Maturation of hypothalamic-pituitary-gonadal function in normal human fetuses: circulating levels of gonadotropins, their common a-Subunit and free testosterone, and discrepancy between immunological and biological activities of circulating Follicle-Stimulating Hormone

The recent availability of both cordocentesis, a low risk and effective technique for fetal blood sampling, and ultrasensitive/highly specific two-site immunofluorometric assays (IFMA) for pituitary and chorionic glycoprotein hormone (I-LH, I-FSH, and I-CG) measurement prompted us to study the maturation of hypothalamic-pituitary-gonadal function in 114 normal human fetuses (49 females and 65 males) from IT-40 weeks gestation. The subjects were selected from 216 consecutive cordocenteses carried out for rapid karyotyping and diagnosis of fetal infection or hematological disorders. In addition, FSH bioactivity (B-FSH) was measured by rat Sertoli cell aromatase induction assay, glycoprotein hormone a-subunit (α-SU) by RIA, and circulating free testosterone (fT) by direct analog technique. No significant cross-reactions were recorded in the different measurement methods. In particular, α-SU did not interfere in any IFMA, and CG cross-reactivity in LH IFMA was 0.5%. Circulating I-LH, I-FSH, and B-FSH levels at 17-24 weeks gestation were significantly higher in female than in male fetuses (I-LH, 48 ±4 vs. 6.3 ± 0.7 U/L; I-FSH, 35 ± 2 vs. 0.7 ± .0.1 U/L; B-FSH, 131 ± 17 vs. 43.4 ± 5.4 U/L). During the last weeks of gestation, a significant decrease in I-LH and I-FSH levels was seen in both female and male fetuses (I-LH, 0.24 ± 0.05 and 1.0 ± 0.3 U/L; I-FSH, 0.45 ± 0.1 and 0.5 ± 0.1 U/L), while serum B-FSH remained elevated, but the previously recorded difference between sexes disappeared (54.3 ± 7.2 and 58.7 ± 7.3 U/L). Circulating I-CG and α-SU levels at midgestation were elevated in both female and male fetuses (I-CG, 117 ± 29 and 191 ± 44 U/L; α-SU, 143 ± 16 and 105 ± 9 μg/L, respectively) and decreased thereafter (I-CG, 42 ± 9 and 26 ± 6 U/L; α-SU, 60 ± 15 and 37 ± 6 μg/L). Serum fT levels at midgestation were significantly lower in females than in males (4.3 ± 0.9 vs. 10.0 ± 0.8 pmol/L) and increased until term, when the difference between sexes disappeared (16.2 ± 1.8 vs. 17.6 ± 1.6 pmol/L). The present data 1) show that a clear sex difference in I-LH, I-FSH, and fT secretion characterizes fetal hypothalamic-pituitary-gonadal maturation at midgestation and that the increase in fT contributes to gonadotropin secretion blockade during the third trimester of pregnancy, 2) confirm that circulating I-CG levels are clearly elevated at midgestation and decrease there-after, 3) show that in fetuses of both sexes, there is an enormous excess of circulating α-SU, the levels of which are 10- to 15-fold higher than those expected to be secreted along with complete glycoprotein hormones, and 4) demonstrate for the first time that B-FSH levels in both males and females are higher than those of I-FSH. Although the source and biochemistry of this FSH-like material remain to be elucidated, the secretion of FSH molecules with increased bioactivity may assure gonadal maintenance and growth during fetal life.