Longitudinal Evaluation of Reproductive Endocrine Function in Men With ACTH-Dependent Cushing Syndrome

Abstract

Abstract Context Hypogonadism may be caused by Cushing syndrome (CS) and may intensify its adverse consequences. Objective This work aimed to determine the frequency of male hypogonadism before and after curative surgery for CS, and its cause. Methods Post hoc analyses of prospective cohort studies were conducted at a clinical research center. Study participants were men with adrenocorticotropic hormone (ACTH)-dependent CS: cohort 1 (C1) (n = 8, age 32.5 ± 12 years; studied 1985-1989) and cohort 2 (C2) (n = 44, 42.7 ± 15.1 years; studied 1989-2021). Interventions included the following: C1: every 20-minute blood sampling for 24 hours before and 1 to 40 months after surgical cure. Three individuals underwent gonadotropin-releasing hormone (GnRH) stimulation tests pre and post surgery. C2: Hormone measurements at baseline and 6 and 12 months (M) post cure. Main outcome measures included the following: C1: LH, FSH, LH pulse frequency, and LH response to GnRH. C2: LH, FSH, testosterone (T), free T, free thyroxine, 3,5,3′-triiodothyronine, thyrotropin, and urine free cortisol (UFC) levels and frequency of hypogonadism pre and post surgery. Results C1: mean LH and LH pulse frequency increased after surgery (P < .05) without changes in LH pulse amplitude, mean FSH, or peak gonadotropin response to GnRH. C2: 82% had baseline hypogonadism (total T 205 ± 28 ng/dL). Thyroid hormone levels varied inversely with UFC and cortisol. LH, total and free T, and sex hormone-binding globulin increased at 6 and 12 M post surgery, but hypogonadism persisted in 51% at 6 M and in 26% at 12 M. Conclusion Hypogonadism in men with CS is widely prevalent but reversible in approximately 75% of patients 1 year after surgical cure and appears to be mediated through suppression of hypothalamic GnRH secretion, and modulated by thyroid hormones.