In sheep, the ACTH secretory response to CRH in vivo or in vitro changes as a function of development, with peak responses occurring several weeks before term (145 days of gestation). CRH-stimulated ACTH secretion is mediated via the G protein-coupled CRH type I (CRH R1) receptor. We used a quantitative ribonuclease protection assay and Western immunoblotting to determine messenger RNA (mRNA) and protein levels of the CRH R1 receptor in immature and mature fetuses and adults. In addition, we precociously elevated fetal plasma cortisol levels to determine whether the fetal CRH R1 receptor is sensitive to increases in plasma cortisol.CRH R1 receptor mRNA levels decreased markedly throughout gestation and into the transition to adult life (immature fetus, 1.24 Ϯ 0.17; mature fetus, 0.75 Ϯ 0.13; adult, 0.18 Ϯ 0.093 pg/g total anterior pituitary RNA). Also, continuous cortisol infusion in immature fetuses significantly decreased CRH R1 mRNA levels by 41%. Similar decreases were noted in protein levels. Thus, the decreased ACTH response to CRH stimulation during late gestation may be related to decreased CRH R1 receptor expression. In addition, plasma cortisol levels may influence corticotroph responsiveness to CRH by decreasing CRH R1 receptor expression. (Endocrinology 141: 2870 -2876, 2000) C RH, A 41-AMINO acid neuropeptide produced in the paraventricular nucleus of the hypothalamus, is a major regulator of pituitary secretion of ACTH. In the fetus, ACTH plays an important role in the maturation of the adrenal gland and the resultant rise in plasma glucocorticoids during late gestation. In fetal sheep this rise in plasma cortisol in late gestation is essential for triggering the initiation of parturition as well as the preparation of the fetus for extrauterine life. Therefore, the mechanisms that control pituitary responsiveness to ACTH throughout fetal life are critical for the timely delivery of the fetus and survival of the neonate (1, 2).ACTH secretory responses, particularly those involved with CRH, appear to vary as a function of development. The relative responsiveness of the fetal pituitary to CRH stimulation is greater before 130 days of gestation (dg), with less mature fetal pituitaries exhibiting a greater ACTH secretory response to CRH stimulation than mature pituitaries both in vitro and in vivo. (3-9). Interestingly, adrenalectomy of fetuses at around 120 dg can prevent the loss of corticotroph responsiveness to CRH during late gestation (8).The maturation of the corticotroph response to CRH depends on changes occurring among the population of ACTHsecreting cells. During early gestation, CRH stimulation increases the proportion of corticotrophs actively secreting ACTH. However, during late gestation CRH is unable to recruit nonsecreting corticotrophs (9). Therefore, the maturation of the fetal hypothalamic-pituitary-adrenal axis may involve alterations in the secretory responses of individual corticotrophs, a process that may rely upon plasma cortisol levels. An important determinant of c...