This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pitteloud, N. Articles by Crowley, W. F. Search for Related Content PubMed PubMed Citation Articles by Pitteloud, N. Articles by Crowley, W. F., Jr.

Predictors of Outcome of Long-Term GnRH Therapy in Men with Idiopathic Hypogonadotropic Hypogonadism

Reproductive Endocrine Unit of the Department of Medicine, National Center for Infertility Research (N.P., F.J.H., A.D., P.A.B., W.F.C.), and Biostatistic Center (H.L.), General Clinical Research Center, Massachusetts General Hospital, Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: Nelly Pitteloud, M.D., Reproductive Endocrine Unit and National Center for Infertility Research, Bartlett Hall Extension 5, Massachusetts General Hospital, Boston, Massachusetts 02114. E-mail: . npitteloud{at}partners.org

Abstract

GnRH treatment is successful in inducing virilization and spermatogenesis in men with idiopathic hypogonadotropic hypogonadism (IHH). However, a small subset of IHH men, poorly characterized to date, fail to reach a normal testicular volume (TV) and produce sperm on this therapy. To determine predictors of outcome in terms of TV and sperm count, we studied 76 IHH men (38% with anosmia) undergoing GnRH therapy for 12–24 months.

The population was 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. Pulsatile GnRH therapy was initiated at 5–25 ng/kg per pulse sc and titrated to attain normal adult male testosterone (T) levels. LH, FSH, T, and inhibin B (I_B) levels were measured serially, and maximum sperm count was recorded. A longitudinal mixed effects model was used to determine predictors of final TV.

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%), I_B levels (93%), and sperm in their ejaculate (100%). However, given their prior complete puberty and thus primed gonadotropes and testes, group 3 responded faster, normalizing androgen production by 2 months and completing spermatogenesis by 6 months. In contrast, group 1 failed to normalize TV (11 ± 0.4 ml) and I_B levels (92 ± 6 pg/ml) by 24 months, despite normalization of their FSH levels (11 ± 2 IU/liter). Similarly, sperm counts of group 1 plateaued well below the normal range (median of 3 x 10⁶/ml) with 18% remaining azoospermic. The independent predictors of outcome of long-term GnRH therapy were: 1) the presence of some prior pubertal development (positive predictor; group effect (ß) = 4.3; P = 0.003); 2) a baseline I_B less than 60 pg/ml (negative predictor; ß = -3.7; P = 0.009); and 3) prior cryptorchidism (negative predictor; ß = -1.8; P = 0.05). 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 LH-Leydig cell-T axis is achieved more uniformly than the FSH-Sertoli cell-I_B 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 I_B greater than 60 pg/ml, and absence of cryptorchidism.

This article has been cited by other articles:

				P. Bougneres, M. Francois, L. Pantalone, D. Rodrigue, C. Bouvattier, E. Demesteere, D. Roger, and N. Lahlou Effects of an Early Postnatal Treatment of Hypogonadotropic Hypogonadism with a Continuous Subcutaneous Infusion of Recombinant Follicle-Stimulating Hormone and Luteinizing Hormone J. Clin. Endocrinol. Metab., June 1, 2008; 93(6): 2202 - 2205. [Abstract] [Full Text] [PDF]

				P. A. Boepple, F. J. Hayes, A. A. Dwyer, T. Raivio, H. Lee, W. F. Crowley Jr, and N. Pitteloud Relative Roles of Inhibin B and Sex Steroids in the Negative Feedback Regulation of Follicle-Stimulating Hormone in Men across the Full Spectrum of Seminiferous Epithelium Function J. Clin. Endocrinol. Metab., May 1, 2008; 93(5): 1809 - 1814. [Abstract] [Full Text] [PDF]

				S. Salenave, P. Chanson, H. Bry, M. Pugeat, S. Cabrol, J. C. Carel, A. Murat, P. Lecomte, S. Brailly, J.-P. Hardelin, et al. Kallmann's Syndrome: A Comparison of the Reproductive Phenotypes in Men Carrying KAL1 and FGFR1/KAL2 Mutations J. Clin. Endocrinol. Metab., March 1, 2008; 93(3): 758 - 763. [Abstract] [Full Text] [PDF]

				F. Cerrato, J. Shagoury, M. Kralickova, A. Dwyer, J. Falardeau, M. Ozata, G. Van Vliet, P. Bouloux, J. E Hall, F. J Hayes, et al. Coding sequence analysis of GNRHR and GPR54 in patients with congenital and adult-onset forms of hypogonadotropic hypogonadism Eur. J. Endocrinol., November 1, 2006; 155(suppl_1): S3 - S10. [Abstract] [Full Text] [PDF]

				P. A. Kumar, N. Pitteloud, P. A.M. Andrews, A. Dwyer, F. Hayes, W. F. Crowley Jr, and M. Dym Testis morphology in patients with idiopathic hypogonadotropic hypogonadism Hum. Reprod., April 1, 2006; 21(4): 1033 - 1040. [Abstract] [Full Text] [PDF]

				M. M. Grumbach A Window of Opportunity: The Diagnosis of Gonadotropin Deficiency in the Male Infant J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 3122 - 3127. [Abstract] [Full Text] [PDF]

				G S Harrison, M E Wierman, T M Nett, and L M Glode Gonadotropin-releasing hormone and its receptor in normal and malignant cells Endocr. Relat. Cancer, December 1, 2004; 11(4): 725 - 748. [Abstract] [Full Text] [PDF]

				Y. Xia, Y. Sidis, and A. Schneyer Overexpression of Follistatin-Like 3 in Gonads Causes Defects in Gonadal Development and Function in Transgenic Mice Mol. Endocrinol., April 1, 2004; 18(4): 979 - 994. [Abstract] [Full Text] [PDF]