties such as anaesthesia, sedation, anticonvulsant effects, and anxiolytic effects, recent reports have also indicated adverse effects such as anxiety, irritability, and aggression. It has actually been suggested that several GABA(A) receptor modulators, including allopregnanolone, have biphasic effects, in that low concentrations increase an adverse, anxiogenic effect whereas higher concentrations decrease this effect and show beneficial, calming properties. The allopregnanolone increase during the luteal phase in fertile women, as well as during the addition of progesterone in HT, has been shown to induce adverse mood in women. The severity of these mood symptoms is related to the allopregnanolone serum concentrations in a manner similar to an inverted U-shaped curve. Negative mood symptoms occur when the serum concentration of allopregnanolone is similar to endogenous luteal phase levels, while low and high concentrations have less effect on mood. It has also been shown that progesterone/allopregnanolone treatment in women increases the activity in the amygdala (as measured with functional magnetic resonance imaging) in a similar way to the changes seen during anxiety reactions. However, it is evident that only certain women experience adverse mood during progesterone or GABA(A) receptor modulator treatments. Women with premenstrual dysphoric disorder (PMDD) have severe luteal phase related symptoms; in this phase, they show changes in GABA(A) receptor sensitivity and GABA concentrations that are related to the severity of the condition. These findings suggest that negative mood symptoms in women with PMDD are caused by the paradoxical effect of allopregnanolone mediated via the GABA(A) receptor. CONCLUSION: Progesterone and progestagens induce negative mood, most probably via their GABA(A) receptor active metabolites. In postmenopausal women treated with progesterone and animals treated with allopregnanolone, there is a bimodal association between serum allopregnanolone concentration and adverse mood, resembling an inverted U-shaped curve. In humans, the maximal effective concentration of allopregnanolone for producing negative mood is within the range of physiological luteal phase serum concentrations.
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- Hedström, Helena, et al.
(författare)
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Studies of pharmacokinetic and pharmacodynamic properties of isoallopregnanolone in healthy women
- 2009
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Ingår i: Psychopharmacology. - : Springer Science and Business Media LLC. - 0033-3158 .- 1432-2072. ; 203:1, s. 85-98
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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- Lindahl, Magnus S., et al.
(författare)
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Increased cortisol responsivity to adrenocorticotropic hormone and low plasma levels of interleukin-1 receptor antagonist in women with functional hypothalamic amenorrhea
- 2007
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Ingår i: Fertility and Sterility. - : Elsevier BV. - 0015-0282 .- 1556-5653. ; 87:1, s. 136-142
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To assess the hypothalamic-pituitary-adrenal (HPA) axis at all levels, to determine the origin of the previously reported hypercortisolism in patients with functional hypothalamic amenorrhea. A secondary aim was to evaluate factors outside the central nervous system which are known to affect the HPA axis, i.e., circulating levels of interleukin-6 (IL-6), interleukin-1 receptor antagonist (IL-1Ra), and fat mass-adjusted leptin levels, in patients with functional hypothalamic amenorrhea and healthy controls. DESIGN: Cross-sectional study. SETTING: Umeå University Hospital, Umeå, Sweden. PATIENTS: Fifteen subjects with hypothalamic amenorrhea, and 14 age- and weight-matched controls. INTERVENTIONS: None. MAIN OUTCOME MEASURES: We collected blood samples four times during a 24-hour interval for analysis of cortisol, leptin, IL-1Ra, and IL-6 levels. We performed a low-dose oral dexamethasone test and a low-dose ACTH test. We measured body-fat percentage using a dual-energy X-ray absorptiometer. RESULTS: Patients with hypothalamic amenorrhea had increased diurnal cortisol levels (P<.001). The cortisol response to intravenous low-dose ACTH was increased in functional hypothalamic amenorrhea patients compared to control subjects (P<.01), but they had similar rates of dexamethasone suppression. Patients with hypothalamic amenorrhea also had decreased diurnal leptin (P<.05), and decreased diurnal IL-1Ra levels (P<.05), compared to controls. Body-fat percentage was the main predictor of leptin levels. CONCLUSION: The present study suggests novel links for the development of functional hypothalamic amenorrhea, including increased adrenal responsiveness and impairments in proinflammatory cytokine pathways.
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- Nyberg, Sigrid, et al.
(författare)
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Allopregnanolone decrease with symptom improvement during placebo and gonadotropin-releasing hormone agonist treatment in women with severe premenstrual syndrome
- 2007
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Ingår i: Gynecological Endocrinology. - : Informa UK Limited. - 0951-3590 .- 1473-0766. ; 23:5, s. 257-266
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Neurosteroids such as allopregnanolone and pregnanolone are suggested to be of importance for the pathophysiology of premenstrual dysphoric disorder. The aim of this study was to investigate whether the luteal-phase serum concentrations of these neurosteroids are associated with improvement of premenstrual symptoms in 12 women with severe premenstrual syndrome after treatment with low-dose gonadotropin-releasing hormone agonist and placebo. METHODS: Daily ratings for mood and physical symptoms were made prior to treatment and throughout the study. Serum progesterone, allopregnanolone and pregnanolone were assessed in the luteal phase (cycle day -9 to cycle day -1). Based on their symptom ratings, subjects were grouped as either buserelin responders (n = 6) or placebo responders (n = 6). RESULTS: Buserelin responders displayed decreased levels of allopregnanolone (p < 0.05) and progesterone (p < 0.05) in parallel with improvement of symptoms. During the placebo treatment, the placebo responders had lower serum allopregnanolone concentrations than buserelin responders (p < 0.05). This was associated with improvement in symptoms compared with pre-treatment ratings. CONCLUSION: Treatment response, whether induced by buserelin or placebo, appears to be associated with a decrease in allopregnanolone concentration.
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- Nyberg, Sigrid, 1953-
(författare)
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Premenstrual dysphoric disorder in relation to neuroactive steroids and alcohol
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Introduction: Premenstrual Dysphoric Disorder (PMDD) is a condition that affects about 2-6% of women of reproductive age. The relation to ovarian steroids is apparent as symptoms are absent during anovulatory cycles. Neuroactive steroids like allopregnanolone have effect in the brain and on brain function and have been proposed to play an important role for the symptomatology of premenstrual symptoms and in the interaction between the GABAA receptor and alcohol. High doses of alcohol elevate allopregnanolone levels both in rats and humans. Allopregnanolone is a positive modulator of the GABAA receptor with sedative, anxiolytic and anticonvulsant effect in both human and animals. Aims: The aim was to investigate if a low dose (100μg) of GnRH agonist (buserelin) is effective for the treatment of PMDD and if allopregnanolone serum levels during treatment are associated to symptom severity. Furthermore, the studies aimed at investigating the effect of a low dose of alcohol upon saccadic eye movements in women with PMDD, and control subjects in different phases of the menstrual cycle, and to evaluate if there was a difference in response to alcohol between men and healthy women. We also wanted to see if this low dose of alcohol could have an effect on serum allopregnanolone levels in women with PMDD and control subjects in the follicular and luteal phases of the menstrual cycle. Methods: The effect of low dose (100μg) of GnRH agonist (buserelin) on premenstrual symptoms was evaluated in a randomized, placebo controlled, double-blinded cross-over trial. 27 PMDD patients were randomized to either GnRH agonist intranasally once a day or placebo for two months before the crossover. The main outcome measure was the daily symptom ratings for mood and physical symptoms made by the patients. In a subgroup of 12 women, grouped as buserelin responders and placebo responders, luteal phase serum progesterone, allopregnanolone, and pregnanolone was measured together with daily ratings for mood and physical symptoms. Alcohol responsiveness was measured in PMDD patients, female control subjects and men by comparing the effect of a low dose (0.2g/kg) of intravenous alcohol or placebo infusion upon saccadic eye movements. Blood samples for measurement of allopregnanolone and cortisol were taken throughout the alcohol/placebo challenges. Results: Low dose GnRH agonist was effective as treatment of premenstrual irritability and depression. Anovulatory cycles were confirmed in 56% of the subjects, particularly in older women. Buserelin as well as placebo responders displayed decreased allopregnanolone and progesterone levels in parallel with symptom improvement. PMDD patients displayed blunted saccadic eye movement response to alcohol infusion, especially in the luteal phase. Control subjects did not change their response to alcohol between cycle phases. We found no difference in saccadic eye movement sensitivity to alcohol between males and females. Allopregnanolone levels significantly decreased in the luteal phase following the alcohol infusion. Conclusions: Low dose GnRH agonist is effective in treatment of premenstrual depression and irritability but is likely to induce anovulation with increasing age. Independent of whether buserelin or placebo treatment was given decreased levels of allopregnanolone appear to be related to symptom improvement. Women with PMDD have altered saccadic eye movement sensitivity in response to alcohol, particularly in the luteal phase. The low dose of alcohol did not induce any difference in saccade measurements between males and females. Low dose of alcohol does not result in increased peripheral levels of allopregnanolone.
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- Segebladh, Birgitta, et al.
(författare)
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Evaluation of different add-back estradiol and progesterone treatments to gonadotropin-releasing hormone agonist treatment in patients with premenstrual dysphoric disorder
- 2009
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Ingår i: American Journal of Obstetrics and Gynecology. - : Elsevier BV. - 0002-9378 .- 1097-6868. ; 201:2, s. 139.e1-
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The aim of this study was to investigate which add-back hormone replacement therapy would be most beneficial in terms of mood effects for patients with premenstrual dysphoric disorder who are receiving gonadotropin-releasing hormone agonist therapy. STUDY DESIGN: Three different add-back hormone replacement treatments were evaluated in a randomized, double-blinded, cross-over clinical trial in 27 patients premenstrual dysphoric disorder. The add-back treatments consisted of 1.5 mg estradiol and 400 mg progesterone, 1.5 mg estradiol and placebo, and 0.5 mg estradiol and 400 mg progesterone. The primary outcome measure was daily symptom ratings for mood and physical symptoms. RESULTS: The highest dose of estradiol in combination with progesterone was associated with the most pronounced symptom recurrence, both in comparison with a lower dose of estradiol together with progesterone and estradiol-only treatment. CONCLUSION: Based on the findings of the present study, long-cycle add-back treatment to avoid frequent progestagen use appears to be most beneficial for patients with premenstrual dysphoric disorder.
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