Prolactinomas (PRLomas) constitute approximately half of all pituitary adenomas and approximately one-fifth of them are diagnosed in males. The clinical presentation of PRLomas results from direct prolactin (PRL) action, duration and severity of hyperprolactinemia, and tumor mass effect. Male PRLomas, compared to females, tend to be larger and more invasive, are associated with higher PRL concentration at diagnosis, present higher proliferative potential, are more frequently resistant to standard pharmacotherapy, and thus may require multimodal approach, including surgical resection, radiotherapy, and alternative medical agents. Therefore, the management of PRLomas in men is challenging in many cases. Additionally, hyperprolactinemia is associated with a significant negative impact on men’s health, including sexual function and fertility potential, bone health, cardiovascular and metabolic complications, leading to decreased quality of life. In this review, we highlight the differences in pathogenesis, clinical presentation and treatment of PRLomas concerning the male sex.

Endogenous Cushing’s syndrome (CS) is associated with increased morbidity and mortality. Early diagnosis and initiation of therapy are essential, but effective treatment remains a challenge. In a long-term follow-up, biochemical control of hypercortisolemia, especially when severe, is difficult to achieve. Life-threatening hypercortisolemia is difficult to control due to the limitations of pharmacotherapy, including its side effects, and may require etomidate infusion in the intensive care unit (ICU) to rapidly lower cortisol levels. The effectiveness of hypercortisolemia management can be increased by a dual blockade of cortisol production. We report the efficacy, safety, and tolerability of combined therapy with two steroidogenesis inhibitors, etomidate, and osilodrostat, in a 32-year-old woman diagnosed with severe ACTH-dependent hypercortisolemia, subsequently maintaining a stable level of cortisol with osilodrostat monotherapy. This approach enabled achievement of relatively rapid control of the hypercortisolemia while using an etomidate infusion and concomitant increasing doses of oral osilodrostat applying a “titrations strategy.” Our experience shows that it is worth taking advantage of the synergistic anticortisolic action of etomidate with osilodrostat.

Purpose: Severe Cushing’s syndrome (SCS) is a life-threatening endocrine condition that requires prompt medical intervention. Intravenous etomidate infusion is considered to be the most effective in rapid cortisol overproduction inhibition. This single-center retrospective study aimed to present the safety and effectiveness of intravenous, low-dose, lipid-formulated etomidate infusion in patients with SCS. Methods: Seven patients with complicated SCS related to ectopic ACTH syndrome (n = 6) or Cushing’s disease (n = 1) who received low-dose etomidate infusion as a part of their cortisol-lowering treatment between April 2019 and April 2024 in the Department of Internal Medicine, Endocrinology and Diabetes of Medical University of Warsaw were included in the study. A continuous etomidate infusion was initiated at 0.01–0.02 mg/kg/h. Results: In all patients, rapid control of hypercortisolemia was achieved with a median time of 30 h (range: 12–48 h). Median serum cortisol concentration reduced from 101.9 μg/dL (range: 78.2–119.6 μg/dL) before etomidate to 19.5 μg/dL (range: 18.3–22.5) after 72 h of etomidate treatment. Etomidate infusion was followed by etomidate and osilodrostat combined treatment and then osilodrostat monotherapy in four patients; one patient underwent adrenalectomy, and two patients died during etomidate infusion due to complications of advanced malignancy. Conclusions: This study shows that low-dose and short-term lipid formulation etomidate therapy is highly effective in severe hypercortisolemia management. Combined therapy with etomidate and osilodrostat is well tolerated and could serve as a bridge in long-term SCS treatment.

Osilodrostat is a potent oral steroidogenesis inhibitor that has emerged as the new medical agent for patients with Cushing’s disease (CD) requiring long-term medical therapy for hypercortisolemia control. Its efficacy and safety have been assessed in clinical trials; however, real-world evidence is still scarce. This study aimed to investigate the long-term treatment (156 weeks) clinical and biochemical effect of osilodrostat in six patients with CD at a single center in Poland, initially participating in the LINC4 study. At week 36, all six patients met the key secondary endpoint of the LINC4 trial, achieving normalization of median urinary free cortisol. Osilodrostat treatment allowed for complete disease control in all patients and none of the patients was excluded due to the lack of treatment effectiveness in 156 weeks of follow-up. All patients demonstrated significant improvement from baseline on most metabolic and cardiovascular parameters, which was most evident at week 36 and sustained throughout the study period. This study supports and strengthens the role of osilodrostat as an effective long-term medical treatment in patients with CD. We also present three patient case histories in detail to highlight the clinical situations that endocrinologists might face during osilodrostat therapy.

Osilodrostat is a potent oral steroidogenesis inhibitor that is an effective medical therapy in the management of patients with endogenous Cushing syndrome. However, due to its high therapeutic potential, it is associated with a high risk of inducing adrenal insufficiency (AI). Recently, it has also been reported that patients may experience prolonged adrenal suppression during osilodrostat treatment that persists despite its withdrawal. In this paper, we present a male patient with persistent Cushing’s disease (CD) who experienced several episodes of AI during long-term treatment with osilodrostat. Ultimately, due to the patient’s very low dose of osilodrostat, it was decided to discontinue the therapy after 270 weeks in total. Following the cessation of osilodrostat, the patient commenced treatment with recombinant human growth hormone due to severe growth hormone deficiency, which revealed an underlying cortisol deficiency, likely caused by a prolonged adrenocortical blockage induced by osilodrostat, requiring the initiation of hydrocortisone replacement therapy. During and after the osilodrostat therapy, we additionally observed a low serum concentration of dehydroepiandrosterone sulfate (DHEA-S) despite elevated plasma adrenocorticotrophin. This finding suggested potential inhibition of adrenal steroidogenesis upstream of 11β-hydroxylase. A urine steroid profile performed 40 weeks after discontinuing osilodrostat showed reduced or borderline excretion of cortisol metabolites, as well as significantly decreased excretion of DHEA metabolites. Finally, 62 weeks after the last exposure to osilodrostat, the patient presented with clinical and biochemical features of relapse of hypercortisolemia, and osilodrostat was reintroduced. This case highlights the importance of close monitoring in patients treated with osilodrostat, as hypocortisolemia can arise suddenly and unexpectedly at any point during treatment, even in those on stable doses. Additionally, it indicates that osilodrostat has the potential to induce prolonged adrenal blockade, even after treatment has ceased. The unexpected persistence of adrenal suppression suggests unknown long-term effects of osilodrostat that require further investigation.

Ectopic ACTH syndrome (EAS) remains one of the most demanding diagnostic and therapeutic challenges for endocrinologists. Thymic neuroendocrine tumors account for 5%–10% of all EAS cases. We report a unique case of a 31-year-old woman with severe EAS caused by primary metastatic combined large-cell neuroendocrine carcinoma and atypical carcinoid of the thymus. The patient presented with severe hypercortisolemia, which was successfully controlled with continuous etomidate infusion. Complex imaging initially failed to detect thymic lesion; however, it revealed a large, inhomogeneous, metabolically active left adrenal mass infiltrating the diaphragm, suspected of primary disease origin. The patient underwent unilateral adrenalectomy, which resulted in hypercortisolemia resolve. The pathology report showed an adenoma with adrenal infarction and necrosis. The thymic tumor was eventually revealed a few weeks later on follow-up imaging studies. Due to local invasion and rapid progression, only partial resection of the thymic tumor was possible, and the patient was started on radio- and chemotherapy.