Emerging observations in cystic fibrosis (CF) suggest that female subfertility may not be solely cervico-ovarian transport-related and that ovarian physiology could be directly modulated by CFTR dysfunction and its pharmacologic correction. As more patients initiate CFTR modulators-particularly triple therapy (elexacaftor/tezacaftor/ivacaftor)-the field lacks consolidated data on ovarian reserve, ovulatory dynamics, and assisted reproduction outcomes in this population.
Key questions for discussion and data sharing:
- Ovarian reserve metrics: Have you observed differences in AMH, antral follicle count, or ovarian volume in women with CF compared with age/BMI-matched controls? Do these parameters change after initiation of CFTR modulators or with nutritional rehabilitation? Any correlation with CF-related diabetes, chronic pulmonary inflammation burden, or corticosteroid exposure?
- Ovulatory function: In cohorts tracked with mid-luteal progesterone, LH surge monitoring, or folliculometry, does ovulation frequency change after starting CFTR modulators? Any signal for altered cycle length variability, luteal phase sufficiency, or functional ovarian cyst frequency post-therapy?
- Mechanistic considerations: CFTR is expressed in reproductive tissues; have any groups profiled follicular fluid (pH, bicarbonate/chloride, lactate, cytokines) or granulosa cell biomarkers in CF versus non-CF patients? Any evidence that modulators normalize follicular microenvironment or cumulus expansion pathways relevant to oocyte competence?
- ART protocolization: For controlled ovarian stimulation in CF, are lower/higher gonadotropin doses needed to achieve similar follicular recruitment? Any differences in OHSS risk or fluid/airway management challenges during retrieval? Peri-procedural standards you employ for airway clearance, anesthesia risk stratification, and antibiotic prophylaxis in patients colonized with Pseudomonas or other organisms?
- Pharmacology and drug-drug interactions: With lumacaftor/ivacaftor (strong CYP3A induction), reduced efficacy of combined hormonal contraception is established. What are you using for contraception in patients pursuing cycle regulation or pre-ART suppression? For triple therapy, although major CYP3A induction is not expected, have you seen clinically meaningful interactions with exogenous estradiol/progestins or gonadotropins (e.g., altered serum levels, breakthrough bleeding, atypical stimulation response)?
- Metabolic milieu: As weight and insulin dynamics improve on modulators, have you observed shifts toward hyperandrogenism or polycystic ovarian morphology, or conversely resolution of hypothalamic anovulation? Any trends in SHBG, total/free testosterone, or LH:FSH ratio pre- versus post-modulator?
- Reproductive lifespan: Menarche timing is often delayed pre-modulator; is there evidence yet of catch-up trajectory or altered menopausal timing in long-term treated cohorts?
- Neoplasia and surgical considerations: Any epidemiologic signals regarding ovarian tumor histotypes in CF or CFTR carriers? For CF patients undergoing pelvic surgery, have you adapted approaches for opportunistic salpingectomy or fertility preservation given anesthesia and pulmonary considerations?
If anyone has:
- Prospective pre/post-CFTR modulator data (AMH, AFC, ovulation tracking, follicular fluid analyses, embryo metrics).
- Standardized ART/anesthesia pathways specific to CF.
- Pharmacokinetic observations of reproductive hormones or gonadotropins in patients on lumacaftor/ivacaftor versus triple therapy.
Please share protocols, outcomes, and pitfalls. Identifying whether ovarian factors meaningfully contribute to subfertility in CF-and whether CFTR modulation mitigates them-would inform counseling, contraception, and individualized ART planning.