CRF activity in fetal rat hypothalamus, in late pregnancy.

The corticosterone content of the adrenal glands was determined in 21-day-old rat fetuses: (1) before and after encephalectomy or decapitation (hypophysectomy); (2) after ACTH treatment of the encephalectomized or decapitated (hypophysectomized) fetuses; and (3) after administration of crude extracts (0.1 N HCl) of hypothalamic or cortical tissue from 20-day-old rat fetuses. A peak in the corticosterone content of the adrenals was observed 10 min after ACTH injection to enceaphlectomized or decapitated fetuses. A rise in corticosterone concentration was noted 5 and 10 min after the encephalectomized fetuses were given an injection of hypothalamic extract. This extract was devoid of appreciable ACTH activity when tested in decapitated fetuses. Cortical extract was inactive in encephalectomized or decapitated fetuses. These data suggest that fetal hypothalamic extract contains some CRF activity and that the fetal pituitary gland is responsive to the CRF.     

Evidence that control of fetal thyrotropin secretion is independent of both the fetal and maternal hypothalamus

Propylthiouracil (PTU) administered to pregnant rats from day 18-21 of gestation caused a significant increase in maternal and fetal thyroid weight and plasma TSH. Fetal encephalectomy on day 18 did not significantly affect basal or PTU-stimulated pituitary-thyroid function. Destruction of the basal hypothalamus in the mother on day 13 or 16 markedly reduced maternal plasma TSH and thyroxine and prevented a PTU-induced increase in thyroid size, but did not affect fetal pituitary-thyroid function. Plasma PRL, was undetectable in both intact and encephalectomized fetuses at 21 days but was increased greater than 6-fold to approximately 2 microgram/ml in the mothers by maternal hypothalamic destruction. We conclude that fetal pituitary-thyroid function in the rat is not dependent on either fetal or maternal hypothalamic TRH.     

Modulation of growth hormone secretion by thermogenically derived free fatty acids in the perinatal lamb.

To evaluate the hypothesis that the rapid fall in circulating GH concentrations at birth is secondary to the initiation of nonshivering thermogenesis and the consequent rise in FFA levels, a series of experiments was performed in late-gestation fetal sheep. By sequentially cooling the fetus by means of a coil placed around the fetal thorax, ventilating with oxygen via an exteriorized tracheostomy tube, and separating the fetus from the placenta by occluding the umbilical cord, nonshivering thermogenesis could be induced in utero. In the first protocol (n = 6) cooling alone had no effect on fetal plasma FFA levels, oxygenation elevated FFAs slightly from 64 +/- 7 mu Eq/liter to 183 +/- 29 mu Eq/liter, and cord occlusion caused a further marked rise (P less than 0.005) to 635 +/- 69 mu Eq/liter. Neither cooling nor ventilation affected fetal plasma GH concentrations which fell (P less than 0.001) from 160 +/- 17 ng/ml to 65 +/- 13 ng/ml upon cord occlusion. When the cord occluder was removed FFA levels fell (P less than 0.001) and GH concentrations rose (P less than 0.001) once more, and when the cord was again occluded FFA levels rose (P less than 0.001) and GH concentrations fell (P less than 0.001). In a second protocol nine fetuses were cooled, ventilated, and the umbilical cord occluded. Once more, plasma FFA levels rose (P less than 0.001) and GH concentrations fell (P less than 0.001); when thermogenesis was inhibited by the infusion of the adenosine agonist N6-(L-2-phenyl isopropyl)-adenosine, FFA levels fell from 725 +/- 88 mu Eq/liter to 265 +/- 56 mu Eq/liter and GH concentrations rose from 54 +/- 13 ng/ml to 323 +/- 73 ng/ml. In two further protocols the possibility that PIA was acting directly on GH secretion was excluded in six fetuses with low plasma FFA levels and in three fetuses with elevated plasma FFA levels secondary to a fatty acid emulsion infusion. These studies provide direct evidence that the pattern of change in plasma GH concentrations at birth in the sheep is determined in part by the rise in plasma FFAs of thermogenic origin.     

The effect of glucose and free fatty acids on growth hormone (GH)-releasing factor-mediated GH secretion in rats

We have examined the effect of glucose and FFA on GH-releasing factor (GHRF)-mediated GH secretion in rats under pentobarbital anesthesia. Hyperglycemia did not affect GH secretion induced by administration of 20, 100, and 200 ng GHRF/100 g body weight. In contrast, GH response to 50 ng GHRF/100 g body weight in lipid heparin-treated rats, which showed high plasma FFA levels, was significantly suppressed compared with the control group (plasma peak GH: control, 1526 +/- 263 ng/ml; lipid-heparin group, 377 +/- 69 ng/ml P less than 0.05, mean +/- SEM). This suppressive effect of FFA on GH secretion was abolished by pretreatment with antisomatostatin serum (ASS) (GH level at 4 min after GHRF administration: ASS-saline group, 1606 +/- 210 ng/ml; ASS-lipid-heparin group, 1531 +/- 174 ng/ml; mean +/- SEM). These results suggest that hyperglycemia does not change the GH response to GHRF and that elevation of plasma FFA suppresses GHRF-induced GH secretion by the stimulation of somatostatin secretion in rats.     

Hormone ontogeny in the ovine fetus. XXVI. A sex difference in the effect of castration on the hypothalamic-pituitary gonadotropin unit in the ovine fetus

The detection of pulsatile ovine LH (oLH) secretion in the sheep fetus by 81 days gestation (term 147 days), the suppression of fetal gonadotropin secretion by chronic administration of an LH-releasing factor agonist or antagonist, and the capacity of N-methyl; D-aspartate (a neuroexcitatory amino acid analog) to evoke a fetal oLH pulse strongly support a functional LH-releasing factor pulse-generator in the ovine fetus. In light of the sex difference in fetal gonadal function and gonadotropin secretion before day 114, we postulated that fetal castration would have a discordant effect on the pattern of gonadotropin secretion in males and females. Fetal sheep were either castrated (male = 11; female = 9) or sham operated (male = 9; female = 6) at 110-115 days gestation. Chronic indwelling arterial and venous catheters were implanted, and animals were studied for up to 30 days. During each study period fetal arterial blood samples were drawn every 15 min for 5 h and the plasma assayed for oFSH and oLH by specific RIAs. Multiple studies were performed on each fetus. In all fetuses (both intact and castrated) a decrease in oLH pulse frequency occurred after day 130. In female fetuses before day 130, castration had no effect on mean oLH pulse frequency (sham, 0.72 +/- 0.19 pulses/5 h; castrate, 0.50 +/- 0.13 pulses/5 h; P greater than 0.05). After day 130, pulsatile oLH secretion decreased in both intact and castrated female fetuses to undetectable levels during the sampling period. In contrast, castration significantly (P less than 0.001) increased mean oLH pulsatility in males before and after day 130 (less than 130 days, sham, 1.06 +/- 0.24 pulse/5 h; castrate, 2.70 +/- 0.22 pulse/5 h; greater than 130 days, sham, 0.18 +/- 0.12 pulses/5 h; castrate, 1.65 +/- 0.26 pulses/5 h). Mean oLH pulse amplitude was increased by castration only in the male fetuses (sham, 3.89 +/- 0.87 ng/ml; castrate, 6.02 +/- 0.39 ng/ml; P less than 0.05). oFSH pulses were infrequent in both sexes and not influenced by castration. The mean plasma concentration of oFSH was greater in intact female fetuses than in intact males (female, 5.65 +/- 1.15 ng/ml vs. male, 2.07 +/- 0.45 ng/ml; P less than 0.01). Castration increased the mean value for plasma oFSH in males (4.40 +/- 0.43 ng/ml; P less than 0.001) but had no effect in females (3.83 +/- 0.64 ng/ml; P greater than 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)     

EFFECT OF ORAL ADMINISTRATION OF MELATONIN ON GH RESPONSES TO GRF 1–44 IN NORMAL SUBJECTS

In order to investigate the role of melatonin on the neuroregulation of GH secretion, eight healthy male volunteers each underwent four separate tests in random order separated by at least 1 week. Following oral administration of melatonin (500 mg at -60 min and at -30 min) plasma GH levels were higher than after placebo at 45 min (mean +/- SEM 2.9 +/- 0.8 vs 0.9 +/- 0.4 ng/ml, P less than 0.01) and 60 min (mean +/- SEM 2.9 +/- 0.4 vs 0.8 +/- 0.1 ng/ml, P less than 0.05). Likewise, after prior administration of melatonin, GH responses to GRF 1-44 (1 micrograms/kg i.v. at 0 min) were greater than placebo plus GRF at 15 min (mean +/- SEM 22.4 +/- 6.1 ng/ml vs 11.3 +/- 2.3 ng/ml, P less than 0.05), 45 min (mean +/- SEM 26.2 +/- 5.3 ng/ml vs 13.3 +/- 2.5 ng/ml, P less than 0.01) and 60 min (mean +/- SEM, 24.7 +/- 7.4 ng/ml vs 11.1 +/- 2.5 ng/ml, P less than 0.05). In contrast we did not observe any effect of either 10(-9)M, 10(-7)M melatonin on in-vitro basal GH release and GH responses to 10(-8)M GRF by rat anterior pituitary cells in monolayer culture. These data suggest that melatonin plays a facilitatory role in the neuroregulation of GH secretion, probably by acting at the hypothalamic level.     

Evidence that cortisol inhibits basal adrenocorticotropin secretion in the sheep fetus by 0.70 gestation

To ascertain if reductions in fetal plasma cortisol cause increases in fetal plasma ACTH, we treated pregnant ewes or their fetuses with aminoglutethimide (10 mg/kg BW) and metyrapone (20 mg/kg BW) and measured the hormonal responses with RIAs. When given to fetuses (n = 9) at 0.90 +/- 0.01 gestation (term-145 days), the steroid synthesis inhibitors reduced fetal plasma cortisol from 35.1 +/- 11.9 to 18.5 +/- 6.2 ng/ml (P less than 0.01) and plasma ACTH increased from 37 +/- 7 to 189 +/- 74 pg/ml (P less than 0.02). Thus, late in gestation cortisol from the fetal adrenal suppresses basal fetal ACTH secretion. Blockade of steroid biosynthesis in pregnant ewes carrying intact fetuses at 0.76 +/- 0.02 gestation (n = 11) or adrenalectomized fetuses at 0.81 +/- 0.01 gestation (n = 6) also reduced cortisol and increased ACTH in fetal plasma. In intact fetuses cortisol declined from 9.4 +/- 2.0 to 3.6 +/- 0.9 ng/ml (P less than 0.05), and ACTH increased from 46 +/- 8 to 183 +/- 67 (P less than 0.01); cortisol declined in adrenalectomized fetuses from 2.1 +/- 0.4 to 1.1 +/- 0.3 ng/ml (P less than 0.01), and ACTH increased from 106 +/- 13 to 400 +/- 104 pg/ml (P less than 0.01). Cortisol infusions into intact and adrenalectomized fetuses prevented both the decline in steroid concentration caused by the biosynthesis inhibitors given to the ewe and the increase in fetal plasma ACTH concentration. These data indicate that reductions in plasma cortisol in adrenalectomized fetuses or intact fetuses at a time in development when the fetal adrenal produces little cortisol cause compensatory increases in fetal plasma ACTH concentration. The simplest explanation for these observations is that from approximately 0.70 gestation, basal fetal ACTH secretion is tonically inhibited by cortisol circulating in fetal plasma. This cortisol can originate from sources other than the fetal adrenal.     

In vivo adrenocorticotropin (1-24)-induced accumulation of cyclic adenosine monophosphate by ovine fetal adrenal cells is inhibited by concomitant infusion of metopirone

Activation of the ovine fetal adrenal gland after pulse ACTH (P-ACTH) administration is associated with an increase in plasma cortisol levels. We have investigated whether cortisol may play a role in this adrenal activation process. The ability of fetal adrenal cells to accumulate cAMP in response to ACTH in vitro was compared in fetuses (day 132 of gestation) that had received infusions (100 h) in utero of 1) saline or saline + tartrate (0.5 ml for 15 min/2 h) (n = 4); 2) P-ACTH (66.6 ng/min for 15 min/2 h) (n = 4); 3) P-ACTH + metopirone (31.3 mg/h) (n = 4), to inhibit 11 beta-hydroxylase activity. Control fetuses showed no significant increase in plasma cortisol levels throughout the infusion and there was no significant accumulation of cAMP by fetal adrenal cells in vitro in response to ACTH. There was a significant (P less than 0.05) increase in plasma cortisol concentrations from 2.21 +/- 0.47 (mean +/- SEM) ng/ml at 0 h to 35.7 +/- 11.6 ng/ml at 96 h in fetuses receiving P-ACTH in vivo. In these fetuses there was a significant (P less than 0.05) accumulation of cAMP after addition of ACTH by fetal adrenal cells in vitro (mean increment delta = 48 pmol). This rise in plasma cortisol was prevented in fetuses receiving P-ACTH + metopirone. Further, metopirone treatment prevented the increase in fetal adrenal weight and accumulation of cAMP after in vitro ACTH that normally followed ACTH treatment in vivo. This effect was not overcome by further addition of guanylylimido-diphosphate. These experiments raise the possibility that cortisol might mediate the increase in cAMP accumulation resultant upon in vivo P-ACTH treatment.     

Control of gonadotropin secretion in the ovine fetus. III. Effect of castration on serum follicle-stimulating hormone levels during the last trimester of gestation

Gonadal involvement in fetal FSH regulation was examined by studying FSH levels in 13 female (7 castrate and 6 sham control) and 13 male (8 castrate and 5 sham control) chronically catheterized ovine fetuses operated upon in utero at 106-115 days gestation (term = 147 days). These fetuses had been studied previously for pulsatile LH secretion every 2-7 days over a 2- to 38-day period until fetal delivery or death. From each study day, 3 1-h spaced blood samples (1.5-2.0 ml) were taken for FSH determination by RIA (NIH FSH-S8 standard), and the results were averaged. The overall mean was then calculated for each fetus. In female fetuses, there was no significant difference in mean serum FSH levels between castrates [53.4 +/- 5.0 ng/ml (+/- SEM)] and controls (52.5 +/- 14.4 ng/ml). In contrast, serum FSH levels in the eugonadal males were significantly (P less than 0.001) lower (23.4 +/- 8.0 ng/ml) than those in castrate males (56.9 +/- 7.1 ng/ml, a value comparable to those observed in both female groups). Mean serum FSH levels declined significantly (P less than 0.001) in castrate fetuses of both sexes after 125 days (61.5 +/- 5.6 vs. 42.4 +/- 7.7 ng/ml in females; 64.1 +/- 6.1 vs. 51.5 +/- 8.6 ng/ml in males). In the males, the FSH decline did not reach sham control levels, which remained unchanged with advancing gestation. Moreover, mean serum FSH levels were significantly higher in a group of 4 male fetuses (62.2 +/- 13.7 ng/ml) castrated at 121-130 days gestation compared to values in 3 age-matched sham castrate controls (22.1 +/- 2.6 ng/ml; P less than 0.001). The increment in serum FSH levels in castrate compared to sham castrate male fetuses demonstrates an important role for the fetal testis in FSH regulation from 106 days gestation until term. The lack of a detectable castration effect on the relatively high serum FSH levels in eugonadal females indicates that the fetal ovary does not play a similar role and suggests that in females, FSH is secreted in a functionally castrate mode. The decline in FSH levels after 125 days in castrate fetuses of both sexes may result at least in part from the previously reported coincident rise in circulating levels of feto-placental sex steroids and/or PRL.(ABSTRACT TRUNCATED AT 400 WORDS)     

Handling during pregnancy in the blue fox (Alopex lagopus): the influence on the fetal pituitary-adrenal axis

Previous studies revealed that handling is a stressor for farmed blue foxes. The present study was designed to examine the effects of a 1-min daily handling stress applied to pregnant blue fox vixens on the function of the fetal pituitary-adrenal system. Plasma concentrations of adrenocorticotropin hormone (ACTH), cortisol, and progesterone, adrenal content of cortisol and progesterone, in vitro adrenal production of these steroids and response to ACTH, and adrenal weights were measured in control (C; n = 73) and stressed (S; n = 58) fetuses. The ACTH levels were lower in stressed fetuses than in the controls (C: males, 128.6 +/- 6.1 pg/ml; females, 165.9 +/- 6.1 pg/ml; S: males, 122.3 +/- 5.4 pg/ml; females, 145.0 +/- 8.1 pg/ml; P < 0.05). In contrast, increased plasma cortisol concentrations in both sexes were demonstrated in stressed compared with control fetuses (C: males, 9.2 +/- 0.4 ng/ml; females, 9.2 +/- 0.4 ng/ml; S: males, 11.8 +/- 0.7 ng/ml; females, 13.2 +/- 0.7 ng/ml; P < 0.00001). The same difference was observed in plasma progesterone concentrations (C: males, 1.54 +/- 0.07 ng/ml; females, 1.49 +/- 0.10 ng/ml; S: males, 1.86 +/- 0.11 ng/ml; females, 1.74 +/- 0.10 ng/ml; P < 0.01). Prenatal stress did not change the baseline adrenal production of cortisol but prevented the cortisol response to ACTH in female fetuses and decreased the progesterone production in both sexes. Additionally, prenatally stressed fetuses of both sexes had significantly lower adrenal weights than controls (C: males, 9.4 +/- 0.3 mg; females, 9.5 +/- 0.4 mg; S: males, 8.1 +/- 0.3 mg; females, 8.2 +/- 0.4 mg; P < 0.001). These results indicate that prenatal handling stress induces a dysregulation of the pituitary-adrenal axis in the fetus and suggest that increased plasma glucocorticoids in the stressed dam can cross the placenta and influence the fetal hypothalamicpituitary-adrenal axis.     

Serum luteinizing hormone and follicle-stimulating hormone and the response to luteinizing hormone-releasing factor in children and adolescents with isolated growth hormone deficiency

Serum concentrations of LH and FSH were measured in 95 patients (62 males and 33 females) with presumed isolated GH deficiency [chronological age range, 5-17 yr; bone age (BA) range, 2-15.5 yr] before and after the iv administration of 100 micrograms LRF. The results were compared to those of patients of similar skeletal maturity, derived from a population of 136 children (79 males and 57 females) with constitutional short stature. Mean serum LH concentrations were similar in the GH-deficient and control patients of either sex within the age ranges studied. Mean basal FSH concentrations in males with GH deficiency were similar to the controls between BA 2 to less than 10 yr and more than 12 to 15.5 yr. The mean peak, peak minus basal, and integrated responses of LH concentrations after the iv administration of LRF were not significantly different in patients with GH deficiency from the responses in normal short children of similar ages. After LRF administration, GH-deficient males of BA between 2 and less than 10 yr had diminished FSH responses. The mean peak concentration was 1.9 +/- 0.2 ng/ml in GH-deficient males (n = 34) and 2.8 +/- 0.3 ng/ml (less than 0.05) in control males (n = 45). GH-deficient males of BA between 10-12 yr had slightly elevated mean peak and total integrated FSH concentrations; in GH-deficient patients (n = 15), these values were 2.7 +/- 0.2 ng/ml and 2.1 +/- 0.2 ng X min ml-1, respectively; and in controls (n = 18), they were 1.8 +/- 0.2 ng/ml (P less than 0.05) and 1.5 +/- 0.2 ng X min ml-1 (P less than 0.05). In the BA range from 4-8 yr, the mean peak response to LRF was diminished in GH-deficient females (n = 24; 4.0 +/- 0.4 ng/ml) compared to that in control females (n = 18; 6.0 +/- 0.9 ng/ml; P less than 0.05). In the BA range from more than 8 to 13 yr, the corresponding mean peak FSH concentration in GH-deficient females (n = 9) was 3.2 +/- 0.3 ng/ml; in control females (n = 39), it was 4.9 +/- 0.4 ng/ml (P less than 0.05). This study fails to confirm previous reports that LRF-evoked LH release is diminished in patients with isolated GH deficiency compared to that in normal short children of similar skeletal maturity. Small differences in group mean FSH concentrations were noted, but these findings are of limited clinical importance because an extensive degree of overlap of individual FSH concentrations was found in all comparisons between GH-deficient patients and normal children.     

Effect of ether inhalation by adrenalectomized pregnant rats on the adrenal corticosterone concentration in norma, decapitated, and encephalectomized fetuses.

The influence of decapitation or encephalectomy (total removal of the brain leaving the pituitary in place) on the adrenal corticosterone concentration of the 20-day-old rat fetus has been studied in normal pregnant rats, in adrenalectomized pregnant rats, and in adrenalectomized pregnant rats subjected to the stress conditions of inhalation of ether for 40 min. Decapitation or encephalectomy of the fetus always results in a drop in adrenal corticosterone concentration within 4 h which is prevented in 15 min by injecting 3.2 mU of hog ACTH into the decapitated fetus. In mothers adrenalectomized in order to avoid a negative feedback reaction of maternal corticosteroids on the fetal pituitary-adrenal system, ether inhalation causes an important rise in adrenal corticosterone concentration in normal fetuses but not in decapitated or encephalectomized ones. Thus ether, which crosses the placental barrier, is a stressor agent for the fetal rat.     

Depression of growth hormone and cortisol response to insulin-induced hypoglycemia after prolonged oral delta-9-tetrahydrocannabinol administration in man.

Six hospitalized volunteer male subjects were given insulin, 0.15 U/kg, before and after 14 days of administration of delta-9-tetrahydrocannabinol (THC) at a dose of 210 mg/day. A diminished maximal serum human growth hormone (GH) increase followed the prolonged THC ingestion. The mean maximal GH response was: 52.6 ng/ml +/- 8.7 (+/-SE) before THC and 18.8 ng/ml +/- 6.7 (+/-SE) during THC, P less than 0.01; corresponding cortisol responses were 20.1 mug/dl +/- 3.0 before THC and 10.0 mug/dl +/- 1.1 during THC, P less than 0.05. The data suggest suppression of the hypothalamic-pituitary axis after prolonged high dose THC use. This is consistent with other reported endocrine effects of marijuana in man.     

Hormone ontogeny in the ovine fetus: XXI. The effect of insulin-like growth factor-I on plasma fetal growth hormone, insulin and glucose concentrations

We infused intravenously recombinant human Insulin-like Growth Factor-I (IGF-I; 1 microgram/kg/min for 120 minutes after an acute dose of 25 micrograms/kg) into chronically catheterized ovine fetuses (124-132 days gestation) to study its effect on the secretion of fetal ovine Growth Hormone (oGH). In all IGF-I infused fetuses, oGH concentrations fell during the infusion. The maximal change in the concentration of oGH (mean +/- SEM) was -54 +/- 10 ng/ml in contrast to +7 +/- 6 ng/ml in saline controls (p less than 0.005), a decrease of 33 +/- 4% (controls: +6 +/- 5%; p less than 0.005). By 60 minutes after the infusion of IGF-I was completed, the concentration of plasma oGH was comparable to control and pre-infusion values. In IGF-I infused fetuses, the mean concentration of insulin also decreased (p less than 0.02), whereas glucose levels remained unaltered. The results suggest that the lack of inhibitory feedback by the relatively low levels of circulating IGF-I is one factor in the hypersecretion of GH by the fetus.     

Human growth hormone and somatomedin C suppress the spontaneous release of growth hormone in unanesthetized rats

To investigate the feedback control of GH secretion, we examined the effects of human GH (hGH) and somatomedin C (SmC) on spontaneous GH secretory surges in unanesthetized, freely moving rats. Under pentobarbital anesthesia a right atrial catheter and an intracerebroventricular cannula were placed 7-10 days before the experimentation. For iv studies, hGH (0.3 U/ml.h) was infused for 6 h after an iv loading dose (0.3 U) at the beginning of the experiments. For intraventricular injections, hGH (0.1 U/10 microliter) or SmC (500 ng/10 microliter) were injected into the lateral ventricle 2 h before the experiments. The equivalent dose of crystalline BSA diluted in the same vehicle solutions was administered to the same rat as a control on a separate day. Venous blood samples were collected every 20 min for 6 h. Intravenous and intraventricular administration of crystalline BSA did not affect the typical rat GH (rGH) surges which appeared about every 3 h and reached peak values of more than 300 ng/ml. The iv infusion of hGH significantly inhibited the amplitude of rGH surges compared to controls (planimetric areas under the secretory profile 752 +/- 172 vs. 1921 +/- 183, P less than 0.01, n = 6). rGH secretion was similarly inhibited by intraventricular hGH (701 +/- 127 vs. 2208 + 225, P less than 0.01, n = 6) and by intraventricular SmC (537 +/- 70 vs. 1503 +/- 114, P less than 0.01, n = 6). These findings suggest that both GH and SmC are active in the feedback regulation of rGH secretion.     

Longitudinal study of serum placental GH in 455 normal pregnancies: correlation to gestational age,fetal gender,and weight

Placental GH is thought to be responsible for the rise in maternal IGF-I during pregnancy and is considered to be important for fetal growth. In this prospective longitudinal study of healthy pregnant women, we investigated determinants of placental GH in maternal serum. Serum was obtained from 455 women with normal singleton pregnancies at approximately 19 and 28 wk gestation. Serum placental GH concentrations were measured by a highly specific immunoradiometric assay, and fetal size was measured by ultrasound. Data on birth weight, gender, prepregnancy body mass index (BMI), parity, and smoking habits were obtained from medical records. Serum placental GH concentrations were detectable in serum from all women as early as 14 wk gestation and increased during pregnancy in all individuals (P < 0.001). Placental GH levels at second examination were found to be higher in women carrying female fetuses [median, 9.0 ng/ml; 95% confidence interval (CI), 4.7-23.0] compared with women carrying male fetuses (median, 8.2 ng/ml; 95% CI, 3.96-19.4; P = 0.004). Similarly, the increase in placental GH between 19 and 28 wk gestation was significantly larger in female fetus bearers than in male fetus bearers (P = 0.002). Placental GH at second examination was positively correlated with gestational age (P = 0.002) and negatively correlated with prepregnancy BMI (P = 0.039). Placental GH correlated with fetal weight at approximately 28 wk gestation (P = 0.002) but did not predict birth weight at term. Our study supports the role of maternal placental GH in the regulation of fetal growth. In conclusion, we found that 1) placental GH levels correlated significantly with fetal size at 28 wk gestation; 2) GH levels were measurable in serum from all women as early as 14 wk gestation; 3) maternal prepregnancy BMI and smoking were determinants of placental GH levels, although their specific effects on the serum maternal levels of placental GH remain to be seen; and 4) women carrying female fetuses have significantly higher placental GH levels compared with women carrying male fetuses at 28 wk gestation.     

The fetal adrenals of the rat: correlations between growth, cytology, and hormonal activity, with and without ACTH deficiency.

Growth, ultrastructure, and corticosterone content were studied in the adrenals of rat fetuses in late pregnancy, between Days 19 and 21. In the fetuses of intact mothers, the hypophysial corticostimulating activity decreased between Days 19 and 21. Ablation of the fetal hypothalamus by total removal of the brain, leaving the hypophysis in situ (encephalectomy), induced atrophy of the adrenals, changes in adrenal ultrastructure, and decrease in the adrenal corticosterone content. Such modifications were also observed in response to the ablation of the pituitary gland by decapitation. The hypothalamus was involved in the control of ACTH release in late pregnancy. When mothers were adrenalectomized on Day 14, in the absence of hypothalamic tissue, the pituitary gland of the encephalectomized fetuses showed some corticostimulating activity; indeed, the adrenals of these fetuses were heavier on Day 21 than those of the decapitated fetuses but smaller than those of the littermate controls, and the adrenal corticosterone content was also greater than in the decapitated but less than in the controls. Encephalectomy induced modifications in adrenal cytology less marked than those induced by decapitation. These data suggest that the pituitary gland and the hypothalamo-hypophysial complex are the sites of the corticosteroid-induced inhibition of the corticostimulating activity of the fetal hypophysis.     

Growth hormone secretory patterns in young, middle-aged and old female rats

Pulsatile growth hormone (GH) secretion was compared in young (5 months), middle-aged (11 months) and old (25-29 months) female Sprague-Dawley rats under nonanesthetized, free-moving conditions. Mean plasma GH levels were 99.1 +/- 9.3 ng/ml in young rats, 56.3 +/- 5.8 ng/ml in middle-aged rats and 49.7 +/- 4.9 ng/ml in old rats (p less than 0.01 for young vs. middle-aged and old rats). In young females, 10 out of 17 rats had GH pulses with peak levels greater than 200 ng/ml, in 6 middle-aged females all GH peaks were below 200 ng/ml, and in old females 13 out of 17 rats showed GH peaks of less than 100 ng/ml. The average peak (amplitude) of GH pulses in the old rats (69.3 +/- 8.3 ng/ml) was lower than in the young rats (130.4 +/- 17.5 ng/ml, p less than 0.01) and somewhat lower than in the middle-aged rats (87.0 +/- 8.9 ng/ml). There was no change in intervals between GH pulses. Pituitary GH content in middle-aged and old females (1,189 +/- 60 and 1,100 +/- 89 micrograms, respectively) was significantly lower (p less than 0.05 and p less than 0.01, respectively) than in young female rats (1,464 +/- 76 micrograms). Somatostatin content in the median eminence of old rats (22.4 +/- 1.9 ng) was significantly lower than in young rats (28.5 +/- 1.6 ng, p less than 0.05). It is concluded that GH secretion is reduced in aging female rats, but unlike in aging male rats the decrease is seen at an earlier age.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of hCG in regulation of the fetal zone of the human fetal adrenal gland.

It has been suggested that hCG is a trophic hormone for the fetal zone of the human fetal adrenal gland. To test this hypothesis, the isolated fetal zones of adrenals from eight fetuses (12-17-week gestation age) were superfused in the presence or absence of hCG. Dehydroepiandrosterone sulfate (DHAS) was measured in the superfusion effluent. A significant increase in DHAS production was observed in the presence of hCG. DHAS secretion decreased during the first 60 min in the control and experimental superfusions from 83 +/- 10.0 (mean +/- SE) to 71 +/- 8.0, and from 90 +/- 9.0 to 70 +/- 6.0 ng/100 mg/ml, respectively. In the presence of hCG (250 ng/ml), DHAS secretion increased significantly (P less than 0.01) over the controls to 116 +/- 12.0 at 120 min, and remained above the controls thereafter. These results support the hypothesis that hCG is one of the regulators of DHAS production by the human fetal adrenal gland early in gestation. As we found that ACTh stimulated DHAS secretion in a previous study and as there is indirect evidence for a role of ACTH in DHAS regulation late in pregnancy, these observations suggest dual regulation by hCG and ACTH early in pregnancy, and a possible transition to ACTH regulation of the fetal zone of the human fetal adrenal after midgestation.     

Serum cortisol binding capacity and cortisol concentration in the pregnant baboon and its fetus during gestation.

The cortisol binding capacity of serum from 11 pregnant baboons (38 samples) and from 7 baboon fetuses delivered prematurely or at term was measured after removal of endogenous steroids. Values for maternal serum collected between 60 and 120 days after mating (59.0 +/- 6.4 mug/100 ml, mean +/- SD) were greater than those for serum collected at term (42.3 +/- 4.9 mug/100 ml). The cortisol-binding capacity of fetal serum collected between 100 and 132 days' gestation was similar to that of the corresponding maternal sample, but at term was only 50% of the maternal value. The rate of clearance of cortisol from both fetal and maternal serum may therefore increase progressively during the last trimester of pregnancy. This effect is likely to be more marked in the fetus. The cortisol binding capacity of 15 serum samples from 9 non-pregnant baboons was 33.4 +/- 5.5 mug/100 ml. Mestranol2 (administered 200 mug/day im for 15 days) significantly increased the serum cortisol binding capacity. The concentration of cortisol in maternal serum from 7 pregnant baboons (10 samples) was 44.0 +/- 8.4 mug/100 ml and was independent of the state of gestation. In fetal serum the cortisol concentration was 4 mug/100 ml before 168 days' gestation and reached 49 mug/100 ml after normal delivery at term. These findings suggest that the mechanisms for production of cortisol by the fetus mature as gestation progresses. The physiological significance of the marked difference between the cortisol concentration and the cortisol binding capacity of fetal serum awaits elucidation.