Idiopathic Hypogonadotropic Hypogonadism
Predictors of Outcome of Long-Term GnRH
Researchers in Boston, Massachusetts determined that in men with idiopathic hypogonadotropic hypogonadism (IHH) the independent predictors of outcome of long-term gonadotropin-releasing hormone (GnRH) therapy are: 1) the presence of some prior pubertal development (positive predictor); 2) a baseline inhibin B (IB) less than 60 pg/ml (negative predictor); and 3) prior cryptorchidism (negative predictor). Notably, anosmia was not an independent predictor of outcome when adjusted for other baseline variables.
"Our conclusions are: 1) pulsatile GnRH therapy in IHH men is very successful in inducing androgen production and spermatogenesis; 2) normalization of the luteinizing hormone (LH)-Leydig cell-testosterone (T) axis is achieved more uniformly than the follicle stimulating hormone (FSH)-Sertoli cell-IB axis during GnRH therapy; and 3) favorable predictors for achieving an adult testicular size and consequently optimizing spermatogenesis are prior history of sexual maturation, a baseline IB greater than 60 pg/ml, and absence of cryptorchidism," wrote Nelly Pitteloud and colleagues ("Predictors of Outcome of Long-Term GnRH Therapy in Men with Idiopathic Hypogonadotropic Hypogonadism," The Journal of Clinical Endocrinology & Metabolism)
IHH is a disorder that selectively affects the secretion or function of GnRH (Hoffman and Crowley, 1982). GnRH treatment is successful in inducing virilization and spermatogenesis in most men with IHH. However, a small subset of IHH men fail to reach a normal testicular volume (TV) and produce sperm with this treatment (Ley and Leonard, 1985; Kliesch et al., 1995;Weinstein and Reitz, 1974; Hoffman and Crowley, 1982; Finkel et al., 1985). This subset is, to date, poorly characterized.
The authors sought to determine the efficacy of 2 years of pulsatile GnRH therapy in a cohort of IHH men (in terms of normalization of T secretion, stimulation of testicular growth, and spermatogenesis) and to define the predictors of outcome of long-term GnRH therapy (in terms of TV and sperm count).
Seventy-six IHH men, aged 18 - 55 years (38% with anosmia) undergoing GnRH therapy for 12 - 24 months were recruited from the Reproductive Endocrine Clinic of the Massachusetts General Hospital between 1979 and 1999.
These men were stratified according to the baseline degree of prior pubertal development: absent (group 1, n = 52), partial (group 2, n = 18), or complete (adult onset HH; group 3, n = 6). Cryptorchidism was recorded in 40% of group 1, 5% of group 2, and none in group 3.
Puslatile GnRH therapy was initiated at 5 - 25 ng/kg per pulse sc and titrated to attain normal adult male testosterone (T) levels. The doses of GnRH at the time of T normalization for each patient were significantly higher for group 1 compared with groups 2 and 3. Moreover, for the duration of GnRH therapy, the dose required to maintain T levels in the normal adult range remained significantly higher in those with no prior pubertal development compared with groups 2 and 3.
LH (97%) and T (93%) levels were normalized in the majority of IHH men. Groups 2 and 3 achieved a normal adult testicular size (92%), FSH (96%), IB levels (93%), and sperm in their ejaculate (100%). Group 3 responded faster, normalizing androgen production by two months and completing spermatogenesis by six months. This was attributed to their prior complete puberty and thus primed gonadotropes and testes. In contrast, group 1 failed to normalize TV and IB levels by 24 months, despite normalization of their FSH levels. Similarly, sperm counts of group 1 plateaued well below the normal range, with 18% remaining azoospermic.
"Long-term pulsatile GnRH therapy in this large cohort of IHH men proved effective in stimulating normal gonadotropin and T secretion," wrote the authors. "However, although testicular growth occurred in most IHH men, a significant spectrum of responses was apparent, depending largely on the history of prior pubertal development. Moreover, FSH stimulation of IB production from Sertoli cells and spermatogenesis also differed according to the degree of pubertal development. In addition to a prior history of pubertal development, baseline IB levels greater than 60 pg/ml and absence of cryptorchidism were strong positive predictors of testicular growth on GnRH therapy."
"In conclusion, administration of pulsatile GnRH to IHH men represents a unique human model to investigate male reproductive physiology," wrote Pitteloud et al. "Our large cohort provides a cross-section of pubertal development affording insight into testicular physiology. GnRH therapy was very successful in inducing sexual maturation. Although normalization of LH/Leydig cell/T production was achieved in most IHH men, a limitation in seminiferous tubule growth was encountered in those patients with no prior puberty as evidenced by failure to achieve normal IB levels, sperm count, and testicular size. The cause of this suboptimal response is still unclear but points to the critical neonatal window for normal gonadal development. Our analysis further identifies prior history of sexual maturation, a baseline IB greater than 60 pg/ml, and absence of cryptorchidism as favorable predictors of outcome of GnRH therapy."
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