Advertisement

Allopregnanolone levels and reactivity to mental stress in premenstrual dysphoric disorder

  • Susan S Girdler
    Correspondence
    Address reprint requests to Susan S. Girdler, Ph.D., University of North Carolina, CB #7175, Medical Research Bldg. A, Chapel Hill NC 27599
    Affiliations
    Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA (SSG, KCL, CAP, ALM)

    Department of Psychology, University of North Carolina at Chapel Hill, Chapel Hill, North CarolinaUSA (SSG, PAS, KCL)
    Search for articles by this author
  • Patricia A Straneva
    Affiliations
    Department of Psychology, University of North Carolina at Chapel Hill, Chapel Hill, North CarolinaUSA (SSG, PAS, KCL)
    Search for articles by this author
  • Kathleen C Light
    Affiliations
    Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA (SSG, KCL, CAP, ALM)

    Department of Psychology, University of North Carolina at Chapel Hill, Chapel Hill, North CarolinaUSA (SSG, PAS, KCL)
    Search for articles by this author
  • Cort A Pedersen
    Affiliations
    Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA (SSG, KCL, CAP, ALM)
    Search for articles by this author
  • A.Leslie Morrow
    Affiliations
    Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA (SSG, KCL, CAP, ALM)

    Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA (ALM), University of North Carolina at Chapel Hill
    Search for articles by this author

      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.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

      1. American Psychiatric Association (1994): Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC: American Psychiatric Association.

        • Barbaccia M.L
        • Roscetti G
        • Trabucchi M
        • Mostallino M.C
        • Purdy R.H
        • Biggio G
        Time-dependent changes in rat brain neuroactive steroid concentrations and GABAA receptor function after acute stress.
        Neuroendocrinology. 1996; 63: 166-172
        • Bitran D
        • Purdy R.H
        • Kellogg C.K
        Anxiolytic effect of progesterone is associated with increases in cortical allopregnanolone and GABAA receptor function.
        Pharmacol Biochem Behav. 1993; 45: 423-428
        • Brot M.D
        • Akwa Y
        • Purdy R.H
        • Koob G.F
        • Britton K.T
        The anxiolytic-like effects of the neurosteroid allopregnanolone.
        Eur J Pharmacol. 1997; 325: 1-7
        • Concas A
        • Mostallino M.C
        • Porcu P
        • Follesa P
        • Barbaccia M.L
        • Trabucchi M
        • 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; 95: 1384-1389
      2. Dalton K (1964): Premenstrual Syndrome. London: Heinemann.

        • Follesa P
        • Floris S
        • Tuligi G
        • Mostallino M.C
        • Concas A
        • Biggio G
        Molecular and functional adaptation of the GABA65 receptor complex during pregnancy and after delivery in the rat brain.
        Eur J Neurosci. 1998; 10: 2905-2912
        • Fontana A.M
        • Badawy S
        Perceptual and coping processes across the menstrual cycle.
        Behav Med. 1997; 22: 152-159
        • Freeman E.W
        • Rickels K
        • Sondheimer S.J
        • Polansky M
        A double-blind trial of oral progesterone, alprazolam, and placebo in treatment of severe premenstrual syndrome.
        JAMA. 1995; 274: 51-57
        • Genazzani A.R
        • Petraglia F
        • Bernardi F
        • Casarosa E
        • Salvestroni C
        • Tonetti A
        • et al.
        Circulating levels of allopregnanolone in humans.
        J Clin Endocrinol Metab. 1998; 83: 2099-2103
        • Girdler S.S
        • Pedersen C.A
        • Stern R.A
        • Light K.C
        Menstrual cycle and premenstrual syndrome.
        Health Psychol. 1993; 12: 180-192
        • Guo A.-L
        • Petraglia F
        • Criscuolo M
        • Ficarra G
        • Nappi R.E
        • Palumbo M.A
        • et al.
        Evidence for a role of neurosteroids in modulation of diurnal changes and acute stress-induced corticosterone secretion in rats.
        Gynecol Endocrinol. 1995; 9: 1-7
        • Hammarback S
        • Damber J.-E
        • Backstrom T
        Relationship between symptom severity and hormone changes in women with premenstrual syndrome.
        J Clin Endocrinol Metab. 1989; 68: 125-130
        • Heim C
        • Ehlert U
        • Hellhammer D.H
        The potential role of hypocortisolism in the pathophysiology of stress-related bodily disorders.
        Psychoneuroendocrinology. 2000; 25: 1-35
        • Janis G.C
        • Devaud L.L
        • Mitsuyama H
        • Morrow A.L
        Effects of chronic ethanol consumption and withdrawal on the neuroactive steroid 3alpha-hydroxy-5alpha-pregan-20-one in male and female rats.
        Alcoholism Clin Exp Res. 1998; 22: 2055-2061
        • LeMelledo J.-M
        • Driel M.V
        • Coupland N.J
        • Lott P
        • Jhangri G.S
        Response to flumazenil in women with premenstrual dysphoric disorder.
        Am J Psychiatry. 2000; 157: 821-823
        • Nutt D.J
        • Glue P
        • Lawson C
        • Wilson S
        Flumazenil provocation of panic attacks.
        Arch Gen Psychiatry. 1990; 47: 917-925
        • Parry B.L
        • Berga S.L
        • Kripke D.F
        • Klauber M.R
        • Laughlin G.A
        • Yen S.S.C
        • et al.
        Altered waveform of plasma nocturnal melatonin sescretion in premenstrual depression.
        Arch Gen Psychiatry. 1990; 47: 1139-1146
        • Parry B.L
        • Gerner R.H
        • Wilkins J.N
        • Halaris A.E
        • Carlson H.E
        • Hershman J.M
        • et al.
        CSF and endocrine studies of premenstrual syndrome.
        Neuropsychopharmacology. 1991; 5: 127-137
        • Patchev V.K
        • Hassan A.H.S
        • Holsboer F
        • Almeida O.F.X
        The neurosteroid tetrahydroprogesterone attenuates the endocrine response to stress and exerts glucocorticoid-like effects on vasopressin gene transcription in the rat hypothalamus.
        Neuropsychopharmacology. 1996; 15: 533-540
        • Patchev V.K
        • Shoaib M
        • Holsboer F
        • Almeida O.F.X
        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; 62: 265-271
        • Paul S.M
        • Purdy R.H
        Neuroactive steroids.
        FASEB J. 1992; 6: 2311-2322
        • Pearlstein T.B
        • Frank E
        • Rivera-Tovar A
        • Thoft J.S
        • Jacobs E
        • Mieczkowski T.A
        Prevalance of axis I and axis II disorders in women with late luteal phase dysphoric disorder.
        J Affect Disord. 1990; 20: 129-134
        • Purdy R.H
        • Moore P.H
        • Rao P.N
        • Hagino N
        • Yamaguchi T
        • Schmidt P
        • et al.
        Radioimmunoassay of 3 alpha-hydroxy-5 alpha-pregnan-20-one in rat and human plasma.
        Steroids. 1990; 55: 290-296
        • Purdy R.H
        • Morrow A.L
        • Moore P.H
        • Paul S.M
        Stress-induced elevations of γ-aminobutyric acid type A receptor-active steroids in the rat brain.
        Proc Natl Acad Sci U S A. 1991; 88: 4553-4557
        • Rabin D.S
        • Schmidt P.J
        • Campbell G
        • Gold P.W
        • Jensvold M
        • Rubinow D.R
        • et al.
        Hypothalamic-pituitary-adrenal function in patients with the premenstrual syndrome.
        J Clin Endocrinol Metab. 1990; 71: 1158-1162
        • Rapkin A.J
        • Morgan M
        • Goldman L
        • Brann D.W
        • Simone D
        • Mahesh V.B
        Progesterone metabolite allopregnanolone in women with premenstrual syndrome.
        Obstet Gynecol. 1997; 90: 709-714
        • Redei E
        • Freeman E.W
        Preliminary evidence for plasma adrenocorticotropin levels as biological correlates of premenstrual symptoms.
        Acta Endocrinol. 1993; 128: 536-542
      3. Reid RL (1985): Premenstrual syndrome. In: Leventhal JM, Hoffman JJ, Keith LG, Taylor PH, editors. Obstetrics, Gynecology and Fertility. Chicago: Year Book Medical Publishers, pp. 4–57.

        • Romeo E
        • Strohle A
        • Spalletta G
        • di Michele F
        • Hermann B
        • Holsboer F
        • et al.
        Effects of antidepressant treatment on neuroactive steroids in major depression.
        Am J Psychiatry. 1998; 155: 910-913
        • Roy-Byrne P.P
        • Rubinow D.R
        • Gwirtsman H
        • Hoban M.C
        • Grover G.N
        Cortisol response to dexamethasone in women with premenstrual syndrome.
        Neuropsychobiology. 1986; 16: 61-63
        • Rubinow D.R
        • Hoban C
        • Grover G.N
        • Galloway D.S
        • Roy-Byrne P
        • Andersen R
        • 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; 158: 5-11
        • Schmidt P.J
        • Grover G.N
        • Rubinow D.R
        Alprazolam in the treatment of premenstrual syndrome.
        Arch Gen Psychiatry. 1993; 50: 467-473
        • Siever L.J
        • Davis K.L
        Overview.
        Am J Psychiatry. 1985; 142: 1017-1031
        • Smith S.S
        • Gong Q.H
        • Li X
        • Moran M.H
        • Bitran D
        • Frye C.A
        • Hsu F.-C
        Withdrawal from 3α-OH-5α-pregnan-20-one using a pseudopregnancy model alters the kinetics of hippocampal GABAA-gated current and increases the GABAA receptor α4 subunit in association with increased anxiety.
        J Neurosci. 1998; 18: 5275-5284
        • Sundstrom I
        • Andersson A
        • Nyberg S
        • Ashbrook D
        • Purdy R.H
        • Backstrom T
        Patients with premenstrual syndrome have a different sensitivity to a neuroactive steroid during the menstrual cycle compared to control subjects.
        Clin Neuroendocrinol. 1998; 67: 126-138
        • Sundstrom I
        • Ashbrook D
        • Backstrom T
        Reduced benzodiazepine sensitivity in patients with premenstrual syndrome.
        Psychoneuroendocrinology. 1997; 22: 25-38
        • Uzunova V
        • Sheline Y
        • Davis J.M
        • Rasmusson A
        • Uzunov D.P
        • Costa E
        • et al.
        Increase in the cerebrospinal fluid content of neurosteroids in patients with unipolar major depression who are receiving fluoxetine or fluvoxamine.
        Proc Natl Acad Sci U S A. 1998; 95: 3239-3244
        • Wang M
        • Seippel L
        • Purdy R.H
        • Backstrom T
        Relationship between symptom severity and steroid variation in women with premenstrual syndrome.
        J Clin Endocrinol Metab. 1996; 81: 1076-1082
        • Woods N.F
        • Lentz M
        • Mitchell E
        • Logan H
        Arousal and stress response across the menstrual cycle in women with three perimenstrual symptom patterns.
        Res Nurs Health. 1994; 17: 99-110