All-cause mortality in males with sleep apnoea syndrome: declining mortality rates with age.

The objective of this study was to assess whether an increasing severity of sleep apnoea is associated with increased all-cause mortality hazards and to assess whether the syndrome is associated with excess mortality, in comparison with the general population. Participants included 14,589 adult males, aged 20-93 yrs, referred to the sleep clinics with suspected sleep apnoea or diagnosed with sleep apnoea. Altogether, 372 deaths were recorded after a median follow-up of 4.6 yrs. The crude all-cause mortality rate was 5.55/1,000 patient yrs, increasing with apnoea severity. Cox proportional analysis revealed that both respiratory disturbance index (RDI) and body mass index significantly influenced all-cause mortality hazard but there was no interaction between them. Males with respiratory disturbance index >30 had a significantly higher mortality hazard rate than the reference group of males with RDI < or =10. Comparing mortality rates of males with moderate/severe sleep apnoea to the general population revealed that only males aged <50 yrs showed an excess mortality rate. The hazard of mortality in sleep apnoea increases with apnoea severity as indexed by respiratory disturbance index. Moderate and severe levels of sleep apnoea are moderately associated with an increased risk of all-cause mortality, in comparison with the general population, particularly in males aged <50 yrs. The lack of information about possible confounders and treatment effects should be taken into consideration in the interpretation of these results.

Urinary 6-sulfatoxymelatonin excretion in hyperandrogenic women: the effect of cyproterone acetate-ethinyl estradiol treatment.

Evidence for a relationship between melatonin and the reproductive hormones in humans is based on observations of abnormal melatonin secretion in clinical disorders of the pituitary-gonadal axis. The aim of this study was to investigate melatonin production in hyperandrogenic women before and during treatment with cyproterone acetate and ethinyl estradiol (Diane 35). Twelve women with polycystic ovary syndrome (PCOS), 10 women with idiopathic hirsutism (IH), and 10 women with late onset adrenal hyperplasia due to 21-hydroxylase deficiency (LOCAH) were studied. Patients were treated with Diane 35 for four months. Fasting blood samples for the determination of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone and dihydroepiandrosterone sulfate (DHEAS) and 24-hour urine collections for the determination of 6-sulfatoxymelatonin (aMT6s) excretion were obtained from all patients at baseline and after 4 months of treatment. Results were compared with those obtained in 15 control women. At baseline, women with PCOS and LOCAH had significantly higher testosterone and aMT6s values than women with IH and controls. Diane 35 treatment significantly decreased testosterone, LH, FSH and aMT6s values in PCOS and LOCAH patients compared with pretreatment values. These results indicate that hyperandrogenic women with PCOS and LOCAH have increased melatonin production. The decrease in aMT6s excretion together with reduced serum LH, FSH, DHEAS and testosterone values during treatment with cyproterone acetate-ethinyl estradiol, suggest that sex steroids either directly or through the suppression of gonadotropins, modulate melatonin secretion in these patients.

Urinary 6-sulfatoxymelatonin excretion in hyperandrogenic women with polycystic ovary syndrome: the effect of ethinyl estradiol-cyproterone acetate treatment.

The role of melatonin in human reproduction is still unknown. Data obtained in patients with hypogonadism and precocious puberty suggest that melatonin and the reproductive hormones are interrelated. The aim of this study was to determine melatonin production in hyperandrogenic women. We studied 12 women with polycystic ovary syndrome (PCOS) and 10 women with idiopathic hirsutism (IH). Patients were treated with cyproterone acetate-ethinyl estradiol (Diane 35) for 4 months. Fasting blood samples for the determination of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone and dehydroepiandrosterone sulfate (DHEAS) and 24-h urine collections for the determination of 6-sulfatoxymelatonin (alpha MT6s) excretion were obtained from all patients at baseline and after 4 months of treatment. The results were compared with those obtained in 15 control women. At baseline, women with PCOS had significantly higher LH and testosterone levels than those with IH and controls. Their alpha MT6s values (52.6 +/- 20.3 micrograms/24 h) were significantly higher than the values in women with IH (34.3 +/- 7.1) and controls (30.5 +/- 6.5) (p < 0.001). Diane 35 treatment significantly decreased LH, FSH, testosterone and alpha MT6a values in PCOS (28.0 +/- 13.9 micrograms/24 h) (p < 0.0001). These results indicate that women with PCOS have increased melatonin production. The normalization of alpha MT6s and testosterone values during Diane 35 treatment suggests that sex steroids modulate melatonin secretion in these patients either directly or through the suppression of gonadotropin.

Seminal plasma androgen/oestrogen balance in infertile men.

The hypothesis that the balance between oestrogen and androgen in seminal plasma is important for normal fertility was investigated. We determined the concentrations of oestradiol and testosterone in blood and seminal plasma from 62 infertile men and 32 normozoospermic men. Infertile men were classified according to semen analysis (concentration, motility and morphology): asthenozoospermia, oligozoospermia and oligoteratoasthenozoospermia. Serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were determined in all participants. For all subjects, mean testosterone levels were lower and mean oestradiol were higher in seminal plasma than in blood. Seminal plasma testosterone levels were lower in the infertile groups vs. control men ( p < 0.0002). Oligpzoospermic and oligoteratoasthenozoospermic men had significantly higher seminal plasma oestradiol levels compared with controls ( p < 0.03). The three infertile groups had significantly lower seminal plasma testosterone/oestradiol ratio than control men ( p < 0.001). Sperm analysis data (concentration, motility and morphology) significantly correlated with seminal plasma testosterone/oestradiol ratio. The findings of elevated seminal plasma oestradiol, decreased testosterone and testosterone/oestradiol ratio in infertile men, and the significant correlation between hormone levels and sperm analysis data suggest that the local balance between androgen and oestrogen is important for spermatogenesis.

Seminal plasma melatonin and gonadal steroids concentrations in normal men.

The authors determined semen quality and the concentrations of estradiol, testosterone, and melatonin in blood and seminal plasma of 8 normal men. To investigate the reproducibility of these parameters, semen analysis and hormone concentrations were determined on 3 occasions, 6 weeks apart. All 8 men had normal semen analysis. Blood melatonin (9.7-45.4 pg/mL) and testosterone (3.5-12.3 ng/mL) levels were significantly higher than the comparable seminal plasma levels (0.6-5.0 pg/mL, p <.02; 0.1-0.9 ng/mL, p <.0001, respectively). Seminal plasma estradiol levels (46.9-91.3 pg/mL) were significantly higher than the blood levels (13.3-44.7 pg/mL) (p <.0001). The intraindividual variations in seminal plasma estradiol levels ranged between 8.7 and 13.8%. There was no correlation between sperm concentration, motility or morphology and blood or seminal plasma hormone levels. Also, blood and seminal plasma hormone levels were not correlated. These results indicate that in normospermic men seminal plasma estradiol levels are higher than blood hormone levels, suggesting local production of estradiol. This may imply that estrogen and/or the balance andorgen/estrogen is important in normal human spermatogenesis.

Increased urinary 6-sulfatoxymelatonin excretion in women with non-classical steroid 21-hydroxylase deficiency.

OBJECTIVES: To determine melatonin production in hyperandrogenic women. MATERIAL AND METHODS: Seventeen women with late onset adrenal hyperplasia due to 21-hydroxylase deficiency (LOCAH) and 15 control women were studied in early follicular phase of the menstrual cycle. Fasting serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E(2)), testosterone, dihydroepiandrosterone sulfate (DHEA-S), 17-hydroxyprogesterone (17-OHP) as well as the peak 17-OHP response to ACTH (250 microg IV) and 24h urinary 6-sulfatoxymelatonin (aMT6s) were determined in all participants. RESULTS: All 17 hyperandrogenic women were carrying mutations of the CYP21 gene. Women with LOCAH had significantly higher serum testosterone, DHEA-S, 17-OHP and ACTH stimulated 17-OHP values compared with controls. Their aMT6s values (44.6+/-20.3 microg/24h) were significantly higher than the values in control women (31.5+/-20.3) (p<0.03). The urinary aMT6s values were positively correlated with testosterone (p<0.04), DHEA-S (p<0.02) and peak 17-OHP (p<0.04). CONCLUSIONS: Women with LOCAH have increased melatonin production. There is a relationship between adrenal androgens and melatonin in these women.

Actigraphic sleep-wake patterns and urinary 6-sulfatoxymelatonin excretion in patients with Alzheimer's disease.

Recent studies suggest melatonin, due to its antioxidant and free-radical-scavenging actions, may play a role in the neuroprotection against amyloid, which is implicated in the pathogenesis of Alzheimer's disease (AD). In this study, we determined urinary 6-sulfatoxymelatonin (aMT6s) excretion together with actigraphic sleep-wake patterns of untreated male patients with AD who lived at home. Results were compared with those obtained from normal age-matched elderly and normal young male subjects. Similar measurements were also performed in another group of patients with AD who were treated with a cholinesterase inhibitor (Donepezil, Aricept). Total 24h aMT6s values were significantly reduced in elderly controls (19.9h +/- 5.2 microg/ 24h), in those with untreated AD (12.7 +/- 4.4 microg/24h), and in patients treated for AD (12.4 +/- 4.4 microg/24h) compared with normal young men (32.8 +/- 3.1 microg/24h). A day-night difference in aMT6s was evident in all young controls, in 50% of elderly controls, in only 20% of patients with untreated AD, and in 67% of those with AD receiving Aricept. Sleep quality (expressed as sleep efficiency, wake time, and long undisturbed sleep duration) was better in young and elderly controls compared with the two groups of patients with AD. There was no significant correlation between aMT6s values or sleep patterns and the severity of cognitive impairment in patients with AD. Taken together, these data suggest that disrupted sleep, decreased melatonin production, and partial lack of day-night difference in melatonin secretion were observed equally in normal elderly and in patients with AD. Our results do not permit drawing any conclusion as to whether changes in urinary aMT6s excretion is correlated with disturbed sleep in patients with AD.

Disruption of the nocturnal testosterone rhythm by sleep fragmentation in normal men.

Recently, we have demonstrated that in normal men the nocturnal testosterone rise antedated the first rapid eye movement (REM) sleep episode by about 90 min and was correlated with REM latency. To further elucidate whether the diurnal testosterone rhythm is a sleep-related phenomenon or controlled by the circadian clock, we determined serum testosterone levels in 10 men during the ultrashort 7/13 sleep-wake cycle paradigm. Using this schedule, subjects experienced partial sleep deprivation and fragmented sleep for a 24-h period. Serum testosterone levels were determined every 20 min between 1900-0700 h with simultaneous sleep recordings during the 7-min sleep attempts. The results were compared with those obtained in men during continuous sleep. Although mean levels and area under the curve of testosterone were similar in both groups, fragmented sleep resulted in a significant delay in testosterone rise (03:24 h +/- 1:13 vs. 22:35 h +/- 0:22). During fragmented sleep, nocturnal testosterone rise was observed only in subjects who showed REM episodes (4/10). Our findings indicate that the sleep-related rise in serum testosterone levels is linked with the appearance of first REM sleep. Fragmented sleep disrupted the testosterone rhythm with a considerable attenuation of the nocturnal rise only in subjects who did not show REM sleep.

Can we consider medical residents as shift workers?

Although medical residents are characterized by long working hours, night shifts and high levels of work load, it is unclear if their work schedule can be classified as shift work, or if it has a similar impact on residents' well-being. The present paper compared the profile of complaints about sleep or daytime functioning of medical residents to that of rotating shift workers and day workers, of similar ages. Sixty-one residents (aged: 32.2 +/- 2.2 years), after 2 years of residency, participated in the study. The two control groups with a similar age range (26-40 years) were chosen, and included 94 rotating shift workers and 146 day workers. All subjects completed self-administered questionnaires on their sleep habits, and their sleep-wake cycle was monitored by a wrist-worn actigraph. Ten percent of the residents complained about difficulties falling asleep, 34% complained about morning tiredness, 14% complained about mid-sleep awakening, and 20% about prolonged fatigue. The residents slept significantly less than the day workers, and their sleep efficiency was significantly higher. When examining their subjective complaints profile, residents complained more than day workers and their answers were more similar to those of rotating shift workers, therefore they can be considered to be characterized as shift workers.

Obstructive sleep apnoea syndrome as a risk factor for hypertension: population study.

OBJECTIVE: To assess whether sleep apnoea syndrome is an independent risk factor for hypertension. DESIGN: Population study. SETTING: Sleep clinic in Toronto. PARTICIPANTS: 2,677 adults, aged 20-85 years, referred to the sleep clinic with suspected sleep apnoea syndrome. OUTCOME MEASURES: Medical history, demographic data, morning and evening blood pressure, and whole night polysomnography. RESULTS: Blood pressure and number of patients with hypertension increased linearly with severity of sleep apnoea, as shown by the apnoea-hypopnoea index. Multiple regression analysis of blood pressure levels of all patients not taking antihypertensives showed that apnoea was a significant predictor of both systolic and diastolic blood pressure after adjustment for age, body mass index, and sex. Multiple logistic regression showed that each additional apnoeic event per hour of sleep increased the odds of hypertension by about 1%, whereas each 10% decrease in nocturnal oxygen saturation increased the odds by 13%. CONCLUSION: Sleep apnoea syndrome is profoundly associated with hypertension independent of all relevant risk factors.

Long-term melatonin administration does not alter pituitary-gonadal hormone secretion in normal men.

The role of melatonin in the regulation of reproduction in humans is still controversial. In the present study the effects of melatonin were examined, 6 mg given orally every day at 1700 h for 1 month in a double-blind, placebo controlled fashion, on the nocturnal secretory profiles of luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone and inhibin beta in six healthy adult men. Serum concentrations of LH, FSH, testosterone and inhibin beta were determined before and after treatment every 15 min from 1900 to 0700 h over 3 nights in a controlled dark-light environment with simultaneous polysomnographic sleep recordings. The following sleep parameters were determined: total recording time, sleep latency, actual sleep time, sleep efficiency, rapid eye movement (REM) sleep latency and percentages of sleep stages 2, 3/4 and REM. There were no statistically significant differences in all sleep parameters between baseline and placebo or between baseline and melatonin except for longer REM latency and lower percentage REM at baseline than under melatonin treatment. These are explained as reflecting first-night effect at baseline. The mean nocturnal LH, FSH, testosterone and inhibin beta integrated nocturnal secretion values did not change during the treatment period. Likewise, their pulsatile characteristics during melatonin treatment were not different from baseline values. Taken together, these data suggest that long-term melatonin administration does not alter the secretory patterns of reproductive hormones in normal men.

Relationship between rapid eye movement sleep and testosterone secretion in normal men.

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.

Melatonin administered in the afternoon decreases next-day luteinizing hormone levels in men: lack of antagonism by flumazenil.

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) gamma-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 decreases 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.

Daily and seasonal variations in the concentration of melatonin in the human pineal gland.

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.

The effects of substituting zopiclone in withdrawal from chronic use of benzodiazepine hypnotics.

Twenty-four volunteers (19 women and five men) with insomnia and a history of chronic use of benzodiazepine hypnotics participated in a randomized, double blind, controlled clinical trial. The study was designed to assess the effects of substituting zopiclone (ZOP)- as an hypnotic- among chronic users of flunitrazepam (FLU), and to compare the subsequent withdrawal of ZOP with placebo controlled withdrawal of FLU. During the 5 weeks of a withdrawal protocol, sleep and physiological parameters were assessed by polysomnographic measures for 11 nights and by nightly actigraphic recordings for weeks 1, 3, and 5. Subjective effects of the withdrawal process were evaluated with daily sleep diaries, and with various weekly self-report symptom checklists. Paired t-tests performed on differences in objective sleep parameters between baseline and the last weeks of the withdrawal program showed a significant decrease in sleep quality within the FLU group, but not in the ZOP group. Subjective sleep diaries consistently reflected the objectively measured changes in sleep throughout the withdrawal program, indicating significant changes in sleep parameters only in the FLU group. The results obtained from the self report inventories aimed at assessing withdrawal symptoms, however, revealed no differences between the baseline week and the termination week of the program in any of the groups. After completing the pharmacological withdrawal, all subjects received a short-term cognitive behavioral intervention focused on improving their coping strategies with symptoms of insomnia; they were evaluated immediately after concluding the intervention, and at 3 and 12 month follow- ups.

Abnormal melatonin secretion in hypogonadal men: the effect of testosterone treatment.

OBJECTIVE: 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. DESIGN: Prospective, controlled. SUBJECTS: 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. MEASUREMENTS: 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. RESULTS: 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. CONCLUSIONS: 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.

Changing from communal to familial sleep arrangement in the Kibbutz: effects on sleep quality.

Sleep was actigraphically investigated in 27 Kibbutz children while sleeping in communal sleeping houses, and 1 year after changing to familial sleeping arrangements. Three independent control groups of city-living children were also recorded. Two of them were age-comparable, and the third control group was included in order to examine possible effects of the Gulf War on the communal sleep group. The results showed that the sleep quality of Kibbutz children improved significantly after moving to familial sleep. Comparison with the data from the two control groups revealed a greater resemblance between sleep of the Kibbutz children after moving to live with their families and that of the city-living children. Comparing the sleep of the children in communal sleep to that of the additional group of children examined during the Gulf War strengthened the above results, i.e. the communal sleep group that was investigated before the war slept worse than the control children that were investigated during the war. After discarding developmental and physical condition-related changes, it was concluded that the improvement in sleep quality was due to the children's increased sense of security when sleeping with their families.

Nonreplicability of seasonal rhythm in REM sleep in a subtropical climate.

The present paper attempts to replicate Askenasy and Goldstein's (1995) findings of seasonality in rapid eye movement (REM) sleep measures in patients recorded in Israel. Analysis of sleep stage data of 706 nonselected male sleep apnea patients failed to find seasonality in REM sleep measures. In contrast, our data revealed stability of REM time with a maximum difference between seasons of 7.0 minutes. Age differences were found in sleep efficiency, true sleep time, and amount and percentage of REM sleep, with patients over 60 having a lower sleep efficiency, shorter true sleep, and REM sleep time than patients under 60. Rapid eye movement latency was also found to differ according to apnea severity, with patients who had > 40 apneas and hypopneas per hour of sleep having a longer latency than those with fewer apneas and hypopneas.

Immunohistochemical localization of gonadotropin and gonadal steroid receptors in human pineal glands.

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.