Cinacalcet hydrochloride reduces the serum calcium concentration in inoperable parathyroid carcinoma.

BACKGROUND: Management of inoperable parathyroid carcinoma presents a challenge because until recently, effective medical therapy was not available. Morbidity and mortality result primarily from severe hypercalcemia. We assessed the ability of the calcimimetic cinacalcet HCl to reduce serum calcium in patients with parathyroid carcinoma as well as its effect on PTH concentrations, bone turnover markers, safety, and health-related quality of life variables. METHODS: Twenty-nine patients with parathyroid carcinoma were enrolled in this open-label, single-arm study consisting of titration and maintenance phases. Cinacalcet doses were titrated (30 mg twice daily to 90 mg four times daily) for 16 wk or until serum calcium was no more than 10.0 mg/dl. The study endpoint was the proportion of patients with at least a 1 mg/dl reduction in serum calcium at the end of the titration phase (responders). RESULTS: Mean (+/- se) serum calcium (14.1 +/- 0.4 mg/dl) and PTH (697 +/- 94 pg/ml) were markedly elevated at baseline. At the end of the titration period, serum calcium was reduced by at least 1 mg/dl in 62% of patients (mean decline to 12.4 +/- 0.5 mg/dl). In the 18 responders, serum calcium fell from 15.0 +/- 0.5 to 11.2 +/- 0.3 mg/dl (P < 0.001). The greatest reductions in serum calcium were observed in patients with highest baseline calcium levels. PTH levels decreased, but not significantly, to 635 +/- 73 pg/ml (-4.6%). Adverse events included nausea, vomiting, headache, and fracture. CONCLUSIONS: Cinacalcet effectively reduces hypercalcemia in approximately two thirds of patients with inoperable parathyroid carcinoma and may represent an important new treatment option for these patients.

Insulin and insulin-receptor autoantibodies in children with newly diagnosed IDDM before insulin therapy.

Twenty-nine children, aged 1-15 yr, with newly diagnosed insulin-dependent diabetes mellitus (IDDM) had sera taken before insulin therapy to be examined for the presence of insulin-receptor antibodies by measuring the inhibition of binding of radiolabeled insulin to IM-9 lymphocytes in both whole serum and purified IgG fractions. Groups of children with long-standing IDDM and autoimmune endocrine disease as well as a normal control group were studied. A positive result, defined as binding greater than or equal to 2 SD below the mean zero standard, was found in 3 (10.3%) of the 29 newly diagnosed diabetic patients. As a group, they showed significantly greater binding inhibition than the normal control group for both whole serum and purified IgG (one-tailed t test, P less than .05 and P less than .002, respectively). Insulin autoantibodies were also measured by a sensitive radioimmunoassay technique. A positive result, defined as binding greater than 3 SD above the normal control pooled sera, was found in 9 (37.5%) of 24 of the newly diagnosed IDDM group tested. All 3 subjects positive for insulin-receptor antibodies were also positive for insulin autoantibodies, whereas 6 of the 21 receptor-antibody-negative subjects were positive for insulin autoantibodies (Fisher's exact test, P = .0415). This suggests the possibility that the presence of insulin autoantibodies is a prerequisite for the development of insulin-receptor antibodies, i.e., as an anti-idiotypic response. Insulin-receptor antibodies and insulin autoantibodies may play a currently undefined pathophysiologic role in the development of IDDM.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypothyroidism, triiodothyronine antibodies, and hyperprolactinemia.

This report describes the development of triiodothyronine (T3) antibodies in a patient with Hashimoto's thyroiditis that resulted in compensated hypothyroidism and hyperprolactinemia. The patient, a 23-year-old woman, had a small goiter, modest elevation of thyrotropin (TSH) and prolactin (PRL) levels, and a markedly elevated T3 level. Circulating antibodies to T3 were demonstrated that presumably rendered the T3 physiologically inactive. Saturation of antibody binding sites by incremental dosages of liothyronine (triiodothyronine) sodium (12.5 to 87.5 microgram/day) resulted in normalization of both the TSH and PRL levels.

Control of gonadotropin secretion in the ovine fetus. IV. Male-specific entrainment of the hypothalamic control of luteinizing hormone secretion by testosterone in the female ovine fetus.

The role of testosterone (T) in the sex-specific entrainment of hypothalamic LH regulation was studied in five castrate and four sham-castrate chronically catheterized female fetuses androgenized by the prior administration of T cypionate (200 mg, im, every 2 weeks) to pregnant ewes from 30-86 days gestation (term = 147 days). Eight female and three male castrate fetuses served as controls. After a 2-week washout period all fetuses were operated upon in utero between 106-116 days and were studied longitudinally over a 2- to 35-day period. LH pulsatility was determined from blood samples obtained every 15 min over a standard 3-h observation period and assayed for LH by RIA (NIH LH-S16 standard). LH pulse frequency in the castrate androgenized females (41 pulses in 19 observation periods; 1 pulse/1.4 h) was significantly higher than that in non-androgenized female controls (18 pulses in 28 observation periods; 1 pulse/4.7 h observation), but was similar to that in castrate males (23 pulses in 28 observation periods; 1 pulse/1.3 h). Furthermore, LH pulse frequency in the sham castrate androgenized females (26 pulses in 13 observation periods; 1 pulse/1.5 h) was comparable to that in castrate androgenized females as well as that in castrate males. The enhanced LH pulsatility in androgenized female fetuses strongly suggests that T exposure between 30-86 days results in male-specific entrainment of hypothalamic LH regulation. Moreover, the comparable enhancement of LH pulse frequency in both sham castrate and castrate androgenized female groups suggests that in the T-exposed fetus T withdrawal alone is sufficient to result in enhanced LH pulsatility. These findings strongly suggest that T of fetal testicular origin results in male-specific entrainment of hypothalamic function and may be an important feature of male neural organization in this species.

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)

Control of gonadotropin secretion in the ovine fetus: the effects of a specific gonadotropin-releasing hormone antagonist on pulsatile luteinizing hormone secretion.

To demonstrate the dependence of fetal pituitary LH secretion endogenous GnRH, we studied the effects of bolus iv administration of a specific GnRH antagonist analog [GnRH-Ant; (N-acetyl-D-p-chloro-Phe1,2,D-Trp3,D-Arg6,D-Ala10)GnRH] on pulsatile LH release in 10 chronically cannulated ovine fetuses of 104-129 days gestation (term, 147 days). Vehicle alone was given to 13 control fetuses of 107-125 days gestation. Blood samples for LH determination by RIA (NIH LH S16 standard) were taken after injection of either GnRH-Ant (175-300 micrograms dissolved in 1 ml 5% dextrose in water) or vehicle alone for 1.75-5 h. The efficacy of GnRH receptor blockade was then assessed by a bolus iv challenge with 50 micrograms synthetic GnRH. The mean (+/- SEM) observation period per animal was similar for the two groups (3.8 +/- 0.2 h for GnRH-Ant; 3.6 +/- 0.2 h for controls). The frequency of spontaneous pulsatile LH secretion was significantly decreased in the fetuses given GhRH-Ant (2 pulses over 38 h total observation vs. 13 pulses over 47.3 h in control fetuses; P = 0.006). The average interpulse interval was 19.0 h in the GnRH-Ant group compared to 3.6 h in controls. Although the mean pulse amplitude was lower in the GnRH-Ant group (2.8 +/- 1.2 vs. 7.6 +/- 1.1 ng/ml for controls), this difference was not statistically significant (P = 0.065, by one-tailed t test). The mean peak serum LH concentration in response to the GnRH challenge was significantly blunted in the GnRH-Ant group (4.6 +/- 0.8 vs. 20.6 +/- 1.8 ng/ml for controls; P less than 0.001). These results indicate that GnRH-Ant administration causes a virtual cessation of pulsatile LH discharge. As this GnRH-Ant blocks GnRH action at the receptor level, these data demonstrate that pulsatile LH secretion in the ovine fetus is dependent on endogenous GnRH release as early as 104 days gestation.

Control of gonadotropin secretion in the ovine fetus. II. A sex difference in pulsatile luteinizing hormone secretion after castration.

Gonadal involvement in the control of fetal LH secretion was examined by studying LH pulsatility in 12 chronically catheterized male (9 castrate and 3 sham-control) and 12 female (8 castrate and 4 sham-control) ovine fetuses operated upon in utero at 106-116 days gestation (term = 147 days). Fetuses were studied longitudinally over a 2- to 30-day period in castrates and over a 2- to 37-day period in controls. LH pulsatility was determined from blood samples obtained every 15 min over a standard 3-h observation period and assayed for LH by RIA (NIH LH S16 standard). In female fetuses there was no significant difference in LH pulse frequency between castrates (25 pulses in 32 periods; 1 pulse/3.8 h of observation) compared to controls (15 pulses in 15 periods; 1 pulse/3.0 h). LH pulse frequency was similar in the sham-castrate males (11 pulses in 17 periods; 1 pulse/4.6 h). In contrast, LH pulse frequency was significantly higher in the castrate male group (90 pulses in 42 periods; 1 pulse/1.4 h) compared to that in each of the other 3 groups (P less than 0.005). LH pulse frequency did not vary with gestational age in castrate and control females or in control males. In castrate males, however, LH pulse frequency declined significantly (P less than 0.005) with advancing gestation from 80 pulses in 32 periods (1 pulse/1.2 h) before 130 days compared to 10 pulses in 10 periods (1 pulse/3.0 h) after 130 days. Thus, LH pulse frequency was indistinguishable in castrate vs. eugonadal males after 130 days. The absence of a castration effect on LH pulsatility in male fetuses older than 130 days was confirmed in an additional group of 8 male fetuses (5 castrate and 3 sham-controls) operated upon at 121-130 days gestation and studied over a 2- to 20-day period. Overall, LH pulse amplitude was similar in male [4.7 +/- 0.5 ng/ml (+/- SE)] and female (3.9 +/- 0.5 ng/ml) fetuses and did not vary as a function of gonadal status or gestational age. The postcastration increment in LH pulse frequency in the castrate male fetus from 108-130 days gestation delineates a role of the fetal testis in feedback regulation of LH secretion at this stage of development. The absence of a postcastration rise in LH pulse frequency in the castrate female indicates that the fetal ovary does not play a similar role.(ABSTRACT TRUNCATED AT 400 WORDS)

Serial serum levels of gonadotropins, prolactin and sex steroids in the nonpregnant and pregnant chimpanzee.

Serum levels of FSH, LH, chorionic gonadotropin (CG), prolactin, estrone (E1), estradiol-17Beta (E2), estriol (E3) and progesterone were measured at 2-3-day intervals in 4 chimpanzees through 2-3 menstrual cycles, and serially through subsequent pregnancies. The hormone patterns of the menstrual cycles were similar to those in man, with high levels of FSH in the early follicular phase, followed by rising E2 concentrations to a peak (up to 35 ng/dl) at or just before a midcycle LH/FSH peak. In most cycles there was a secondary E2 rise and progesterone rose to values above 500 ng/dl during the luteal phase. There was no consistent pattern in prolactine levels through 3 menstrual cycles. A simultaneous increase in E2 and LH/CG levels and a fall in FSH about 10 days postovulation indicated fertilization and implantation. Other early signs of pregnancy were persistent luteal range progesterone concentrations and rising levels of E1 and E3. Peak CG levels (56-154 IU/ml) occurred 30-50 days after the midcycle LH/FSH peak, followed by a decline and then a small secondary rise to (to 1 IU/ml) before term. E1, E2 and E3 levels rose more rapidly after 80 days to a peak at term (E1: 180-300 ng/dl; E2: 500-800 ng/dl; and E3:400-1000 ng/dl). Progesterone levels showed one peak coincident with the CG peak, and a secondary rise after about 80 days to maximal values at term of 49-120 ng/ml. Prolactin levels increased during pregnancy with irregular fluctuations (7-127 ng/ml). These findings indicate in contrast to observations in rhesus monkeys and baboons, that the hormonal patterns during pregnancy in the chimpanzee are remarkably similar to those in man. Thus, the chimpanzee should prove to be an ideal model for research directly applicable to human reproduction.

Further studies on adrenarche in nonhuman primates.

Serum concentrations of dehydroepiandrosterone (DHA), DHA sulfate, and cortisol were measured in 52 chimpanzees (aged 0.5--10 yr), 76 Macaca mulatta (aged 0.25--5 yr), and 80 Macaca nemestrina (aged 0.5--9 yr). Sexual maturation was assessed by age and by the presence of menarche or the appearance of perineal turgescence in the females and by measurement of serum testosterone in the males. In an additional group of 10 young adult female M. mulatta, four repeated determinations of these same steroids at 30-min intervals demonstrated that the stress of capture and venipuncture caused a significant rise in serum levels of not only cortisol but also of DHA and DHA sulfate. The chimpanzees demonstrated an age-related rise in serum concentrations of DHA and DHA sulfate relative to cortisol which began before the onset of puberty and thus closely resembled human adrenarche. In M. mulatta, serum DHA levels showed no change with age, while DHA sulfate values decreased progressively both before and during puberty. The pattern in M. nemestrina was similar, with stable DHA and declining DHA sulfate levels before and during puberty. However, in the oldest group (aged 6--9 yr) of mature M. nemestrina, there was a significant postpubertal rise of both DHA and DHA sulfate with no change in serum cortisol. These data suggest that monkeys, just as higher primates, may show increasing adrenal secretion of C19 steroids at around 6--9 yr. This adrenarchal process appears to be completely independent of sexual maturation and probably merely reflects the influence of progressive adrenal growth and the resulting impact of changing intraadrenal steroid concentrations upon steroidogenesis in the zona reticularis.

Effects of naloxone and an enkephalin analog on serum prolactin, cortisol, and gonadotropins in the chimpanzee.

To assess a possible regulatory influence of opioids upon anterior pituitary function in the chimpanzee, we evaluated the effects of the specific opiate receptor antagonist naloxone and the agonistic enkephalin analog [D-Ala2, MePhe4,Met(o)-ol]enkephalin (FK 33-824; Sandoz) on serum levels of PRL, cortisol, FSH, and LH. Under ketamine anesthesia, the following were administered by iv injection during the early follicular phase of successive menstrual cycles in nine female chimpanzees: naloxone (10 mg; n = 7) or saline vehicle (n = 7) randomly assigned in the first two cycles, FK 33-824 0.25 mg (n = 3) in the third cycle, FK 33-824 0.50 mg (n = 4) in the fourth cycle, and FK 33-824 (0.50 mg) immediately preceded by naloxone (10 mg; n = 4) in the last cycle. Five pretreatment and 12 posttreatment serum samples were obtained at 10- to 15-min intervals for subsequent RIA. Naloxone caused a significant reduction in PRL levels from a pretreatment mean of 29.3 ng/ml to a mean of 11.1 ng/ml at 180 min. Values from 60-180 min were significantly below the saline control group at comparable times. A dose-related increment in PRL levels was seen after FK 33-824 administration, with mean peak values at 30 min of 61.0 and 92.3 ng/ml after the low and high doses, respectively. Naloxone pretreatment markedly attenuated the response to high dose FK 33-824. Cortisol levels rose in all groups throughout the study period, a presumed effect of the ketamine anesthesia. Compared to the saline group, no effects of FK 33-824 were observed. Naloxone, given alone or with FK 33-824, had a small, but significant, stimulatory effect on cortisol from 60-120 min posttreatment compared to the control group. Naloxone caused a significant increment in LH levels from a pretreatment mean of 11.7 micrograms/dl to a peak of 19.1 micrograms/dl at 30 min and in FSH level from 33.2 micrograms/dl before therapy to 40.0 micrograms/dl at 45 min. There was no influence of FK 33-824 on gonadotropin levels, although the high dose did blunt the response to naloxone. Taken together, these effects suggest that opiate agonists and endogenous opioid pathways may modulate anterior pituitary function in the chimpanzee, as in man.

Pituitary gonadotropin function during human pregnancy: serum FSH and LH levels before and after LHRH administration.

Pituitary gonadotropin reserve was evaluated in 8 normal pregnant women (13-35 weeks gestation) by measuring serum concentrations of FSH and LH (betaLH assay) before and after an IV bolus of 100 mug LHRH. Basal levels of FSH and LH were low or undetectable. LHRH administration failed to stimulate FSH release but did result in a small short-lived rise in LH levels. These findings provide further evidence that pituitary gonadotropin synthesis and release are inhibited during pregnancy.

Studies on human sexual development. IV. Fetal pituitary and serum, and amniotic fluid concentrations of prolactin.

Prolactin concentrations were measured in 161 amniotic fluid specimens from 8-40 weeks fetal age and the levels compared with those observed in 45 fetal and neonatal cord sera and in 42 fetal pituitary specimens. Amniotic fluid prolactin levels rose steeply between 12-16 weeks gestation, and then declined to term; the calculated total amniotic fluid content of prolactin showed a similar pattern, but the peak was later, at about 26 weeks gestation. Amniotic fluid concentrations consistently exceeded fetal serum prolactin levels, even during the last trimester, when fetal serum and pituitary levels were highest. The data are compatible with a fetal origin for amniotic fluid prolactin, but only if one assumes that flux of prolactin out of amniotic fluid compartment is negligible, that the fetal kidney in mid-pregnancy clears prolactin at a rate virtually equal to the glomerular filtration rate, and the fetal pituitary shows secretion characteristics quite different from those of the adult gland.

The control of steroidogenesis by human fetal adrenal cells in tissue culture. III. The effects of various hormonal peptides.

The effects upon production of cortisol and dehydroepiandrosterone (DHA) by human fetal adrenal cells in tissue culture were studied using commercial hCG (0.5 and 5 IU/ml), purified hCG (0.7-6.7 IU/ml), the alpha-subunit of hCG (200 and 1000 ng/ml), human GH (50 and 200 ng/ml), human PRL (0.1-100 ng/ml), alpha-MSH (0.1-10 ng/ml), corticotropin-like intermediate lobe peptide (200 ng/ml), human beta-lipotropin (0.1 and 0.2 ng/ml), and beta-endorphin (100 ng/ml). Although each peptide was added to the culture medium in a concentration either similar to that observed in the fetal circulation or (where such information was not available) in amounts several times greater than those effective for ACTH in this system, none demonstrated any significant stimulation of steroid production. In particular, repeated studies with hCG showed that this hormone had no stimulating effect upon DHA production, neither in cultures of whole adrenals nor in cultures of separated fetal zone and definitive zone cells. Furthermore, none of these peptides showed a synergistic effect upon DHA production when they were added to cultures together with concentrations of alpha-ACTH-(1-24) (10(2)-10(3) pg/ml) previously demonstrated to represent the middle of the dose-response curve. Indeed, the only significant interactions with alpha-ACTH-(1-24) observed in these studies were a slight reduction in cortisol production produced by corticotropin-like intermediate lobe peptide and apparent inhibition of DHA production by beta-lipotropin and GH. The data do not lend credence to the suggestion that any of these peptides plays an important role in vivo in stimulating fetal adrenal steroidogenesis.

The control of steroidogenesis by human fetal adrenal cells in tissue culture. I. Responses to adrenocorticotropin.

A technique of monolayer tissue culture of human fetal adrenal cells was developed in order to study steroidogenic responses to factors such as ACTH. The daily production of 12 steroids [pregnenolone, 17-hydroxy pregnenolone, dehydroepiandrosterone (DHA), DHA sulfate, progesterone, 17-hydroxyprogesterone, androstenedione, testosterone, corticosterone, 11-desoxycortisol, cortisol, and aldosterone) was measured by RIA. Initially, fresh fetal adrenal cells produced DHA, DHA sulfate, 17-hydroxypregnenolone, and small amounts of cortisol, but in the absence of ACTH, the production of all steroids declined during culture to low levels. The addition of physiological amounts (1-10(4) pg/ml) of either alpha ACTH-1(1-24) or alpha ACTH-(1-39) or coculture with fetal pituitary cells elicited a progressive rise in steroid production during the first 4-6 days of incubation. The lowest ACTH doses elicited a proportionately greater adrenal androgen response (as reflected in the DHA to cortisol ratio), but with increasing ACTH dosage, there was greater stimulation of cortisol production, which equalled or exceeded that of DHA. The data demonstrate that fetal adrenal cells may be maintained in short term culture and can respond to physiological amounts of ACTH. The progressive increase in the production of cortisol and other delta 4, 3-ketosteroids in vitro suggests that the characteristic fetal pattern of steroidogenesis may result from the interaction of ACTH with some circulating inhibitor of adrenal 3 beta-hydroxysteroid dehydrogenase.

Studies on human sexual development. VI. Concentrations of unconjugated dehydroepiandrosterone, estradiol, and estriol in amniotic fluid throughout gestation.

Concentrations of unconjugated dehydroepiandrosterone, estradiol, and estriol were measured in samples of amniotic fluid from uneventful pregnancies of 9-40 weeks conceptual age. There was no apparent influence of fetal sex upon the levels of these steroids. Dehydroepiandrosterone concentrations rose slightly from 9-20 weeks, and then showed little further change. Estradiol concentrations declined slightly from 9-20 weeks; after 32 weeks gestation, there was a 2-fold rise to term. Estriol levels rose in almost exponential fashion throughout gestation.

Studies on human sexual development. V. Concentrations of testosterone, 17-hydroxyprogesterone and progesterone in human amniotic fluid throughout gestation.

Concentrations of unconjugated testosterone, 17-hydroxyprogesterone (170HP) and progesterone were measured by radioimmunoassay in amniotic fluid (AF) specimens from normal pregnancies of 9-40 weeks gestation. In two-thirds of samples from pregnancies with male fetuses. AF testosterone exceeded the upper limit found in female samples, with minimal overlap in the 12-18 week period of gestation. Although AF testosterone levels associated with male and female fetuses were both significantly lower toward term, the sex-difference persisted. Between 9-19 weeks gestation, fetal sex was also found to influence AF 170HP, a steroid thought to be predominantly of placental and fetal adrenal origin; in this case, female levels exceeded male. Awareness of the influence of sex and gestation upon AF concentrations of these steroids is an important prerequisite for their application to the prenatal diagnosis of endocrine disease (e.g., congenital adrenal hyperplasia). There was no sex difference in AF progesterone concentrations at 12-18 weeks gestation. The median progesterone concentration at 34-40 weeks was higher with female fetuses, but this difference may be related to a difference in gestational age between AF samples obtained from male and female fetuses.

The control of steroidogenesis by human fetal adrenal cells in tissue culture. IV. The effect of exposure to placental steroids.

The effect upon steroidogenesis of adding various steroids produced by the placenta was studied in short term cultures of human fetal adrenal cells. The addition of high concentrations (10(3) ng/ml) of estrone or estriol inhibited the production of cortisol, but only the former elicited a parallel increase in dehydroepiandrosterone (DHA) production. Estradiol was effective in inhibiting delta-4-3-ketosteroid production at concentrations of 10-100 ng/ml, levels which approach those found in the fetal circulation, while DHA production was increased at concentrations of 1 microgram/ml. The addition of progesterone (4 microgram/ml) to the medium caused increased production of cortisol and corticosterone, but had no effect on DHA production. Pregnenolone (4 microgram/ml) increased the basal production of DHA and slightly impaired both basal and ACTH-stimulated aldosterone production, but had no effect on cortisol production. The data demonstrate that the many fetal and placental factors which have been studied to date, only ACTH and estrogens can interact to produce the characteristic fetal pattern of steroidogenesis. Preliminary studies indicate that this effect-stimulated aldosterone production, but had no effect on cortisol production. The data demonstrate that the many fetal and placental factors which have been studied to date, only ACTH and estrogens can interact to produce the characteristic fetal pattern of steroidogenesis. Preliminary studies indicate that this effect-stimulated aldosterone production, but had no effect on cortisol production. The data demonstrate that the many fetal and placental factors which have been studied to date, only ACTH and estrogens can interact to produce the characteristic fetal pattern of steroidogenesis. Preliminary studies indicate that this effect of estrogen is not influenced by other peptide hormones such as hCG, human prl, beta-lipotropin, corticotropin-like intermediate lobe peptide, or beta-endorphin. A revised model of the fetoplacental steroidogenic unit is presented which may explain both normal and fetal hyperplasia and postnatal involution of the adrenal cortex and the variations from this pattern seen in apituitary children.

Correlation of Nb2 bioassay and radioimmunoassay values for human serum prolactin.

The availability of a sensitive and specific bioassay (BA) for PRL in human serum has made possible a comparative assessment of PRL bioactivity and immunoactivity in normal and abnormal serum specimens. Serum was studied from 20 normal subjects and 54 patients with a variety of disorders relating to PRL secretion. The correlation between the results of both assays was very close in all subjects. The mean BA/RIA ratio in normal subjects was 0.90, with a range from 0.67-1.33, and in patients with disordered PRL secretion the mean BA/RIA ratio was 0.94, with a range from 0.53-1.58. Similar results were obtained with PRL stimulatory testing using TRH, metoclopramide, and domperidone, and samples of culture medium from both PRL-secreting and non-PRL-secreting human pituitary tumor cultures. In one patient with a high proportion of "big, big" PRL and hyperprolactinaemia a BA/RIA ratio of 2.47 was found, a value well outside the normal range. However another patient with a similar history had a ratio of 0.82, in the range observed in normal subjects. These findings indicate that in a wide variety of clinical disorders the correlation between PRL bioactivity in the Nb2 system and immunoactivity in human serum samples is remarkably good under basal and stimulated conditions. One exception was found, but the nature of the underlying PRL abnormality in this patient remains to be investigated.

Studies on human sexual development. III. Fetal pituitary and serum, and amniotic fluid concentrations of LH, CG, and FSH.

Fetal sera (9-20 weeks fetal age, n = 80) and pituitary glands (9.5-20 weeks, n = 36) obtained from hysterotomy specimens, and amniotic fluids (amniocentesis; 8-40 weeks, n = 123) were assayed for FSH, LH (betaLH assay) and CG (betaCG assay). Results are expressed as mass of pure hormone. Prior to 12 weeks fetal age, pituitary, serum and amniotic fluid concentrations of LH and FSH were low or unmeasurable. In contrast, levels of CG in serum and in amniotic fluid were clearly measurable prior to 12 weeks. There was a definite CG peak at 11-14 weeks with levels up to 550 ng/ml in serum and 7400 ng/ml in amniotic fluid. Although LH levels began to rise at 12 weeks, when CG levels started to decline, serum levels of LH from 14-20 weeks in males (2-13 ng/ml) were still lower than the majority of CG levels at this time (6-115 ng/ml). These observations suggest that CG is the primary stimulus to the fetal Leydig cell which results in testosterone secretion (peak 11-17 weeks) and masculine differentiation of the genital tract. Significantly lower concentrations of both FSH and LH were observed in pituitary, serum and amniotic fluid between 12-20 weeks fetal age in males compared to females. This may be a result of feedback inhibition by the higher concentrations of testosterone in males at this time. Amniotic fluid FSH and LH concentrations correlated with their respective serum and pituitary values (P less than 0.01) indicating that amniotic fluid may provide a convenient index of fetal serum concentrations.

Pituitary-gonadal relations in infancy: 2. Patterns of serum gonadal steroid concentrations in man from birth to two years of age.

Testosterone, estradiol, 170H-progesterone, and androstenedione (except in cord samples) concentrations were determined in cord sera (30 male and 14 female) and in peripheral sera from infants (121 male and 110 female), age 1 day to 2 years. Male and female cord serum levels of these steroids were not significantly different. In both sexes levels during the first week were lower than those in cord sera. In male infants serum testosterone and 170H-progesterone levels rose sharply in the second week of life, reached a peak at 1-2 months, and then declined to the range seen in later childhood by 6 months of age; male serum androstenedione and estradiol concentrations were higher during the first 2 months of life, but no distinct pattern of rise and fall was seen. In girls serum testosterone levels fell in the first week to the range seen throughout childhood; serum concentration of estradiol, androstenedione, and 17OH-progesterone in girls were markedly variable, with many values above the childhood range being seen, particularly in the first 6 months. These data provide further evidence of active Leydig cell function in male infants. They suggest that there is also ovarian secretion of sex steroids in some female infants in response to the elevated FSH and LH levels which are seen at this time.