Functional Gonadotropin Deficiency

Men with chronic renal failure have reduced circulating total and free testosterone concentrations, unchanged sex hormone-binding globulin (SHBG) and elevated immunoreactive LH, FSH, and inhibin-a; however, these changes are largely reversed after successful transplantation (1). Although this pattern is consistent with a primarily defect in testicular function, there is also strong evidence for defective neuroendocrine regulation as an important functional aspect of the reproductive dysfunction in uremia. The increase in gonadotropins is less than expected in castrated men who are nonuremic or controls with a similar degree of androgen deficiency (16), indicating a defect in neuroendocrine regulation leading to reduced LH secretion. Indeed, the increase in gonadotropins is largely explained by the substantial (~70%) reduction in renal filtration and whole-body clearance rate of LH, which, in the presence of decreased testosterone secretion, indicates significantly reduced LH secretion. Evidence supporting a hypogonadotropic state (1) includes (a) the regularity of delayed puberty in adolescents with chronic renal failure, (b) a blunted acute testosterone response to human chorionic gonadotropin (hCG) stimulation with restoration of normal circulating testosterone levels by chronic hCG treatment (17), (c) normal or low circulating estradiol levels (18) (which are more consistent with a hypogonadotropic rather than a hypergonadotropic state) because high estradiol results from enhanced LH-induced testicular estradiol secretion, (d) histological features consistent with functional gonadotropin deficiency (19), and (e) short-term responses to gonadotropin stimulation (anti-estrogens, hCG and pulsatile gonadotropin-releasing hormone (GnRH) (20). In addition to impaired LH secretion, a dialyzable gonadotropin inhibitor in uremic serum, which blocks the LH receptor, has been reported (21). As shown in Fig. 1, the pattern of pulsatile and GnRH-stimulated LH secretion also suggests a central defect in the neuroendocrine regulation of gonadotropin secretion in men with chronic renal failure (1,2). Pulsatile secretion of immunoreactive and bioactive LH is severely dampened in uremia but can be restored by renal transplantation (22-25). Using deconvolution analysis, the reduced net LH secretion is attributable to reduced LH secreted per burst with prolongation of LH clearance half-life but no reduction in LH pulse frequency (13,26). More basic and less bioactive LH isoforms (27) and degradation fragments accumulate in uremic serum according to their circulating

Pulse Frequency

Fig. 1. Spontaneous and gonadotropin-releasing hormone (GnRH)-stimulated luteinizing hormone (LH) secretion in an adult man with chronic renal failure and in a normal adult man. Blood samples were obtained every 10 min for 8 h. The arrow indicates the administration of 100 |ig iv GnRH. Note the scale for LH differs, and mean values are 36.5 and 5.41 mlU/mL, respectively, indicating the presence of Leydig cell insufficiency. In the man with chronic renal failure there are low amplitude LH secretory episodes with a normal threefold rise in LH after GnRH stimulation, implying GnRH deficiency. The delay to peak LH and the delayed downstroke are indicative of prolonged LH clearance. (Data courtesy of F. Bruns and S.J. Winters, and are unpublished.)

Fig. 1. Spontaneous and gonadotropin-releasing hormone (GnRH)-stimulated luteinizing hormone (LH) secretion in an adult man with chronic renal failure and in a normal adult man. Blood samples were obtained every 10 min for 8 h. The arrow indicates the administration of 100 |ig iv GnRH. Note the scale for LH differs, and mean values are 36.5 and 5.41 mlU/mL, respectively, indicating the presence of Leydig cell insufficiency. In the man with chronic renal failure there are low amplitude LH secretory episodes with a normal threefold rise in LH after GnRH stimulation, implying GnRH deficiency. The delay to peak LH and the delayed downstroke are indicative of prolonged LH clearance. (Data courtesy of F. Bruns and S.J. Winters, and are unpublished.)

half-times (28), resulting in a skewing of molecular microheterogeneity to less bioac-tive, but more immunoreactive, LH isoforms. These observations suggest that hCG therapy has considerable potential in men with uremia, but no controlled studies have been reported. The efficacy of chronic hCG treatment for reproductive dysfunction has been examined in two prospective but uncontrolled studies. Administering hCG (2-4000 units per week) for 4 mo in 13 men with uremic undergoing regular dialysis did not alter hemoglobin or postdialysis body weight (29). Furthermore, semen parameters were not consistently improved in a subgroup of eight men tested (29). However, in a larger study of 20 men with chronic renal failure, half treated conservatively before inception of dialysis and half having regular hemodialysis, hCG (2000 units on alternate days) treatment for 120 d markedly improved sperm output and quality but only in the group that did not receive dialysis (30). Sexual function was improved, especially in men who did not receive dialysis. These studies suggest that hCG treatment may have a role in managing the reproductive effects of uremia, particularly before dialysis, but well-controlled studies of adequate power are not available. The somatic effects of hCG treatment on androgen-responsive tissues, notably bone, muscle, cognition, and quality of life in uremia, as recently studied in nonuremic older men (31), have not been evaluated in a well-controlled study.

Estrogen blockade, using either anti-estrogens or aromatase inhibitors, also has potential to overcome functional partial gonadotropin deficiency in men with uremia, because hypothalamic and pituitary responsiveness are preserved. This raises the possibility of using anti-estrogens to increase pituitary gonadotropin and endogenous testosterone secretion (20). Short-term clomiphene citrate (100 mg/d for 7 d) treatment can normalize plasma testosterone for at least 3 d after cessation in men with uremia treated by dialysis (n = 34) or renal transplantation (n = 8) (32), but the clinical consequences of increased endogenous testosterone secretion were not reported. A smaller, uncontrolled study of five men who received dialysis previously reported that hormonal responses (rise in gonadotropins and testosterone) to clomiphene citrate (100 mg/d) were sustained for 5-12 mo and led to improved libido, potency, and well-being (20). No studies of aromatase inhibitors in men with chronic renal failure have been reported. Placebo-controlled studies of adequate power and duration, as well as dose optimization, would be required to properly evaluate this interesting but neglected approach to adjunctive treatment in uremia, which must be balanced against the growing understanding of the physiological importance of estrogens in men (33).

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