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Hormones, Mood and Cognition
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Women's and Children's Health.
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Ovarian steroid hormones are neuroactive steroids with widespread actions in the brain, and are thus able to influence mood, behavior and cognition.

In this thesis the effects of progesterone withdrawal and the direct effects of the progesterone metabolite allopregnanolone are evaluated.

Allopregnanolone, through binding to the GABAA receptor complex, enhances inhibitory neurotransmission, thus exerting anxiolytic, sedative and antiepileptic effects.

The acoustic startle response (ASR) is a withdrawal reflex evoked by sudden or noxious auditory stimuli, and can be measured in humans as an eye blink. ASR is significantly increased in several anxiety disorders, and notably also during progesterone withdrawal.

Sensorimotor gating can be assessed by measuring prepulse inhibition of the startle response (PPI). The CNS circuits regulating PPI are sensitive to hormone fluctuations. GABAergic drugs are involved in cognitive impairment and animal studies have indicated that allopregnanolone may inhibit learning.

The main purpose of this research was to evaluate the behavioral effects of progesterone withdrawal on the startle response and sensorimotor gating in PMDD patients and healthy controls, in healthy third trimester pregnant women and healthy postpartum women. A second aim was to evaluate allopregnanolone effects on memory and cognition in healthy women and also on the startle response and PPI.

We found that PMDD patients have an increased startle response across the menstrual cycle and a deficiency in sensorimotor gating during the late luteal phase.

Ovarian steroids affect sensorimotor gating; pregnant women have lower levels of PPI than late postpartum women. Acutely administered allopregnanolone did not affect the ASR or PPI. Allopregnanolone impairs episodic memory in healthy women.

In conclusion, our studies suggest that ovarian steroids, including allopregnanolone, do not influence the startle response. Ovarian steroids affect sensorimotor gating; pregnancy, a condition with high levels of ovarian steroids, suppresses PPI. Theoretically, the variability in PPI across reproductive events is due to effects mediated by the progesterone or estradiol receptors but is not mediated by allopregnanolone. PMDD patients display decreased PPI during the late luteal phase, suggesting underlying pathophysiology in common with other anxiety disorders. The most vulnerable memory system, the episodic memory, is impaired by the allopregnanolone in healthy women.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2008. , 91 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 394
Keyword [en]
startle response; prepulse inhibition; premenstrual dysphoric disorder; menstrual cycle; pregnancy; postpartum period; episodic memory; semantic memory; working memory; progesterone; estradiol; allopregnanolone.
National Category
Clinical Science
Identifiers
URN: urn:nbn:se:uu:diva-9365ISBN: 978-91-554-7332-7 (print)OAI: oai:DiVA.org:uu-9365DiVA: diva2:172815
Public defence
2008-12-05, Rosénsalen, Uppsala University Hospital, Entrance 95/96, Uppsala, 13:15
Opponent
Supervisors
Available from: 2008-11-14 Created: 2008-11-14Bibliographically approved
List of papers
1. Patients with premenstrual dysphoric disorder have increased startle response across both cycle phases and lower levels of prepulse inhibition during the late luteal phase of the menstrual cycle
Open this publication in new window or tab >>Patients with premenstrual dysphoric disorder have increased startle response across both cycle phases and lower levels of prepulse inhibition during the late luteal phase of the menstrual cycle
Show others...
2008 (English)In: Neuropsychopharmacology, ISSN 0893-133X, E-ISSN 1740-634X, Vol. 33, no 9, 2283-2290 p.Article in journal (Refereed) Published
Abstract [en]

Patients with premenstrual dysphoric disorder (PMDD) experience their most intense symptoms during the late luteal phase. The aim of the current study was to compare acoustic startle response and prepulse inhibition in PMDD patients and controls during the follicular and late luteal phases of the menstrual cycle. Following two months of prospective daily ratings on the Cyclicity Diagnoser scale, 30 PMDD patients and 30 asymptomatic controls, between the ages of 20 and 46, were included in the study. The eyeblink component of the acoustic startle reflex was assessed using electromyographic measurements of m. orbicularis oculi. Twenty pulse-alone trials (115 dB 40 ms broad-band white noise) and 40 prepulse-pulse trials were presented. The prepulse stimuli consisted of a 115 dB 40 ms noise burst preceded at a 100 ms interval by 20 ms prepulses that were 72, 74, 78, or 86 dB. PMDD patients had a significantly higher startle response than controls during both phases of the menstrual cycle (p<0.05). PMDD patients exhibited lower levels of prepulse inhibition with 78 dB and 86 dB prepulses compared to control subjects in the luteal (p<0.01) but not in the follicular phase. Whereas control subjects displayed increased PPI during the late luteal phase compared to the follicular phase (p<0.01), PPI magnitude remained unchanged in PMDD patients between cycle phases. Relative to controls, PMDD patients displayed increased startle reactivity across both menstrual cycle phases and deficits in prepulse inhibition of acoustic startle during the late luteal phase. These findings are consistent with an altered response to ovarian steroids among PMDD patients.

Keyword
startle response, prepulse inhibition, premenstrual dysphoric disorder, menstrual cycle, estradiol, progesterone
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-97753 (URN)10.1038/sj.npp.1301599 (DOI)000257622200023 ()17940552 (PubMedID)
Available from: 2008-11-14 Created: 2008-11-14 Last updated: 2017-12-14Bibliographically approved
2. Lower levels of prepulse inhibition of startle response in pregnant women compared to postpartum women
Open this publication in new window or tab >>Lower levels of prepulse inhibition of startle response in pregnant women compared to postpartum women
2008 (English)In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 33, no 1, 100-107 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: During the postpartum period, estradiol and progesterone levels decline from very high levels during late pregnancy to low levels within 48h of parturition. This period is associated with dysphoric states such as the postpartum blues. Animal studies have suggested an enhanced acoustic startle response and deficient prepulse inhibition (PPI) of startle response following progesterone withdrawal and during the postpartum period. The aim of the current study was to compare acoustic startle response and PPI in healthy third trimester pregnant women and healthy postpartum women. METHODS: Twenty-eight healthy pregnant and 21 healthy postpartum women (examined between 48h and 1 week after delivery) were recruited for the study. In addition, to evaluate the time-course of postpartum changes 11 early postpartum women (examined within 48h following delivery) were included in the study. The eyeblink component of the acoustic startle reflex was assessed using electromyographic measurements of m. Orbicularis Oculi. Twenty pulse-alone trials (115dB 40ms broad-band white noise) and 40 prepulse-pulse trials were presented. The prepulse stimuli consisted of a 115dB 40ms noise burst preceded at a 100ms interval by 20ms prepulses that were 72, 74, 78 or 86dB. RESULTS: Pregnant women exhibited lower levels of PPI compared to late postpartum women, p<0.05. There was no difference between pregnant women and postpartum women examined within 48h of delivery. There was no difference in startle response or habituation to startle response between pregnant women and either of the two groups of postpartum women. CONCLUSION: Healthy women display lower levels of PPI during late pregnancy when estradiol and progesterone levels are high compared to the late postpartum period when ovarian steroid levels have declined.

Keyword
Prepulse inhibition, Startle response, Pregnancy, Postpartum, Estradiol, Progesterone
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-97754 (URN)10.1016/j.psyneuen.2007.10.005 (DOI)000253027800011 ()18037247 (PubMedID)
Available from: 2008-11-14 Created: 2008-11-14 Last updated: 2017-12-14Bibliographically approved
3. Allopregnanolone has no effect on startle response and prepulse inhibition of startle response in patients with premenstrual dysphoric disorder or healthy controls
Open this publication in new window or tab >>Allopregnanolone has no effect on startle response and prepulse inhibition of startle response in patients with premenstrual dysphoric disorder or healthy controls
2009 (English)In: Pharmacology, Biochemistry and Behavior, ISSN 0091-3057, E-ISSN 1873-5177, Vol. 92, no 4, 608-613 p.Article in journal (Refereed) Published
Abstract [en]

Background: Allopregnanolone is an endogenous neuroactive steroid  which, through the binding to the GABA(A) receptor. enhances inhibitory   neurotransmission and exerts anxiolytic, sedative and antiepileptic  effects. Following acute administration, allopregnanolone reliably acts as an anxiolytic compound. The primary aim of this study was to investigate if allopregnanolone, administered to healthy women and   women with premenstrual dysphoric disorder (PMDD), would have an anxiolytic effect, expressed as a decreased startle response.   Materials and methods: Sixteen PMDD patients and twelve healthy   controls completed the study. The participants were scheduled for the   startle tests twice in the luteal phase. During the test sessions an intravenous allopregnanolone and placebo bolus injection was administered in double-blinded, randomized order at intervals of 48 h. Following the allopregnanolone/placebo injections startle response and   prepulse inhibition of startle response (PPI) were assessed by   electromyography.   Results: Following the intravenous allopregnanolone administration the   serum concentrations of allopregnanolone increased to 50-70 nmol/l.   corresponding to levels that are seen during pregnancy. The obtained   serum concentrations of allopregnanolone were significantly lower in   PMDD patients than among the healthy controls, p<0.05. The   allopregnanolone injection resulted in significant increases of   self-rated sedation in both groups, p<0.01. Allopregnanolone did not induce any changes in startle response or prepulse inhibition of   startle response in comparison to placebo. No differences in allopregnanolone-induced changes in startle response or PPI could be detected between PMDD patients and controls subjects. Conclusion: Startle response and PPI were unaffected by acute   intravenous administration of allopregnanolone in PMDD patients and healthy controls.

Keyword
Allopregnanolone, Premenstrual dysphoric disorder, Startle response, Prepulse inhibition
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-97755 (URN)10.1016/j.pbb.2009.02.014 (DOI)000266538800008 ()19268499 (PubMedID)
Available from: 2008-11-14 Created: 2008-11-14 Last updated: 2017-12-14Bibliographically approved
4. Allopregnanolone impairs episodic memory in healthy women
Open this publication in new window or tab >>Allopregnanolone impairs episodic memory in healthy women
2008 (English)In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 199, no 2, 161-168 p.Article in journal (Refereed) Published
Abstract [en]

Allopregnanolone is an endogenous neuroactive steroid that, through its binding to the γ-aminobutyric acid (GABA) A receptor, has GABA-active properties. Animal studies indicate that allopregnanolone administration results in diminished learning and memory impairment. The aim of the current study was to investigate the effect of intravenously administered allopregnanolone on episodic memory, semantic memory, and working memory in healthy women.

Twenty-eight healthy women were included in the study. The participants were scheduled for the memory tests twice in the follicular phase. During the test sessions, an intravenous allopregnanolone and placebo infusion were administered in a double-blinded, randomized order at intervals of 48 h. Before and 10 min after the allopregnanolone/placebo injections, memory tasks were performed.The study demonstrated that allopregnanolone impaired episodic memory in healthy women. There was a significant difference between pre- and postallopregnanolone injection episodic memory scores (p < 0.05), whereas there was no change in episodic memory performance following the placebo injections. There was also a significant difference between allopregnanolone and placebo postinjection episodic memory scores (p < 0.05). There were no effects of allopregnanolone on the semantic memory task or working memory task.Intravenous allopregnanolone impairs episodic memory in healthy women, but there is a high degree of individual variability.

Keyword
Allopregnanolone, Healthy women, Follicular phase of menstrual cycle, Episodic memory, Semantic memory, Working memory, Estradiol, Progesterone
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-97756 (URN)10.1007/s00213-008-1150-7 (DOI)000257383100003 ()
Available from: 2008-11-14 Created: 2008-11-14 Last updated: 2017-12-14Bibliographically approved

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