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

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.