Alterations in the reproductive axis function are present to a variable extent in patients with type 1 diabetes mellitus (IDDM). Results from studies in IDDM men have yielded discrepant findings, which may reflect nonuniform patient selection criteria, age, diabetic status, duration of the disease and differences in sampling protocols. To more clearly define the impact of early diabetic alterations in the male reproductive axis, we applied a combined strategy of patient selection restricted to young men with relatively short duration of IDDM, dual control groups, multiparameter deconvolution analysis to assess LH secretory activity, and assessment of time-dependent changes in human chorionic gonadotropin (hCG)-stimulated serum testosterone concentrations. Three groups of subjects were studied: 11 young men with poorly controlled IDDM, 9 well controlled diabetics, and 9 healthy men. All volunteers underwent blood sampling at 10-min intervals before and after 2 consecutive iv pulses of 10 μg GnRH. On a separate day, 40 IU/kg hCG were given im, and blood samples were collected before hCG administration, every 60 min thereafter for 6 h, and then 24, 48, and 72 h after the injection. Mean serum LH concentrations across the basal 6-h sampling period were significantly (P < 0.05) decreased in men with poorly controlled IDDM (11 ± 1.6 IU/liter) compared with those in well controlled diabetics (19 ± 1.8 IU/liter) and healthy controls (19 ± 1.5 IU/liter). Multiple parameter deconvolution analysis revealed a 50% reduction in the mass of LH secreted per burst and the pulsatile LH secretion rate in poorly controlled IDDM (mass of LH secreted/burst, 7 ± 1.1 vs. 12 ± 2.1 and 13 ± 1.5 IU/liter; LH secretion rate, 47 ± 6.3 vs. 78 ± 10 and 87 ± 11 IU/liter·6 h; poorly controlled vs. well controlled IDDM and healthy controls, respectively; P < 0.05 for both parameters). Uncontrolled IDDM patients had significantly (P < 0.05) lower integrated serum LH concentrations after the first and second GnRH pulses (first GnRH pulse, 4460 ± 770 vs. 7250 ± 1200 and 5120 ± 910 IU/liter; second pulse, 4700 ± 615 vs. 7640 ± 881 and 7100 ± 1230 IU/liter; poorly controlled vs. well controlled IDDM and healthy men, respectively) and markedly attenuated LH secretory burst mass after the second GnRH stimulus (49 ± 8.8 vs. 90 ± 13 and 83 ± 19 IU/liter; poorly controlled vs. well controlled IDDM and healthy controls, respectively). The biological to immunological ratio of LH released in baseline conditions was higher in uncontrolled IDDM patients (0.81 ± 0.10) than in controlled IDDM (0.37 ± 0.08) and healthy controls (0.48 ± 0.06; P < 0.01), whereas LH released in response to exogenous GnRH exhibited comparable ratios among the three study cohorts. Baseline serum testosterone levels as well as absolute and incremental responses to exogenous hCG did not differ by degree of metabolic control. Collectively, these results indicate that the function of the hypothalamic-gonadotrope axis is compromised in young men with poorly controlled IDDM, such that the amplitude of spontaneous pulsatile and exogenous GnRH-stimulated LH secretion is attenuated. This central hypogonadotropism is paradoxically associated with the presence in the circulation of gonadotropin molecules with enriched biological activity, which is evidently sufficient to temporarily maintain normal total testosterone concentrations in the earlier stages of IDDM.

In the present study we analyzed physiological changes in the relative distribution of FSH isoforms circulating under baseline conditions throughout the ovarian cycle as well as the forms discharged by GnRH stimulation from putative acutely releasable and reserve pituitary pools. Eight normally menstruating women underwent blood sampling on three occasions, once each during the presumptive early or midfollicular phase (FP), late follicular phase to midcycle (preovulatory phase; PO), and mid- to late luteal phase (LP) of the menstrual cycle. Blood samples were withdrawn at 10-min intervals for a total of 10 h before and after the iv administration of 10 and 90 micrograms GnRH. GnRH-stimulated FSH pulses were analyzed for secretory burst mass, secretory burst amplitude, integrated FSH concentrations, and endogenous FSH half-life by deconvolution. Serum FSH isoforms were separated by preparative chromatofocusing in 30 x 1-cm columns and identified by RIA of eluent fractions. The changes observed in serum FSH isoform distribution were then correlated with the corresponding secretory and clearance estimates of the released FSH molecules. In each phase of the menstrual cycle, a significant rise in serum FSH concentrations was observed after administration of the consecutive low and high dose GnRH pulses. The magnitude of the response in terms of secretory burst mass, secretory amplitude, and area of GnRH-induced FSH peaks was significantly higher during the PO. In all cycle phases, but particularly during the FP and PO, administration of the 90-micrograms GnRH dose elicited higher (1.4- to 1.7-fold) FSH secretory responses than the lower dose. Multiple parameter deconvolution of the GnRH-induced FSH pulses revealed that FSH molecules released in response to 10 micrograms GnRH at PO exhibited significantly (P < 0.01) shorter plasma half-lives (108 +/- 11 min) than those released during the follicular and luteal phases of the same menstrual cycles (apparent plasma half-life of FSH released at FP, 222 +/- 37 and 271 +/- 47 min for 10 and 90 micrograms GnRH-induced FSH pulses, respectively; LP, 244 +/- 41 and 198 +/- 40 min; P = NS, FP vs. LP) and in response to the high dose GnRH challenge at PO (276 +/- 40 min). Under all conditions studied, serum FSH charge isoforms were distributed along a pH range of 7.0 to less than 4.0.(ABSTRACT TRUNCATED AT 400 WORDS)