| 1. |
- Bäckström, Torbjörn, et al.
(författare)
-
Allopregnanolone and mood disorders
- 2014
-
Ingår i: Progress in Neurobiology. - : Elsevier BV. - 0301-0082 .- 1873-5118. ; 113, s. 88-94
-
Tidskriftsartikel (refereegranskat)abstract
- Certain women experience negative mood symptoms during the menstrual cycle and progesterone addition in estrogen treatments. In women with PMDD increased negative mood symptoms related to allopregnanolone increase during the luteal phase of ovulatory menstrual cycles. In anovulatory cycles no symptom or sex steroid increase occurs. This is unexpected as positive modulators of the GABA-A receptor are generally increasing mood. This paradoxical effect has brought forward a hypothesis that the symptoms are provoked by allopregnanolone the GABA-A receptor system. GABA-A is the major inhibitory system in the brain. Positive modulators of the GABA-A receptor include the progesterone metabolites allopregnanolone and pregnanolone, benzodiazepines, barbiturates, and alcohol. GABA-A receptor modulators are known, in low concentrations to induce adverse, anxiogenic effects whereas in higher concentrations show beneficial, calming properties. Positive GABA-A receptor modulators induce strong paradoxical effects e.g. negative mood in 3-8% of those exposed, while up to 25% have moderate symptoms thus similar as the prevalence of PMDD, 3-8% among women in fertile ages, and up to 25% have moderate symptoms of premenstrual syndrome (PMS). The mechanism behind paradoxical reaction might be similar among them who react on positive GABA-A receptor modulators and in women with PMDD. In women the severity of these mood symptoms are related to the allopregnanolone serum concentrations in 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. Low to moderate progesterone/allopregnanolone concentrations in women increases the activity in the amygdala (measured with fMRI) similar to the changes seen during anxiety reactions. Higher concentrations give decreased amygdala activity similar as seen during benzodiazepine treatment with calming anxiolytic effects. Patients with PMDD show decreased sensitivity in GABA-A receptor sensitivity to diazepam and pregnanolone while increased sensitivity to allopregnanolone. This agrees with findings in animals showing a relation between changes in alpha4 and delta subunits of the GABA-A receptor and anxiogenic effects of allopregnanolone. Conclusion: 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.(c) 2013 Elsevier Ltd. All rights reserved.
|
|
| 2. |
- Bäckström, Torbjörn, et al.
(författare)
-
Increased neurosteroid sensitivity - An explanation to symptoms associated with chronic work related stress in women?
- 2013
-
Ingår i: Psychoneuroendocrinology. - : Pergamon Press. - 0306-4530 .- 1873-3360. ; 38:7, s. 1078-1089
-
Tidskriftsartikel (refereegranskat)abstract
- Work related psychosocial stress can be accompanied by so called burnout syndrome with symptoms of mental exhaustion, physical fatigue, and cognitive dysfunction. Underlying mechanisms for acquiring burnout syndrome are not clear. Animal studies show that chronic stress is associated with altered release of GABA-A receptor modulating steroids (GAMS), altered composition of the GABA-A receptor and altered sensitivity to GAMS. In the present study we investigated if such changes occur in women with burnout syndrome. We further asked whether flumazenil (a benzodiazepine antagonist, but with positive modulating effects on GABA-A receptors with altered subunit composition) can block the effect of the GAMS allopregnanolone. Ten women with occupational psychosocial stress and burnout syndrome were compared with twelve healthy controls in an experimental setting. Saccadic eye velocity (SEV) was measured after an injection of allopregnanolone, followed by an injection of flumazenil and a second injection of allopregnanolone. The sensitivity to allopregnanolone was significantly higher in the patients compared to controls after the first injection (p = 0.04) and the difference increased when the response per allopregnanolone concentration unit was compared ( p = 0.006). Following the flumazenil injection the burnout patients (p= 0.016), but not controls, showed a decrease in SEV and flumazenil acted like a positive modulator that is agonistic. There was no significant difference between the groups after second allopregnanolone injection. In conclusion, patients with work related psychosocial stress and burnout syndrome show a different response to GABA-A receptor modulators than controls suggesting a changed GABA-A receptor function in these patients. More precisely we hypothesize that the alpha 4 and delta subunits are up-regulated elevating the responsiveness to allopregnanolone and change the effect of flumazenil, which provides a potential explanation to the burnout syndrome. Flumazenil does not block the effect of allopregnanolone.
|
|
| 3. |
- Hedström, Helena
(författare)
-
GABA-steroid effects in healthy subjects and women with polycystic ovary syndrome
- 2011
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)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.
|
|
| 4. |
- Innala, Eva, 1956-
(författare)
-
Acute intermittent porphyria, women and sex hormones. Screening for hepatocellular carcinoma in porphyria
- 2010
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Porphyrias are inherited disorders with impaired heme biosynthesis. Acute intermittent porphyria (AIP) is the most common porphyria in Sweden. AIP attacks may be life-threatening. Female sex hormones are regarded as important precipitating factors. Hepatocellular carcinoma (HCC) is a severe complication in the older AIP population. The aim of the thesis was to describe the clinical expression of AIP in women, experience of hormonal contraception and hormonal replacement therapies (HRT) and of pregnancies. Secondly, we evaluated gonadotropin-releasing hormone (GnRH) agonist treatment for prevention of menstrual-cycle-related AIP attacks. Thirdly, we evaluated whether an altered sex-steroid metabolism was present in AIP women compared with controls. Finally, we evaluated the benefit of screening for HCC in AIP in a 15-year follow-up study. Methods and results: In a retrospective population-based study in northern Sweden, 166 female AIP gene carriers ≥18 years of age participated. Manifest AIP (MAIP) was reported in 55%; 82% had severe attacks and 39% had menstrual-cycle-related attacks. Hormonal contraceptives were used by 94, and 12 reported that this precipitated AIP attacks. HRT and local vaginal treatments in menopause did not precipitate AIP attacks. Only 10% reported impairment of AIP symptoms during pregnancy. In the retrospective follow-up study of GnRH-agonist treatment, 11 of 14 women improved during treatment. Porphyria attacks were triggered in two women after estradiol add-back and in 5 of 9 women after progesterone add-back. In the sex-steroid metabolism study, levels of s-progesterone, estradiol, allopregnanolone and pregnanolone during the menstrual cycle in 32 AIP gene carriers were compared with 20 healthy controls. Progesterone metabolism in the AIP group differed from controls. In the AIP group levels of allopregnanolone, but not pregnanolone, were significantly lower. In the prospective HCC screening study AIP gene carriers aged >55 years were included. On average 62 subjects participated during 15 years. HCC was diagnosed in 22 of 180 eligible AIP gene carriers in the region (male:female, 12:10, 73% MAIP). The annual incidence of HCC was 0.8%. The risk of HCC was 64-fold higher than in the general population over 50 years of age in this region, and even higher for AIP women (93-fold). Increased 3- and 5-year survival was seen in the regularly screened AIP group. Liver lab tests were not useful in HCC screening. Conclusion: The clinical expression of AIP in women is pronounced and menstrual-cycle-related attacks are common. Hormonal contraceptives can induce AIP attacks and caution is recommended. GnRH-agonist treatment can ameliorate menstrual-cycle-related attacks of porphyria. Dose findings for GnRH-agonists and add-back regimes, especially for progesterone, are intricate. Progesterone metabolism in the AIP group differs from that in healthy controls. HCC screening in AIP gene carriers >50 years of age enables early diagnosis and a possibility for curative treatments. Annual HCC screening with liver imaging is recommended in AIP gene carriers >50 years of age.
|
|
| 5. |
- Innala, Eva, et al.
(författare)
-
Evaluation of gonadotropin-releasing hormone agonist treatment for prevention of menstrual-related attacks in acute porphyria
- 2010
-
Ingår i: Acta Obstetricia et Gynecologica Scandinavica. - : Wiley. - 0001-6349 .- 1600-0412. ; 89:1, s. 95-100
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To describe the benefits and adverse effects of gonadotropin-releasing hormone (GnRH) agonist treatment for prevention of recurrent menstrual attacks in women with acute intermittent porphyria and variegate porphyria. To describe concomitant add-back therapies with estradiol and progesterone and describe their benefits and adverse effects. DESIGN: A retrospective follow-up with questionnaires, interviews and medical records. SETTING: Out-patient care at the Umeå University Hospital in Sweden. POPULATION: Sixteen Caucasian women with DNA-diagnosed porphyria and menstrual-cycle-related porphyria attacks were treated with GnRH agonists during 1984-2000. Fourteen women participated. The mean age when treatment started was 33 years (17-48 years). The duration of treatment varied between 5 months and 9 years. METHODS: GnRH agonists were administered by the intranasal route or by injections. To reduce menopausal symptoms, add-back therapy with low doses of estradiol was administered, and for endometrial protection progesterone was usually administered. MAIN OUTCOME MEASURES: Treatment effects and adverse events as detected in questionnaires, interviews and medical records. RESULTS: Eleven women reported benefits from GnRH agonist treatment with less intense and/or less frequent porphyria attacks, and in four of them attacks almost disappeared. Two women reported no change. One woman had only temporary improvement. Porphyria attacks were triggered by solely estradiol add-back in two women and in five of nine women when progesterone was given. CONCLUSIONS: GnRH agonist treatment can ameliorate menstrual-cycle-related attacks of porphyria. Dose findings for GnRH agonists and add-back regimes especially for progesterone are intricate.
|
|
| 6. |
- Innala, Eva, et al.
(författare)
-
Women with acute intermittent porphyria have a defect in 5 alpha-steroid production during the menstrual cycle
- 2012
-
Ingår i: Acta Obstetricia et Gynecologica Scandinavica. - : John Wiley & Sons. - 0001-6349 .- 1600-0412. ; 91:12, s. 1445-1452
-
Tidskriftsartikel (refereegranskat)abstract
- Objective. To measure serum concentrations of progesterone, estradiol and 5 alpha- and 5 beta-reduced progesterone metabolites in the follicular and luteal phases of the menstrual cycle in women with latent acute intermittent porphyria and manifest acute intermittent porphyria in comparison with healthy control women. Design. A descriptive study with repeated measurements during a complete, ovulatory menstrual cycle. Setting. University hospital out-patient clinic. Population. Thirty-two women with DNA-diagnosed acute intermittent porphyria and 20 healthy control women. Methods. Blood samples for serum progesterone, estradiol, allopregnanolone and pregnanolone were drawn on predefined menstrual cycle days, twice in the follicular phase and three times in the luteal phase. Serum levels of estradiol and progesterone were analysed with commercial kits. Allopregnanolone and pregnanolone levels were analysed with radioimmunoassay following diethylether extraction and celite column chromatography. Main outcome measures. Changes in serum levels of progesterone, estradiol, allopregnanolone and pregnanolone throughout the menstrual cycle. Results. Women with acute intermittent porphyria displayed lower serum concentrations of allopregnanolone in comparison with healthy control women, the difference being most prominent in the luteal phase (p < 0.001). Levels of pregnanolone did not differ significantly between groups. No significant difference was found between women with latent acute intermittent porphyria and manifest acute intermittent porphyria. Conclusions. Decreased levels of the 5 alpha-reduced progesterone metabolite allopregnanolone were found in the menstrual cycle of women with acute intermittent porphyria. This has not been reported previously and could indicate a reduced 5 alpha-reductase type 1 capacity in the ovary and liver among these women.
|
|
| 7. |
- Lindh-Åstrand, Lotta, et al.
(författare)
-
A randomized controlled study of taper-down or abrupt discontinuation of hormone therapy in women treated for vasomotor symptoms
- 2010
-
Ingår i: Menopause. - : Ovid Technologies (Wolters Kluwer Health). - 1072-3714 .- 1530-0374. ; 17:1, s. 72-79
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: The aim of this study was to investigate whether tapering down of combined estrogen plus progestogen therapy (EPT) reduced the recurrence of hot flashes and resumption of therapy compared with abrupt discontinuation. A secondary aim was to evaluate whether health-related quality of life (HRQoL) was affected after discontinuation of EPT and to investigate the possible factors predicting resumption of EPT. Methods: Eighty-one postmenopausal women undergoing EPT because of hot flashes were randomized to tapering down or abrupt discontinuation of EPT. Vasomotor symptoms were recorded in self-registered diaries, and resumption of hormone therapy (HT) was asked for at every follow-up. The Psychological General Well-being Index was used to assess HRQoL. Results: Neither the number nor the severity of hot flashes or HRQoL or frequency of resumption of HT differed between the two modes of discontinuation of EPT during up to 12 months of follow-up. About every other woman had resumed HT within I year. Women who resumed HT after 4 or 12 months reported more deteriorated HRQoL and more severe hot flashes after discontinuation of therapy than did women who did not resume HT. Conclusions: Women who initiate EPT because of hot flashes may experience recurrence of vasomotor symptoms and impaired HRQoL after discontinuation of EPT regardless of the discontinuation method used, abrupt or taper down. Because, in addition to severity of flashes, decreased well-being was the main predictor of the risk to resume HT, it seems important to also discuss quality of life in parallel with efforts to discontinue HT.
|
|
| 8. |
- Lindholm, Åsa, et al.
(författare)
-
No difference in markers of adipose tissue inflammation between overweight women with polycystic ovary syndrome and weight-matched controls
- 2011
-
Ingår i: Human Reproduction. - : Oxford University Press (OUP). - 0268-1161 .- 1460-2350. ; 26:6, s. 1478-1485
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Previous studies have indicated that peripheral circulating markers of inflammation are elevated in women with polycystic ovary syndrome (PCOS), but thus far no studies concerning markers of inflammation in adipose tissue have been published. The aim of the study was to investigate whether patients with PCOS display increased expression of inflammatory markers in adipose tissue. Methods: Twenty overweight patients with PCOS, 10 lean patients with PCOS and 20 overweight controls had subcutaneous fat biopsies and blood samples taken. Adipose tissue levels of mRNA of inflammatory markers were determined by use of real-time PCR. Results: Overweight patients with PCOS had higher relative adipose tissue chemokine ligand 2 (P < 0.01), and its cognate receptor (P < 0.05), tumour necrosis factor-alpha (P < 0.001), interleukin (IL)-10 (P < 0.001) and IL-18 (P < 0.001) and the monocyte/ macrophage markers CD14 (P < 0.01) and CD163 (P < 0.01) mRNA levels compared with lean women with PCOS. There were no differences between overweight patients with PCOS and overweight control subjects in this respect. Within the PCOS group, markers of adipose tissue inflammation correlated significantly with obesity-related metabolic disturbances, but when data were adjusted for age and BMI, most correlations were lost. Conclusions: Overweight, rather than the PCOS diagnosis per se, appears to be the main explanatory variable for elevated adipose tissue inflammation in patients with PCOS.
|
|
| 9. |
- Lindholm, Åsa, et al.
(författare)
-
Tissue plasminogen activator and plasminogen activator inhibitor 1 in obese and lean patients with polycystic ovary syndrome
- 2010
-
Ingår i: Gynecological Endocrinology. - : Informa UK Limited. - 0951-3590 .- 1473-0766. ; 26:10, s. 743-748
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Disturbances in the fibrinolytic system are predictors of future cardiovascular events. The aim of this study was to compare plasminogen activator inhibitor 1 (PAI-1) activity and tissue plasminogen activator (tPA) mass concentration between patients with polycystic ovary syndrome (PCOS) and control subjects. DESIGN: One hundred thirty-five patients with PCOS (lean and obese) and 81 healthy controls were recruited for the study. Blood samples for PAI-1 activity and tPA mass were collected together with anthropometric measures. RESULTS: Obese patients with PCOS displayed increased tPA mass concentration in comparison with controls (p <0.05), and this finding was consistent regardless of whether patients displayed signs of hyperandrogenism or not. When hyperandrogenism was introduced as a prerequisite for the PCOS diagnosis, obese patients with PCOS displayed increased PAI-1 activity as well, p <0.05. Lean patients with PCOS did not differ in terms of PAI-1 activity or tPA mass concentration in comparison to controls. CONCLUSION: Obese women with PCOS have impaired fibrinolysis, in particular if they also display objective biochemical markers of hyperandrogenism.
|
|
| 10. |
- Segebladh, Birgitta, et al.
(författare)
-
Allopregnanolone serum concentrations and diurnal cortisol secretion in women with premenstrual dysphoric disorder
- 2013
-
Ingår i: Archives of Women's Mental Health. - : Springer Science and Business Media LLC. - 1434-1816 .- 1435-1102. ; 16:2, s. 131-137
-
Tidskriftsartikel (refereegranskat)abstract
- Most prior studies in patients with premenstrual dysphoric disorder (PMDD) indicate a blunted hypothalamus-pituitary-adrenal axis function. However, the relationship between neuroactive progesterone metabolites, such as allopregnanolone, and hypothalamus-pituitary-adrenal (HPA) axis function in PMDD patients is relatively sparsely studied. The primary aims of this study were to assess diurnal variation in circulating cortisol and low-dose dexamethasone suppression in PMDD patients and healthy controls, and the relationship between these two HPA axis indices and allopregnanolone serum concentrations. Twenty-six women with prospectively defined PMDD and 30 healthy controls were recruited. Participants underwent diurnal sampling for cortisol serum concentrations and a low-dose dexamethasone suppression test. In addition, morning allopregnanolone serum concentrations were determined. There was no difference in diurnal secretion of cortisol and degree of dexamethasone suppression of cortisol between PMDD patients and healthy controls. However, PMDD patients with high allopregnanolone levels displayed blunted nocturnal cortisol levels in comparison with healthy controls who had low allopregnanolone serum concentrations. In women with PMDD, diurnal secretion of cortisol may be influenced by allopregnanolone levels of the luteal phase. This finding may be attributed to timing of blood sampling in the late luteal phase as well as the individual level of allopregnanolone but could potentially explain the discrepancies in results between studies examining HPA axis function in women with PMDD.
|
|
