Ovarian macrocysts and gonadotrope–ovarian axis disruption in premenopausal women receiving mitotane for adrenocortical carcinoma or Cushing's disease

Abstract

Context: Mitotane is an adrenolytic and anticortisolic drug used in adrenocortical carcinoma (ACC), Cushing's disease (CD), and ectopic ACTH syndrome. Its effects on the ovaries are unknown. Objective: To evaluate the ovarian and gonadotrope effects of mitotane therapy in premenopausal women. Patients: We studied 21 premenopausal women (ACC: nZ13; CD: nZ8; median age 33 years, range 18-45 years) receiving mitotane at a median initial dose of 3 g/day (range 1.5-6 g/day). Methods: Gynecological history was collected and ovarian ultrasound was performed. Four women also underwent ovarian CT or magnetic resonance imaging. Serum gonadotropin, estradiol (E 2 ), androgens, sex hormone-binding globulin (SHBG), and circulating mitotane levels were determined at diagnosis and during mitotane therapy. Results: In the women included, ovarian macrocysts (bilateral in 51%) were detected after a median 11 months (range: 3-36) of mitotane exposure. The median number of macrocysts per woman was two (range: 1-4) and the median diameter of the largest cysts was 50 mm (range: 26-90). Menstrual irregularities and/or pelvic pain were present in 15 out of 21 women at macrocyst diagnosis. In two women, the macrocysts were revealed by complications (ovarian torsion and hemorrhagic macrocyst rupture) that required surgery. Mitotane therapy was associated with a significant decrease in androstenedione and testosterone levels and a significant increase in LH levels. Serum FSH and E 2 levels were also increased, and SHBG levels rose markedly. Conclusions: Mitotane therapy causes significant morphological and ovarian/gonadotrope hormonal abnormalities in premenopausal women. Follicular thecal steroid synthesis appears to be specifically altered and the subsequent increase in gonadotropins might explain the development of macrocysts. The mechanisms underlying these adverse effects, whose exact prevalence in this population still needs to be determined, are discussed. European Journal of EndocrinologyClinical Study S Salenave, V Bernard and others Ovarian effects of mitotane 172:2 141-

MANAGEMENT OF ENDOCRINE DISEASE: Cushing’s syndrome due to ectopic ACTH secretion: an expert operational opinion

“…This adrenolytic drug was first used decades ago for the treatment of adrenocortical cancer (ACC) and later for other causes of Cushing's syndrome (227,228). Mitotane exerts cytotoxic effects on the adrenal cortex and inhibits enzymes in the steroidogenic pathway, thus suppressing cortisol production (228,229,230). Indeed, a number of studies have demonstrated mitotane inhibition of adrenocortical steroid synthesis by inhibition of cholesterol side-chain cleavage (also called human cytochrome P450 (CYP), cholesterol desmolase or 20, 22 desmolase, encoded by CYP11A1) and 11β-hydroxylase (i.e.…”

“…Frequently reported sideeffects include gastrointestinal symptoms, with anorexia, nausea, and sometimes vomiting and diarrhea (203). Other side-effects are hypogonadism, gynecomastia, ovarian macrocysts, hepatotoxicity and hypercholesterolemia (113,230,234,235 ataxia and paraesthesia) reflecting cerebral toxicity occur more frequently at higher plasma concentrations than those allowing the control of hypercortisolism in patients with non-cancerous adrenal glands (236,237). Indeed, control of hypercortisolism in EAS can be obtained with mitotane blood concentrations below 10 mg/L (113,234,235) that are associated with better tolerance than the 14 mg/L threshold recommended in adrenal cortical cancer.…”

Foetal exposure to mitotane/Op'DDD: Post‐natal study of four children

“…Because of its cytolytic effects, adrenal insufficiency may persist after the elimination of the drug. Interference with gonadal function in both males and females is now established . Beside its effects on steroidogenic tissues, this molecule can also adversely affect central nervous system functions and can interfere with cholesterol and hepatic metabolism …”

“…Interference with gonadal function in both males and females is now established. 5,6 Beside its effects on steroidogenic tissues, this molecule can also adversely affect central nervous system functions and can interfere with cholesterol and hepatic metabolism. 7 Foetal exposure to mitotane, used as a therapeutic agent, may be a concern in ACC since this condition is more prevalent in women and may be diagnosed in patients during reproductive age.…”

Updates on the role of adrenal steroidogenesis inhibitors in Cushing’s syndrome: a focus on novel therapies

“…A recent study of premenopausal women demonstrated a high incidence of menstrual disorders and ovarian macrocysts in women receiving mitotane, which may be related to elevated levels of luteinizing hormone, follicle-stimulating hormone, and estrogen as a consequence of mitotane alleviating the negative feedback normally exerted by the ovaries on the production of those hormones [39]. …”