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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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- Bengtsson, Sara K. S., et al.
(författare)
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Isoallopregnanolone antagonize allopregnanolone-induced effects on saccadic eye velocity and self-reported sedation in humans
- 2015
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Ingår i: Psychoneuroendocrinology. - : Elsevier BV. - 0306-4530 .- 1873-3360. ; 52, s. 22-31
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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- Björn, Inger, 1953-, et al.
(författare)
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Increase of estrogen dose deteriorates mood during progestin phase in sequential hormonal therapy
- 2003
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 88:5, s. 2026-2030
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies have indicated that the addition of progestinsduring sequential hormonal replacement therapy (HRT)causes negative mood and physical symptoms. History of premenstrualsyndrome, type of progestin, and dose of progestinhave thus far been shown to influence the progestin-inducedadverse mood symptoms during HRT.The aim of this study was to compare adverse mood effectsof two different doses of estradiol, in combination with a progestin,during postmenopausal HRT. Twenty-eight perimenopausalwomen were included in this randomized, doubleblind,crossover study comparing 2- or 3-mg continuousestradiol, with an addition of 10 mg medroxyprogesteroneacetate on d 17–28 during each treatment cycle. The mainoutcome measures were mood and physical symptoms kept ona daily rating scale. Together with the progestin, the higherdose of estrogen caused significantly more negative moodsymptoms than the lower dose. Tension, irritability, and depressedmood were all significantly augmented during theprogestin phase of cycles with 3mg estradiol (P<0.001). Physicalsymptoms also increased during the progestin phase of3-mg estradiol cycles (P<0.001), whereas positive mood symptomswere less affected. The only positive mood that changedwith estrogen dose was friendliness, which decreased duringthe progestin phase of high estradiol cycles compared withcycles with lower estradiol (P < 0.05).Our conclusion is that an increase of the estrogen doseaccentuates negativemoodand physical symptoms during theprogestin phase of sequential hormonal therapy.
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| 8. |
- Björn, Inger, 1953-, et al.
(författare)
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Negative mood changes during hormone replacement therapy : a comparison between two progestogens
- 2000
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Ingår i: American Journal of Obstetrics and Gynecology. - : Elsevier. - 0002-9378 .- 1097-6868. ; 183:6, s. 1419-1426
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The aim of this study was to compare side effects of medroxyprogesterone acetate and norethindrone acetate during postmenopausal hormone replacement therapy in women with and without a history of premenstrual syndrome. Study Design: Fifty-one postmenopausal women were randomly selected in a double-blind crossover study. The women received 2 mg of estradiol continuously during five 28-day cycles and 10 mg of medroxyprogesterone or 1 mg of norethindrone sequentially for 12 days of each cycle. Daily symptom rating scales were kept. Results: The women showed cyclic changes, with negative mood and physical symptoms culminating during the late progestogen phase and positive mood during the estrogen-only phase. Symptoms declined with time but remained after 5 months. Women with a history of premenstrual syndrome responded strongly to both progestogens. Medroxyprogesterone acetate induced less negative and more positive mood symptoms than norethindrone in women with no history of premenstrual syndrome. In both groups medroxyprogesterone caused more physical symptoms than norethindrone. Conclusion: The addition of medroxyprogesterone to estrogen is preferable to norethindrone with respect to mood symptoms in women without a history of premenstrual syndrome.
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| 9. |
- Björn, Inger, 1953-, et al.
(författare)
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The impact of different doses of medroxyprogesterone acetate on mood symptoms in sequential hormonal therapy
- 2002
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Ingår i: Gynecological Endocrinology. - : Informa Healthcare. - 0951-3590 .- 1473-0766. ; 16, s. 1-8
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to compare adverse mood effects of two different doses of medroxyprogesterone acetate (MPA) during postmenopausal hormone replacement therapy (HRT) in women with and without a history of premenstrual syndrome (PMS). The study was designed as a randomized double-blind cross-over study and included 36 postmenopausal women at three health care areas in northern Sweden. The women received 2 mg estradiol continuously during five 28-day cycles and 10 mg or 20 mg MPA sequentially for 12 days during each cycle. The main outcome measures were mood and physical symptoms noted on a daily rating scale. We found that physical symptoms did not differ between 10 and 20 mg MPA. Both women with a history of PMS and women without responded with more negative mood symptoms with the lower dose of MPA. In women with previous PMS the higher dose of MPA enhanced positive mood symptoms. With respect to mood and physical symptoms, the aim to lower MPA doses in HRT is unwarranted.
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| 10. |
- Bock, David, 1976, et al.
(författare)
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Learning curve for robot-assisted laparoscopic radical prostatectomy in a large prospective multicentre study
- 2022
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Ingår i: Scandinavian Journal of Urology. - : Medical Journals Sweden AB. - 2168-1805 .- 2168-1813. ; 56:3, s. 182-190
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Tidskriftsartikel (refereegranskat)abstract
- Objective Differences in outcome after radical prostatectomy for prostate cancer can partly be explained by intersurgeon differences, where degree of experience is one important aspect. This study aims to define the learning curve of robot-assisted laparoscopic prostatectomy (RALP) regarding oncological and functional outcomes. Materials and methods Out of 4003 enrolled patients in the LAPPRO trial, 3583 met the inclusion criteria, of whom 885 were operated on by an open technique. In total, 2672 patients with clinically localized prostate cancer from seven Swedish centres were operated on by RALP and followed for 8 years (LAPPRO trial). Oncological outcomes were pathology-reported surgical margins and biochemical recurrence at 8 years. Functional outcomes included patient-reported urinary incontinence and erectile dysfunction at 3, 12 and 24 months. Experience was surgeon-reported experience before and during the study. The relationship between surgeon experience and functional outcomes and surgical margin status was analysed by mixed-effects logistic regression. Biochemical recurrence was analysed by Cox regression, with robust standard errors. Results The learning curve for positive surgical margins was relatively flat, with rates of 21% for surgeons who had performed 0-74 cases and 24% for surgeons with > 300 cases. Biochemical recurrence at 4 years was 11% (0-74 cases) and 13% (> 300 cases). Incontinence was stable over the learning curve, but erectile function improved at 2 years, from 38% (0-74 cases) to 53% (> 300 cases). Conclusions Analysis of the learning curve for surgeons performing RALP showed that erectile function improved with increasing number of procedures, which was not the case for oncological outcomes.
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