Neuroendocrine Changes of the Menopausal Transition

  • Andrea Giannini
  • Marta Caretto
  • Tommaso SimonciniEmail author
Part of the ISGE Series book series (ISGE)


During menopausal transition, the ovaries are depleted of follicles, oestradiol and inhibin B production falls, and ovulation and menstruation no longer occur. The loss of ovarian sensitivity to follicle-stimulating hormone (FSH) and luteinizing hormone (LH) and the loss of negative feedback of oestradiol and inhibin B on the hypothalamic–pituitary unit result in increased production and release of gonadotropin release hormone (GnRH), FSH and LH. Increased FSH levels are particularly specific to postmenopause. Modifications of gonadotropins, oestradiol (E2), alterations in the function of noradrenergic and serotoninergic pathways and opioid tone in the hypothalamus cause the onset of vasomotor symptoms and consequent sleep disruption. Thermoregulatory dysfunction might be a result of a maladaptation of the brain to kisspeptin, neurokinin B and dynorphin (KNDy) neuron hypertrophy, which project to the preoptic thermoregulatory area. Mood, cognitive functions and neuroendocrine activity, which are closely related to the impairment of GABAergic, opioid and neurosteroid neurotransmitter milieu in the central nervous system (CNS), occur with climacteric period and during ageing. Failure of the main target of neurosteroids, the GABA-A receptor, to adapt to changes in levels of allopregnanolone over the course of the menopausal transition might lead to depressive symptoms, mood and cognitive dysfunctions.


Menopause Transition Neuroendocrine HPO axis Neurosteroids CNS 


  1. 1.
    Wise PM. Neuroendocrine modulation of the “menopause”: insights into the aging brain. Am J Phys. 1999;277(6 Pt 1):E965–70.Google Scholar
  2. 2.
    Downs JL, Wise PM. The role of the brain in female reproductive aging. Mol Cell Endocrinol. 2009;299(1):32–8.CrossRefGoogle Scholar
  3. 3.
    Butler L, Santoro N. The reproductive endocrinology of the menopausal transition. Steroids. 2011;76(7):627–35.CrossRefGoogle Scholar
  4. 4.
    Santoro N, Isaac B, Neal-Perry G, et al. Impaired folliculogenesis and ovulation in older reproductive aged women. J Clin Endocrinol Metab. 2003;88(11):5502–9.CrossRefGoogle Scholar
  5. 5.
    Woods NF, Mitchell ES. Symptoms during the perimenopause: prevalence, severity, trajectory, and significance in women’s lives. Am J Med. 2005;118(Suppl 12B):14–24.CrossRefGoogle Scholar
  6. 6.
    Woods NF, Smith-DiJulio K, Percival DB, Tao EY, Mariella A, Mitchell S. Depressed mood during the menopausal transition and early postmenopause: observations from the Seattle Midlife Women’s Health Study. Menopause. 2008;15(2):223–32.CrossRefGoogle Scholar
  7. 7.
    Weber MT, Maki PM, McDermott MP. Cognition and mood in perimenopause: a systematic review and meta-analysis. J Steroid Biochem Mol Biol. 2014;142:90–8.CrossRefGoogle Scholar
  8. 8.
    Bromberger JT, Schott LL, Kravitz HM, et al. Longitudinal change in reproductive hormones and depressive symptoms across the menopausal transition: results from the Study of Women’s Health Across the Nation (SWAN). Arch Gen Psychiatry. 2010;67(6):598–607.CrossRefGoogle Scholar
  9. 9.
    Bromberger JT, Schott L, Kravitz HM, Joffe H. Risk factors for major depression during midlife among a community sample of women with and without prior major depression: are they the same or different? Psychol Med. 2015;45(8):1653–64.CrossRefGoogle Scholar
  10. 10.
    Fogle RH, Stanczyk FZ, Zhang X, Paulson RJ. Ovarian androgen production in postmenopausal women. J Clin Endocrinol Metab. 2007;92(8):3040–3.CrossRefGoogle Scholar
  11. 11.
    Freedman RR. Hot flashes: behavioral treatments, mechanisms, and relation to sleep. Am J Med. 2005;118(Suppl 12B):124–30.CrossRefGoogle Scholar
  12. 12.
    McConnell DS, Stanczyk FZ, Sowers MR, Randolph JFJ, Lasley BL. Menopausal transition stage-specific changes in circulating adrenal androgens. Menopause. 2012;19(6):658–63.CrossRefGoogle Scholar
  13. 13.
    Rossmanith WG, Ruebberdt W. What causes hot flushes? The neuroendocrine origin of vasomotor symptoms in the menopause. Gynecol Endocrinol. 2009;25(5):303–14.CrossRefGoogle Scholar
  14. 14.
    Boulant JA. Role of the preoptic-anterior hypothalamus in thermoregulation and fever. Clin Infect Dis. 2000;31(Suppl 5):S157–61.CrossRefGoogle Scholar
  15. 15.
    Woods NF, Carr MC, Tao EY, Taylor HJ, Mitchell ES. Increased urinary cortisol levels during the menopausal transition. Menopause. 2006;13(2):212–21.CrossRefGoogle Scholar
  16. 16.
    Hale GE, Hitchcock CL, Williams LA, Vigna YM, Prior JC. Cyclicity of breast tenderness and night-time vasomotor symptoms in mid-life women: information collected using the Daily Perimenopause Diary. Climacteric. 2003;6(2):128–39.CrossRefGoogle Scholar
  17. 17.
    Gordon JL, Rubinow DR, Thurston RC, Paulson J, Schmidt PJ, Girdler SS. Cardiovascular, hemodynamic, neuroendocrine, and inflammatory markers in women with and without vasomotor symptoms. Menopause. 2016;23(11):1189–98.CrossRefGoogle Scholar
  18. 18.
    Freeman EW, Sammel MD, Lin H, et al. Symptoms associated with menopausal transition and reproductive hormones in midlife women. Obstet Gynecol. 2007;110(2 Pt 1):230–40.CrossRefGoogle Scholar
  19. 19.
    Pines A. Circadian rhythm and menopause. Climacteric. 2016;19(6):551–2.CrossRefGoogle Scholar
  20. 20.
    Andersen ML, Bittencourt LR, Antunes IB, Tufik S. Effects of progesterone on sleep: a possible pharmacological treatment for sleep-breathing disorders? Curr Med Chem. 2006;13(29):3575–82.CrossRefGoogle Scholar
  21. 21.
    Short RA, Bowen RL, O’Brien PC, Graff-Radford NR. Elevated gonadotropin levels in patients with Alzheimer disease. Mayo Clin Proc. 2001;76(9):906–9.CrossRefGoogle Scholar
  22. 22.
    Wober C, Brannath W, Schmidt K, et al. Prospective analysis of factors related to migraine attacks: the PAMINA study. Cephalalgia. 2007;27(4):304–14.CrossRefGoogle Scholar
  23. 23.
    Avis NE, Brambilla D, McKinlay SM, Vass K. A longitudinal analysis of the association between menopause and depression. Results from the Massachusetts Women’s Health Study. Ann Epidemiol. 1994;4(3):214–20.CrossRefGoogle Scholar
  24. 24.
    Freeman EW, Sammel MD, Boorman DW, Zhang R. Longitudinal pattern of depressive symptoms around natural menopause. JAMA Psychiat. 2014;71(1):36–43.CrossRefGoogle Scholar
  25. 25.
    Gordon JL, Girdler SS, Meltzer-Brody SE, et al. Ovarian hormone fluctuation, neurosteroids, and HPA axis dysregulation in perimenopausal depression: a novel heuristic model. Am J Psychiatry. 2015;172(3):227–36.CrossRefGoogle Scholar

Copyright information

© International Society of Gynecological Endocrinology 2019

Authors and Affiliations

  • Andrea Giannini
    • 1
  • Marta Caretto
    • 1
  • Tommaso Simoncini
    • 1
    Email author
  1. 1.Division of Obstetrics and Gynecology, Department of Experimental and Clinical MedicineUniversity of PisaPisaItaly

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