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The Hypothalamic-Pituitary-Gonadal Axis and Women’s Mental Health: PCOS, Premenstrual Dysphoric Disorder, and Perimenopause

The Hypothalamic-Pituitary-Gonadal Axis and Women’s Mental Health: PCOS, Premenstrual Dysphoric Disorder, and Perimenopause

Figure. The hypothalamic-pituitary-gonadal axisFigure.
Table 1 – Major hormones of the HPG axisTable 1 – Major hormones of the HPG axis
Summary - Management of PCOS, premenstrual dysphoric disorder, and perimenopauseTable 2 – Summary of management of PCOS, premenstrual dysphoric disord...

Many psychiatric disorders are more prevalent in women during their reproductive years and at stages of life associated with changes in the hormonal milieu. The neuroendocrine system, including central brain circuits, gonadal functions, and other target organs, has been implicated in the development of psychiatric conditions, such as mood, anxiety, and cognitive disorders. The hypothalamic-pituitary-gonadal (HPG) axis coordinates a tightly regulated feedback loop that consists of gonadotropin-releasing hormone (GnRH) produced by the hypothalamus; follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary; and the sex steroids estrogen, progesterone, and androgens, produced primarily by the ovary, corpus luteum, and adrenals (Table 1; Figure). Cyclic and episodic alterations in the HPG axis across the menstrual cycle and during important reproductive health events, such as pregnancy and menopause, are hypothesized to alter the sensitivity of neurotransmitter systems and the function of neural circuits in ways that increase vulnerability to psychiatric symptoms for some women.

This article reviews basic neuroendocrine function and discusses the evidence base of hormonal contribution to psychiatric symptoms in polycystic ovary syndrome (PCOS), premenstrual dysphoric disorder (PMDD), and perimenopause. Strategies for psychiatrists for both clinical assessment and management of female patients with neuroendocrine dysfunction are provided, and the role of hormonal therapies in exacerbating or alleviating neuropsychiatric symptoms in these conditions is explored (Table 2).


PCOS is one of the most common endocrine disorders in women of childbearing age and is a leading cause of menstrual irregularity and anovulatory infertility. In the US prevalence is 6% to 15%, depending on the criteria used for diagnosis.1 The core features of PCOS include hyperandrogenemia, menstrual irregularities/oligovulation or anovulation, and polycystic ovaries. Women with PCOS also commonly have metabolic disturbances such as reduced insulin sensitivity and obesity.

Presentation and clinical features

The characteristic problems of PCOS can be separated into reproductive/menstrual abnormalities, hyperandrogenemia, and metabolic dysfunction. Hyperandrogenemia is identified clinically by hirsutism, acne, and male-pattern alopecia; or biochemically, with elevated levels of testosterone, dehydroepiandrosterone sulfate, or androstenedione. Irregular or absent ovulation leads to the menstrual abnormalities typical of PCOS, including oligomenorrhea/amenorrhea and dysfunctional uterine bleeding (breakthrough bleeding and menorrhagia).

Infertility is common, and ovulation induction is often necessary for conception. There are increased rates of spontaneous abortion, premature delivery, pregnancy-induced hypertension, and gestational diabetes —independent of weight. Women with PCOS have an elevated risk of endometrial cancer because of less frequent exposure to ovulatory surges of progesterone and menstrual bleeding. They are also more likely to be obese, with rates varying according to environmental and cultural factors.1

Insulin resistance affects more than three-quarters of women with PCOS, even those who are lean. Rates of type 2 diabetes and gestational diabetes are higher in those with PCOS, as is metabolic syndrome.2 The menstrual irregularities of PCOS may improve as women age and androgen levels decrease. Women with a history of PCOS may have persistent hyperandrogenemia and metabolic disturbances after menopause, and they may experience less severe vasomotor symptoms during the menopausal transition.


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