The advances in research on sleep an biological rhythms have recently been applied to the diagnosis and treatment of sleep disorders. A new clinical specialty has developed with the establishment of sleep disorder centers and a diagnostic classification of sleep and arousal disorders. This new nosological approach has evolved from an extensive base of new scientific information concerning descriptive polygraphic and analysis of clinical case series. Four major categories have been defined: (a) disorders of initiating and maintaining sleep (insomnias), (b) disorders of excessive somnolence, (c) disorders of the sleep-wake schedule, and (d) dysfunctions associated with sleep. Within this comprehensive classification certain major pathophysiological advances are described for the "insomnias." These include polysomnographic identification of altered sleep stage patterns in the major effective illnesses, insomnias related to hypnotic drugs and alcohol, sleep disturbances associated with sleep-induced respiratory impairment, and sleep-related periodic movements during sleep (nocturnal myoclonus). Excessive daytime somnolence is primarily associated with the hypersomnia sleep-apnea syndrome and with narcolepsy. The relationship between biological rhythms (chronobiology) and disorders of the human sleep-wake schedules is very actively investigated. The recognition that sleep length, internal organization, and timing within neurophysiological circadian time-keeping systems has lead to better diagnosis of these sleep-wake disorders and new chronotherapeutic regimens. Finally, increasing identification and description of "parasomnias," i.e. dysfunctions associated with sleep, has led sleep research into important new areas that are of general physiological interest. It is now clear that sleep disorders medicine has become a new scientific and clinical discipline in its own right.

During our preliminary studies correlating frequent ocular tension measurements with other physiologic and biochemical parameters in man, we noted that intraocular tension was lowest in the early morning, generally around 3 A.M., in all subjects. This observation is at variance with most published data reporting lowest values during the afternoon. Short-term fluctuations in ocular tension were also observed in this study. Eleven subjects, five normal subjects and six subjects with various types of glaucoma (juvenile glaucoma, steroid-induced glaucoma, unilateral traumatic glaucoma, pigmentary glaucoma, and chronic simple glaucoma) were examined. Each subject was placed at bed rest for a minimum of 24 hours during which time studies were conducted. Glaucoma subjects had their medications discontinued at least 24 hours prior to the start of the testing. Ocular tension was measured hourly or more frequently (every 20 minutes for several hours) using a calibrated MacKay-Marg electronic tonometer. All subjects were able to tolerate this repeated tonometry either with no anesthetic agent or with dilute (1:10 in sterile water) Ophthaine. No corneal damage was noted during or subsequent to the testing. The average of five good traces was recorded as the ocular tension. Other parameters measured in some but not all subjects included plasma samples taken every 20 minutes by venous catheter for assay of endogenous cortisol and growth hormone, and hourly blood pressure, pulse rate, rectal temperature, as well as polygraph recordings of electroencephalogram, EOG, and chin electromyogram done during nocturnal sleep hours (11 P.M. to 7 A.M.). The lowest ocular tension was recorded in all eleven subjects during the early morning hours (2 to 4 A.M.). All six glaucoma subjects had a tension below 20 mm. Hg at this time regardless of the level of their ocular tension during the day. Unexpected was the finding of short-term fluctuations in ocular tension noted in both normal and glaucomatous eyes. Differences of from 5 to 9 mm. Hg were noted in one hour, and 3 to 4 mm. fluctuations were found over 20 minute sampling periods. In all instances both eyes showed fluctuations of intraocular tension in a similar direction at the same time. Fig. 1 is the diurnal record of a 42-year-old white male with unilateral glaucoma secondary to traumatic angle recession. His ocular tension has been difficult to control with any combination of medical therapy. His record shows that without therapy he attains a normal ocular tension in his diseased left eye early in the morning. His normal right eye also has its lowest ocular tension during the same hours. Fig. 2 is a composite of the diurnal traces of all eleven subjects; all had their lowest ocular

Six chromatin-negative young men, ages 16–24 yr, with hypogonadotropic hypogonadism were studied in an attempt to clarify and define the endocrine abnormalities responsible for this disorder. Five of the six patients had associated congenital anomalies involving the skeletal system or midline facial structures. Pituitary function studies showed normal thyroid and adrenal function. Two of 6 patients showed subnormal growth hormone responses to arginine infusion and insulin hypoglycemia, and 4 tested showed subnormal sleep mediated growth hormone release. Evaluation of pituitary-gonadal function showed normal prepubertal concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH) and testosterone. The plasma testosterone response to acute stimulation with human chorionic gonadotropin (hCG) (5000 units daily × 4 days) was subnormal in 3 of 6 patients; however, these 3 patients achieved normal plasma testosterone concentrations after more prolonged hCG administration (5000 units twice weekly for 4–8 weeks). These observations show that hypogonadotropic hypogonadism is associated with a high frequency of congenital abnormalities, subnormal sleep-mediated growth hormone release, plasma LH and FSH concentrations indistinguishable from normal prepubertal boys and normal plasma testosterone responses to long term hCG treatment.

Plasma luteinizing hormone (LH) was measured by radioimmunoassay at 20-min intervals for 24-hr in 5 normal men before and after the daily administration of 100 mg clomiphene citrate for 7 days. The results showed that clomiphene caused a significant (P < 0.001) increase in the 24-hr mean LH concentration in all 5 subjects. The range of the percent increase was 135–245 with a mean of 180%. In spite of the highly significant increase in the 24-hr mean LH concentration there were instances of overlap of isolated LH values in the control and clomiphene studies. Analysis of the 24-hr plasma curves showed that the increased mean LH concentration was achieved by either increasing the amount of LH secreted per secretory episode or the number of major secretory episodes or both. Calculation of the LH production rate from the 24-hr LH secretory patterns showed a mean percent increase of 189% with a range of 149–259. Estimation of the LH "half-life" from the declining phase of the secretory episodes showed a clustering of estimates into 2 groups. The group of lower estimates of 30–78 min agreed with previous reports where LH half-life was determined by either disappearance of labelled LH or endogenous LH after hypophysectomy. These estimates were considered the "true" half-life and were used for calculation of the mean half-life. This assumption is supported by the findings from 5-min sampling studies which show the longer half-lives (80–160 min) almost uniformly are associated with continued secretion during the declining phase of a secretory episode. Comparison of the mean "true" half-life estimates during the control and clomiphene studies showed no significant difference.

Luteinizing hormone (LH) was measured in plasma every 20 minutes for 24 hours in 14 children and adolescents in different stages of sexual maturation and in five adult men. Polygraphic monitoring of nocturnal sleep was carried out simultaneously to identify sleep onset, wakefulness and sleep stages precisely. Prepubertal children and adult men showed no consistent significant difference between mean LH concentrations with subjects asleep and awake. In all pubertal subjects, an increase in LH secretion was associated with sleep that resulted in significantly higher mean LH concentrations than with the subject awake. By experimental delay in sleep onset, synchronization of this LH secretory program with actual sleep was clearly demonstrated. The number of LH secretory episodes during night or day sleep corresponded to the number of sleep cycles of rapid and nonrapid eye movements. This finding of a sleep-associated increase in LH secretory activity provides a biologic index for the identification...

Plasma luteinizing hormone (LH) was measured by radioimmunoassay at 20-min intervals around the clock for 24 hr in 5 normal adult men. During the nocturnal S-hr sleep period, polygraphic monitoring of sleep stages was carried out. All 5 subjects showed episodic secretion of LH characterized by rapid rises and the declining slopes approximated the half-life of LH. Calculation of LH “half-life” from the declining phase of the LH secretory episodes gave variable estimates within subjects and between subjects (65–114 min). The longer T1/2 estimates calculated by this method, contrasted with previous studies where LH half-life was determined directly by the measurement of LH disappearance, is probably the result of small amounts of LH being secreted during the declining phase of the LH secretory episode. This study failed to show a 24-hr LH rhythm or relationship of LH secretory activity to the sleep-wake cycle. The marked temporal variability of the LH system throughout the 24-hr period clearly demonstrates the limitations of the isolated daily LH determination. The finding that the initiation and cessation of LH secretory episodes occurred within narrow, well-defined ranges may be considered evidence in favor of some degree of negative feedback control. Comparison between the LH and cortisol secretory patterns was made in an attempt to characterize differences in endocrine control mechanisms.