Ovarian and Uterine Morphology in Minipuberty: Associations with Reproductive Hormones. A COPANA Study of 302 girls

CONTEXT: 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.

OBJECTIVE: This work aimed to investigate the association between reproductive hormones and ovarian as well as uterine morphology by transabdominal ultrasound scan (TAUS) at minipuberty.

METHODS: 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).

RESULTS: 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).

CONCLUSION: 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.