2nd Department of Obstetrics and Gynecology, Medical School, University of Athens, "Aretaieion" Hospital, Athens, Greece
Address for correspondence: Dr. G. Mastorakos, 3, Neofytou Vamva Street, Athens, GR-10674, Greece. Voice: +30-210-3636230; fax: +30-210-3636229.
mastorak{at}mail.kapatel.gr
Ann. N.Y. Acad. Sci. 997: 136-149 (2003).
The principal modulators of the hypothalamic-pituitary-adrenal
(HPA) axis are corticotropin-releasing hormone (CRH) and arginine-vasopressin
(AVP). Corticotropin-releasing hormone is not exclusively produced
in the hypothalamus. Its presence has been demonstrated at peripheral
inflammatory sites. Ovulation and luteolysis bear characteristics
of an aseptic inflammation. CRH was found in the theca and stromal
cells as well as in cells of the corpora lutea of human and
rat ovaries. The cytoplasm of the glandular epithelial cells
of the endometrium has been shown to contain CRH and the myometrium
contains specific CRH receptors. It has been suggested that
CRH of fetal and maternal origin regulates FasL production,
thus affecting the invasion (implantation) process through a
local auto-paracrine regulatory loop involving the cytotrophoblast
cells. Thus, the latter may regulate their own apoptosis. During
pregnancy, the plasma level of circulating maternal immunoreactive
CRH increases exponentially from the first trimester of gestation
due to the CRH production in the placenta, decidua, and fetal
membranes. The presence in plasma and amniotic fluid of a CRH-binding
protein (CRHbp) that reduces the bioactivity of circulating
CRH by binding is unique to humans. Maternal pituitary ACTH
secretion and plasma ACTH levels rise during pregnancy—though
remaining within normal limits—paralleling the rise of
plasma cortisol levels. The maternal adrenal glands during pregnancy
gradually become hypertrophic. Pregnancy is a transient, but
physiologic, period of hypercortisolism. The diurnal variation
of plasma cortisol levels is maintained in pregnancy, probably
due to the secretion of AVP from the parvicellular paraventricular
nuclei. CRH is detected in the fetal hypothalamus as early as
the 12th week of gestation. CRH levels in fetal plasma are 50%
less than in maternal plasma. The circulating fetal CRH is almost
exclusively of placental origin. The placenta secretes CRH at
a slower rate in the fetal compartment. AVP is detected in some
neurons of the fetal hypothalamus together with CRH. AVP is
usually detectable in the human fetal neurohypophysis at 11
to 12 weeks gestation and increases over 1000-fold over the
next 12 to 16 weeks. The role of fetal AVP is unclear. Labor
appears to be a stimulus for AVP release by the fetus. The processing
of POMC differs in the anterior and intermediate lobes of the
fetal pituitary gland. Corticotropin (ACTH) is detectable by
radioimmunoassay in fetal plasma at 12 weeks gestation. Concentrations
are higher before 34 weeks gestation, with a significant fall
in late gestation. The human fetal adrenal is enormous relative
to that of the adult organ. Adrenal steroid synthesis is increased
in the fetus. The major steroid produced by the fetal adrenal
zone is sulfoconjugated dehydroepiandrosterone (DHEAS). The
majority of cortisol present in the fetal circulation appears
to be of maternal origin, at least in the nonhuman primate.
The fetal adrenal uses the large amounts of progesterone supplied
by the placenta to make cortisol. Another source of cortisol
for the fetus is the amniotic fluid where cortisol converted
from cortisone by the choriodecidua, is found. In humans, maternal
plasma CRH, ACTH, and cortisol levels increase during normal
labor and drop at about four days postpartum; however, maternal
ACTH and cortisol levels at this stage are not correlated. In
sheep, placental CRH stimulates the fetal production of ACTH,
which in turn leads to a surge of fetal cortisol secretion that
precipitates parturition. The 10-day-long intravenous administration
of antalarmin, a CRH receptor antagonist, significantly prolonged
gestation compared to the control group of animals. Thus, CRH
receptor antagonism in the fetus can also delay parturition.
The HPA axis during the postpartum period gradually recovers
from its activated state during pregnancy. The adrenals are
mildly suppressed in a way analogous to postcure Cushing's syndrome.
Provocation testing has shown that hypothalamic CRH secretion
is transiently suppressed at three and six weeks postpartum,
normalizing at 12 weeks.
