Endocrine and metabolic alterations in obstructive sleep apnea syndrome.

Obstructive sleep apnea syndrome (OSAS) is a common disorder with important clinical consequences for affected individuals. It is characterized by a repetitive upper airway occlusion leading to apnea and asphyxia, typically occurring 100-600 times/night, with arousal being required to re-establish airway patency (1). The associated consequences include daytime sleepiness, decreased cognitive performance, decreased quality of life and an increased risk of automobile accidents. There is also evidence that OSAS may lead to adverse cardiovascular consequences such as hypertension, myocardial infarction and stroke. The most important epidemiological risk factors for sleep apnea are male gender and obesity (1, 2). The increased risk of sleep apnea in male subjects is poorly understood with prior studies focusing on differences in airway anatomy, pharyngeal dilator muscle function and ventilatory control mechanisms (1, 2). OSAS is commonly associated with obesity, particularly visceral obesity. Obese patients with OSAS present with several metabolic and endocrine abnormalities, including insulin resistance, changes in the activity of GH/IGF-I axis and of gonadal axis (2, 3). It is likely that these alterations are not simply due to overweight but depend upon hypoxia and/or sleep fragmentation, that are peculiar to the syndrome. Among endocrine disturbances, changes of gonadal axis are common in patients with OSAS, who frequently present with a hypogonadotropic hypogonadism likely due to alteration of hypothalamic-pituitary control of gonadotropin synthesis and release. In particular, decreased morning testosterone concentrations have been found in male patients with OSAS and reverted to normality after three months of nasal continuous positive airway pressure (nCPAP) treatment (2). Gonadotropin levels have been found reduced both basally and after GnRH stimulation but only partially reverted by hypoxia correction (2). A significant correlation between LH/testosterone profiles and the severity of OSAS is recorded, thus suggesting that sleep fragmentation and, to a lesser extent, hypoxia in addition to the degree of obesity may be responsible for the central suppression of testosterone in these patients. However, it has been suggested that androgen levels can directly influence the prevalence and severity of sleep-disordered breathing and some reports have demonstrated that administration of exogenous androgens to both men and women can induce or precipitate apnea (4, 5). However, these studies were performed with non physiological doses of testosterone esters and the impairment of the respiratory drive could be due to the very high peaks of circulating testosterone levels following the injection. Endocrine alterations in OSAS can be partially responsible and influence some metabolic changes which connote this syndrome. In particular, both GH hyposecretion and hypogonadism can concur to worsen insulin sensitivity as well as lipid and protein metabolism (2, 3). In this issue of the Journal of Endocrinological Investigation, Gambineri and co-workers present a simple but straightforward study on the relationship between testosterone levels and OSAS (6). A group of obese patients with OSAS was compared with a group of patients with simple obesity and no sleep and ventilatory disturbances. The results of the study confirmed the existence in subjects with OSAS of lower total and free testosterone levels in comparison to simple obesity, suggesting a role of hypoxia itself or sleep fragmentation on this endocrine impairment. Thus, OSAS seems to be an additional factor in reducing testosterone levels in obesity, although the underlying mechanisms remain poorly understood. The Authors also addressed the study to the metabolic pattern which connotes patients with OSAS and which is mainly due to obesity and hypogonadism. In fact, androgens stimulate lipolysis, while they inhibit lipoprotein lipase activity particularly at the visceral level. The role of testosterone in the regulation of lipid metabolism is supported by the evidence that hypogonadal men invariably present enlarged visceral fat that can be completely reversed by testosterone replacement (7). Moreover, a significant relationship exists between testosterone levels and parameters of the metabolic syndrome, including insulin resistance and lipid abnormalities, which are consistently associated with obesity, particularly the abdominal phenotype. The more marked hypotestosteronemia in OSAS could concur to the worsening of the metabolic profile of obese subjects with OSAS. The suggestion by Gambineri et al. of a beneficial therapy with low-dose androgens in patients with OSAS is appropriate. Several reports indicate positive effects of androgen treatment on metabolic abnormalities in both hypogonadal and obese men, in whom testosterone supplementation has been found to selectively reduce visceral fat and improve lipid abnormalities and insulin sensitivity (7), though adverse effects on the severity of the sleep apnea were observed as previously mentioned (4, 5). The new testosterone preparations, whose pharmacokinetic permits the maintenance of more “physiological” circulating androgen levels in men (8), could prevent the negative effects on sleep apnea. Further studies on a larger number of patients are needed, in order to verify the potential benefits of the treatment with low doses of testosterone in patients with OSAS.