George P. Chrousos, MD; David J. Torpy, MB, BS; Philip W. Gold, MD
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.
Stress generally inhibits the female reproductive system ( ) primarily through the hypothalamic-pituitary-adrenal axis [left] through 1) suppression of hypothalamic gonadotropin-releasing hormone secretion by corticotropin-releasing hormone [CRH] and CRH-induced β-endorphin; 2) inhibition of hypothalamic gonadotropin-releasing hormone (GnRH), pituitary luteinizing hormone (LH), and ovarian estradiol [E ] secretion by cortisol; and 3) cortisol-induced target tissue resistance to estradiol. The locus ceruleus-norepinephrine system ( ) provides positive input to the reproductive system, which is frequently overcome by the stress-activated hypothalamic-pituitary-adrenal axis. However, sexual stimulation and GnRH neuron activation may render the gonadal axis resistant to suppression by the hypothalamic-pituitary-adrenal axis. Through estradiol, the reproductive system provides positive input to both components of the stress system by stimulating CRH secretion and inhibiting reuptake and catabolism of catecholamines. α-MSH = melanocyte-stimulating hormone; ACTH = adrenocorticotropic hormone; AVP = arginine-vasopressin; FSH = follicle-stimulating hormone; NE (α) = norepinephrine stimulation via α-noradrenergic receptors; POMC = proopiomelanocortin. Solid line = stimulation; dotted line = inhibition.
Generally, this adipose tissue-derived hormone inhibits the hypothalamic-pituitary-adrenal axis and stimulates the reproductive system. Leptin inhibits the hypothalamic-pituitary-adrenal axis at both the hypothalamic and adrenocortical levels. By contrast, leptin provides positive input to the female reproductive axis through inhibition of the hypothalamic-pituitary-adrenal axis and arcuate proopiomelanocortin (POMC) neuronal system and through activation of the locus ceruleus-norepinephrine system (LC/NE). Leptin-induced inhibition of hypothalamic neuropeptide Y (NPY) secretion participates in both the inhibition of the hypothalamic-pituitary-adrenal axis and the activation of the locus ceruleus-norepinephrine system. The inhibitory effect of proopiomelanocortin neurons on the expression of neuropeptide Y via α-melanocyte-stimulating hormone (α-MSH) and melanocortin receptor type 4 should be noted. ACTH = adrenocorticotropic hormone; CRH = corticotropin-releasing hormone; E = estradiol; FSH = follicle-stimulating hormone; GnRH = gonadotropin-releasing hormone; LH = luteinizing hormone. Solid line = stimulation; dotted line = inhibition.
The increasing activity of the reproductive axis during puberty and the decreasing activity of the same axis during the first stages of menopause are associated with changes in the activity of the stress system, represented here by changes in hypothalamic corticotropin-releasing hormone (CRH) secretion. The monthly concurrent fluctuation of ovarian estradiol and hypothalamic CRH secretion is also shown (see for details).
The decreased activity of the reproductive axis in the late luteal and early follicular phases is associated with concurrent changes in the activity of the stress system, represented here by changes in hypothalamic corticotropin-releasing hormone (CRH) secretion.
The increasing levels of corticotropin-releasing hormone (CRH) in the last trimester, along with the decreasing levels of CRH-binding protein, may participate in the initiation and progression of labor. The decreased secretion of estradiol and hypothalamic CRH in the postpartum period is associated with changes in the activity of the stress system, represented here by decreased CRH secretion. ACTH = adrenocorticotropic hormone.
The hypothalamic-pituitary-adrenal axis in the nonpregnant ( ), pregnant ( ), and postpartum ( ) states. Heuristic, simplified representation of the secretion of the hypothalamic-pituitary-adrenal axis hormones in the morning and afternoon, corresponding to the states shown in the upper panels. During pregnancy, placental corticotropin-releasing hormone (CRH)-induced hypercortisolism suppresses the hypothalamic CRH neuron. In the immediate postpartum period, the loss of placental CRH and of estradiol input to the hypothalamic CRH neuron results in a period of low hypothalamic CRH secretion and, hence, increased vulnerability to mood disturbances, such as postpartum blues, depression, or psychosis, or to autoimmune disorders, such as postpartum thyroiditis. In the nonpregnant state, the pulsatility and circadian rhythm of the hypothalamic-pituitary-adrenal axis are maintained by pulsations of hypothalamic CRH and arginine-vasopressin (AVP). In the pregnant state, peripheral placental CRH usurps the role of hypothalamic CRH and causes hypercortisolism while pulsatility and circadian rhythm are maintained by arginine-vasopressin. In the postpartum state, hypothalamic (portal) CRH is initially suppressed and gradually returns to normal. During this period, pulsatility and circadian rhythm are possibly maintained by portal arginine-vasopressin as input from portal CRH gradually increases over time; the predominance of arginine-vasopressin might explain the decreased cortisol suppressibility by dexamethasone previously seen in the early postpartum period. ACTH = adrenocorticotropic hormone; E = estradiol; P = progesterone. Solid line = stimulation; dotted line = inhibition. Adapted from .
Anoxic conditions, such as preeclampsia or eclampsia; increased concentrations of inflammatory cytokines associated with intrauterine infection or inflammation; and increased levels of cortisol arising from any kind of physical or emotional stress may promote premature labor through the secretion of placental and fetal membrane corticotropin-releasing hormone.
Chrousos GP, Torpy DJ, Gold PW. Interactions between the Hypothalamic-Pituitary-Adrenal Axis and the Female Reproductive System: Clinical Implications. Ann Intern Med. 1998;129:229–240. doi: https://doi.org/10.7326/0003-4819-129-3-199808010-00012
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Published: Ann Intern Med. 1998;129(3):229-240.
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