Cushing-induced Male Hypogonadism: Deciphering a Prevalent Yet Understudied Relationship

Despite being first described in 1970s, the relationship between testosterone deficiency and Cushing disease has seldom been reported in men (1). Indeed, because Cushing disease predominantly affects women, most clinical reports of reproductive sequelae have focused on menstrual disturbances or ovarian dysfunction (2). More than 40 years later, the impact of hypercortisolism on the hypothalamic-pituitary gonadal (HPG) axis in men has recently been revitalized by novel information provided by 3 cohort studies from different countries (3-5). The most recent, detailed, and largest of these studies is published in the current issue of the Journal of Clinical Endocrinology and Metabolism. Shekhar et al describe the consequences of active and cured adrenocorticotropic hormone (ACTH)-dependent Cushing syndrome on the HPG axis in 52 men (5). The results of Shekhar et al represent post hoc analyses of composite prospective cohorts over a long timeframe (1985-2021) (5). The prevalence of testosterone deficiency in men with Cushing syndrome (including 34 patients with Cushing disease and 18 with ectopic ACTH secretion) was as high as 86% at baseline. However, half the patients recovered within 6 months, and an additional quarter of patients recovered 12 months following surgical remission of cortisol excess. In addition to total testosterone, luteinizing hormone (LH) and free testosterone levels also improved 6 and 12 months following cure, indicating that recovery occurs at the HPG level. Shekhar et al have also conducted frequent (20-minute) blood sampling in 8 individuals with Cushing disease over 24 hours, suggesting for the first time that an increased number of LH pulses occurs after disease remission. This provides mechanistic insights to Cushing-associated hypogonadism, since an apulsatile LH profile suggests a neuroendocrine dysregulation occurring at the level of the gonadotropin-releasing hormone (GnRH) neuron or its regulatory elements.