Pregnancy dramatically affects the hypothalamic-pituitary-adrenal axis leading to increased circulating cortisol and ACTH levels during gestation, reaching values in the range seen in Cushing's syndrome (CS). The cause(s) of increased ACTH may include placental synthesis and release of biologically active CRH and ACTH, pituitary desensitization to cortisol feedback, or enhanced pituitary responses to corticotropin-releasing factors. In this context, challenges in diagnosis and management of disorders of the hypothalamic-pituitary-adrenal axis in pregnancy are discussed. CS in pregnancy is uncommon and is associated with fetal morbidity and mortality. The diagnosis may be missed because of overlapping clinical and biochemical features in pregnancy. The proportion of patients with primary adrenal causes of CS is increased in pregnancy. CRH stimulation testing and inferior petrosal sinus sampling can identify patients with Cushing's disease. Surgery is a safe option for treatment in the second trimester; otherwise medical therapy may be used. Women with known adrenal insufficiency that is appropriately treated can expect to have uneventful pregnancies. Whereas a fetal/placental source of cortisol may mitigate crisis during gestation, unrecognized adrenal insufficiency may lead to maternal or fetal demise either during gestation or in the puerperium. Appropriate treatment and management of labor are reviewed.

/pdf/the-hypothalamic-pituitary-adrenal-axis-in-pregnancy-4xacp189q5.pdf

The Hypothalamic-Pituitary-Adrenal Axis in Pregnancy: Challenges in Disease Detection and Treatment

The complex mechanisms controlling human parturition involves mother, fetus, and placenta, and stress is a key element activating a series of physiological adaptive responses. Preterm birth is a clinical syndrome that shares several characteristics with term birth. A major role for the neuroendocrine mechanisms has been proposed, and placenta/membranes are sources for neurohormones and peptides. Oxytocin (OT) is the neurohormone whose major target is uterine contractility and placenta represents a novel source that contributes to the mechanisms of parturition. The CRH/urocortin (Ucn) family is another important neuroendocrine pathway involved in term and preterm birth. The CRH/Ucn family consists of four ligands: CRH, Ucn, Ucn2, and Ucn3. These peptides have a pleyotropic function and are expressed by human placenta and fetal membranes. Uterine contractility, blood vessel tone, and immune function are influenced by CRH/Ucns during pregnancy and undergo major changes at parturition. Among the others, neurohormones, relaxin, parathyroid hormone-related protein, opioids, neurosteroids, and monoamines are expressed and secreted from placental tissues at parturition. Preterm birth is the consequence of a premature and sustained activation of endocrine and immune responses. A preterm birth evidence for a premature activation of OT secretion as well as increased maternal plasma CRH levels suggests a pathogenic role of these neurohormones. A decrease of maternal serum CRH-binding protein is a concurrent event. At midgestation, placental hypersecretion of CRH or Ucn has been proposed as a predictive marker of subsequent preterm delivery. While placenta represents the major source for CRH, fetus abundantly secretes Ucn and adrenal dehydroepiandrosterone in women with preterm birth. The relevant role of neuroendocrine mechanisms in preterm birth is sustained by basic and clinic implications.

Neuroendocrine Mechanisms in Pregnancy and Parturition

The mechanisms involved in human pregnancy maintenance and parturition are highly complex and involve mother, fetus and placenta. The "final common pathway" to delivery is composed by inflammatory and endocrine interactive paths that tip the balance in favor of coordinated uterine contractility and cervical dilation. These mechanisms involve a shift from progesterone to estrogen dominance, CRH action, increased sensitivity to oxytocin, gap junction formation, and increased prostaglandins activity. Complementary changes in the cervix involve a decrease in progesterone dominance and the actions of prostaglandins and relaxin, via connective tissue alterations, leading to cervical softening and dilation. Neuronal, hormonal, inflammatory and immune pathways participate in initiation of labor and the utero-placental unit plays a major role in the synthesis and release of parturition mediators.

Endocrinology of human parturition

CRH and CRH-related peptides such as urocortin mediate their actions in the human myometrium via activation of two distinct classes of CRH receptors, R1 and R2. These heptahelical receptors are able to stimulate a number of different intracellular signals; one key mediator of G protein-activated intracellular signaling is the cascade of p42/p44, mitogen-activated protein kinase (MAPK). We therefore hypothesized that activation of MAPK might mediate CRH and or/urocortin actions in the myometrium. In cultured human pregnant myometrial cells, urocortin but not CRH was able to induce MAPK phosphorylation and activation, suggesting that in the human myometrium these two peptides have distinct actions and biological roles. To identify the particular receptor subtypes mediating this phenomenon, all known CRH receptors present in the human myometrial cells were stably expressed individually in HEK293 and CHO cells, and their ability to activate MAPK was tested. The R1alpha and R2beta, but not the R1beta, R1c, or R1d, receptor subtypes were able to mediate urocortin-induced MAPK activation. The signaling components were further investigated; activation of Gs, Go, or Gi proteins did not appear to be involved, but activation of Gq with subsequent production of inositol triphosphates (IP3) and protein kinase C (PKC) activation correlated with MAPK phosphorylation. Studies on Gq protein activation using [alpha-32P]-GTP-gamma-azidoanilide and IP3 production in cells expressing the R1alpha or R2beta CRH receptors demonstrated that urocortin was 10 times more potent than CRH. Moreover, urocortin (UCN) generated peak responses that were 50-70% greater than CRH in activating the Gq protein and stimulating IP3 production. In conclusion, UCN acting thought multiple receptor subtypes can stimulate myometrial MAPK via induction of the Gq/phospholipase C/IP3/PKC pathway, whereas CRH-induced activation of this pathway appears to be insufficient to achieve MAPK activation.

Urocortin, but not corticotropin-releasing hormone (CRH), activates the mitogen-activated protein kinase signal transduction pathway in human pregnant myometrium: An effect mediated via R1α and R2β CRH receptor subtypes and stimulation of Gq-proteins

The determinants of bone mineral density (BMD) at multiple sites were examined in a fit college population. Subjects were 755 males (mean age = 18.7 years) entering the United States Military Academy. A questionnaire assessed exercise frequency and milk, caffeine, and alcohol consumption and tobacco use. Academy staff measured height, weight, and fitness. Calcaneal BMD was measured by peripheral dual-energy x-ray absorptiometry (pDXA). Peripheral-quantitative computed tomography (pQCT) was used to measure tibial mineral content, circumference and cortical thickness. Spine and hip BMD were measured by DXA in a subset (n = 159). Mean BMD at all sites was approximately one standard deviation above young normal (p < 0.05). African Americans had significantly higher hip, spine and heel BMD and greater tibial mineral content and cortical thickness than Caucasians and Asians. In Caucasians (n = 653), weight was a significant determinant of BMD at every skeletal site. Prior exercise levels and milk intake positively related to bone density and size, while caffeine had a negative impact. There was an apparent interaction between milk and exercise in BMD at the heel, spine, hip and tibial mineral content and cortical thickness. Our data confirm the importance of race, body size, milk intake and duration of weekly exercise as determinants of BMD and bone size.

/pdf/determinants-of-bone-mass-and-bone-size-in-a-large-cohort-of-44gnioklto.pdf

Determinants of bone mass and bone size in a large cohort of physically active young adult men

Urocortin is a new member of the CRF family. Multiple biological effects for urocortin have been shown in rats and in some in vitro models, showing a modulatory role in hormonal and behavioral functions. Human placenta expresses urocortin, but no information is available on the possible local biological actions. The aim of the present study was to evaluate the effect of urocortin on placental ACTH and prostaglandin (PG) secretion, as well as on myometrial contractility. Various in vitro models were used. For investigating the effect of urocortin on ACTH release, primary cultures of human trophoblast cells were used. Culture media, collected before and after 3 h exposure to different doses of urocortin and ACTH, were measured by RIA. Trophoblast tissue explants were incubated for 24 h in the presence of increasing doses of urocortin, and prostaglandin E2 (PGE2) levels were measured by RIA. Strips of myometrial tissue were incubated in an organ bath and connected to an isometric smooth-muscle transducer in the presence of urocortin, with or without prostaglandin F2a (PGF2a). In all these experiments, the effect of astressin (a CRF receptor antagonist) on urocortin-induced actions and the effect of equimolar doses of CRF were evaluated. A dose-related increase of trophoblast ACTH or PGE2 was induced by urocortin, whereas astressin inhibited urocortin-stimulated ACTH or PGE2 release. Equimolar doses of CRF showed a similar effect on both ACTH and PGE2. Urocortin increased PGF2a-induced myometrial contractility, and this effect was completely abolished by the addition of astressin. The present study showed that human urocortin stimulates placental secretion of ACTH and PGE2, and modulates myometrial contractility, suggesting a role for this peptide in placental and intrauterine CRF pathways. (J Clin Endocrinol Metab 84: 1420 ‐1423, 1999)

Urocortin stimulates placental adrenocorticotropin and prostaglandin release and myometrial contractility in vitro.

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Urocortin stimulates placental adrenocorticotropin and prostaglandin release and myometrial contractility in vitro.