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Pituitary-Testicular Function in Nephropathic Cystinosis

Constance L. Chik, MD, PhD; Aaron Friedman, MD; George R. Merriam, MD; and William A. Gahl, MD, PhD
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From the National Institutes of Health, Bethesda, Maryland; the University of Wisconsin, Madison, Wisconsin. Requests for Reprints: William A. Gahl, MD, PhD, Chief, Human Genetics Branch, Building 10, Room 9S-242, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892. Acknowledgments: The authors thank the nursing staff of 9 West of the National Institutes of Health Clinical Center for their dedicated work and the late Dr. T. Kuwabara of the National Eye Institute for performing the light microscopic examinations of the testis. Grant Support: Dr. Chik was supported by a fellowship from the Medical Research Council of Canada.

Copyright 2004 by the American College of Physicians

Ann Intern Med. 1993;119(7_Part_1):568-575. doi:10.7326/0003-4819-119-7_Part_1-199310010-00004
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Objective: To evaluate reproductive function in patients with cystinosis and in renal transplant recipients without cystinosis.

Design: Cross-sectional study.

Setting: Clinical Center, National Institutes of Health.

Patients: Ten male patients, 15 to 28 years old, with nephropathic cystinosis and renal allografts formed the study group; 11 renal transplant recipients who had a primary renal disorder other than cystinosis and were matched with study patients for age and renal function served as the control group.

Measurements: Tanner staging, serum gonadotropin determinations, and testosterone and testosterone-binding globulin assessments. Selected patients also had a human chorionic gonadotropin (HCG) stimulation test, a gonadotropin-releasing hormone (GnRH) stimulation test, and serial sampling for luteinizing hormone (LH).

Main Results: Although testosterone levels were within normal limits in 7 of 10 patients with cystinosis, the mean testosterone level in patients with cystinosis was 11.5 2.0 nmol/L compared with 24.2 3.0 nmol/L in control patients (P < 0.005). No patient with cystinosis reached Tanner stage 5 (full pubertal development), whereas 9 of 11 control patients did. Seven of 10 patients with cystinosis had elevations in LH or follicle-stimulating hormone (FSH) levels, suggesting testicular failure. These patients also had normal LH and FSH responses after GnRH stimulation, increased LH pulse frequency, and reduced testosterone response after HCG stimulation. In comparison, only 3 of 11 control patients had minimally elevated gonadotropin levels, and all 11 had normal testosterone levels. Microscopic testicular examination in one patient showed cystine crystals, germinal dysplasia, increased fibrosis, and Leydig cell hyperplasia.

Conclusions: Abnormalities in the pituitary-testicular axis are common in male patients with cystinosis. These changes appear to be related to the disease cystinosis and not to treated renal failure per se.


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Figure 1.
Serum testosterone, luteinizing hormone, and follicle-stimulating hormone levels in patients with cystinosis and in control patients. Top.Bottom.

Bivariate plot of the serum testosterone level against the luteinizing hormone level. Bivariate plot of the serum testosterone level against the follicle-stimulating hormone level. The widths of the rectangles represent the ranges of values between the 5th and 95th percentiles of luteinizing hormone or follicle-stimulating hormone values in normal men, and the heights of the rectangles represent a similar range of testosterone values in normal men.

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Figure 2.
Episodic secretion of luteinizing hormone in seven patients with cystinosis.

Serum luteinizing hormone (LH) concentrations were determined at 20-minute intervals.

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Figure 3.
Gonadotropin subunit and bioactive luteinizing hormone measurements in patients with cystinosis. Top.Bottom.closed circler

-Subunit (LH ), luteinizing hormone- (LH ), and follicle-stimulating hormone- (FSH ) levels. Bioactive and immunoreactive luteinizing hormone (LH) levels in three patients with cystinosis who had normal LH levels and in seven patients with elevated LH levels ( ). The line in the bottom panel represents the best least-squares fit to the data ( = 0.89).

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Figure 4.
Light microscopic examination of testis specimen from patient 7. Top.Bottom.

Hematoxylin and eosin stain of a formalin-fixed specimen showing increased fibrosis (top arrow), residual seminiferous tubules (bottom arrow), and Leydig cell hyperplasia (upper right). Polarized light-bright field examination of absolute alcohol-fixed specimen showing numerous cystine crystals.

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