Poorly controlled type I diabetes mellitus in young men selectively suppresses luteinizing hormone secretory burst mass.

Abstract

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 micro g 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.