Hypothalamicpituitarygonad Axis

The overall organization of the hypothalamic-pituitary-gonad (HPG) axis is similar to the other major neuroendocrine axes. A "pulse" generator in the arcuate nucleus of the hypothalamus controls gonadotropin-releasing hormone (GnRH) secretion, which occurs in a pulsatile fashion [99]. GnRH is released into the portal circulation connecting the hypothalamus and anterior pituitary, where it binds to gonadotrophs and promotes the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) into the systemic circulation [100]. These hormones then bind to Leydig's cells in the testes to promote testosterone secretion or the ovaries to promote oestrogen secretion. In females, FSH also promotes the development of ovarian follicles and the synthesis and secretion of androgen-binding proteins and inhibin. Inhibin acts directly on the anterior pituitary to inhibit FSH secretion without affecting LH release. In both sexes, testosterone/estradiol generated by the testes / ovaries feed back on the pituitary and hypothalamus to inhibit further FSH, LH and GnRH release.

Despite the significantly higher rates of depression in women, data on HPG abnormalities in psychiatric disorders remain remarkably limited. Early studies showed no differences in plasma concentrations of LH and FSH in depressed postmenopausal women compared with non-depressed matched control subjects [101]. However, a later study showed decreased plasma LH concentrations in depressed postmenopausal women compared to matched controls [102]. In a more recent study, significantly lower estra-diol levels were detected in women with depression, but the blood levels of other reproductive hormones fell within the normal range [103]. Because estradiol affects a number of neurotransmitter systems, including norepin-ephrine and serotonin, these results merit further study.

The response to administration of exogenous GnRH in depressed patients has also been investigated. Normal LH and FSH responses to a high dose of GnRH (250 ^g) have been reported in male depressed and female depressed (pre- and postmenopausal) patients [104], whereas a decreased LH response to a lower dose of GnRH (150 ^g) has been reported in pre- and postmenopausal depressed patients [102]. Unden et al. [105] observed no change in basal or TRH/luteinizing hormone-releasing hormone (LHRH)-stimulated LH concentrations in a depressed cohort including both sexes, though depressed males with an abnormal DST response showed a significantly higher increase in FSH compared to the controls.

The prevalence of mood disorders in women, including premenstrual syndrome (PMS) and post-partum depression, also deserves mention. PMS is a cyclic recurrence of symptoms both somatic (oedema, fatigue, breast tenderness, headaches) and psychological (depression, irritability, and affective lability). The symptoms start following ovulation and disappear within the first day or two of menses, followed by a symptom-free interval between menses and the next ovulation. In some cases (5-10%), symptoms may be severe enough to interfere with normal functioning, leading to the diagnosis of premenstrual dysphoric disorder (PMDD) [106]. GnRH agonists, which produce a "clinical ovariectomy'' by down-regulation of GnRH

receptors in the pituitary and reduced gonadotropin secretions, have been shown to be an effective treatment for PMS, suggesting that the HPG axis is involved in the manifestation of symptoms [107]. However, significant variations in HPG axis function have yet to be identified in women especially susceptible to PMS.

Post-partum mood disorders are also common, occurring in approximately 10% of women after childbirth. Both post-partum depression and the less frequent post-partum psychosis show their highest prevalence in the first three months after childbirth [108]. The timing of these syndromes would suggest that neuroendocrine dysregulation may contribute to their expression, but no major abnormalities in HPG axis function were detected in a prospective investigation of post-partum disorders [109]. Additional research on the HPG axis in depression and in other mood states is needed.

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