Kristiina Kask

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

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.

Urogenital disorders in women with adjuvant endocrine therapy after early breast cancer.

OBJECTIVE To investigate the prevalence of urogenital symptoms and vaginal atrophy in postmenopausal breast cancer patients on adjuvant endocrine therapy. STUDY DESIGN A population-based, cross-sectional study on postmenopausal breast cancer patients on adjuvant endocrine treatment and age-matched control subjects. Vaginal atrophy was assessed by gynecologic examination and atrophy-related symptoms by validated questionnaires. RESULTS In all, 57.6% of aromatase inhibitor-treated and 32.4% of tamoxifen-treated breast cancer patients rated at least 1 vaginal atrophy symptom as moderate/severe, which was significantly more common than in control subjects (P < .01). Aromatase inhibitor-treated patients more often had moderate or severe vaginal atrophy (P < .05), a more atrophic cytohormonal evaluation, and significantly higher vaginal pH (P < .05) than all control subjects, irrespective of hormonal use. CONCLUSION Our findings indicate that the frequency of vaginal atrophy symptoms, particularly in aromatase inhibitor-treated women, might have been underestimated in previous clinical trials.

The effect of premenstrual dysphoric disorder and menstrual cycle phase on brain activity during response inhibition

BACKGROUND Premenstrual dysphoric disorder (PMDD) has generally not been associated with impulsive behavior. However, some studies suggest that women with PMDD have higher impulsivity scores than healthy controls and that brain activity during response inhibition may vary across the menstrual cycle. Therefore, our aim was to unravel potentially important cognitive aspects of PMDD by investigating brain activity during response inhibition in women with PMDD and healthy controls in relation to menstrual cycle phase. METHODS Fourteen PMDD patients and 13 healthy controls performed a Go/NoGo task to measure brain activity during response inhibition by use of event-related functional magnetic resonance imaging. RESULTS Women with PMDD displayed decreased activity during both menstrual cycle phases compared to healthy controls in several task-related parietal areas. A significant group by phase interactions was found in the left insula, driven by enhanced activity among healthy controls in the follicular phase and by enhanced insula activity during the luteal phase among PMDD patients. LIMITATIONS The limitations of the present study are the relatively limited sample size, the relatively small number of NoGo trials and the lack of a baseline contrast for the NoGo trials. CONCLUSIONS During response inhibition women with PMDD have reduced activity in areas associated with attention and motor function which is unrelated to menstrual cycle phase. Insular cortex activity, involved in both affective and cognitive processing, was significantly activated during the luteal phase among PMDD women. These findings are relevant for the understanding of how ovarian steroids influence mood symptoms in women.

Allopregnanolone has no effect on startle response and prepulse inhibition of startle response in patients with premenstrual dysphoric disorder or healthy controls

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.

Patients with premenstrual dysphoric disorder have increased startle modulation during anticipation in the late luteal phase period in comparison to control subjects.

The acoustic startle response (ASR) is a withdrawal reflex to sudden or noxious auditory stimuli and, most importantly, an unbiased measure of emotional processing of appetitive and aversive stimuli. By exposing subjects to fearful situations, such as aversive pictures, the ASR may be enhanced, suggesting that amygdala modulates the startle circuit during threat situations. As one previous study, investigating affective modulation of the ASR in women with premenstrual dysphoric disorder (PMDD), discovered no difference during picture viewing it is possible that the mood changes observed in PMDD relate to anxious anticipation rather than to direct stimulus responding. Hence we sought to examine the effects of PMDD on picture anticipation and picture response. Sixteen PMDD patients and 16 controls watched slide shows containing pleasant and unpleasant pictures and positive and negative anticipation stimuli during the follicular and luteal phase of the menstrual cycle. Simultaneously, semi-randomized startle probes (105 dB) were delivered and the ASR was assessed with electromyography. Compared with control subjects, PMDD patients displayed an enhanced startle modulation by positive and negative anticipation stimuli in the luteal phase of the menstrual cycle. This finding was mainly driven by increased modulation in the luteal phase in comparison to the follicular phase among PMDD patients but also by an increased modulation in patients compared to controls during luteal phase. This suggests that the neural circuits underlying response to emotional anticipation are more sensitive during this period and emphasize the need of examining the neural correlates of anticipatory processes in women with PMDD.

Lower levels of prepulse inhibition of startle response in pregnant women compared to postpartum women

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.

Patients with adverse mood effects from combined oral contraceptives have lower levels of prepulse inhibition than healthy controls

BACKGROUND Negative mood symptoms remain one of the major reasons for discontinuation of oral contraceptive pills. The aim of this study was to compare acoustic startle response and prepulse inhibition (PPI) in women with different experience of oral contraceptive pills. METHODS Thirty women currently on combined oral contraceptives (COCs) with no reports of adverse mood symptoms, 28 women currently on COCs and experiencing mood-related side effects from treatment, 27 women who had discontinued COC use for reasons other than adverse mood symptoms and 32 women who had discontinued COC use due to adverse mood effects were included. The eyeblink component of the acoustic startle reflex was assessed using electromyographic measurements of musculus 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 Patients with adverse mood effects of COCs exhibited lower levels of PPI with 86dB prepulse compared to COC users with no adverse effects of COCs (p<0.05). There was no difference in PPI between the two groups of prior COC users. No significant difference was found between the groups regarding acoustic startle response. CONCLUSION Relative to COC users with no reports of adverse mood symptoms, subjects suffering from COC-induced negative mood displayed deficits in PPI of acoustic startle. The fact that there was no difference in PPI between the two groups of prior COC users indicates that deficient PPI is related to adverse mood effects caused by COCs.

Higher than expected estradiol levels in aromatase inhibitor-treated, postmenopausal breast cancer patients.

ABSTRACT Objective Vaginal estradiol is considered contraindicated in aromatase inhibitor (AI)-treated patients because of the risk of elevated estrogen levels. This leaves limited treatment options for patients experiencing gynecological symptoms. However, in clinical practice, no precise estimation has been performed of circulating estrogens and aromatase index in postmenopausal breast cancer patients on long-lasting AI or tamoxifen treatment. Methods Steroid hormones were measured using liquid chromatography tandem mass spectrometry (LC–MS/MS) and extraction radioimmunoassay (RIA). Postmenopausal AI-treated patients (n =33) were compared with tamoxifen-treated patients (n =34) and controls without vaginal treatment (n =56), with vaginal estradiol (n =25), or with estriol (n =11) treatment. Results By use of LC–MS/MS, median (range) estradiol plasma concentrations were 16.7 (2.4–162.6), 31.0 (13.4–77.1), 27.2 (7.8–115.8) and 33.3 (20.3–340.1) pmol/l in AI-treated breast cancer patients, tamoxifen-treated breast cancer patients, postmenopausal controls and postmenopausal controls on vaginal estradiol, respectively. The AI-treated group and subgroups had significantly lower estradiol and estrone concentrations than all other groups (p <0.05). There was extensive interindividual variation in estradiol concentration within the AI-treated group, measured using both LC–MS/MS (2.3–182.0 pmol/l) and extraction RIA (2.4–162.6 pmol/l). The AI-treated group had lower aromatase index compared to all other groups (p <0.05–0.001). Conclusion Circulating estrogen levels may have been underestimated in previous longitudinal studies of AI-treated breast cancer patients. Additional studies are required to further evaluate the role of circulating estrogens in breast cancer patients suffering from gynecological symptoms.

Lower levels of prepulse inhibition in luteal phase cycling women in comparison with postmenopausal women

Menopause denotes the end of the reproductive period in a womans life and is characterized by gradually declining plasma levels of ovarian hormones. Mounting evidence suggests that prepulse inhibition (PPI) is sensitive to fluctuations in estradiol and progesterone. Deficits in PPI are associated with conditions characterized by increased levels of ovarian steroids, such as the mid-luteal phase of the menstrual cycle and the third trimester of pregnancy. The aim of the current study was to further elucidate ovarian steroid-related effects on PPI by examining 43 women with regular menstrual cycles, 20 healthy postmenopausal women without hormone replacement treatment (HRT) and 21 healthy postmenopausal women with ongoing estradiol-only or estradiol and progesterone therapy (EPT). Cycling women were tested during the late luteal phase of the menstrual cycle while postmenopausal women were tested on any arbitrary day. The PPI was measured by electromyography. Cycling women exhibited lower levels of PPI than postmenopausal women (p<0.05). There were no differences in PPI between postmenopausal HRT users and non-users. However, postmenopausal women with estradiol serum concentrations in the cycling range had lower PPI than postmenopausal women with low estradiol concentrations (groupxPPI interaction, p<0.05). In conclusion, the results further suggest a role for the ovarian steroids in PPI regulation as PPI is increased in postmenopausal women in comparison to regularly menstruating women examined during the late luteal phase. Furthermore, postmenopausal women with estradiol levels in the cycling range had lower PPI than postmenopausal women with low estradiol levels.

Emotion Reactivity Is Increased 4-6 Weeks Postpartum in Healthy Women: A Longitudinal fMRI Study

Marked endocrine alterations occur after delivery. Most women cope well with these changes, but the postpartum period is associated with an increased risk of depressive episodes. Previous studies of emotion processing have focused on maternal–infant bonding or postpartum depression (PPD), and longitudinal studies of the neural correlates of emotion processing throughout the postpartum period in healthy women are lacking. In this study, 13 women, without signs of post partum depression, underwent fMRI with an emotional face matching task and completed the MADRS-S, STAI-S, and EPDS within 48 h (early postpartum) and 4–6 weeks after delivery (late postpartum). Also, data from a previous study including 15 naturally cycling controls assessed in the luteal and follicular phase of the menstrual cycle was used. Women had lower reactivity in insula, middle frontal gyrus (MFG), and inferior frontal gyrus (IFG) in the early as compared to the late postpartum assessment. Insular reactivity was positively correlated with anxiety in the early postpartum period and with depressive symptoms late postpartum. Reactivity in insula and IFG were greater in postpartum women than in non-pregnant control subjects. Brain reactivity was not correlated with serum estradiol or progesterone levels. Increased reactivity in the insula, IFG, and MFG may reflect normal postpartum adaptation, but correlation with self-rated symptoms of depression and anxiety in these otherwise healthy postpartum women, may also suggest that these changes place susceptible women at increased risk of PPD. These findings contribute to our understanding of the neurobiological aspects of the postpartum period, which might shed light on the mechanisms underlying affective puerperal disorders, such as PPD.