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 17–40 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 α-subunit (α-SU) by RIA, and circulating free testosterone (f T) 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 f T 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 f T secretion characterizes fetal hypothalamic-pituitary- gonadal maturation at midgestation and that the increase in f T 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 thereafter, 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.