Biomedical subjects
Publications and source records attributed to R M Boyar.
Testicular development in a patient with deletion of the distal (fluorescent) segment of the Y chromosome is described. The presence of a normal dose of H-Y antigen was demonstrated by Goldberg's cytotoxicity test. It is concluded that the distal fluorescent segment of the Y chromosome is void of genes regulating H-Y antigen activity.
Plasma PRL was measured at 20-min intervals in six patients with Parkinson's disease under various treatment protocols. In addition, 24-h mean GH levels were measured. The results of these studies showed that two untreated patients with Parkinson's disease had normal 24-h mean PRL levels with the normal increase during sleep. During chronic treatment with L-dopa-carbidopa (Sinemet), the 24-h PRL level was 12.8 +/- 4.9 ng/ml (mean +/- SD) and there was persistence of augmented PRL secretion during sleep. The 24-h mean GH level ranged from 1.5-4.4 ng/ml, with a mean of 2.5 ng/ml. The addition of a dopamine agonist (Lergotrile mesylate) resulted in a significant (P less than 0.01) suppression of the 24-h mean PRL levels and abolition of the normal sleep augmentation after 2 weeks of therapy. This suppression was maintained in one patient who was restudied 4 months after the addition of dopamine agonist therapy to L-dopa-carbidopa. The 24-h mean GH levels did not change significantly after the addition of the dopamine agonist when compared to L-dopa-carbidopa alone. These results suggest a dichotomy between the PRL and GH responses to combined L-dopa-carbidopa and dopamine agonist therapy. In addition, the preservation of normal PRL regulation in the two untreated patients with Parkinson's disease suggests that dopaminergic neurons are not universally affected in this disorder.
In eight teenage patients with Turner's syndrome, LH and FSH were measured at 20-min intervals for 24 h. The 24-h mean LH and FSH levels ranged from 20.2-70.5 mIU/ml and 60.4-229 mIU/ml, respectively. There was a significant positive correlation between the individual LH and FSH levels in the eight patients; the common correlation coefficient was 0.449 (P less than 0.001). The 24-h mean estradiol level was measurable in only two of the patients and the 24-h mean testosterone level for the eight patients was 0.10 ng/ml. The mean LH concentration during sleep was significantly higher (P less than .01) than during waking. The mean FSH concentration during sleep was also significantly higher (P less than 0.05) than during waking. The LH and FSH peak levels after LRH were significantly correlated with the 24-h mean LH (r = 0.918; P less than 0.01) and FSH concentrations (r = 0.754; P less than 0.05), respectively.
Four patients with androgen insensitivity had plasma LH and FSH measured at 20-min intervals for 24 h and at 15- to 30-min intervals for 3 h after the injection of LRH. Twenty-four-hour mean testosterone (T), estradiol, and androstenedione (delta 4) levels were also measured. Patients with androgen insensitivity had significantly elevated LH levels (P less than 0.05) and an increase in the number of LH secretory episodes (P less than 0.001) compared to normal subjects. The amplitude of the LH secretory episodes, expressed as the absolute increment, was significantly higher than normal controls (P less than 0.005). The LH response to LRH (absolute increment) was twice that of normal, but was not significantly different from normal subjects. The 24-h mean FSH levels were normal in three of the patients and elevated in one. This patient had the mildest degree of androgen insensitivity on clinical exam and the greatest degree of testicular atrophy. The 24-h mean T, estradiol, and delta 4 levels were higher than normal, but only the delta 4 was significantly increased (P less than 0.05). To determine if the elevated LH levels were in response to a decrease in the free T level, we measured T-binding capacity (TBG), TBG was higher than normal controls but was not significantly different, suggesting that elevated LH levels were probably in response to a decrease in T action at the hypothalamic-pituitary level. This was further supported by the inability of prolonged dihydrotestosterone administration to affect LH secretion in one of the patients with the Reifenstein syndrome.
The concentration of PRL was measured every 20 min for 24 h in six prepubertal and three adolescent boys. In both groups, PRL secretory episodes occurred throughout the 24-h period. In all subjects, the mean concentration of PRL was significantly higher during sleep than during wakefulness; the mean concentration during the entire 24-h period, during sleep or during wakefulness, was not different between the prepubertal subjects and the adolescents. These data suggest the absence of an ontogenetic change for PRL secretion in boys. During acute sleep-wake reversal, two of three pubertal boys showed significantly higher PRL during daytime sleep than during nocturnal wakefulness. This suggest that PRL release in adolescent boys is linked with sleep, rather than with clock time.
Four normal pubertal boys had plasma LH and melatonin measured at 20-minute intervals for 24-hours. All four subjects showed a significant augmentation of LH and melatonin during nocturnal sleep. There was also a significant correlation between the LH and melatonin levels (P less than 0.001). These data indicate that the peripheral concentrations of melatonin which occur during sleep are insufficient to prevent spontaneous LH secretion during puberty.
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We studied cortisol secretion and metabolism in 10 women with anorexia nervosa. The 24-hour mean plasma cortisol concentration was 8.9 mug per deciliter (controls, 4.9) (P less than 0.01). Secretory patterns showed normal circadian rhythms. Cortisol half-life was prolonged from 60 to 78 minutes (P less than 0.01), and metabolic clearance rate was decreased from 359 to 177 liters per day (P less than 0.001). Cortisol production was normal (19.4 mg per day). Urinary cortisol was slightly elevated in two of five patients. These findings, as well as the increased tetrahydrocortisol/tetrahydrocortisone ratio (1.2 vs 0.65, P less than 0.01), also appear in hypothyroid patients. Thyroid-function studies showed normal total and free thyroxine and thyrotropin, but low plasma tri-iodothyronine levels (52.7+/-13.2 vs. 137.8+/-24.1 ng per deciliter in the controls, P less than 0.001). In five additional patients with anorexia nervosa studied before and after short-term tri-iodothyronine administration, metabolic abnormalities decreased as plasma tri-iodothyronine levels rose to or above normal.
A 43-year-old man with a 36-year history of virilization due to an adrenal carcinoma is presented. The initial presentation at age 7 with precocious puberty and epiphyseal bone fusion suggested increased androgen effect at a very early age. The patient's 36-year course before his death suggested either a very slow growing adrenal carcinoma or untreated congenital adrenal hyperplasia that progressed to an adrenal carcinoma. Endocrine evaluation showed markedly increased DHEA and DHEA-sulfate levels. These were associated with elevated plasma and urinary estradiol levels and suppressed LH and FSH plasma concentrations. The 24-hour mean levels of cortisol and testosterone were normal. Studies of the circadian periodicity of cortisol showed a disturbed temporal pattern but a normal 24-hour mean concentration that correlated with a normal cortisol production rate. The 24-hour LH secretory pattern showed a decrease in the normal episodic fluctuation of this hormone over the 24-hour period.
Two adult men with feminizing adrenal cortical carcinoma had measurements of their 24-h plasma corticosteroid and gonadotropin patterns as well as 24-h mean hormone levels of estradiol, estetrol, 11-desoxycortisol, DHEA-S, DHEA and testosterone. Cortisol, 11-desoxycortisol and estrogen production rates were also measured. The 24-h corticosteroid patterns showed preservation of the normal 24-h episodic and circadian patterns, albeit at higher levels. The cortisol production rates were markedly elevated despite only moderate elevation of the 24-h mean cortisol level. There were elevated plasma 11-desoxycortisol levels and a markedly elevated 11-desoxycortisol production rate in one patient and THS excretion in the other. The plasma estradiol levels, urinary excretion and production rates were markedly elevated. In addition, there was a decrease in the specific activity of estriol compared with estrone and estradiol as well as measurable levels of estetrol in both patients. These latter observations coupled with the urinary immunoassayable hCG in one patient suggest that these tumors may be functioning like trophoblastic tissue. The possibility that estetrol may serve as an additional marker for tumors of trophoblastic origin is of additional interest.
A 27-year-old woman with secondary amenorrhea and some of the somatic stigmata of Turner's syndrome was found to have a ring chromosome. Laparoscopy and ovarian biopsy showed hypoplastic ovaries and an absence of primordial follicles. Endocrine evaluation showed a normal 24-h mean LH level (12.5 mIU/ml), an elevated FSH level (28 mIU/ml) and a normal plasma estradiol level (64 pg/ml). The augmented FSH and normal LH response to LH-RH is similar to what is found in men with germinal cell aplasia (Sertoli-cell only). The synchronous initiations of normal LH and abnormally augmented FSH secretory episodes in this patient suggests the absence or decrease of some factor normally produced by the ovarian follicle which modulates the release of FSH in response to LH-RH.
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Eight ergot alkaloids and ergoline derivatives, effective prolactin inhibitors, were tested for activity against DMBA-induced rat mammary carcinomas. Compounds were administered daily, 5 times/week for 4 weeks, and rats were observed for an additional 4 weeks. Groups treated with androgen and estrogen were used as positive controls. Those ergot compounds and ergolines that proved to be highly effective in reducing tumor size or in inducing regression of tumors to nonpalpability were Deprenon (D-6-methyl-8-ergolin-I-ylacetic acid amide) and ergocryptine; effective to an intermediate degree were Dironyl [N-(D-6-methyl-8-isoergolin-I-yl)-N',N'-diethylurea], ergocornine, and Lysenyl [N-(D-6-methyl-8-isoergolenyl)-N',N'-diethyl-urea]; and effective to a minimal degree were Lergotrile (2-chloro-6-methylergoline-8beta-acetonitrile), CB-154, and 6605-VUFB (D-6-methyl-8-cyanomethylergolin-I). Remission of many individual carcinomas was brief, and duration of complete regression (all tumors in the rat were nonpalpable) was less than 10 weeks.
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The influence of age and sex on the peripheral metabolism of testosterone was studied by giving intravenous tracers of 14C-testosterone to 21 prepubertal children (13 boys and 8 girls), 39 young adults 18-43 years old (23 men and 16 women), and 10 elderly adults 68-86 years old (6 men and 4 women). Studies were also carried out in 2 sexually immature young adults, one 18-year-old 45 XO phenotypic female with gonadal agenesis and one 18-year-old 45 XO, 46 XX mosaic female with gonadal dysgenesis; the latter was restudied after prolonged estrogen-progestagen therapy. Age and sex influences were observed only with respect to the androsterone/etiocholanolone (A/E) ratio; a sex difference in diol metabolite formation was not observed. Prepubertal children showed no sex difference in A/E ratio, which averaged 1.7 +/- 0.28 in boys and 1.9 +/- 0.42 in girls. Young adult men showed a slightly lower A/E ratio, averaging 1.5 +/- 0.10, while females showed a much greater decrease in A/E ratio, to 0.9 +/- 0.09, so that there was a highly significant (P less than .001) sex difference in this age group. The decreased averages were due to disappearance of the higher end of the ranges seen in prepubertal children; the lower limit of the ranges remained the same. Elderly adult men showed a further fall in the A/E ratio, to 1.0 +/- 0.11, and elderly women also showed a further fall, to 0.4 +/- 0.04; a highly significant (P less than .005) sex difference remained. Once again, the fall in average A/E ratio from young adults to elderly adults was due to disappearance of the higher end of the ranges in the former, the lower limits of the ranges were the same in both groups. Of the 2 sexually immature young women, one showed an A/E ratio of 1.3, just below the upper limit for young adult women, and the other showed a ratio of 1.8, well above that limit and thus typical of prepubertal girls. Estrogen-progestagen therapy of the second girl decreased the A/E ratio to 1.4, the upper limit for young adult women. It was concluded that there is a fundamental aging effect in both sexes which causes a gradual progressive decrease of the mean A/E ratio as a result of progressive disappearance of the higher individual A/E values while the lower end of the range of values remains constant; superimposed on this gradual decrease is an acute pubertal decrease in females, probably mediated by the development of the estrogen-progestagen milieu characteristic of sexually mature women.
An 18-year-old phenotypic girl with XY gonadal agenesis had endocrine studies. The patient had a small amount of sexual hair, a slightly enlarged clitoris, normal labia and no posterior fusion. Her vagina was of normal length, but no cervix was palpable. At laparoscopy, no gonads, uterus or fallopian tubes were identified. The buccal smear was chromatin negative and the karyotype was 46XY. The 24 h LH plasma pattern was qualitatively similar to that found in normal late pubertal subjects, but the values were in the castrate range. The 24h mean plasma concentrations of testosterone and dihydrotestosterone were 16.4 ng/dl and 14.2 ng/dl, respectively. Urinary estrogen excretion was 15 and 19 mug/day. These clinical and endocrine findings suggest that the patient was a genetic male in whom Mullerian regression occurred normally; however, the testes probably ceased functioning early in gestation preventing normal development of the Wolffian system. This set of events resulted in agenesis of the gonaductal system and female external genitalia. The patient represents the second example of this variation of male pseudohermaphroditism associated with XY gonadal agenesis.
The metabolism of 14C-testosterone was studied in 8 severely underweight young women with anorexia nervosa. The urinary androsterone/etiocholanolone (A/E) ratio was uniformly low, in a range characteristic of hypothyroidism; the patients also showed low plasma concentrations of triiodothyronine (T3). Clinical remission as manifested by weight gain was accompanied by concomitant increases of the A/E ratio and the plasma T3 concentration to or toward normal. The administration of T3 also resulted in a shift of the A/E ratio toward normal. These data demonstrate that the low plasma T3 concentrations in patients with anorexia nervosa may be related to the development of one of the characteristic biochemical abnormalities found in clinical hypothyroidism, namely a decreased A/E ratio. These data suggest that the "low T3 syndrome" may be associated with biochemical hypothyroidism.
Six young men with idiopathic hypogonadotropic hypogonadism had 24-h frequent blood sampling studies for measurement of LH, FSH and testosterone. Five of the patients had LH and FSH measured after administration of 100 mug LH-RH during waking and then during sleep. Four of the patients had testicular biopsies performed. The results of the present studies showed that 4 of the patients had no evidence of episodic LH, FSH, or testosterone secretion. The two patients who showed significant sleep related pulses of LH had the highest 24 h mean testosterone concentrations, the best responses to exogenous LH-RH and the most differentiated testicular biopsies. Sleep had no effect on the release of LH or FSH in response to LH-RH. These sutdies suggest that the clinical and laboratory heterogeneity of idiopathic hypogonadotropic hypogonadism may be the result of differences in the degree of endogenous LH-RH deficiency.