Elsevier

Biological Psychiatry

Volume 49, Issue 9, 1 May 2001, Pages 788-797
Biological Psychiatry

Original article
Allopregnanolone levels and reactivity to mental stress in premenstrual dysphoric disorder

https://doi.org/10.1016/S0006-3223(00)01044-1Get rights and content

Abstract

Background: This study was designed to examine basal and stress-induced levels of the neuroactive progesterone metabolite, allopregnanolone, in women with premenstrual dysphoric disorder (PMDD) and healthy control subjects. Also, because evidence suggests that allopregnanolone negatively modulates the hypothalamic–pituitary–adrenal axis, plasma cortisol levels were examined. An additional goal was to investigate the relationship between premenstrual symptom severity and luteal phase allopregnanolone levels.

Methods: Twenty-four women meeting prospective criteria for PMDD were compared with 12 controls during both the follicular and luteal phases of confirmed ovulatory cycles, counterbalancing phase at first testing. Plasma allopregnanolone and cortisol were sampled after an extended baseline period and again 17 min following the onset of mental stress. Owing to low follicular phase allopregnanolone levels, only luteal phase allopregnanolone and cortisol were analyzed.

Results: During the luteal phase, PMDD women had significantly greater allopregnanolone levels, coupled with significantly lower cortisol levels, during both baseline and mental stress. Moreover, significantly more controls (83%) showed the expected stress-induced increases in allopregnanolone compared with PMDD women (42%). Premenstrual dysphoric disorder women also exhibited a significantly greater allopregnanolone/progesterone ratio than control subjects, suggesting alterations in the metabolic pathways involved in the conversion of progesterone to allopregnanolone. Finally, PMDD women with greater levels of premenstrual anxiety and irritability had significantly reduced allopregnanolone levels in the luteal phase relative to less symptomatic PMDD women. No relationship between symptom severity and allopregnanolone was observed in controls.

Conclusions: These results suggest dysregulation of allopregnanolone mechanisms in PMDD and that continued investigations into a potential pathophysiologic role of allopregnanolone in PMDD are warranted.

Introduction

Premenstrual dysphoric disorder (PMDD) is estimated to afflict 5–8% of women in their reproductive years (American Psychiatric Association 1994). Despite more than 60 years of research into this disorder, the underlying pathophysiologic mechanisms remain elusive. Owing to the cyclical nature of the mood changes in PMDD, much attention has been paid to the gonadal steroid hormones, particularly progesterone. Although progesterone deficiency was a long-standing hypotheses in PMDD (Dalton 1964), the majority of controlled trials have failed to find that progesterone is superior to placebo in reducing premenstrual symptoms (Freeman et al 1995). In fact, the rationale for progesterone therapy in PMDD is not supported by studies of gonadal hormone levels in this disorder because they have produced a striking lack of consistency in results. For example, reported findings include decreased progesterone in the luteal phase (Wang et al 1996), increased progesterone in the luteal phase (Halbreich et al 1986; Redei and Freeman, 1993; Watts et al 1985) or no differences in luteal phase progesterone (Girdler et al 1993, Parry et al 1990; Rubinow et al 1988) in PMDD women versus controls. Thus, despite the overwhelming evidence for an obligatory role of the gonadal hormones in the pathophysiology of PMDD, it is generally agreed that neither a deficiency nor excess in progesterone levels is etiologically relevant to the disorder (Rubinow and Schmidt 1992).

However, although differences in absolute levels of gonadal hormones may not be of clinical relevance in PMDD, PMDD women may be more sensitive to the mood modulatory effects of gonadal hormones (Hammarback et al 1989), or there may be alterations in the conversion of these hormones to their neuroactive metabolites and a differential sensitivity to these metabolites in PMDD. Of particular relevance to PMDD may be the neuroactive steroid allopregnanolone (3α-hydroxy-5α-pregnan-20-one). Allopregnanolone is the A-ring-reduced metabolite of progesterone and is produced not only by ovary and adrenals but also de novo in brain (Paul and Purdy 1992). Owing to its lipophilicity, even peripherally produced allopregnanolone readily crosses the blood brain barrier where it rapidly alters CNS excitability, producing behavioral effects within seconds to minutes Paul and Purdy 1992, Purdy et al 1991. Allopregnanolone is a potent modulator of GABAA receptors (nanomolar concentrations) via dose-dependent enhancement of GABA-induced Cl ion channels, and it is through this mechanism that it exerts profound anxiolytic effects (Brot et al 1997).

Allopregnanolone has also been shown to be stress sensitive in rat models, with CNS levels rising quickly following acute stress Barbaccia et al 1996, Purdy et al 1991. Although peripheral increases in stress-induced allopregnanolone are more delayed (Paul and Purdy 1992), studies using adrenalectomized animals indicate that peripheral sources of stress-induced allopregnanolone contribute significantly to central levels (Purdy et al 1991). Animal models also suggest that stress-induced increases in allopregnanolone serve to negatively modulate hypothalamic-pituitary-adrenal (HPA) axis activity, thereby facilitating the recovery of physiologic homeostasis in this system following stressful stimuli. Specifically, allopregnanolone prevents CRF release and gene expression in the hypothalamus as well as CRF-induced anxiety (Patchev et al 1994). Allopregnanolone also significantly attenuates the elevation of plasma ACTH and corticosterone following stress Guo et al 1995, Patchev et al 1996. Although there have been no studies examining stress-induced neurosteroids in humans to date, a recent study (Genazzani et al 1998) employing endocrine challenge paradigms in men and women found that both GnRH and CRH administration increased serum allopregnanolone levels whereas suppression of adrenal steroidogenesis markedly reduced allopregnanolone. These results suggest that in humans, both ovary and adrenal cortex are major sources of circulating allopregnanolone and indicate that neuroactive steroids may be stress sensitive.

There have been only three studies that have examined neurosteroids in prospectively diagnosed PMDD women. These studies have yielded mixed results, finding either no diagnosis-related difference in allopregnanolone levels (Schmidt et al 1993), significantly lower allopregnanolone levels in PMDD women compared with controls (Rapkin et al 1997), or no difference in levels, but when menstrual cycles were divided into high and low allopregnanolone cycles for PMDD women, low allopregnanolone cycles were associated with worse premenstrual symptoms (Wang et al 1996). There are several methodologic differences in these studies that could contribute to the discrepant findings. For example, differences in the diagnostic criteria employed could contribute to the inconsistencies since some Rapkin et al 1997, Wang et al 1996, but not all (Schmidt et al 1993) of these studies used DSM criteria. Additionally, in the prior studies, either psychiatric histories were not assessed (Wang et al 1996), they were assessed in the PMDD women but not controls (Schmidt et al 1993), or women with psychiatric histories were excluded (Rapkin et al 1997). Because reduced allopregnanolone levels have been documented in major depression Romeo et al 1998, Uzunova et al 1998, and because a history of major depression may be more common in PMDD (Pearlstein et al 1990), study-related differences in psychiatric comorbidity could contribute to the mixed results. Despite the discrepancies, the results of these studies still raise the possibility that allopregnanolone plays a role in PMDD, although none has provided definitive evidence for whether differences in allopregnanolone levels exist for PMDD women, or whether PMDD women are simply more sensitive to the mood modulatory effects of allopregnanolone, or both.

Thus, with the use of strict DSM diagnostic criteria for PMDD and careful assessment of current and past psychiatric disorders in both PMDD and control subjects, the purpose of this study was twofold. Our first objective was to examine allopregnanolone levels and the relationship to premenstrual symptomatology in both PMDD women and controls. Our second objective was to provide an initial assessment of allopregnanolone reactivity to mental stress in PMDD women and controls, and to examine whether allopregnanolone levels were related to measures of HPA axis activation (i.e., cortisol) in human female subjects as has been documented in animal models.

Section snippets

Subjects

Subjects were recruited through newspaper advertisement. A total of 28 PMDD and 28 control subjects completed testing as part of a larger protocol designed to investigate neuroendocrine and cardiovascular reactivity to stress and sensitivity to ischemic pain (results to be reported elsewhere). Of the total 56 women who completed all aspects of the larger protocol, plasma samples were available for assay of allopregnanolone in 25 PMDD women and 13 control subjects. Thus, cortisol levels were

Demographics and psychiatric histories

As summarized in Table 1, there were no significant group differences in any demographic measure or in prior histories of psychiatric disorders (Table 1).

Progesterone, allopregnanolone, and the menstrual cycle

As expected, both the PMDD women and control subjects evidenced a significant increase in their progesterone levels in their luteal versus follicular phase [main effect of Phase, F(1,34) = 123.6, p = .0001]. Although both the PMDD women and control subjects showed expected follicular (0.41 ng/mL vs. 0.67 ng/mL, respectively) and luteal phase

Discussion

The results of our study indicate that PMDD may be associated with alterations in both the levels of the neurosteroid allopregnanolone and allopregnanolone reactivity to mental stress. Specifically, although we observed that PMDD women exhibited significantly greater luteal phase baseline and stress levels of allopregnanolone than control subjects, PMDD women tended to show decreases in allopregnanolone levels from baseline to stress whereas the control subjects showed the expected increase.

Our

Acknowledgements

This work was supported by the National Institutes of Health (NIH) Grants Nos. MH-51246 (SSG) and AA10564 (ALM), NIH Clinical Research Center Grant No. RR-00046, National Institute of Mental Health Clinical Research Center Grant No. MH-33127, and the Foundation of Hope for the Research and Treatment of Mental Illness.

The authors are also grateful to Sara Benjamin for her services as study coordinator, Dot Faulkner for manuscript preparation, and Whitehall Laboratories for their generous

References (40)

  • American Psychiatric Association (1994): Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC:...
  • M.L Barbaccia et al.

    Time-dependent changes in rat brain neuroactive steroid concentrations and GABAA receptor function after acute stress

    Neuroendocrinology

    (1996)
  • A Concas et al.

    Role of brain allopregnanolone in the plasticity of γ-aminobutyric acid type A receptor in rat brain during pregnancy and after delivery

    Proc Natl Acad Sci U S A

    (1998)
  • Dalton K (1964): Premenstrual Syndrome. London:...
  • P Follesa et al.

    Molecular and functional adaptation of the GABA65 receptor complex during pregnancy and after delivery in the rat brain

    Eur J Neurosci

    (1998)
  • A.M Fontana et al.

    Perceptual and coping processes across the menstrual cycleAn investigation in a premenstrual syndrome clinic and a community sample

    Behav Med

    (1997)
  • E.W Freeman et al.

    A double-blind trial of oral progesterone, alprazolam, and placebo in treatment of severe premenstrual syndrome

    JAMA

    (1995)
  • A.R Genazzani et al.

    Circulating levels of allopregnanolone in humansGender, age, and endocrine influences

    J Clin Endocrinol Metab

    (1998)
  • S.S Girdler et al.

    Menstrual cycle and premenstrual syndromeModifiers of cardiovascular reactivity in women

    Health Psychol

    (1993)
  • A.-L Guo et al.

    Evidence for a role of neurosteroids in modulation of diurnal changes and acute stress-induced corticosterone secretion in rats

    Gynecol Endocrinol

    (1995)
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