ContextIn young adults, sleep affects the regulation of growth hormone (GH)
and cortisol The relationship between decreased sleep quality in older adults
and age-related changes in the regulation of GH and cortisol is unknownObjectiveTo determine the chronology of age-related changes in sleep duration
and quality (sleep stages) in healthy men and whether concomitant alterations
occur in GH and cortisol levelsDesign and SettingData combined from a series of studies conducted between 1985 and 1999
at 4 laboratoriesSubjectsA total of 149 healthy men, aged 16 to 83 years, with a mean (SD) body
mass index of 241 (23) kg/m2, without sleep complaints or histories
of endocrine, psychiatric, or sleep disordersMain Outcome MeasuresTwenty-four–hour profiles of plasma GH and cortisol levels and
polygraphic sleep recordingsResultsThe mean (SEM) percentage of deep slow wave sleep decreased from 189%
(13%) during early adulthood (age 16-25 years) to 34% (10%) during midlife
(age 36-50 years) and was replaced by lighter sleep (stages 1 and 2) without
significant increases in sleep fragmentation or decreases in rapid eye movement
(REM) sleep The transition from midlife to late life (age 71-83 years) involved
no further significant decrease in slow wave sleep but an increase in time
awake of 28 minutes per decade at the expense of decreases in both light non-REM
sleep (−24 minutes per decade; P<001) and
REM sleep (−10 minutes per decade; P<001)
The decline in slow wave sleep from early adulthood to midlife was paralleled
by a major decline in GH secretion (−372 µg per decade; P<001) From midlife to late life, GH secretion further
declined at a slower rate (−43 µg per decade; P<02) Independently of age, the amount of GH secretion was significantly
associated with slow wave sleep (P<001) Increasing
age was associated with an elevation of evening cortisol levels (+193 nmol/L
per decade; P<001) that became significant only
after age 50 years, when sleep became more fragmented and REM sleep declined
A trend for an association between lower amounts of REM sleep and higher evening
cortisol concentrations independent of age was detected (P<10)ConclusionsIn men, age-related changes in slow wave sleep and REM sleep occur with
markedly different chronologies and are each associated with specific hormonal
alterations Future studies should evaluate whether strategies to enhance
sleep quality may have beneficial hormonal effects

https://jamanetwork.com/journals/jama/articlepdf/192981/JCI00039.pdf

Age-related changes in slow wave sleep and REM sleep and relationship with growth hormone and cortisol levels in healthy men.

To define the roles of circadian rhythmicity (intrinsic effects of time of day independent of the sleep or wake condition) and sleep (intrinsic effects of the sleep condition, irrespective of the time of day) on the 24-h variation in glucose tolerance, eight normal men were studied during constant glucose infusion for a total of 53 h. The period of study included 8 h of nocturnal sleep, 28 h of continuous wakefulness, and 8 h of daytime sleep. Blood samples for the measurement of glucose, insulin, C-peptide, cortisol, and growth hormone were collected at 20-min intervals throughout the entire study. Insulin secretion rates were derived from C-peptide levels by deconvolution. Sleep was polygraphically monitored. During nocturnal sleep, levels of glucose and insulin secretion increased by 31 +/- 5% and 60 +/- 11%, respectively, and returned to baseline in the morning. During sleep deprivation, glucose levels and insulin secretion rose again to reach a maximum at a time corresponding to the beginning of the habitual sleep period. The magnitude of the rise above morning levels averaged 17 +/- 5% for glucose and 49 +/- 8% for calculated insulin secretion. Serum insulin levels did not parallel the circadian variation in insulin secretion, indicating the existence of an approximate 40% increase in insulin clearance during the night. Daytime sleep was associated with a 16 +/- 3% rise in glucose levels, a 55 +/- 7% rise in insulin secretion, and a 39 +/- 5% rise in serum insulin. The diurnal variation in insulin secretion was inversely related to the cortisol rhythm, with a significant correlation of the magnitudes of their morning to evening excursions. Sleep-associated rises in glucose correlated with the amount of concomitant growth hormone secreted. These studies demonstrate previously underappreciated effects of circadian rhythmicity and sleep on glucose levels, insulin secretion, and insulin clearance, and suggest that these effects could be partially mediated by cortisol and growth hormone.

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Modulation of glucose regulation and insulin secretion by circadian rhythmicity and sleep.

To evaluate the effects of obesity on the hypothalamo-pituitary-testicular axis, we compared total and free (FT) testosterone (T), androstenedione, dehydroepiandrosterone and its sulfate, and 5 alpha-androstane-3 alpha, 17 beta-diol glucuronide, and estradiol levels in a group of 35 obese [body mass index (BMI), > 30] men (aged 17-61 yr) to levels in a nonobese control group. We observed a highly significant negative correlation (P < 0.001) between plasma (F)T levels and BMI and a significant positive correlation (P < 0.01) between E2 levels and BMI. There were no differences between the obese and the nonobese men in levels of androstenedione, dehydroepiandrosterone sulfate, and 5 alpha-androstane-3 alpha, 17 beta-diol glucuronide. Insulin levels were significantly higher in obese men and were significantly (P < 0.02) correlated with the waist hip girth ratio. To evaluate the role of the hypothalamo-pituitary complex in the decreased (F)T levels in obese men, diurnal (0800-2000 h) LH pulsatility was studied in eight obese middle-aged men and eight age-matched controls. The pulsatility of plasma cortisol levels was also studied. Whereas LH pulse frequency was similar in the obese and control subjects, mean diurnal LH levels, mean diurnal LH pulse amplitude, and the sum of all diurnal LH pulse amplitudes and secretory masses were significantly lower in the obese than in the controls. Moreover, there was a highly significant correlation between the sum of LH pulse amplitudes and plasma (F)T levels. This decrease in LH pulse amplitude is not an isolated phenomenon of hypothalamo-pituitary dysfunction in obese men, because the pulse amplitude of plasma cortisol levels was also decreased. The decreased LH pulse amplitude together with the normal respond of Leydig cells to hCG stimulation reported in the literature suggest by inference that the decreased FT levels in obese men are the consequence of a hypogonadotropism. The decreased LH pulse amplitude and the decreased amplitude of cortisol pulses, and hence probably of ACTH pulses, point toward a general alteration of hypothalamo-pituitary function in obese men.

Attenuated luteinizing hormone (LH) pulse amplitude but normal LH pulse frequency, and its relation to plasma androgens in hypogonadism of obese men.

Cushing's disease (CD), or pituitary-dependent Cushing's syndrome, is a severe endocrine disease caused by a corticotroph pituitary tumor and associated with increased morbidity and mortality. The first-line treatment for CD is pituitary surgery, which is followed by disease remission in around 78% and relapse in around 13% of patients during the 10-year period after surgery, so that nearly one third of patients experience in the long-term a failure of surgery and require an additional second-line treatment. Patients with persistent or recurrent CD require additional treatments, including pituitary radiotherapy, adrenal surgery, and/or medical therapy. Pituitary radiotherapy is effective in controlling cortisol excess in a large percentage of patients, but it is associated with a considerable risk of hypopituitarism. Adrenal surgery is followed by a rapid and definitive control of cortisol excess in nearly all patients, but it induces adrenal insufficiency. Medical therapy has recently acquired a more important role compared to the past, due to the recent employment of novel compounds able to control cortisol secretion or action. Currently, medical therapy is used as a presurgical treatment, particularly for severe disease; or as postsurgical treatment, in cases of failure or incomplete surgical tumor resection; or as bridging therapy before, during, and after radiotherapy while waiting for disease control; or, in selected cases, as primary therapy, mainly when surgery is not an option. The adrenal-directed drug ketoconazole is the most commonly used drug, mainly because of its rapid action, whereas the glucocorticoid receptor antagonist, mifepristone, is highly effective in controlling clinical comorbidities, mainly glucose intolerance, thus being a useful treatment for CD when it is associated with diabetes mellitus. Pituitary-directed drugs have the advantage of acting at the site responsible for CD, the pituitary tumor. Among this group of drugs, the dopamine agonist cabergoline and the somatostatin analog pasireotide result in disease remission in a consistent subgroup of patients with CD. Recently, pasireotide has been approved for the treatment of CD when surgery has failed or when surgery is not an option, and mifepristone has been approved for the treatment of Cushing's syndrome when associated with impairment of glucose metabolism in case of the lack of a surgical indication. Recent experience suggests that the combination of different drugs may be able to control cortisol excess in a great majority of patients with CD.

The Treatment of Cushing's Disease

Plasma ACTH, cortisol, and GH concentrations were measured at 15-min intervals for 24 h in 11 men suffering from major depressive illness during an acute episode of depression and during clinical remission following antidepressant treatment with either electroconvulsive therapy or amitriptyline. Seven age-matched normal men also were studied. During the acute phase of the illness, the patients had abnormally short rapid eye movement sleep latencies, hypercortisolism, early timing of the nadirs of the ACTH-cortisol rhythms, and shorter nocturnal periods of quiescent cortisol secretion. GH was hypersecreted during wakefulness, and a major pulse occurred before, rather than after, sleep onset. After treatment, rapid eye movement sleep latencies were lengthened, and cortisol levels returned to normal due to a decrease in the magnitude of episodic pulses. Moreover, the timing of the circadian rhythms of ACTH and cortisol as well as the duration of the quiescent period of cortisol secretion were normalized. The amount of GH secreted during wakefulness decreased to normal values, with fewer significant GH pulses. The major elevation of GH secretion in the early part of the night occurred later than that during the depressive episode. These results demonstrate that a disorder of circadian rhythmicity characterizes acute episodes of major depressive illness and that this chronobiological abnormality as well as the hypersecretion of ACTH, cortisol, and GH are state rather than trait dependent.

24-hour profiles of adrenocorticotropin, cortisol, and growth hormone in major depressive illness: effect of antidepressant treatment.

The characteristics of pituitary hormonal responses to insulin-induced hypoglyeemia were investigated in 16 normal men In all subjects, levels of blood sugar fell below 35 mg/100 ml A statistically significant increase in mean plasma levels of prolactin, ACTH, cortisol and growth hormone was observed Prolactin levels increased in all subjects but one; individual peak values were 14–84 times greater than base levels The kinetics of prolactin, GH and ACTH responses were similar; in particular, the onset of release (25 min) of prolactin, GH and ACTH was similar After dexamethasone administration, insulin tolerance tests were repeated in a number of subjects using adequate amounts of insulin to achieve hypoglycemia equivalent to that obtained in the control experiments The administration of 1 mg of dexamethasone the evening before the test suppressed basal levels of ACTH and cortisol and the ACTH—but not the cortisol—response to hypoglycemia Both basal levels of prolactin and prolactin response to hy

Effects of Glucocorticoids on Pituitary Hormonal Responses to Hypoglycemia. Inhibition of Prolactin Release

Hourly integrated concentrations (IC) of growth hormone (GH), prolactin (PRL) and cortisol were determined by a continuous sampling procedure in six obese women, before and at the end of a 12 day fast, and in eight normal controls under basal conditions. Hormonal 24 h IC and nyctohemeral variations were calculated from these data. Nyctohemeral rhythms were investigated by the periodogram method. A significant increase over basal values of 24 h IC of PRL, GH and cortisol was observed at the end of the fasting period. Nyctohemeral variations--but not nyctohemeral rhythm--of IC-GH were found in normal subjects. They were abolished in obese patients under basal conditions but restored during fasting. The circadian rhythm of cortisol was not altered in obesity. A shift of the normal nyctohemeral rhythm of PRL was observed in obese patients, but the normal pattern was restored during fasting.

Simultaneous study of cortisol, growth hormone and prolactin nyctohemeral variations in normal and obese subjects. Influence of prolonged fasting in obesity

Radioimmunoassay of human growth hormone using a charcoal-dextran separation procedure.

The 24-hour profile of plasma levels of immunoreactive beta-MSH (IR-beta MSH), ACTH and cortisol was obtained at 15-min intervals in six normal males in summer and winter In the radioimmunoassay used, dilution curves of human beta-MSH and human beta-LPH were not parallel A seasonal variation in basal pituitary-adrenal secretion, with higher levels in winter than in summer, was demonstrated A circadian rhythm was found to be significant for ACTH, IR-beta MSH and cortisol in all investigations Whereas ACTH and cortisol patterns were largely concordant in all studies, there was a significant desynchronization of the circadian rhythm of IR-beta MSH as compared to ACTH in five cases Eighty-three percent of the secretory spikes of cortisol but only 68% of the IR-beta MSH spikes were concomitant with an ACTH spike Correlations between maximal levels of concomitant spikes were higher during the quiescent period of pituitary-adrenal secretion (2200--0400) for ACTH-cortisol whereas for ACTH-IR-beta MSH, highest correlations were found during the active early morning secretory phase (0400--1000) For the three plasma constituents studied, longer apparent half-lives were found to occur when the basal level before spiking was already elevated, suggesting that ACTH, beta-LPH and cortisol are secreted in bursts superimposed on a continuous basal secretion Absolute increments of concentration appeared to be relatively independent of the level before spiking It is suggested that the dissociations between ACTH and IR-beta MSH fluctuations in plasma observed here result from in vitro proteolysis of beta-LPH

E. Virasoro

Papers

Effects of Glucocorticoids on Pituitary Hormonal Responses to Hypoglycemia. Inhibition of Prolactin Release

Simultaneous study of cortisol, growth hormone and prolactin nyctohemeral variations in normal and obese subjects. Influence of prolonged fasting in obesity

Radioimmunoassay of human growth hormone using a charcoal-dextran separation procedure.

Seasonal, circadian and episodic variations of human immunoreactive β-MSH, ACTH and cortisol

The endocrinometabolic effects of beclomethasone dipropionate in asthmatic patients