Reduced benzodiazepine sensitivity in patients with premenstrual syndrome: A pilot study

Sundström, Inger; Ashbrook, Donald W.; Bäckström, Torbjörn

doi:10.1016/s0306-4530(96)00035-2

Cited by 116 publications

(72 citation statements)

References 34 publications

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“…PMDD women also report more traumatic life stress, including sexual and physical abuse histories (Paddison et al, 1990;Golding & Taylor, 1996Girdler et al, 2003Girdler et al, , 2007. Since allopregnanolone is stress responsive, at least in animal models (Purdy et al, 1991;Barbaccia et al, 1996Barbaccia et al, , 1997, greater allostatic load in PMDD resulting from more severe life stress could contribute to the elevated allopregnanolone concentrations that we have seen in PMDD women (Girdler et al, 2001) and result in the documented alterations in GABA A receptor function in PMDD (Sundstrom et al, 1997a(Sundstrom et al, , 1997b(Sundstrom et al, , 1998, including alterations in the agonism properties of the GABA A receptor as animal models (Smith et al, 2006) and human studies of PMDD suggest (Le Melledo et al, 2000). This could then explain the seemingly paradoxical association between increasing allopregnanolone concentrations in the luteal phase and increased dysphoric mood states in PMDD.…”

Section: Allopregnanolone Responses To Stress In Pmddmentioning

confidence: 83%

“…Behaviorally, PMDD women also generally report less sedation in response to the i.v. benzodiazepines (Sundstrom et al, 1997a(Sundstrom et al, , 1997b. The clinical significance of these results comes from their findings that when PMDD women are divided into lower versus higher symptom severity groups, the more severe PMDD symptom groups respond with less of a reduction in SEV (Sundstrom et al, 1997b(Sundstrom et al, , 1998 and with lower sedation ratings (Sundstrom et al, 1998) in response to benzodiazepines.…”

Section: Hpa Axis and Gaba A Receptor Function In Pmddmentioning

confidence: 98%

“…Since benzodiazepines, acting via the GABA A receptor, are known to reduce SEV in a dose-dependent fashion (Hommer et al, 1986), SEV is believed to be a sensitive measure of benzodiazepine/GABA A receptor sensitivity in humans. Using placebo-controlled designs, Sundstrom and colleagues have shown in a series of studies that PMDD women show less of a reduction in SEV to intravenous diazepam (Sundstrom et al, 1997a), midazolam (Sundstrom et al, 1997b), and pregnanolone (Sundstrom et al, 1998) than non-PMDD controls. Behaviorally, PMDD women also generally report less sedation in response to the i.v.…”

Section: Hpa Axis and Gaba A Receptor Function In Pmddmentioning

confidence: 99%

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Neurosteroids in the context of stress: Implications for depressive disorders

Girdler

Klatzkin

2007

Pharmacology & Therapeutics

132

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Animal models indicate that the neuroactive steroids 3α,5α-THP (allopregnanolone) and 3α,5α-THDOC (allotetrahydroDOC) are stress responsive, serving as homeostatic mechanisms in restoring normal GABAergic and hypothalamic-pituitary-adrenal (HPA) function following stress. While neurosteroid increases to stress are adaptive in the short term, animal models of chronic stress and depression find lower brain and plasma neurosteroid concentrations and alterations in neurosteroid responses to acute stressors. It has been suggested that disruption in this homeostatic mechanism may play a pathogenic role in some psychiatric disorders related to stress. In humans, neurosteroid depletion is consistently documented in patients with current depression and may reflect their greater chronic stress. Women with the depressive disorder, premenstrual dysphoric disorder (PMDD), have greater daily stress and a greater rate of traumatic stress. While results on baseline concentrations of neuroactive steroids in PMDD are mixed, PMDD women have diminished functional sensitivity of GABA A receptors and our laboratory has found blunted allopregnanolone responses to mental stress relative to non-PMDD controls. Similarly, euthymic women with histories of clinical depression, which may represent a large proportion of PMDD women, show more severe dysphoric mood symptoms and blunted allopregnanolone responses to stress versus never-depressed women. It is suggested that failure to mount an appropriate allopregnanolone response to stress may reflect the price of repeated biological adaptations to the increased life stress that is well documented in depressive disorders and altered allopregnanolone stress responsivity may also contribute to the dysregulation seen in HPA axis function in depression.

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Section: Allopregnanolone Responses To Stress In Pmddmentioning

confidence: 83%

Section: Hpa Axis and Gaba A Receptor Function In Pmddmentioning

confidence: 98%

Section: Hpa Axis and Gaba A Receptor Function In Pmddmentioning

confidence: 99%

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Neurosteroids in the context of stress: Implications for depressive disorders

Girdler

Klatzkin

2007

Pharmacology & Therapeutics

132

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“…First, studies report both abnormalities of peripheral neurosteroid levels (albeit inconsistently) and the neurosteroid response to stress in women with PMDD (Wang et al, 1996;Rapkin et al, 1997;Monteleone et al, 2000;Lombardi et al, 2004;Klatzkin et al, 2006). Second, women with PMDD show the following: lowered cortical GABA levels (Epperson et al, 2002); blunted luteal phase cortical inhibition ; and altered sensitivities of saccadic eye velocity to both neurosteroids and benzodiazepines (Sundstrom et al, 1997a;Sundstrom et al, 1997b;Sundstrom et al, 1998). Finally, the most effective therapy for PMDD, selective serotonin reuptake inhibitors (SSRIs), activate 3α-hydroxy steroid There were no effects of diagnosis on plasma hormone levels, thus, values reported are those from both women with PMDD and control women.…”

Section: Discussionmentioning

confidence: 99%

5α-Reductase Inhibition Prevents the Luteal Phase Increase in Plasma Allopregnanolone Levels and Mitigates Symptoms in Women with Premenstrual Dysphoric Disorder

Martinez¹,

Rubinow

Nieman

et al. 2015

Neuropsychopharmacol

121

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Changes in neurosteroid levels during the luteal phase of the menstrual cycle may precipitate affective symptoms. To test this hypothesis, we stabilized neurosteroid levels by administering the 5α-reductase inhibitor dutasteride to block conversion of progesterone to its neurosteroid metabolite allopregnanolone in women with premenstrual dysphoric disorder (PMDD) and in asymptomatic control women. Sixteen women with prospectively confirmed PMDD and 16 control women participated in one of two separate randomized, doubleblind, placebo-controlled, cross-over trials, each lasting three menstrual cycles. After one menstrual cycle of single-blind placebo, participants were randomized to receive, for the next two menstrual cycles, either double-blind placebo or dutasteride (low-dose 0.5 mg/ day in the first eight PMDD and eight control women or high-dose 2.5 mg/day in the second group of women). All women completed the daily rating form (DRF) and were evaluated in clinic during the follicular and luteal phases of each menstrual cycle. Main outcome measures were the DRF symptoms of irritability, sadness, and anxiety. Analyses were performed with SAS PROC MIXED. In the low-dose group, no significant effect of dutasteride on PMDD symptoms was observed compared with placebo (ie, symptom cyclicity maintained), and plasma allopregnanolone levels increased in women with PMDD from follicular to the luteal phases, suggesting the absence of effect of the lowdose dutasteride on 5α-reductase. In contrast, the high-dose group experienced a statistically significant reduction in several core PMDD symptoms (ie, irritability, sadness, anxiety, food cravings, and bloating) on dutasteride compared with placebo. Dutasteride had no effect on mood in controls. Stabilization of allopregnanolone levels from the follicular to the luteal phase of the menstrual cycle by blocking the conversion of progesterone to its 5α-reduced neurosteroid metabolite mitigates symptoms in PMDD. These data provide preliminary support for the pathophysiologic relevance of neurosteroids in this condition.

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“…This effect may be more pronounced in women with PMS. Sundstrom et al (41) noted that women with PMS exhibited less sedation and less decrease in saccadic eye velocity (SEV) compared with controls in response to i.v. diazepam, midazolam or pregnanolone ± all positive allosteric modulators of GABA A (30,41).…”

Section: Discussionmentioning

confidence: 99%

Neuroactive steroid-serotonergic interaction: responses to an intravenous L-tryptophan challenge in women with premenstrual syndrome

Rasgon

Serra²,

Biggio³

et al. 2001

European Journal of Endocrinology

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Objective: To evaluate the circulating concentrations of the neuroactive steroids in response to an i.v. L-tryptophan (L-TP) challenge across the menstrual cycle in women with premenstrual syndrome (PMS) and in controls. Method: An i.v. L-TP challenge was administered eight times during 1 month to five women with prospectively documented PMS and five age-and body mass-matched controls. Progesterone, allopregnanolone pregnenolone and 3a-5a-tetrahydrocorticosterone were assessed 15 and 0 min before, and at 30, 60 and 90 min after the challenge, across the menstrual cycle. Results: In response to L-TP challenge, only allopregnanolone concentrations were significantly increased across the cycle and this increase was of a greater magnitude in women with PMS. Pregnenolone and 3a-5a-tetrahydrocorticosterone concentrations were not affected in women with PMS or controls after L-TP challenge. Conclusions: The data provide evidence for possible interaction between the serotonergic system and the neuroactive steroid, allopregnanolone. Women with PMS demonstrated a more significant increase in allopregnanolone concentrations in response to L-TP challenge, which could be due to an initial low basal serotonergic tone in the luteal phase in the PMS group.

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Reduced benzodiazepine sensitivity in patients with premenstrual syndrome: A pilot study

Cited by 116 publications

References 34 publications

Neurosteroids in the context of stress: Implications for depressive disorders

Neurosteroids in the context of stress: Implications for depressive disorders

5α-Reductase Inhibition Prevents the Luteal Phase Increase in Plasma Allopregnanolone Levels and Mitigates Symptoms in Women with Premenstrual Dysphoric Disorder

Neuroactive steroid-serotonergic interaction: responses to an intravenous L-tryptophan challenge in women with premenstrual syndrome

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