Selective effects of CPAP on sleep apnoea-associated manifestations.

BACKGROUND: Visceral adiposity and obstructive sleep apnoea (OSA) may be independently associated with daytime sleepiness/low performance, insulin resistance, hypercytokinaemia, and/or hypertension. The objectives of this study are to simultaneously test these associations at baseline and after 3 months of continuous positive airway pressure (CPAP) therapy. MATERIALS AND METHODS: Sixteen obese men with OSA; 13 non-apnoeic, obese controls, and 15 non-obese controls were monitored in the sleep laboratory for four consecutive nights. Objective measures of daytime sleepiness and performance, serial 24 h plasma measures of interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-alpha), TNF receptor 1 (TNF-r1) and adiponectin, fasting blood glucose and insulin, visceral adiposity and blood pressure were obtained. Sleep apnoeics were re-assessed using the same protocol after 3 months of CPAP. RESULTS: At baseline, IL-6, TNF-r1, and insulin resistance were highest in OSA patients, intermediate in obese controls, and lowest in non-obese controls (P < 0.05). Visceral fat was significantly greater in sleep apnoeics than obese controls and predicted insulin resistance and IL-6 levels, whereas OSA predicted TNF-r1 levels (P < 0.05). CPAP decreased daytime sleepiness and blood pressure (P < 0.05), but did not affect fasting glucose or insulin or around the clock adiponectin, IL-6, TNF-alpha, or TNF-r1 levels. CONCLUSIONS: In obese sleep apnoeics, visceral fat is strongly associated with insulin resistance and inflammation. CPAP decreases sleepiness and moderates hypertension but does not affect visceral adiposity, insulin resistance, hypoadiponectinaemia or hypercytokinaemia, all of which are independent risk factors for cardiovascular disease and diabetes.

Hypothalamic-pituitary-adrenal axis activity in obese men with and without sleep apnea: effects of continuous positive airway pressure therapy.

CONTEXT: Previous studies on the association between the hypothalamic-pituitary-adrenal axis activity and sleep apnea (SA) and obesity are inconsistent and/or limited. OBJECTIVE: In this study, we evaluated the activity of the hypothalamic-pituitary-adrenal axis in nonpsychologically distressed obese subjects with and without SA and examined the impact of continuous positive airway pressure (CPAP) in SA patients. DESIGN AND PARTICIPANTS: In study I, four-night sleep laboratory recordings and serial 24-h plasma measures of cortisol were obtained in 45 obese men with and without apnea and nonobese controls. Sleep apneic patients were reassessed after 3 months of CPAP use. In study II, 38 obese men with and without sleep apnea and nonobese controls were challenged with ovine CRH administration after four nights in the sleep laboratory. RESULTS: The sleep patterns were similar between obese and nonobese controls. Twenty-four-hour plasma cortisol levels were highest in nonobese controls, intermediate in obese apneic patients, and lowest in obese controls (8.8 +/- 0.4 vs. 8.1 +/- 0.3 vs. 7.5 +/- 0.3 microg/dl, P < 0.05). CPAP tended to reduce cortisol levels in the apneic patients (difference -0.7 +/- .4 microg/dl, P = 0.1). CRH administration resulted in a higher ACTH response in both obese groups, compared with nonobese controls; the three groups were not different in cortisol response. CONCLUSIONS: Nonpsychologically distressed, normally sleeping, obese men had low cortisol secretion. The cortisol secretion was slightly activated by SA and returned to low by CPAP use. The low cortisol secretion in obesity through its inferred hyposecretion of hypothalamic CRH might predispose the obese to sleep apnea.

CRF receptor antagonists: utility in research and clinical practice.

CRF, CRF-related peptides and CRF receptors constitute a complex physiological system which has a key role in facilitating the adaptation of the organism to the stressful stimuli of the environment. The behavioral, endocrine, autonomic and immune branches of stress response are considered to be under the coordinating effects of CRF and its related peptides. The effects of these peptides are mediated through two distinct receptors, types 1 and 2 CRF receptors (CRF(1) and CRF(2)). The two receptors are encoded by separate genes and belong to the G-coupled receptor superfamily. The wide influence of the CRF system on physiological processes in both brain and periphery, suggests the implication of the respective peptides in the pathophysiology of numerous disorders which involve dysregulated stress responses. The potential use of CRF antagonists in such disorders is currently under intense investigation. Furthermore, such compounds have been invaluable in elucidating the physiology of the CRF system. This review will focus on existing data on the structural and pharmacological characteristics as well as the experimental and potential clinical uses of non-peptide, small molecule CRF antagonists.

Potential uses of corticotropin-releasing hormone antagonists.

Corticotropin-releasing hormone (CRH), its natural homologs urocortins (UCN) 1, 2, and 3, and several types of CRH receptors (R), coordinate the behavioral, endocrine, autonomic, and immune responses to stress. The potential use of CRH antagonists is currently under intense investigation. Selective antagonists have been used experimentally to clarify the role of CRH-related peptides in anxiety and depression, addictive behavior, inflammatory disorders, acute and chronic neurodegeneration, and sleep disorders, as well as preterm labor.

Identification and characterization of opioid-binding sites present in the Ishikawa human endometrial adenocarcinoma cell line.

Normal epithelial cells of human endometrium, and Ishikawa human endometrial adenocarcinoma cells (an in vitro model for the study of steroid hormone effects on human endometrium) have been found to express and secrete opioid peptides deriving from proenkephalin, prodynorphin, and proopiomelanocortin. These opioids may act locally, affecting the uterine tissues. In the present study, we identified and characterized opioid-binding sites on the Ishikawa cell line, producing evidence for the mechanism of local opioid action. We used an acid shock before the receptor assay to dissociate any endogenously bound peptide. The acidification improved specific binding by 2- to 4.5-fold. Characterization of opioid binding using different radiolabeled opioids and effectors has shown the existence of a low concentration of delta-sites (Kd, 6.20 nmol/L; 4,890 sites/cell), no mu-sites, low affinity kappa 1-sites (Kd, 10.8 nmol/L; 276,000 sites/cell), kappa 2-sites with high affinity for ethylketocyclazocine (Kd, approximately 1 nmol/L) and low affinity for diprenorphine (Kd, approximately 8 nmol/L) at a concentration of 93,000 sites/cell, and high affinity kappa 3-sites (Kd, 3.6 nmol/L; 77,000 sites/cell). In conclusion, our report characterizes opioid sites in a particular and homogeneous cell type of human endometrium, i.e. in epithelial cells. The coexistence of opioid sites and their endogenous ligands in the Ishikawa cell line makes these cells a good model for the study of autocrine/paracrine interactions of opioids in nonneural tissues.

Marked decrease in sleepiness in patients with sleep apnea by etanercept, a tumor necrosis factor-alpha antagonist.

The proinflammatory cytokines, TNFalpha and IL-6, are elevated in obstructive sleep apnea (OSA) and have been proposed as mediators of excessive daytime sleepiness in humans. We tested the effects of etanercept, a medication that neutralizes TNFalpha and is approved by the FDA for the treatment of rheumatoid arthritis, in eight obese male apneics. These patients participated in a pilot, placebo-controlled, double-blind study during which nighttime polysomnography, multiple sleep latency test, and fasting blood glucose and plasma levels of IL-6, C-reactive protein, insulin, and adiponectin were obtained. There was a significant and marked decrease in sleepiness by etanercept, which increased sleep latency during the multiple sleep latency test by 3.1 +/- 1.0 min (P < 0.05) compared with placebo. Also, the number of apneas/hypopneas per hour was reduced significantly by the drug compared with placebo (52.8 +/- 9.1 vs. 44.3 +/- 10.3; adjusted difference, -8.4 +/- 2.3; P < 0.05). Furthermore, IL-6 levels were significantly decreased after etanercept administration compared with placebo (3.8 +/- 0.9 vs. 1.9 +/- 0.4 pg/ml; adjusted difference, -1.9 +/- 0.5; P < 0.01). However, no differences were observed in etanercept vs. placebo in the levels of fasting blood glucose and plasma C-reactive protein, insulin, and adiponectin. We conclude that neutralizing TNFalpha activity is associated with a significant reduction of objective sleepiness in obese patients with OSA. This effect, which is about 3-fold higher than the reported effects of continuous positive airway pressure on objective sleepiness in patients with OSA (0.9 vs. 3.1 min), suggests that proinflammatory cytokines contribute to the pathogenesis of OSA/sleepiness.

The corticotropin-releasing hormone (CRH) in normal and tumoral epithelial cells of human endometrium.

CRH is produced by several intrauterine sites, including placenta and desidua, during pregnancy. However, no data are available regarding the presence of CRH in the nonpregnant uterus. We now report that CRH is produced in the epithelial cells of normally cycling human uterus and in an endometrial epithelial cell-derived tumor. Specifically, we have found that: 1) Northern blot hybridization analysis of normal glandular endometrium as well as of Ishikawa human endometrial adenocarcinoma cells showed the presence of the CRH messenger RNA; the size of the transcript seemed to be identical to that present in human placenta and rat hypothalamus; 2) immunoreactive CRH (ir-CRH) was detectable in normal dispersed glandular endometrial cells as well as in the Ishikawa adenocarcinoma cells; 3) gel filtration chromatography of normal glandular endometrial and Ishikawa cell extracts and their culture media showed that most ir-CRH present had the mol wt of the authentic CRH peptide; in addition, a larger form of ir-CRH was also present in both normal and tumoral endometrial epithelial cell extracts; the latter most probably correspondents to CRH precursor molecules; and 4) immunofluorescence staining of CRH in normal glandular endometrial and Ishikawa cells revealed a cytoplasm rich in granules positive for ir-CRH. Our findings suggest that CRH may play an important role in the physiological events taking place within the uterine cavity, since CRH seems to be present in nonpregnant as well as pregnant uteri. Since CRH is expressed in normal endometrial epithelial cells and in an epithelial tumoral cell line, we propose the use of the Ishikawa cell line as a convenient model for the in vitro study of endometrial CRH.

Adverse effects of modest sleep restriction on sleepiness, performance, and inflammatory cytokines.

Total sleep restriction in humans is associated with increased daytime sleepiness, decreased performance, and hormonal/metabolic disturbances. The effects of mild chronic sleep restriction that mimic real life are not known. To assess the effects of modest sleep restriction from 8 to 6 h/night for 1 wk, 25 young, healthy, normal sleepers (12 men and 13 women) were studied for 12 consecutive nights in the sleep laboratory. After 1 wk of sleep restriction, although subjects' nighttime sleep was deeper, subjects were significantly sleepier (multiple sleep latency test) and performed worse in four primary variables of psychomotor vigilance test (both P < 0.01). Furthermore, 24-h secretion of IL-6 was increased by 0.8 +/- 0.3 pg/ml (P < 0.05) in both sexes, whereas TNFalpha was increased only in men. Also, the peak cortisol secretion was lower after sleep restriction than at baseline, and this difference was stronger in men (55.18 +/- 24.83 nmol/liter; P < 0.05) than in women (35.87 +/- 24.83 nmol/liter; P < 0.16). We conclude that in young men and women, modest sleep loss is associated with significant sleepiness, impairment of psychomotor performance, and increased secretion of proinflammatory cytokines. Given the potential association of these behavioral and physical alterations with health, well-being, and public safety, the idea that sleep or parts of it are optional should be regarded with caution.

Corticotropin releasing hormone (CRH) in normal and pregnant uterus: physiological implications.

Corticotropin-releasing hormone, is a hypothalamic neuropeptide, responsible not only for the endocrine but also the autonomic, immunological and behavioural responses of mammalian organisms to stress. CRH is also expressed in female reproductive tissues, such as placenta and uterus. Multiple sites within the pregnant uterine cavity express the CRH gene, including the trophoblasts, fetal membranes (chorion, amnion) and decidua. The trophoblastic syncytium appears to be the major source of placental CRH. It is postulated that placental CRH influences the HPA axis of either mother or fetus and participates at the initiation of labour. Recent findings show that human and rat uterus express the CRH gene. Epithelial cells of both species are the main source of endometrial CRH, while stroma does not seem to express it, unless it differentiates to decidua. Estrogens and glucocorticoids inhibit and prostaglandin E2 stimulates the promoter of human CRH gene in transfected human endometrial cells, suggesting that endometrial CRH gene expression is under the control of these agents. Moreover, in rats, endometrial CRH expression is significantly higher at the implantation sites, compared to that at the inter-implantation uterine regions. Given the proinflammatory/vasoregulatory properties of CRH, we hypothesize that endometrial CRH may participate in the regulation of intrauterine phenomena, such as blastocyst implantation, endometrial vascularization and myometrial contractility.

Endometrial and placental CRH as regulators of human embryo implantation.

Epithelial cells of the human endometrium and differentiated endometrial stromal cells express the corticotropin-releasing hormone (CRH) gene. CRH is also produced by human placental cytotrophoblast. Endometrial and placental CRH are under the endocrine control of gonadal steroids as well as under autocrine/paracrine regulation by prostanoids and interleukins. Human endometrium, myometrium and placenta express the relevant receptors. Human trophoblast and decidualized endometrial cells also express Fas ligand (FasL), a pro-apoptotic molecule. These findings suggest that intra-uterine CRH may participate in local inflammatory phenomena associated with blastocyst implantation, while FasL may assist with maternal immune tolerance to the semi-allograft embryo. A nonpeptidic CRH receptor type 1 (CRH-R1)-specific antagonist decreased the expression of FasL by human trophoblasts, suggesting that CRH regulates the pro-apoptotic potential of these cells in an auto-paracrine fashion. Invasive trophoblasts promoted apoptosis of activated Fas-expressing human T lymphocytes, an effect potentiated by CRH and inhibited by the CRH antagonist. Female rats treated with the CRH antagonist in the first 6 days of gestation had a dose-dependent decrease of endometrial implantation sites and live embryos as well as markedly diminished endometrial FasL expression. However, embryos of mothers lacking T cells (nude rats) and embryos of syngeneic matings were not rejected when mothers were treated with antalarmin, suggesting that the effect of antalarmin on embryonic implantation is not due to a nonspecific toxicity of this compound but a specific effect on T cells. Our data suggest important physiological roles of endometrial and placental CRH in the regulation of blastocyst implantation and early maternal tolerance.

Stress and the female reproductive system.

The hypothalamic-pituitary-adrenal (HPA) axis, when activated by stress, exerts an inhibitory effect on the female reproductive system. Corticotropin-releasing hormone (CRH) inhibits hypothalamic gonadotropin-releasing hormone (GnRH) secretion, and glucocorticoids inhibit pituitary luteinizing hormone and ovarian estrogen and progesterone secretion. These effects are responsible for the "hypothalamic" amenorrhea of stress, which is observed in anxiety and depression, malnutrition, eating disorders and chronic excessive exercise, and the hypogonadism of the Cushing syndrome. In addition, corticotropin-releasing hormone and its receptors have been identified in most female reproductive tissues, including the ovary, uterus, and placenta. Furthermore, corticotropin-releasing hormone is secreted in peripheral inflammatory sites where it exerts inflammatory actions. Reproductive corticotropin-releasing hormone is regulating reproductive functions with an inflammatory component, such as ovulation, luteolysis, decidualization, implantation, and early maternal tolerance. Placental CRH participates in the physiology of pregnancy and the onset of labor. Circulating placental CRH is responsible for the physiologic hypercortisolism of the latter half of pregnancy. Postpartum, this hypercortisolism is followed by a transient adrenal suppression, which may explain the blues/depression and increased autoimmune phenomena observed during this period.

Participation of maternal and fetal CRH in early phases of human implantation: the role of antalarmin.

The hypothalamic neuropeptide corticotropin-releasing hormone (CRH) is produced by several tissues of the female reproductive system. It is also secreted at inflammatory sites and possesses potent pro-inflammatory properties influencing both innate and acquired immune processes. Uterine CRH participates in local immune early pregnancy phenomena, such as decidualization of endometrial strom a and protection of the fetus from maternal immune system. This is maintained through induction of the expression of apoptotic FasL on invasive extravillous trophoblast and maternal decidual cells at the fetal-maternal interface. Furthermore, CRH increases apoptosis of activated T lymphocytes through FasL induction participating in the process of implantation and early pregnancy. Female rats treated with the non-peptidic CRH receptor 1 (CRHR1) specific antagonist antalarmin, in the first 6 days of gestation, have undergone a decrease of endometrial implantation sites and live embryos and markedly diminished endometrial FasL expression.

Endometrial corticotropin-releasing hormone. Its potential autocrine and paracrine actions.

Corticotropin-releasing hormone (CRH) is expressed at several peripheral tissues including normal epithelial cells of human and rodent uterus. However, its biological role is unknown in both species. To clarify this role we studied the regulation of CRH promoter in endometrial cells. We performed homologous transfection experiments in Ishikawa cells, a human endometrial cell line, using a 0.9-kb fragment of the 5'-flanking region of human CRH gene coupled to luciferase. We found that the activity of the 5'-flanking region of the CRH gene is stimulated by cAMP and EGF and inhibited in a receptor-mediated, dose-dependent fashion by estradiol and dexamethasone. The antiglucocorticoid RU 486 acted as a glucocorticoid agonist suppressing CRH gene activation, whereas progesterone was devoid of any activity. Prostaglandin E2 and interleukins-1 and -6 stimulated CRH activation, and the prostanoid inhibitor indomethacin suppressed it, most probably by inhibiting endogenous prostaglandins. These findings suggest that endometrial CRH gene expression may be under the negative control of estrogens and glucocorticoids and under the positive control of PGE2, IL-1, and IL-6. Considering the involvement of CRH in proinflammatory phenomena, we postulate that endometrial CRH, in association with uterine prostanoids and cytokines, may participate in intrauterine inflammatory processes of early pregnancy, such as decidualization and blastocyst implantation.

Endometrial corticotropin-releasing hormone: expression, regulation, and potential physiological implications.

Our findings show that human and rat uterus express the CRH gene. Epithelial cells of both species are the main source of endometrial CRH, while stroma does not seem to express it, unless it differentiates to decidua. Immunoreactive CRH, produced by endometrial cells, has the chromatographic characteristics of authentic hypothalamic CRH, while the size of its mRNA in both human and rat uterus is similar to or identical with its counterpart, present in placenta and hypothalamus (1.3 kb). Estrogens and glucocorticoids inhibit and prostaglandin E2 stimulates the promoter of human CRH gene in transfected human endometrial cells, suggesting that endometrial CRH gene expression is under the control of these agents. Moreover, in rats, endometrial CRH expression is significantly higher at implantation sites, compared to that at interimplantation uterine regions. Given the proinflammatory/vasoregulatory properties of CRH, we hypothesize that endometrial CRH may participate in the regulation of intrauterine phenomena, such as blastocyst implantation, endometrial vascularization, and myometrial contractility.

Endometrial and myometrial corticotropin-releasing hormone (CRH): its regulation and possible roles.

In human endometrium, both epithelial and stroma cells produce corticotropin-releasing hormone (CRH). Both types of cells also possess specific CRH-binding sites indicating a local effect of endometrial CRH. The transcription of the CRH gene in human endometrium is under the control of steroid hormones and locally produced prostanoids and interleukins. Endometrial CRH interacts with locally produced prostaglandins and interleukins. Based on these observations it can be hypothesized that CRH, prostaglandins and interleukins form a network responsible for the communication between epithelial and stromal cells, at the level of the endometrium, and between endometrial and myometrial cells at the level of uterus. The net product of these interaction is the micro-regulation of the decidualizing process and the preparation of endometrium for the implantation/nidation of the conceptus. Indeed, this network may represent the core of the intrauterine neuroendocrine-immune interactions involved in the decidualization of stroma and implantation of blastocyst. In addition, this network appears to be essential for the fine-tuning of myometrial tone.

Estrogens and glucocorticoids induce the expression of c-erbB2/NEU receptor in Ishikawa human endometrial cells.

We investigated the effects of estrogens and other steroid hormones on c-erbB2 gene expression in Ishikawa human endometrial adenocarcinoma cells. We have found that the c-erbB2/NEU transcripts are present in the Ishikawa endometrial cell line as well as in human endometrial adenocarcinoma cells. Both cell types express the 4.6 and 2.3 kb c-erbB2 mRNAs. Estradiol significantly increased in a time- and dose-dependent manner the content of c-erbB2 mRNA and the concentration of NEU protein in Ishikawa cell extracts, while progesterone was devoid of any activity. The effect of estradiol was partially reversed by the antiestrogen 4-hydroxytamoxifen, which, however, given alone exhibited agonist effects. Glucocorticoid dexamethasone augmented in a time- and dose-dependent fashion the content of c-erbB2 mRNA and the concentration of NEU protein in Ishikawa cell extracts. The antiglucocorticoid RU 486 acted as a glucocorticoid agonist increasing c-erbB2 gene activation. To our knowledge, this is the first report documenting the induction by steroid hormones of c-erbB2 gene expression in neoplastic human endometrial cells. Our data support the hypothesis that the oncogenic effect of estrogens on human endometrial cells may be partially mediated by its effect on the expression of the c-erbB2 proto-oncogene. The finding that glucocorticoids may induce endometrial c-erbB2 gene expression suggests that they may participate in the emergence of uterine neoplasias.

Corticotropin-releasing hormone (CRH) is expressed at the implantation sites of early pregnant rat uterus.

We have shown previously that the epithelial cells of human endometrium produce CRH. The biological role of endometrial CRH is not yet known. Among other things, CRH appears to be involved in the inflammatory process, acting as an autocrine/paracrine proinflammatory regulator. Since the reaction of endometrium to the invading blastocyst has characteristics of an aseptic inflammatory reaction, we have hypothesized that endometrial CRH may participate in the inflammatory phenomena taking place at the implantation site of blastocyst. In the present study we demonstrate a higher content of immunoreactive (IR)-CRH and CRH mRNA in the implantation sites of early pregnant rat uterus compared to the inter-implantation regions. Specifically we have found that: a) rat uterus contained a 1.3 kb CRH transcript, similar or identical in size to that present in human placenta, b) the size of the IR-CRH present in uterine extracts was similar to authentic hypothalamic CRH, c) Northern blot analysis showed that the content of CRH mRNA in uterus at the implantation sites was 3.5 fold higher compared to that in the inter-implantation regions and finally, d) immunohistochemical localization of IR-CRH in early pregnant rat uterus revealed positive staining of the luminal epithelial cells in both implantation and inter-implantation uterine regions, while decidualized stromal cells were positive only at the implantation sites. Our data suggest that endometrial CRH may play a role in the implantation of blastocyst.

Corticotropin-releasing hormone receptor antagonists: an update.

The corticotropin-releasing hormone (CRH) family, CRH, CRH-related peptides and their receptors (R) play major roles in coordinating the behavioral, endocrine, autonomic, and immune responses to stress. The wide influence of the CRH system on physiologic processes in both brain and periphery implicates the respective peptides in the pathophysiology of numerous disorders characterized by dysregulated stress responses. CRH peptides and their receptors are being explored as therapeutic targets for intervention in stress-related disorders. Selective antagonists have been used experimentally to elucidate the role of CRH-related peptides in disease processes, such as anxiety and depression, sleep disorders, addictive disorders, inflammatory disorders, acute and chronic neurodegeneration and preterm labor. The development of effective antagonists with no significant side effects remains a challenge.

Corticotropin-releasing hormone, stress and human reproduction: an update.

The stress system has suppressive effects on female and male reproductive function. Corticotrophin-releasing hormone (CRH), the principal regulator of stress, has been identified in the female and male reproductive system. Reproductive CRH participates in various reproductive functions that have an inflammatory component, where it serves as an autocrine and paracrine modulator. These include ovarian and endometrial CRH, which may participate in the regulation of steroidogenesis and the inflammatory processes of the ovary (ovulation and luteolysis) and the endometrium (decidualization and blastocyst implantation) and placental CRH, which is secreted mostly during the latter half of pregnancy and is responsible for the onset of labor. It has been suggested that there is a "CRH placental clock" which determines the length of gestation and the timing of parturition and delivery. The potential use of CRH-antagonists is presently under intense investigation. CRH-R1 antagonists have been used in animal studies to elucidate the role of CRH in blastocyst implantation and invasion, early fetal immunotolerance and premature labor. The present review article focuses on the potential roles of CRH on the physiology and pathophysiology of reproduction and highlights its participation in crucial steps of pregnancy, such as implantation, fetal immune tolerance, parturition and fetal programming of the hypothalamic-pituitary-adrenal (HPA) axis.

CRH-like peptides in human reproduction.

CRH and Urocortins 1, 2 and 3 comprise the, so far identified, members of the CRH family of peptides in humans. Their actions are mediated through two distinct receptors, CRHR1 and CRHR2, encoded by different genes. CRH-like peptides and their receptors have been identified in reproductive tissues, such as the ovary, uterus as well as fetal and placental membranes. The participation of the "CRH family" of peptides and receptors in the physiology of these organs is currently under intense investigation. During the estrus cycle, endometrial CRH acts as a fine tuner of stromal cells decidualization. CRH is produced by embryonic trophoblast and maternal decidual cells and plays important roles in implantation. CRH also participates in the control of trophoblast invasion. Furthermore, placental CRH and Urocortin are involved in the mechanisms controlling maintenance of pregnancy and the onset of labor. The level of participation of urocortins 2 and 3 in these phenomena is currently under investigation. This review will focus on existing data on the expression and regulation of the CRH family of peptides and their receptors in the female reproductive system, as well as in their potential biologic role(s) in human reproductive functions.