Ovarian and Uterine Morphology in Minipuberty: Associations With Reproductive Hormones: a COPANA Study of 302 Girls.

Abstract

Female minipuberty is characterized by complex dynamics of circulating reproductive hormones, while the relationship between ovarian and uterine morphology and reproductive hormones remains to be elucidated. This work aimed to investigate the association between reproductive hormones and ovarian as well as uterine morphology by transabdominal ultrasound scan (TAUS) at minipuberty. A secondary analysis was conducted from The Copenhagen Analgesic Study (COPANA) (ClinicalTrials.gov NCT04369222) of healthy infant girls (n = 302, aged 3.4 months [0.4] mean [±SD]: mamma tissue diameter [mm], n = 300). TAUS: uterine volume (n = 230), endometrial thickness (n = 255), ovarian volume, antral follicle count (total/2-4 mm/≥5 mm) (n = 203). Blood samples (n = 269/302 = 89%): antimüllerian hormone (AMH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), inhibin B (immunoassays), progesterone (PROG), androstenedione (Adione), testosterone (T), estrone (E1), estradiol (E2) (liquid chromatography-tandem mass spectrometry). Statistics: Pearson/Spearman correlation coefficient (parametric/nonparametric data). Total follicle count correlated positively with ovarian volume (r = 0.606; P < .001), AMH (r = 0.378; P < .001), inhibin B (r = 0.251; P < .001), and negatively with FSH concentrations (r = -0.327; P < .001). Larger follicles (≥5 mm) correlated positively with AMH (r = 0.264; P < .001), inhibin B (r = 0.230; P = .002), E1 (r = 0.209; P = .004), E2 (r = 0.269; P < .001), PROG (r = 0.160; P = .031), and T (r = 0.210; P = .004) and negatively with FSH (r = -0.183; P = .015). Circulating E1 and E2 levels correlated with the size of estrogen-responsive tissue sizes: E2 vs uterine volume (r = 0.134; P = .054), E2 vs endometrial thickness (r = 0.155; P = .020), E1 and E2 vs mammary tissue diameter (r = 0.213 and r = 0.198, respectively; both P < .001). Correlations between reproductive hormones and the number of antral follicles suggest that negative feedback in the female hypothalamic-pituitary-gonadal axis is established during minipuberty, with ovarian activity promoting uterine and glandular breast tissue growth. We provide normative data of infant ovarian and uterine morphology directly implementable to a clinical setting.