SAT336 A Successful Ovulation Induction And Embryo Generation In A Woman With P450-oxidoreductase Deficiency From Mutation G539R, Which Preferentially Impairs 17,20-lyase Activity

Abstract

Abstract Disclosure: S. Charoensri: None. M. Thakur: None. R.J. Auchus: None. Introduction: Cytochrome P450 oxidoreductase (POR) deficiency is an autosomal recessive disorder causing decreased activity of several P450 enzymes, including CYP21A2, CYP17A1, and CYP19A1 that are essential for steroidogenesis in the adrenals and gonads. Female POR deficiency patients are typically manifested with genital ambiguity, abnormal menstruation, and infertility. Very few pregnancies have been documented from these patients. Case presentation: During an evaluation for infertility, a 35-year-old woman with late menarche, irregular cycles, and unruptured ovarian follicles was diagnosed with POR deficiency due to compound heterozygous pathogenic variant c.1615G>C (G539R) and a large deletion c.1669+5_1669+32del in the POR gene. Because mutation G539R preferentially impairs the 17,20-lyase activity of CYP17A1, she underwent in-vitro fertilization (IVF) with the protocol that has been used successfully to achieve pregnancy in incomplete 17-hydroxylase deficiency. Oral dexamethasone of 0.5 mg/day was given to suppress the adrenal-derived progesterone. After one menstrual cycle induced with estradiol and progesterone priming, leuprolide acetate was used to down-regulate endogenous gonadotropin secretion, then the oocyte maturation was induced with recombinant follicle-stimulating hormone (rFSH) and highly purified menotrophin. In the first cycle, 6 eggs were retrieved, 2 that were mature and fertilized with intracytoplasmic sperm injection (ICSI); however, none advanced to the blastocyst stage. She underwent the same protocol in a second IVF cycle with higher rFSH dosing. Despite increasing dexamethasone to 1.5 mg/day, progesterone rose to 4.9 ng/mL, while estradiol peaked at 120 pg/mL, consistent with progesterone accumulation in the developing ovarian follicles due to POR deficiency. From 6 eggs retrieved, 5 eggs were mature and all fertilized, and 3 developed past day 3. On day 6, one embryo (grading 5BB) was biopsied for preimplantation genetic testing and frozen. The second phase of the treatment plan is to lower adrenal-derived progesterone with a combination of hydrocortisone and prednisolone, prepare the endometrium with estradiol followed by progesterone, and perform embryo transfer. Conclusions: Very few examples of pregnancy in women with POR deficiency have been reported, and we describe the first example of successful ovulation induction and embryo generation in a woman with POR deficiency caused by the G539R mutation, which preferentially impairs 17,20-lyase activity. The complex array of steroid excess and deficiencies, from both adrenal and ovarian origin, must be systematically managed during assisted reproduction treatment for these women. Presentation: Saturday, June 17, 2023