Biomedical subjects
Publications and source records attributed to C Faiman.
A female chimpanzee developed premature sex skin swelling, breast budding, advanced bone age, and moderate estrogen effect of the vaginal cytology. Extensive radiographic and hormonal studies excluded all the known causes of precocious puberty and pseudopuberty, yielding a diagnosis of idiopathic true precocious puberty. To our knowledge this is the first observation of idiopathic true precocious puberty in a chimpanzee.
Nine patients with premature ovarian failure, one of whom had the associated autoimmune disorders rheumatoid arthritis, Hashimoto's thyroiditis, and vitiligo, were examined for the presence of a serum factor which would interfere with gonadotropin-receptor interaction in a bovine testicular membrane system. Sera from nine premenopausal and nine postmenopausal women served as control subjects. Mean displacement of radiolabeled follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from receptors was not significantly different among the three groups. However, the greatest interference with FSH-receptor interaction was detected in the patient with both premature ovarian failure and autoimmune diseases. No differences in mean serum levels of IgG, IgM, and IgA were found among the premature ovarian failure and the two control groups, nor were immunoglobulin levels different in the otherwise unique subject (premature ovarian failure and autoimmunity). Our study suggests that anti-gonadotropin receptor factors are unlikely to be involved in the majority of patients with premature ovarian failure. However, an anti-FSH receptor factor, possibly an antibody, may be present in some patients, particularly those who have concomitant autoimmune disorders.
A 31-year-old man with previously untreated Kallmann's syndrome received T therapy alone. His wife has subsequently borne two children, and HLA testing confirms that he is probably the natural father.
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.
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.
A method for the determination of delta 5 3 beta-hydroxysteroid dehydrogenase-isomerase (3 beta-HSD) activity in intact isolated Leydig cells was established. This method utilizes the conversion of [7-3H]dehydroepiandrosterone (1.04 mumole) to androstenedione and expresses the activity of the enzyme as mumoles of androstenedione produced/microgram DNA/h. The reaction is limited to 0.5 - 4 micrograms DNA of Leydig cells/ml (equivalent to 0.1-0.8 million of Leydig cells/ml) and to 1 h of incubation at 34 degree C. The 3 beta-HSD activity of 44 suspensions of Leydig cells isolated from adult rats was found to be 1.13 +/- 0.03 (SE) mumoles/microgram DNA/h. This new method for direct measurement of 3 beta-HSD activity in intact Leydig cells was found to be rapid, easy to perform and highly reproducible.
The developmental pattern of prolactin receptors was examined in intact interstitial cells isolated from testes of 19-day old foetuses (F19), 1 to 45-day immature (N1 to N45) and adult animals. The prolactin binding activity in F19 interstitial cells is low, being 27% of that found in cells of the adult. There is an abrupt 60% increase in prolactin binding immediately after birth (N1), followed by a slow, but gradual, increase for the next 34 and adulthood which follows an increment in serum prolactin concentrations after day 24. Equilibrium analysis revealed that the receptors In interstitial cells from N1, N34 and adults have similar affinity (Kd = 2.7 to 3.3 x 10(-10)M) for prolactin. However, cells from adults contain twice as many prolactin receptors per cell as that of immature animals. This increase in prolactin receptors may play a role in the modulation of interstitial (Leydig) cell function during sexual maturation.
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.
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.
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In order to assess a possible influence of endogenous opioids upon gonadotrophin secretion in women, we examined the effects of i.v. administration of 10 mg naloxone, a specific opiate antagonist, in ten normal menstruating women, in thirteen women with amenorrhoea and/or hyperprolactinaemia and in two women with putative deficiency of gonadotrophin-releasing hormone (GnRH). In thirteen subjects, a saline vehicle control study (randomized order of administration) was also performed. In the normal women, naloxone failed to elicit changes in serum gonadotrophin levels when administered during the early follicular phase of the menstrual cycle. However, significant increments of LH were observed from 30 to 165 min following naloxone administration during the late follicular phase. Similar LH responses occurred in the amenorrhoeic and hyperprolactinaemic women. There was a tendency towards a concomitant increment in FSH levels, which reached statistical significance variably from 60 to 105 min post-naloxone. The LH response to naloxone in individual subjects showed a significant (P less than 0.01) quadratic (U-shaped) relationship to the log basal oestradiol concentration. No response to naloxone was observed in the two patients with GnRH deficiency despite a brisk response to an exogenous GnRH bolus. Taken together, these data suggest that central nervous system inhibitory opioid pathways may be involved in the regulation of LH secretion in normal women and that excessive production of endogenous opioids may play a role in the pathophysiology of some amenorrhoeic conditions.
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.
Preparations of dispersed human fetal adrenal cells from the inner third of the gland and from the subcapsular area were maintained in culture, and their ultrastructure and steroid production were studied. The former type of preparation contained only fetal zone cells, while the latter contained definitive zone cells together with varying numbers of fetal zone cells. Both types could be cultured with equal ease, but during short term culture, fetal and definitive zone cells became morphologically indistinguishable. The patterns of steroid production and, in particular, the relative production of delta 4,3-ketosteroids and delta 5,3 beta-hydroxysteroids were similar in both preparations, as were their dose-response relationships during incubation with alpha ACTH-(1-24). Although considerable variability in total steroid production was observed between cells from different adrenal glands, in no specimen was any evidence for functional zonation of the fetal adrenal cortex observed in vitro. The results suggest that the apparently unique histological appearance and function of the fetal adrenal cortex may only reflect intense stimulation by ACTH secondary to the combined influences of a rapid cortisol MCR and of some inhibitor of fetal adrenal 3 beta-hydroxysteroid dehydrogenase activity.
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.
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.
In order to assess whether long-term low-dose glucocorticoid administration results in suppression of the hypothalamic-pituitary-adrenal (H-P-A) axis, we examined the response of plasma cortisol to insulin-induced hypoglycemia in 23 women treated with prednisone (5 mg/day) compared with that in 19 untreated women. Basal AM levels of plasma cortisol were unaffected (mean +/- SE, 11.6 +/- 0.9 versus 11.2 +/- 0.7 microgram/dl). The plasma cortisol increment at 609 minutes after insulin-induced hypoglycemia was significantly smaller in the treated group than in the untreated group (6.7 +/- 1.0 versus 11.6 +/- 1.2 microgram/dl, p less than 0.005). Thirteen of 23 women (56.5%) in the steroid-treated group compared to one of 19 (5.3%) in the untreated group, showed a rise in plasma cortisol of less than 6 microgram/dl at 60 minutes. Furthermore, a similar reduction in the increment of plasma cortisol was also found in a subset of 10 women tested both before and during prednisone treatment. These results indicate that the concept that low doses of glucocorticoids are free of suppressive effects on H-P-A function is not justified.