Adult-onset idiopathic hypogonadotropic hypogonadism--a treatable form of male infertility

BACKGROUND: Men with isolated gonadotropin-releasing hormone (GnRH) deficiency typically present with an absence of pubertal development. We describe an adult-onset form of idiopathic hypogonadotropic hypogonadism that develops after puberty. METHODS: We studied 10 men (age, 27 to 57 years) with normal sexual maturation, idiopathic infertility, sexual dysfunction, low serum testosterone concentrations, and apulsatile secretion of luteinizing hormone on frequent blood sampling. All the men had otherwise normal anterior pituitary hormone secretion and sellar anatomy. We compared the results of semen analyses and measurements of testicular volume, serum testosterone, inhibin B, and gonadotropins in these men with the results in 24 men with classic GnRH deficiency before and during GnRH-replacement therapy and in 29 normal men of similar age. RESULTS: Serum gonadotropin concentrations in the men with adult-onset GnRH deficiency were similar before and during pulsatile GnRH administration to those in the men with classic GnRH deficiency. However, as compared with men with classic GnRH deficiency, men with adult-onset hypogonadotropic hypogonadism had larger mean (+/-SD) testicular volumes (18+/-5 vs. 3+/-2 ml, P<0.001), serum testosterone concentrations (78+/-34 vs. 49+/-20 ng per deciliter [2.7+/-1.2 vs. 1.7+/-0.7 nmol per liter], P=0.004), and serum inhibin B concentrations (119+/-52 vs. 60+/-21 pg per milliliter, P<0.001). Treatment with GnRH reversed the hypogonadism and restored fertility in each of the five men who received long-term therapy. CONCLUSIONS: The recognition of adult-onset hypogonadotropic hypogonadism in men as a distinct disorder expands the spectrum of GnRH deficiency and identifies a treatable form of male infertility

Defective regulation of glycoprotein free alpha-subunit in males with isolated gonadotropin-releasing hormone deficiency--a clinical research center study

During long term replacement with a GnRH regimen that restores their gonadotropin and sex steroid levels to normal, men with idiopathic hypogonadotropic hypogonadism (IHH) exhibit excessive secretion of pituitary free alpha-subunit (FAS). To characterize further the dose and duration of exogenous GnRH required to elicit this response, FAS, LH, FSH, and testosterone were determined during the first 8 weeks of GnRH administration in 10 men with IHH. The GnRH dose was increased stepwise every 2 weeks from 5 to 100 ng/kg every 2 h. Hormonal responses were compared with normative data for both pubertal boys and adult men. Low baseline levels of LH (mean +/- SEM, 0.9 +/- 0.03 IU/L), FSH (2.5 +/- 0.4 IU/L), FAS (148 +/- 21 ng/L), and testosterone (2.5 +/- 0.3 nmol/L) increased progressively after GnRH replacement. Mean FAS levels and pulse amplitudes significantly exceeded those in normal adult men by 4-6 weeks when their LH responses to GnRH administration remained below adult norms. By week 8 (50 ng GnRH/kg every 2 h), mean levels of LH, FSH, and FAS (13.7 +/- 2.1 IU/L, 15.4 +/- 4.0 IU/L, 627 +/- 75 ng/L, respectively) significantly exceeded adult male concentrations (P < 0.03). However, mean LH and FSH concentrations were not significantly different from midpubertal controls, in whom FAS levels were comparable to those in normal adults, verifying the excessive nature of FAS secretion relative to intact gonadotropins in the IHH patients. As this imbalance between FAS and dimeric gonadotropin secretion was established early in the current study when low doses of GnRH presumably resulted in low levels of receptor occupancy in vivo, it does not appear to result from partial pituitary desensitization induced by pharmacological GnRH stimulation. Rather, it appears to represent an inherent property of the GnRH-deficient state that is unmasked when GnRH input to the pituitary is restored. Further work will be necessary to elucidate the mechanism of this apparent defect in FAS regulation in GnRH-deficient men

Contour of the GnRH pulse independently modulates gonadotropin secretion in the human male

GnRH pulse frequency, amplitude, and interpulse interval have all been demonstrated to regulate gonadotropin secretion individually. We tested the hypothesis that the contour of the GnRH pulse also modulates gonadotropin output in 10 men with isolated GnRH deficiency in whom a fixed GnRH dose was administered at a constant physiologic frequency by either instantaneous bolus or by 1-, 5-, or 30-min infusions. LH, FSH and free alpha subunit (FAS) responses were also compared to spontaneous gonadotropin secretion in normal adult men. While the LH and FAS pulses following the instantaneous bolus and 1-min infusion of GnRH were indistinguishable, further increases in the duration of gonadotrope stimulation by GnRH were associated with progressive decreases in all parameters of gonadotropin secretion (mean levels, amplitude, peak levels, AUC). FSH secretion was also decreased following variations in the contour of the GnRH pulse, although overall changes were less dramatic than for LH and FAS. The LH pulses following the bolus GnRH stimulation were indistinguishable from spontaneous LH pulses occurring in normal men whereas those stimulated by the 1-, 5-, and 30-min infusions of GnRH became progressively blunted with the lowest levels of secretion occurring after the longest infusion. In sharp contrast, FAS pulse parameters in the GnRH-deficient subjects greatly exceeded those of normal men regardless of the contour of the GnRH stimulus, whereas mean FSH levels were all modestly (although significantly) higher than those of normal adult men. These results demonstrate that the pituitary is sensitive to subtle changes in the contour of the GnRH stimulus, with a more prolonged duration of GnRH stimulation resulting in a diminished pituitary response. Alterations of the contour of endogenous GnRH secretion may represent an additional mechanism for altering gonadotrope function and provide additional evidence for the differential regulation of LH, FAS, and FSH by GnRH. However, the previously reported elevated levels of FAS secretion in GnRH-deficient men undergoing long-term GnRH replacement are not explained by abnormalities of GnRH contour

Inhibin B in males with gonadotropin-releasing hormone (GnRH) deficiency: changes in serum concentration after shortterm physiologic GnRH replacement--a clinical research center study

To examine the role of inhibin B in the feedback regulation of FSH secretion in the human male, we determined serial levels in 18 men with idiopathic hypogonadotropic hypogonadism (IHH) during their initial 8 weeks of GnRH replacement. Pulsatile GnRH was administered every 2 h, with the dose increased at 2-week intervals (5-50 ng/kg/bolus). Every 2 weeks, sera were assayed for inhibin B, FSH, LH, and testosterone. Serial comparisons were performed within the IHH group as well as vs. normal men (n = 20). The baseline inhibin B level in IHH patients averaged 68 +/- 11 pg/mL (mean +/- SEM), significantly less than that in normal men (239 +/- 14 pg/mL; P < 0.001). After 8 weeks of pulsatile GnRH, inhibin B levels in the IHH patients increased significantly to 118 +/- 14 pg/mL (P = 0.003). During GnRH replacement, FSH concentrations correlated negatively with inhibin B concentrations at all doses. Patients previously treated with testosterone began with somewhat lower inhibin B levels but demonstrated a significantly greater increase in serum concentrations than patients who had received prior gonadotropin or GnRH therapy. A history of cryptorchidism did not have a significant impact on inhibin B concentrations before or during GnRH replacement. The low inhibin B levels in IHH men at baseline and their prompt increase in response to pulsatile GnRH suggest acute regulation by gonadotropin stimulation of the testis. The variation in inhibin B levels at baseline and in response to GnRH suggest that prior gonadotropin exposure and seminiferous tubular development also modulate inhibin B secretion. The consistent negative correlation between FSH and inhibin B during the induction of sexual maturation with GnRH supports the role of gonadal inhibin B secretion as an important endocrine regulator of FSH in the human male

Fanconi-Bickel syndrome and autosomal recessive proximal tubulopathy with hypercalciuria (ARPTH) are allelic variants caused by GLUT2 mutations.

CONTEXT: Many inherited disorders of calcium and phosphate homeostasis are unexplained at the molecular level. OBJECTIVE: The objective of the study was to identify the molecular basis of phosphate and calcium abnormalities in two unrelated, consanguineous families. PATIENTS: The affected members in family 1 presented with rickets due to profound urinary phosphate-wasting and hypophosphatemic rickets. In the previously reported family 2, patients presented with proximal renal tubulopathy and hypercalciuria yet normal or only mildly increased urinary phosphate excretion. METHODS: Genome-wide linkage scans and direct nucleotide sequence analyses of candidate genes were performed. Transport of glucose and phosphate by glucose transporter 2 (GLUT2) was assessed using Xenopus oocytes. Renal sodium-phosphate cotransporter 2a and 2c (Npt2a and Npt2c) expressions were evaluated in transgenically rescued Glut2-null mice (tgGlut2-/-). RESULTS: In both families, genetic mapping and sequence analysis of candidate genes led to the identification of two novel homozygous mutations (IVS4-2A>G and R124S, respectively) in GLUT2, the gene mutated in Fanconi-Bickel syndrome, a rare disease usually characterized by renal tubulopathy, impaired glucose homeostasis, and hepatomegaly. Xenopus oocytes expressing the [R124S]GLUT2 mutant showed a significant reduction in glucose transport, but neither wild-type nor mutant GLUT2 facilitated phosphate import or export; tgGlut2-/- mice demonstrated a profound reduction of Npt2c expression in the proximal renal tubules. CONCLUSIONS: Homozygous mutations in the facilitative glucose transporter GLUT2, which cause Fanconi-Bickel syndrome, can lead to very different clinical and biochemical findings that are not limited to mild proximal renal tubulopathy but can include significant hypercalciuria and highly variable degrees of urinary phosphate-wasting and hypophosphatemia, possibly because of the impaired proximal tubular expression of Npt2c