Douglas S. Rabin

The maternal hypothalamic–pituitary–adrenal axis in the third trimester of human pregnancy

OBJECTIVE The third trimester of pregnancy is characterized by a mildly hyperactive hypothalamic–pituitary–adrenal (HPA) axis, possibly driven by elevated circulating levels of corticotrophin releasing hormone (CRH) of placental origin. In‐vitro studies have demonstrated that glucocorticoids and oestrogen stimulate while progesterone inhibits the expression of CRH mRNA and/or protein, suggesting that several potential interactions between the placenta and the HPA axis may exist.

Sex differences in sensitivity of the hypothalamic-pituitary-adrenal axis.

Two studies examined sex differences in responsiveness of the hypothalamic-pituitary-adrenal cortical axis, a major component of the stress response. The first measured pituitary-adrenal responses to ovine corticotropin-releasing hormone (oCRH) in 24 health men and 19 healthy women. Plasma adrenocorticotropin hormone (ACTH) response to oCRH were significantly greater among women than among men. In contrast, cortisol concentrations were similar in both groups, though elevations were more prolonged in women. Differences in corticotropin-releasing activity between men and women may help account for these findings; such differences in central components of the stress response might play a role in the known epidemiological differences in diseases of stress system dysregulation between men and women.

Stress and Reproduction: Physiologic and Pathophysiologic Interactions between the Stress and Reproductive Axes

Stress is a ubiquitous feature of life. Although its prevalence as a factor in health and disease is difficult to ascertain, it is arguably a significant risk to the well being of the overall population. Stress and the response to stressful events, on the other hand, have played an important part in human survival and evolution. From earliest times, people have dealt with harsh elements and adverse situations requiring both behavioral and physiological responses to protect themselves and their societies.

Human Placenta and the Hypothalamic-Pituitary-Adrenal Axis

Maternal plasma bound and free cortisol rises during pregnancy, while maternal plasma IR-ACTH is initially low but soon rises inspite of the further increase of plasma free cortisol. This rise of plasma ACTH during pregnancy, can not be attributed to changes of plasma levels of estrogens or progesterone. It is possible that the human placenta is responsible for the rise in maternal plasma ACTH during pregnancy. There are two possible mechanisms by which this effect could occur: 1) by the placental secretion of CRH into the maternal circulation, which stimulates the maternal pituitary to secrete ACTH, and 2) the secretion of placental POMC-derived peptides. Recent data indicate that the human placenta is capable of both of these actions: A) The POMC and CRH genes are expressed in human placenta; B) the human term placenta is able to secrete both CRH and POMC-derived peptides in vitro; C) the CRH present in the plasma of pregnant women is bioactive and in sufficient levels to be effective on maternal pituitary; D) synthetic hCRH can stimulate the release of placental POMC peptides in vitro. We conclude that the human placenta may be a modulator of the HPA axis during pregnancy in a number of possible ways. Additional experimental work should clarify the intriguing interaction between the HPA axis and the human placenta during pregnancy, labor and delivery.

The Clinical Implications of Corticotropin-Releasing Hormone

We now appreciate that the brain is the most prolific of all endocrine organs producing scores of neurohormones within and beyond the boundaries of the endocrine hypothalamus. The idea that the brain functions as a gland, however, is not new. Indeed, the evolution of thought leading to the identification of corticotropin releasing hormone (CRH) began around 400 B.C. (1,2). At this time, Hippocrates, in his work entitled De Glandulis, states explicitly, “The flesh of the glands is different from the rest of the body, being spongy and full of veins; they are found in the moist part of the body where they receive humidity... and the brain is a gland as well as the mammae.”