- [Show abstract] [Hide abstract] ABSTRACT: The relation between the pituitary-gonadal hormones' rhythm and sleep physiology in men is not fully elucidated. To examine whether the reproductive hormones are correlated with sleep architecture, we determined the nocturnal serum levels of testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) in six healthy young men. Serum hormone levels were obtained every 15 minutes from 1900 to 0700 hours with simultaneous polysomnographic sleep recordings. Hourly testosterone levels were lowest when subjects were awake (1900-2200 hours) than during sleep (2300-0700 hours). Testosterone nocturnal rise antedated the first REM by about 90 minutes. The rise in testosterone levels was slower when REM latency was longer. Mean nocturnal testosterone levels did not correlate with the number of rapid eye movement (REM) episodes. Also, pre-non-REM (NREM) testosterone levels were higher as compared with the pre-REM periods and lower during the first NREM period as compared with other nocturnal NREM periods. Serum LH levels disclosed a nocturnal rise that preceeded a similar rise in testosterone by about an hour. We conclude that in young adult men, testosterone levels begin to rise on falling asleep, peak at about the time of first REM, and remain at the same levels until awakening.
- [Show abstract] [Hide abstract] ABSTRACT: The role of melatonin in the regulation of human reproduction remains unclear. In the present study, we examined the influence of exogenous melatonin on pulsatile luteinizing hormone (LH), diurnal rhythm of testosterone, and endogenous melatonin profile in six healthy young adult males. To test the hypothesis that the effect of melatonin on LH or testosterone secretory patterns may be mediated through the benzodiazepine-(BNZ) γ-amino-butyric acid (GABA) receptor complex, a benzodiazepine receptor antagonist (Flumazenil) was administered. The study design comprised four 10-h (4:00 pm–2:00 am) testing periods. During each experimental period, subjects were given an oral dose of placebo, or 3 mg melatonin or 10 mg flumazenil, at 5:00 pm, in a randomized, double-blind, partially repeated Latin square design in the following combinations: placebo-placebo, placebo-melatonin, flumazenil-placebo, and flumazenil-melatonin. The following day, serum samples were obtained every 20 min between 4:00 pm and 2:00 am in a controlled light-dark environment for the determination of LH and melatonin levels. Serum testosterone concentrations were determined every 20 min between 7:00 and 8:00 am and 7:00 and 8:00 pm. A significant decrease in mean serum LH levels (p < 0.02) was observed in the melatonin-treated groups as compared with placebo-flumazenil groups. There was no change in LH pulse frequency, testosterone levels, or in melatonin onset time and amplitude. No additional effect of flumazenil on LH or testosterone levels was observed. These data indicate that an evening melatonin administration decrease the next-day LH secretion in normal adult males without altering testosterone levels or the endogenous nocturnal melatonin secretory pattern. This effect of melatonin is not mediated through the benzodiazepine-GABA receptor complex.
- [Show abstract] [Hide abstract] ABSTRACT: Auditory Brainstem Evoked Potentials (ABEPs) and pure tone audiograms were obtained from 24 patients with parathyroid dysfunction (17 hypercalcemia and 7 hypocalcemia) and 12 patients with thyroid dysfunction (6 hyperthyroid and 6 hypothyroid) and from 10 control subjects. ABEPs were characterized by I-V interpeak latency difference at 10/sec click rate and by the effect of increasing stimulus rate to 55/sec. None of the ABEP measures were significantly affected by levels of serum calcium, thyroid hormones or their interactions. Moreover no correlation was found between biochemical and electrophysiological measures. This stability of ABEP measures contrasts with earlier reports on acute effects of calcium and thyroid hormonal levels on auditory brainstem evoked potentials. We propose that chronic calcium or thyroid hormonal homeostatic changes are associated with adaptive mechanisms resulting in normal function of the auditory brainstem.
- [Show abstract] [Hide abstract] ABSTRACT: We present 3 women who were referred for evaluation of stress-related mild-to-moderate hyperprolactinemia. This frequent finding may mistakenly be considered a clinical problem, and lead to inappropriate investigation and therapy. We emphasize the importance of serial blood sampling for prolactin determination. We collected blood samples repeatedly under resting conditions from an indwelling venous brachial catheter, every 30 minutes for a total of 6 samples. All 3 patients had normal prolactin levels 30-60 minutes after starting the test. Neither further investigation nor medical therapy were needed and these anxious patients were reassured that their hyperprolactinemia was factitious.
- [Show abstract] [Hide abstract] ABSTRACT: To elucidate whether pineal melatonin secretion is affected by changes in day length, we determined the concentration of melatonin in human pineal glands obtained at autopsy from 66 male subjects, aged 16–84 years over a period of 12 consecutive months. Based on the time of death, a day–night difference in pineal melatonin levels was evident only in the long photoperiod (April–September) with significantly higher melatonin concentrations occurring at night (2200–1000 h). Nighttime values in the long photoperiod were significantly higher than the nighttime values during the short photoperiod (October–March). During the short photoperiod, the data suggested a possible phase-delay in melatonin secretion. Day–night difference was evident in young subjects (30–60 years), but not in elderly subjects (61–84 years). Elderly subjects had lower total melatonin levels (day and night values) although statistically not significant. Therefore, melatonin levels did not decline with age and when the data were analyzed by age there was no significant day–night difference in melatonin levels. These data indicate that the concentration of melatonin in the human pineal is augmented only during the long photoperiod. The results suggest a partial effect of photoperiod on melatonin secretion in humans. This may result from living in an artificial light environment or due to other nonphotic signals involved in generating melatonin rhythm.
- [Show abstract] [Hide abstract] ABSTRACT: A 27-year-old woman with no previous personal or family history of thyroid disease was referred to us for the evaluation of thyroid nodule, five months postpartum. Thyroid scintigraphy demonstrated a left cold nodule. Fine needle aspiration cytology of the nodule showed a mixture of colloid, follicular cells and lymphocytes, suggesting lymphocytic thyroiditis. Thyroid function tests were normal and thyroid autoantibodies were negative. After two months the thyroid nodule was not palpated and thyroid scintigraphy returned to normal. Thyroid function tests remained normal twelve months after delivery. These findings suggest that postpartum thyroiditis may present as a localized transient form and should be considered in the differential diagnosis of painless solitary nodule that appears postpartum.
- [Show abstract] [Hide abstract] ABSTRACT: Synovial sarcoma (SS), a malignant mesenchymal tumor, has a biphasic growth pattern characteristically. Histologically and cytologically the tumor can pose diagnostic difficulty when the epithelial component is predominant. A 22-year-old female presented with a rapidly enlarging mass on the lower left side of the neck. Fine needle aspiration of the tumor yielded abundant, discohesive round-oval cells mingled with amorphous hyaline material, raising a suspicion of medullary carcinoma of the thyroid. In addition, air-dried, Giemsa-stained smears demonstrated rosettelike structures with central magenta globular material, mimicking adenoid cystic carcinoma. However, histologic examination of the excised tumor, including immunohistochemical and ultrastructural studies, proved it to be a typical SS with copious basement membrane accumulations. The cytologic appearance of SS can be confusing. However, a false diagnosis may be avoided if adequate needle sampling is ensured and clinical correlation considered.
- [Show abstract] [Hide abstract] ABSTRACT: We describe two male patients, aged 17 and 47 years, with clinical and biochemical features of pheochromocytoma. Both patients had normal-sized adrenal glands on abdominal CT scan and abnormal unilateral uptake of I-123 metaiodobenzylguanidine (MIBG) on scintigraphy. The surgical adrenalectomy revealed normal macroscopic glands in both patients. Histological examination showed adrenal medullary hyperplasia with adrenal cortico-medullary ratios of 2:1 and 4:1. Unilateral adrenalectomy resulted in amelioration of symptoms and normalization of catecholamines excretion. DNA examination for RET protooncogene revealed no mutations in exons 10, 11, 13, 14 and 16. Our results suggest that diffuse adrenal medullary hyperplasia may be the initial pathological change in the adrenal gland leading, subsequently, to the development of nodular hyperplasia and adrenal medullary tumor. These results indicate that the syndrome of pheochromocytoma may occur as an unilateral adrenal medullary hyperplasia in patients without evidence for multiple endocrine neoplasia.
- [Show abstract] [Hide abstract] ABSTRACT: We have recently demonstrated that GnRH deficient male patients have increased nocturnal melatonin secretion, whereas hypergonadotrophic hypogonadal males have decreased melatonin levels. We were interested in determining whether testosterone (T) treatment (when T levels were well matched with pubertal control values) has an effect on melatonin secretory profiles in these patients. Prospective, controlled. Six male patients with idiopathic hypogonadotrophic hypogonadism (IGD), six males with hypergonadotrophic hypogonadism due to Klinefelter's syndrome (KS) and seven controls. Patients were examined before and during the administration of 250 mg testosterone enanthate/month for four months. Serum samples for melatonin levels were obtained every 15 minutes from 1990 to 0700 h in a controlled light-dark environment. The results of FSH, LH, T and oestradiol (E2) (determined at hourly intervals) and melatonin profiles, were compared with the pre-treatment values in each group, and with values obtained in the control group. All 12 patients had low pre-treatment T levels (1.4 +/- 0.7 in IGD and 2.0 +/- 0.4 in KS vs. 19.8 +/- 2.3 nmol/l in controls) and attained normal levels after four months of T treatment (19.5 +/- 7 in IGD and 22.7 +/- 3.8 nmol/l in KS). Serum LH, FSH and E2 levels (11 +/- 4 IU/l, 24 +/- 10 IU/l and 113 +/- 12 pmol/l, respectively) were still elevated in KS during T treatment as compared with values in controls (2 +/- 1 IU/l, 2 +/- 1 IU/l and 67 +/- 4 pmol/l, respectively). In IGD, serum LH (0.12 +/- 0.1 IU/l) and FSH (0.16 +/- 0.2 IU/l) levels during T treatment were suppressed. Pretreatment melatonin levels in IGD were greater than those in age-matched pubertal controls while in KS, melatonin levels were lower than values in controls. Melatonin levels were equal in all 12 hypogonadal patients and controls when T levels were well matched. Mean (+/- SD) dark-time melatonin levels decreased from 286 +/- 18 to 157 +/- 26 pmol/l in IGD and increased from 92 +/- 19 to 183 +/- 48 pmol/l in KS (vs 178 +/- 59 pmol/l in controls). The integrated melatonin values decreased in IGD (from 184 +/- 14 to 102 +/- 21 pmol/min. 1 x 10(3)) and increased in KS (from 64 +/- 13 to 123 +/- 40, vs. 116 +/- 39 pmol/min. 1 x 10(3) in controls). No correlations were found between melatonin and LH, FSH or E2 levels. These data indicate that male patients with GnRH deficiency have increased nocturnal melatonin secretion while in hypergonadotrophic hypogonadal males melatonin secretion is decreased. Testosterone treatment normalized melatonin concentrations in these patients. Taken together, the results suggest that GnRH, gonadotrophins and gonadal steroids modulate pineal melatonin in humans.
- [Show abstract] [Hide abstract] ABSTRACT: In this study, we used the "ultrashort sleep-wake paradigm" (7/13), which measures sleep propensity three times an hour for 29 h, from 0700 to 1200 the next day, on 6 healthy male subjects concomitantly with melatonin plasma level. Melatonin was measured once an hour during the morning and early afternoon of the first day and three times an hour from 1600 to 1000 the following morning. Rectal temperature was measured continuously for four subjects. Subjects underwent the 7/13 paradigm three times, and in all three sessions consistent phase relationships were found between the nocturnal onset of melatonin secretion and opening of the nocturnal sleep gate; also, there was an inverse relationship between melatonin and core body temperature and an almost perfect out-of-phase relationship between sleep propensity and temperature, with the temperature peak falling precisely in the middle of the "forbidden zone" for sleep, i.e., the early evening nadir in sleepiness. On the basis of these phase relationships and previous findings from our laboratory on the effects of exogenous melatonin on the sleep propensity function, we conclude that melatonin participates in sleep-wake regulation in humans.
- [Show abstract] [Hide abstract] ABSTRACT: Recently, we have demonstrated that male patients with gonadotropin-releasing hormone (GnRH) deficiency had increased nocturnal melatonin secretion that decreased to normal levels during testosterone treatment. The purpose of the current study was to examine if the abnormally increased melatonin levels in these patients were associated with pulsatile secretory patterns, and, if these were modified during testosterone administration. Characteristics of nocturnal melatonin and luteinizing hormone (LH) secretion were compared in six normal young males, six males with idiopathic hypogonadotropic hypogonadism (IGD), and in six males with constitutional delayed puberty (DP). Patients were examined in the untreated state and following the administration of 250 mg testosterone enanthate/month for 4 months. Serum samples for melatonin and LH levels were obtained every 15 min from 19.00 hr to 07.00 hr in a controlled light-dark environment. Pulse detection and pulse characteristics were determined by the program ULTRA. In comparison with normal controls, untreated IGD patients showed significantly higher pulse frequency, lower relative increments and shorter half-life times for melatonin. Similar findings were observed in DP patients, although statistically of borderline significance. Treatment with testosterone normalized melatonin pulse characteristics in both IGD and DP patients. The secretory pattern of LH release in these patients was characterized by significantly higher relative and absolute increments and shorter half-life time without any significant change in the number of LH pulses. Taken together, these data suggest that melatonin is secreted in a pulsatile pattern in normal adult males and in male patients with GnRH deficiency. The abnormally increased nocturnal melatonin secretion observed in these patients may indicate that the pineal pulse generator is expressing an altered activity pattern within its normal capabilities. Testosterone administration normalized melatonin secretory patterns in IGD and DP patients. The lack of relationship between the pulsatile LH and melatonin secretory patterns suggest an independent signal for the nocturnal pulsatile melatonin and LH secretions.
- [Show abstract] [Hide abstract] ABSTRACT: Recently, we demonstrated that melatonin secretion was increased in male patients with GnRH deficiency and decreased to normal levels during testosterone treatment. These data suggested that gonadal steroids modulate melatonin secretion, probably by activating specific receptors in the pineal gland. We used immunohistochemistry to localize gonadotropin (LH and FSH) and gonadal steroid (androgens and estrogens) receptors in human pineal glands. Tissues were obtained at autopsy from 25 males, aged 19-87 yr, and five prepubertal children, aged 0.2-10 yr. Positive staining for all four types of receptors (LH, FSH, androgen, and estrogen) in the pineal parenchymal cells, pinealocytes, was evident in all 30 glands examined. Double staining revealed that nuclear receptors (androgen or estrogen) co-existed with cytoplasmatic receptors (LH or FSH) in the same cells. The results demonstrate the presence of gonadotropin and gonadal steroid receptors in human pinealocytes from infancy to old age.
- [Show abstract] [Hide abstract] ABSTRACT: We describe a 13 year-old Ethiopian girl with vitamin D deficiency rickets. Hypercalcemia, increased serum alkaline phosphatase and PTH levels, together with low serum levels of 25-hydroxyvitamin D and 24,25-dihydroxyvitamin D suggested the co-existence of primary hyperparathyroidism. The surgical removal of a parathyroid adenoma led to bone healing and normalization of blood chemistry. We conclude that vitamin D deficiency masked the hyperparathyroidism and hypercalcemia, while excess PTH secretion delayed the cure of rickets until successful parathyroidectomy had been carried out.
- [Show abstract] [Hide abstract] ABSTRACT: Recently abnormal melatonin secretion was demonstrated in hypogonadal male patients which was normalized during testosterone administration. These results suggested that both gonadal steroids and gonadotropins may modulate melatonin secretion, probably by activating specific receptors in the pineal gland. We used immunohistochemistry to localize luteinizing hormone, follicle stimulating hormone, estrogen and androgen receptors in human pineal glands. Tissues were obtained at autopsy from 53 adult males (aged 19–94 years) over a period of 1 year. Positive staining for the four types of receptors was evident in all 53 specimens examined. The percent of positively stained cells revealed a significant seasonal variation of gonadotropin receptors with higher values in the winter than in the summer. Day-night difference was evident only for follicle stimulating hormone-receptors during the summer and winter, with higher values at night. Androgen receptors and estrogen receptors were present in all specimens but did not reveal day-night or seasonal variations. These data demonstrate the presence of gonadotropin and gonadal steroid receptors in the human pineal gland. Gonadotropin receptors exhibited seasonal variation with higher values in the winter.
- [Show abstract] [Hide abstract] ABSTRACT: We have recently demonstrated that GnRH deficient male patients have increased nocturnal melatonin secretion which decreases to normal levels during testosterone treatment. The results suggested that sex steroids, rather than LH, modulate pineal melatonin in an inverse fashion. The purpose of this study was to characterize circulating melatonin levels in untreated males with hypergonadotrophic hypogonadism due to Klinefelter's syndrome (KS). Prospective, controlled. Eleven patients with Klinefelter's syndrome and seven controls. Patients were subdivided into two groups: (1) with low testosterone, and (2) with normal testosterone levels. Serum samples for melatonin concentrations were obtained every 15 minutes from 1900 to 0700 h in a controlled light-dark environment. All patients had elevated FSH, LH and oestradiol (E2) levels. Mean (+/-SD) dark time nocturnal melatonin levels were significantly lower in low testosterone KS (92 +/- 19 pmol/l) compared with 146 +/- 42 pmol/l in normal testosterone KS and 179 +/- 59 pmol/l in controls (P < 0.02). A similar pattern was observed for the mean (+/-SD) peak melatonin levels (165 +/- 41, 236 +/- 59 and 293 +/- 89 pmol/l) in low testosterone KS, normal testosterone KS and controls, respectively (P < 0.01). Integrated nocturnal melatonin secretion values (AUC) were also lower in low testosterone KS (64 +/- 13) compared with 96 +/- 26 in normal testosterone KS and 116 +/- 39 pmol/min 1 x 10(3) in controls (P < 0.02). The time of melatonin peak and the time of the nocturnal melatonin rise as well as the light-time mean (+/-SD) serum melatonin levels were similar in all three groups. No correlations were found between melatonin and LH, FSH, or E2 levels. Melatonin secretion is decreased in male patients with low testosterone hypergonadotrophic hypogonadism whereas in normal testosterone Klinefelter's syndrome patients, melatonin secretory profiles are normal. The results suggest that the suppression of melatonin secretion in these patients is mediated by GnRH (either directly or indirectly) and/or oestradiol.
- [Show abstract] [Hide abstract] ABSTRACT: Hypokalemic periodic paralysis is an uncommon complication of thyrotoxicosis, and very rare as a presenting symptom. It is most frequent in east Asian and Japanese males, but extremely rare in others. Only 1 case has previously been reported from Israel. We present a 29-year-old Arab man who presented with sudden paralysis of both legs. Physical examination revealed signs of thyrotoxicosis, and laboratory tests showed profound hypokalemia. Oral potassium resulted in rapid disappearance of symptoms, and after restoration of the euthyroid state, there were no further attacks. This case shows that thyrotoxic hypokalemic periodic paralysis is not confined to males of east Asian and Japanese origin, and that adequate treatment with oral potassium and antithyroid drugs is successful, and should be given as soon as possible.
Technion - Israel Institute of Technology
H̱efa, Haifa, Israel
- Ruth and Bruce Rappaport Faculty of Medicine