Development of Obesity-Associated Secondary Hypogonadism
Sleep disorders are increasingly being recognized as an important facet of the complex interactions between obesity, T2DM and male SH. In men, sleep is known to influence the function of the HPT axis through various neuro-endocrine mechanisms. Testosterone levels also vary according to sleep stage (through variations of LH secretion). OSA is characterized by repetitive collapse of the pharyngeal airway during sleep, which leads to hypoxia and sleep fragmentation. Although there is a paucity of knowledge about the impact of the nocturnal apnoeic events on the reproductive system, changes in sleep efficiency and architecture are known to affect HPT function. Studies, however, did not show a consistent benefit of continuous positive airway pressure (CPAP) on androgen levels, and the commonest pattern noted after CPAP use is an increase in SHBG and total testosterone, but not free testosterone levels. Lower testosterone levels associated with OSA in men may be attributed to differences in sleep patterns and sleep fragmentation. OSA is known to be independently associated with reduced LH pulse amplitude and decreased mean serum levels of LH and testosterone in men, and also with disruption of the association between a rise in serum testosterone levels and the appearance of first REM sleep. In OSA patients, circulating leptin levels were found to be higher than in nonapnoeic controls, and this was independent of BMI and age. Therefore, leptin may also mediate effects of OSA on the development of MOSH. A recent study found that in obese men with severe OSA, testosterone therapy mildly worsens sleep-disordered breathing in a time-limited manner. As the larynx is an androgen-dependent tissue, current guidelines recommend against TRT in hypogonadal men with untreated severe OSA, as OSA may theoretically worsen in this scenario.
In addition to sleep quality influencing male HPT function (both directly and indirectly), it is also likely that MOSH influences sleep quality. One such mechanism that may mediate the effects of MOSH on sleep quality is via the serotoninergic system. There is evidence that sex hormones modulate respiratory control mechanisms through the serotoninergic system and sex hormones affect serotonin-related functions. Androgenic effects on the serotoninergic system appear to be indirect, reflecting testosterone conversion into oestradiol in the central nervous system. Aromatase converts testosterone to oestradiol, which in turn mediates most of the actions of testosterone on the serotoninergic system. Depletion of gonadal hormones may decrease serotonin uptake in the hypoglossal and phrenic motor nuclei, thereby affecting long-term respiratory control, and lower levels of oestradiol reduce serotonin activity in several areas of the brain. The development of OSA in men with MOSH adds to the pathogenic complexity and inter-relatedness of male obesity, SH, T2DM and OSA.
As discussed above, there is a relationship between male obesity and the development of SH. Male SH may in turn worsen sleep quality (through effects on serotoninergic and other mechanisms) and there are also direct adverse effects of obesity on sleep quality. To further complicate the picture, a recent study on the effect of sleep apnoea on reproductive function in severely obese men concluded that sleep apnoea negatively affects testosterone levels independently of BMI. The complex interactions between sleep, metabolism, glycaemia and reproductive function in obese men remains incompletely understood, and should be a focus for future research in this field.
MOSH and Sleep Disorders
Sleep disorders are increasingly being recognized as an important facet of the complex interactions between obesity, T2DM and male SH. In men, sleep is known to influence the function of the HPT axis through various neuro-endocrine mechanisms. Testosterone levels also vary according to sleep stage (through variations of LH secretion). OSA is characterized by repetitive collapse of the pharyngeal airway during sleep, which leads to hypoxia and sleep fragmentation. Although there is a paucity of knowledge about the impact of the nocturnal apnoeic events on the reproductive system, changes in sleep efficiency and architecture are known to affect HPT function. Studies, however, did not show a consistent benefit of continuous positive airway pressure (CPAP) on androgen levels, and the commonest pattern noted after CPAP use is an increase in SHBG and total testosterone, but not free testosterone levels. Lower testosterone levels associated with OSA in men may be attributed to differences in sleep patterns and sleep fragmentation. OSA is known to be independently associated with reduced LH pulse amplitude and decreased mean serum levels of LH and testosterone in men, and also with disruption of the association between a rise in serum testosterone levels and the appearance of first REM sleep. In OSA patients, circulating leptin levels were found to be higher than in nonapnoeic controls, and this was independent of BMI and age. Therefore, leptin may also mediate effects of OSA on the development of MOSH. A recent study found that in obese men with severe OSA, testosterone therapy mildly worsens sleep-disordered breathing in a time-limited manner. As the larynx is an androgen-dependent tissue, current guidelines recommend against TRT in hypogonadal men with untreated severe OSA, as OSA may theoretically worsen in this scenario.
In addition to sleep quality influencing male HPT function (both directly and indirectly), it is also likely that MOSH influences sleep quality. One such mechanism that may mediate the effects of MOSH on sleep quality is via the serotoninergic system. There is evidence that sex hormones modulate respiratory control mechanisms through the serotoninergic system and sex hormones affect serotonin-related functions. Androgenic effects on the serotoninergic system appear to be indirect, reflecting testosterone conversion into oestradiol in the central nervous system. Aromatase converts testosterone to oestradiol, which in turn mediates most of the actions of testosterone on the serotoninergic system. Depletion of gonadal hormones may decrease serotonin uptake in the hypoglossal and phrenic motor nuclei, thereby affecting long-term respiratory control, and lower levels of oestradiol reduce serotonin activity in several areas of the brain. The development of OSA in men with MOSH adds to the pathogenic complexity and inter-relatedness of male obesity, SH, T2DM and OSA.
As discussed above, there is a relationship between male obesity and the development of SH. Male SH may in turn worsen sleep quality (through effects on serotoninergic and other mechanisms) and there are also direct adverse effects of obesity on sleep quality. To further complicate the picture, a recent study on the effect of sleep apnoea on reproductive function in severely obese men concluded that sleep apnoea negatively affects testosterone levels independently of BMI. The complex interactions between sleep, metabolism, glycaemia and reproductive function in obese men remains incompletely understood, and should be a focus for future research in this field.
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