Development of Obesity-Associated Secondary Hypogonadism
Development of Obesity-Associated Secondary Hypogonadism
Normally, the intact hypothalamic–pituitary–testicular (HPT) axis regulates and maintains testosterone levels in men. The hypothalamus releases gonadotrophin-releasing Hormone (GnRH), a trophic peptide hormone responsible for the release of follicle-stimulating hormone (FSH) and luteinizing Hormone (LH) from the anterior pituitary. LH in turn stimulates the testicular interstitial Leydig cells to release testosterone, and FSH stimulates spermatogenesis within the testicular Sertoli cells. Adequate circulating testosterone levels provide negative feedback inhibition on the hypothalamo–pituitary unit. In male SH, serum levels of LH and FSH are inappropriately low or low/normal, thereby blunting the production of testosterone leading to subnormal circulating levels of testosterone.
Male SH is characterized by low levels of plasma testosterone due to dysfunction of the HPT axis, combined with signs and symptoms of hypogonadism. For the identification of hypogonadism in men, reference ranges for the lower normal level of testosterone have been compiled from large community-based samples that suggest a cut-off value of <12·1 nmol/l for total serum testosterone and a cut-off value for calculated free testosterone of <243 pmol/l to distinguish between normal levels and levels possibly associated with deficiency. In a large community-based study on men aged 40–79 years, the threshold for total testosterone was <8 nmol/l for decreased frequency of sexual thoughts, <8·5 nmol/l for erectile dysfunction, <11 nmol/l for decreased frequency of morning erections and <13 nmol/l for diminished vigour. The strongest predictors for hypogonadism in this age group were found to be decreased sexual thoughts, weakened morning erections, erectile dysfunction and either a total testosterone level of <8 nmol/l or serum testosterone in the range of 8–11 nmol/l and free testosterone <220 pmol/l. In general, plasma samples taken in the morning detect the highest levels of testosterone and demonstrate the best reproducibility. Plasma testosterone measurement, however, may be dependent on pulsatile, diurnal and circannual rhythms as well as laboratory estimation methods.
Biochemically, male SH is characterized by low or low/normal serum LH and FSH levels and low plasma testosterone level. During a GnRH stimulation test in male SH, a reduced or normal response is often inadequate for distinguishing between a hypothalamic or pituitary disorder. However, if the pituitary gland is primed with repeated doses of GnRH, this stimulation test may provide a more sensitive and reliable result. The healthy pituitary gland responds to repeated stimulation with GnRH even if there is hypothalamic disease present. Central defects of the hypothalamus or pituitary result in secondary testicular failure. Male SH may result from hypothalamo–pituitary lesions, disorders and genetic dysfunction, examples being hyperprolactinaemia, pituitary adenomas, Kallman syndrome, haemochromatosis, pineal tumours and as outlined below, obesity is also frequently associated with male SH. Sex hormone binding globulin (SHBG) levels affect interpretation of total testosterone results and SHBG levels may be low in obesity/insulin-resistance states, thus necessitating the measurement of free/bioavailable testosterone for a reliable diagnosis of SH in obese men. However, practically, the measurement of free/bioavailable testosterone levels may currently not be possible everywhere.
The Male Gonadal Axis and Male Secondary Hypogonadism
Normally, the intact hypothalamic–pituitary–testicular (HPT) axis regulates and maintains testosterone levels in men. The hypothalamus releases gonadotrophin-releasing Hormone (GnRH), a trophic peptide hormone responsible for the release of follicle-stimulating hormone (FSH) and luteinizing Hormone (LH) from the anterior pituitary. LH in turn stimulates the testicular interstitial Leydig cells to release testosterone, and FSH stimulates spermatogenesis within the testicular Sertoli cells. Adequate circulating testosterone levels provide negative feedback inhibition on the hypothalamo–pituitary unit. In male SH, serum levels of LH and FSH are inappropriately low or low/normal, thereby blunting the production of testosterone leading to subnormal circulating levels of testosterone.
Male SH is characterized by low levels of plasma testosterone due to dysfunction of the HPT axis, combined with signs and symptoms of hypogonadism. For the identification of hypogonadism in men, reference ranges for the lower normal level of testosterone have been compiled from large community-based samples that suggest a cut-off value of <12·1 nmol/l for total serum testosterone and a cut-off value for calculated free testosterone of <243 pmol/l to distinguish between normal levels and levels possibly associated with deficiency. In a large community-based study on men aged 40–79 years, the threshold for total testosterone was <8 nmol/l for decreased frequency of sexual thoughts, <8·5 nmol/l for erectile dysfunction, <11 nmol/l for decreased frequency of morning erections and <13 nmol/l for diminished vigour. The strongest predictors for hypogonadism in this age group were found to be decreased sexual thoughts, weakened morning erections, erectile dysfunction and either a total testosterone level of <8 nmol/l or serum testosterone in the range of 8–11 nmol/l and free testosterone <220 pmol/l. In general, plasma samples taken in the morning detect the highest levels of testosterone and demonstrate the best reproducibility. Plasma testosterone measurement, however, may be dependent on pulsatile, diurnal and circannual rhythms as well as laboratory estimation methods.
Biochemically, male SH is characterized by low or low/normal serum LH and FSH levels and low plasma testosterone level. During a GnRH stimulation test in male SH, a reduced or normal response is often inadequate for distinguishing between a hypothalamic or pituitary disorder. However, if the pituitary gland is primed with repeated doses of GnRH, this stimulation test may provide a more sensitive and reliable result. The healthy pituitary gland responds to repeated stimulation with GnRH even if there is hypothalamic disease present. Central defects of the hypothalamus or pituitary result in secondary testicular failure. Male SH may result from hypothalamo–pituitary lesions, disorders and genetic dysfunction, examples being hyperprolactinaemia, pituitary adenomas, Kallman syndrome, haemochromatosis, pineal tumours and as outlined below, obesity is also frequently associated with male SH. Sex hormone binding globulin (SHBG) levels affect interpretation of total testosterone results and SHBG levels may be low in obesity/insulin-resistance states, thus necessitating the measurement of free/bioavailable testosterone for a reliable diagnosis of SH in obese men. However, practically, the measurement of free/bioavailable testosterone levels may currently not be possible everywhere.
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