Dr Danielle Hulse1, Dr Samantha Hutchinson1, Dr Kiri Chan2
1Department of Diabetes and Endocrinology Monash Health, Melbourne, Australia, 2Department of Obstetrics and Gynaecology Monash Health, Melbourne, Australia
Biography:
Dr Danielle Hulse is a final year advanced trainee in Endocrinology at Monash Health, Melbourne, with broad experience across tertiary endocrine medicine including reproductive endocrinology, metabolic bone disease, diabetes, and general endocrinology. She has developed a strong interest in women’s health, menopause, osteoporosis and diabetes. Danielle is committed to evidence-based, patient-centred care and improving quality of life for patients with complex hormonal disorders. She has presented research nationally and is transitioning into private practice, where she aims to provide comprehensive, compassionate specialist endocrine care.
To describe a case of reversible ovarian insufficiency associated with nirogacestat and highlight challenges in managing ovarian toxicity from emerging oncology therapies.
We report a 24-year-old premenopausal woman with spindle-cell desmoid tumour treated with nirogacestat. Clinical symptoms, menstrual history, and biochemical markers (FSH, LH, oestradiol, AMH) were assessed, with exclusion of alternative causes of amenorrhoea.
Within 8–10 weeks of commencing therapy, the patient developed secondary amenorrhoea, vasomotor symptoms, fatigue, and biochemical hypergonadotropic hypogonadism (elevated FSH/LH, low oestradiol and AMH). Symptoms significantly impacted quality-of-life, however little published guidance exists regarding management of hypoestrogenic symptoms in patients receiving γ-secretase-inhibitors. Following nirogacestat cessation, symptoms resolved over 2–3 months, with menses return and normalisation of gonadotropins and oestradiol. These findings mirror the DeFi trial, where ovarian dysfunction occurred in 75% of reproductive-aged women, usually within 9-weeks, with recovery after discontinuation. Importantly, ovarian toxicity may also resolve in a proportion of patients despite continuation of therapy.
Nirogacestat induces a reversible hypergonadotropic hypogonadal state, through disruption of NOTCH signalling and impaired folliculogenesis rather than permanent ovarian reserve depletion. Baseline and serial endocrine monitoring during and after, fertility counselling, proactive symptom management using hormonal or non-hormonal options where appropriate, and long-term studies of effects on the hypothalamic-pituitary-ovarian axis are needed.