Endoxifen-induced ovarian hyperstimulation and galactorrhea in an adolescent with severe personality disorder

Dear Sir, Endoxifen is gaining recognition as a novel treatment for managing manic episodes in bipolar disorders and impulsivity in borderline personality disorder (BPD).[1,2] Endoxifen exhibits an inhibitory impact on protein kinase C that is four times more potent than that of its predecessor, tamoxifen. While endoxifen’s psychiatric applications have been increasingly documented, its reproductive endocrine effects remain largely unexplored. Here, we document a report of endoxifen-induced ovarian hyperstimulation in psychiatric practice. A 17-years old female, diagnosed with severe personality disorder (borderline pattern) according to ICD-11, showed minimal response to initial psychopharmacology with sequential trials of mood stabilizers (mainly lithium carbonates up to 600 mg/day or lamotrigine 50 mg/day) along with antipsychotics (aripiprazole up to 10 mg/day or cariprazine 3 mg/day) and dialectical behavior therapy conducted biweekly. However, when endoxifen up to 16 mg/day was administered along with lithium 600 mg/day and escitalopram 20 mg/day, her impulsivity and self-harming behavior reduced significantly. Within a month of this regimen, she developed galactorrhea, secondary amenorrhea, and bloody discharge from the left breast nipple despite normal serum prolactin levels. Hence, consultation liaison with gynecologist and general surgeon was made and she was evaluated further. Her hormonal evaluation revealed markedly elevated estradiol (>1000 pg/mL), elevated testosterone (183 ng/dL), elevated FSH (23.56 mIU/mL), elevated LH (19.62 mIU/L), normal progesterone (2.80 ng/mL), negative beta-hCG (<1.20 mIU/mL), and slightly elevated TSH levels (4.04 µIU/mL). A pelvic ultrasound demonstrated bilateral multiloculated ovarian cysts with normal mammogram and neuroimaging. After discontinuation of endoxifen her hormonal levels normalized (estradiol 203.99 pg/mL, testosterone 37.12 ng/dL, FSH 24.00 mIU/mL, LH 29.04 mIU/L). The gynecology team prescribed oral progesterone 100 mg twice daily for 5 days, after that her menstruation resumed. Lithium and escitalopram were continued, along with ongoing psychotherapy sessions. The Naranjo Adverse Drug Reaction Probability Scale score was 7, indicating a probable adverse drug reaction. This case represents a maiden report of endoxifen-induced ovarian hyperstimulation in a patient with severe personality disorder. The pathophysiology mirrors tamoxifen-related ovarian effects, which induces ovarian cysts in 19.3% of treated patients, with higher incidence in premenopausal women (49.1% vs 1.1%) compared to postmenopausal women.[3] Competitive antagonism at hypothalamic estrogen receptors leads to increased gonadotropin-releasing hormone secretion and subsequent elevation of FSH and LH.[4] Additionally, selective estrogen receptor modulators (SERM) may directly stimulate ovarian follicles and hence can produce massive follicular growth and elevated hormone levels, as observed in our patient. The adolescent reproductive age may have increased susceptibility in our patient, although the severity of hormonal response suggests an exaggerated, possibly idiosyncratic SERM-related effect. Unlike tamoxifen, endoxifen demonstrates a stronger binding affinity for estrogen receptor and is classified as a SERM. While sharing tamoxifen’s SERM properties, endoxifen exhibits distinct pharmacological characteristics. Jadhav in his observational study reported that the risk of adverse effects of endoxifen was dependent on the dose and duration of treatment. The most common adverse effects were hot flashes, fatigue, and mood fluctuations.[5] However, the development of galactorrhea with normal prolactin levels, combined with markedly elevated estradiol, represents a classic presentation of SERM-induced ovarian hyperstimulation. The bilateral, multiloculated nature of the ovarian cysts, combined with extremely elevated hormone levels, necessitated careful exclusion of malignancy. The complete resolution following endoxifen discontinuation confirmed the drug-related etiology and avoided unnecessary surgical intervention in the present case. This case report highlights that Endoxifen is undoubtedly a useful treatment option for impulsivity, but clinicians should exercise caution and monitor for possible reproductive endocrine effects, especially in adolescent and reproductive-age females. Ethical statement This manuscript follows the ethical guidelines of IJME and anonymized data is provided after obtaining written informed consent of the participants/care givers. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.