Role of seminiferous tubular development in determining the FSH versus LH responsiveness to GnRH in early sexual maturation.
BACKGROUND
The onset of sexual maturation at puberty is a unique developmental period from a neuroendocrine perspective in that it is characterized by enhanced FSH secretion and FSH responsiveness to exogenous GnRH (vs. LH) from the gonadotrope, yet the mechanism of these dynamics remains unclear. This study aimed to elucidate this phenomenon using a human disease model of GnRH deficiency (idiopathic hypogonadotropic hypogonadism, IHH) in which GnRH input can be experimentally controlled.


METHODS
25 GnRH-deficient men were selected for study based upon their baseline testicular volumes (TV) and serum inhibin B (I(B)) levels to represent a spectrum of pubertal/testicular development. Subjects underwent: (i) a 12-hour overnight neuroendocrine evaluation for hormonal profiling and determination of endogenous LH secretion pattern, and (ii) a 7-day exposure to a physiologic regimen of exogenous pulsatile GnRH (25 ng/kg every 2 h). Daily measurements of serum testosterone (T) and I(B) levels were made and a 2-hour window of frequent blood sampling was monitored to measure LH and FSH following a single i.v. GnRH bolus (25 ng/kg). All subjects were screened for known loci underlying GnRH deficiency and the response to GnRH was tracked according to genotype.


RESULTS
Among the entire cohort, no changes were noted in serum T or I(B) during the 7 days, thus keeping gonadal feedback relatively constant. However, serum LH and FSH levels increased significantly (p < 0.0001) in the entire cohort. When analyzed by degree of pubertal/testicular development, men with no evidence of prior spontaneous pubertal development (TV <or=3 ml, Group I) showed sharp increases in serum FSH compared to men with some prior evidence of partial puberty (TV >3 ml, Group II, p < 0.0001). Group I exhibited a decreased LH response to GnRH on day 2 compared to day 1 (p < 0.01), which did not recover until day 5 (1-4 vs. 5-7 days, p < 0.0001). Group II displayed robust and equivalent LH responses to GnRH throughout the 7-day study. Genetic studies identified 8 mutations in 4 different loci (DAX1, KAL1, GNRHR, and FGFR1) in this cohort.


CONCLUSIONS
GnRH-deficient men undergoing GnRH-induced sexual maturation display an inverse relationship between FSH responsiveness to GnRH and baseline testicular size and I(B) levels. This observation implies that increasing seminiferous tubule maturity represents the major constraint on FSH responsiveness to GnRH in early puberty. In contrast, LH responsiveness to GnRH correlates directly with duration of GnRH exposure. Attenuated pituitary gonadotropin responses were noted in subjects harboring DAX1 mutations, consistent with known pituitary defects.
Pitteloud
Nelly
N
Harvard Reproductive Endocrine Sciences Center and Reproductive Endocrine Unit of the Department of Medicine, Boston, MA 02114, USA. pitteloud.nelly@mgh.harvard.edu
Thambundit
Apisadaporn
A
Dwyer
Andrew A
AA
Falardeau
John L
JL
Plummer
Lacey
L
Caronia
Lisa M
LM
Hayes
Frances J
FJ
Lee
Hang
H
Boepple
Paul A
PA
Crowley
William F
WF
D000328:Adult; D015331:Cohort Studies; D057137:DAX-1 Orphan Nuclear Receptor / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005640:Follicle Stimulating Hormone / Q000097:blood / Q000378:metabolism*; D005838:Genotype; D007987:Gonadotropin-Releasing Hormone / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007265:Inhibins / Q000097:blood; D007986:Luteinizing Hormone / Q000097:blood / Q000378:metabolism*; D008297:Male; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics; D009929:Organ Size; D011627:Puberty / Q000502:physiology*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics; D011966:Receptors, LHRH / Q000235:genetics; D012671:Seminiferous Tubules / Q000254:growth & development* / Q000473:pathology; D013739:Testosterone / Q000097:blood; D013997:Time Factors
C076266:ANOS1 protein, human; D057137:DAX-1 Orphan Nuclear Receptor; D016326:Extracellular Matrix Proteins; C484844:GNRHR protein, human; C539965:NR0B1 protein, human; D009419:Nerve Tissue Proteins; D011966:Receptors, LHRH; C422364:inhibin B; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D007265:Inhibins; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1