Context: The selective estrogen receptor modulator clomiphene stimulates pituitary-derived gonadotropins to generate sex steroids including estrogen. Estrogen activates SOCS-3, which can inhibit growth hormone-directed JAK/STAT signaling to reduce serum insulin-like growth factor (IGF)-1 levels. Objective: We sought to examine the effects of clomiphene therapy on IGF-1 levels in nonacromegalic male patients treated with clomiphene for underlying hypogonadism. Methods: We identified 20 male subjects with hypogonadism treated with clomiphene citrate for at least 3 months. These patients were treated in an ambulatory, academic, tertiary medical center. The 20 male patients ranged from 27 to 76 years of age and hypogonadism was due to several etiologies, including prolactinomas, clinically nonfunctioning pituitary tumors, Rathke cleft cysts, colloid cysts, or idiopathic causes. Clomiphene citrate 50 mg 3 days per week was administered for a minimum of 3 months. IGF-1 was measured by liquid chromatography-mass spectroscopy before and after clomiphene therapy. Results: Fifteen of 20 (75%) of hypogonadal men treated with clomiphene exhibited a decrease in median (IQR) serum IGF-1 levels of −0.60 (−1.2-0.0) (P < .01). Two of the 20 patients (10%) exhibited a decrease in IGF-1 >2 SD below their age- and sex-matched mean value. Conclusion: Clomiphene therapy can result in a significant reduction in serum IGF-1 levels in some treated hypogonadal men. Given that the decrease in IGF-1 can be >2 SD in some patients and potentially clinically significant, we recommend interval monitoring of serum IGF-1 levels and symptoms of growth hormone deficiency in patients with hypogonadism treated with clomiphene citrate.

Clinically nonfunctioning pituitary tumors (CNFPTs) typically do not cause hormonal excess, progress insidiously, and are often large and invasive at presentation. Complete resection is frequently not attainable; radiotherapy (RT) may effectively limit growth but carries a significant risk of hypopituitarism. Medical therapy with dopamine D2 receptor agonists and/or somatostatin analogs has been explored in CNFPTs but have yielded inconsistent results, and there is an unmet need for novel efficacious and safe medical therapies. The authors used the PubMed database to identify and review articles published from January 1982 to July 2024, that discussed the medical treatment of CNFPTs. The most commonly studied medical therapies were somatostatin receptor ligands (SRLs) and dopamine D2 receptor agonists. Of 111 patients with CNFPTs treated with SRLs, 31 (28%) exhibited tumor shrinkage. Following dopamine agonist treatment in 355 patients, tumor shrinkage occurred in 113 (32%), tumor stabilization in 182 (51%), and tumor growth in 60 (17%). The efficacy of other less commonly employed therapies such as GnRH analogs, PRRT, and temozolomide was also reviewed. Efficacious and safe medical therapies evaluated in robust randomized placebo-controlled clinical trials are needed to improve the management of CNFPTs.