Interactions between the Hypothalamic-Pituitary-Adrenal Axis and the Female Reproductive System: Clinical Implications

The hypothalamic-pituitary-adrenal axis exerts profound, multilevel inhibitory effects on the female reproductive system. Corticotropin-releasing hormone (CRH) and CRH-induced proopiomelanocortin peptides inhibit hypothalamic gonadotropin-releasing hormone secretion, whereas glucocorticoids suppress pituitary luteinizing hormone and ovarian estrogen and progesterone secretion and render target tissues resistant to estradiol. The hypothalamic-pituitary-adrenal axis is thus responsible for the "hypothalamic" amenorrhea of stress, which is also seen in melancholic depression, malnutrition, eating disorders, chronic active alcoholism, chronic excessive exercise, and the hypogonadism of the Cushing syndrome. Conversely, estrogen directly stimulates the CRH gene promoter and the central noradrenergic system, which may explain adult women's slight hypercortisolism; preponderance of affective, anxiety, and eating disorders; and mood cycles and vulnerability to autoimmune and inflammatory disease, both of which follow estradiol fluctuations. Several components of the hypothalamic-pituitary-adrenal axis and their receptors are present in reproductive tissues as autacoid regulators. These include ovarian and endometrial CRH, which may participate in the inflammatory processes of the ovary (ovulation and luteolysis) and endometrium (blastocyst implantation and menstruation), and placental CRH, which may participate in the physiology of pregnancy and the timing of labor and delivery. The hypercortisolism of the latter half of pregnancy can be explained by high levels of placental CRH in plasma. This hypercortisolism causes a transient postpartum adrenal suppression that, together with estrogen withdrawal, may partly explain the depression and autoimmune phenomena of the postpartum period.