Normalizing Ovulation Rate by Preferential Reduction of Hepato-Visceral Fat in Adolescent Girls With Polycystic Ovary Syndrome

Abstract Purpose Polycystic ovary syndrome (PCOS) is an increasingly prevalent disorder in adolescent girls, commonly presenting with hirsutism/oligomenorrhea, commonly treated with an oral contraceptive (OC), and commonly followed by oligoanovulatory subfertility. We tested whether an intervention targeting the reduction of hepato-visceral adiposity is followed by a higher ovulation rate than OC treatment. Methods This randomized, open-label, single-center, pilot proof-of-concept study (12 months on treatment, then 12 months off) was performed in adolescent girls with hirsutism and oligomenorrhea (PCOS by National Institutes of Health; no sexual activity; N = 36; mean age 16 years, body mass index 23.5 kg/m 2 ; 94% study completion). Compared treatments were OC (ethinylestradiol–levonorgestrel) versus low-dose combination of spironolactone 50 mg/d, pioglitazone 7.5 mg/d, and metformin 850 mg/d (SPIOMET). Primary outcome was post-treatment ovulation rate inferred from menstrual diaries and salivary progesterone (12 + 12 weeks). Secondary outcomes included body composition (dual X-ray absorptiometry), abdominal fat (magnetic resonance imaging), insulinemia (oral glucose tolerance test), and androgenemia (liquid chromatography – tandem mass spectrometry). Results SPIOMET was followed by a 2.5-fold higher ovulation rate than OC ( p ≤ .001) and by a 6-fold higher normovulatory fraction (71% vs. 12%; p ≤ .001); oligoanovulation risk after SPIOMET was 65% lower (95% confidence interval, 40%–89%) than after OC. Higher post-treatment ovulation rates related to more on-treatment loss of hepatic fat (r 2  = .27; p Conclusions Early SPIOMET treatment for PCOS normalized post-treatment ovulation rates more than OC. Focusing PCOS treatment on early reduction of hepato-visceral fat may prevent part of later oligoanovulatory subfertility.