Original articleAllopregnanolone levels and reactivity to mental stress in premenstrual dysphoric disorder
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)
- et al.
Anxiolytic effect of progesterone is associated with increases in cortical allopregnanolone and GABAA receptor function
Pharmacol Biochem Behav
(1993) - et al.
The anxiolytic-like effects of the neurosteroid allopregnanoloneInteractions with GABAA receptors
Eur J Pharmacol
(1997) - et al.
The potential role of hypocortisolism in the pathophysiology of stress-related bodily disorders
Psychoneuroendocrinology
(2000) - et al.
The neurosteroid tetrahydroprogesterone attenuates the endocrine response to stress and exerts glucocorticoid-like effects on vasopressin gene transcription in the rat hypothalamus
Neuropsychopharmacology
(1996) - et al.
The neurosteroid tetrahydroprogesterone counteracts corticotropin-releasing hormone-induced anxiety and alters the release and gene expression of corticotropin-releasing hormone in the rat hypothalamus
Neuroscience
(1994) - et al.
Prevalance of axis I and axis II disorders in women with late luteal phase dysphoric disorder
J Affect Disord
(1990) - et al.
Radioimmunoassay of 3 alpha-hydroxy-5 alpha-pregnan-20-one in rat and human plasma
Steroids
(1990) - et al.
Progesterone metabolite allopregnanolone in women with premenstrual syndrome
Obstet Gynecol
(1997) - et al.
Changes in plasma hormones across the menstrual cycle in patients with menstrually related mood disorders and in control subjects
Am J Obstet Gynecol
(1988) - et al.
Reduced benzodiazepine sensitivity in patients with premenstrual syndromeA pilot study
Psychoneuroendocrinology
(1997)