Baseline FSH Predicts Semen Parameter Response in Infertile Men on Clomiphene Citrate

Background: Clomiphene citrate (CC) is a selective estrogen receptor modulator that increases gonadotropin production and may improve spermatogenesis. The purpose of the study was to examine the effects of CC on hormone levels and spermatogenesis in men treated for infertility, and to determine whether it is possible to predict positive treatment outcomes, in terms of hormonal or spermatogenic response to CC prior to treatment. 

Methods: The cases of 90 men, who were prescribed CC for infertility, were retrospectively reviewed. Serum values for follicle stimulating hormone (FSH), luteinizing hormone (LH), total testosterone (TT), free testosterone (FT), sex hormone binding globulin (SHBG), estradiol (E) as well as complete semen analyses were collected before and after CC. Exclusion criteria included azoospermia and men treated with testosterone, human chorionic gonadotropin, or recombinant FSH during the previous 6 months.

Results: Forty-two men (46.7%) with a mean age of 35±6years met the inclusion criteria for analysis. Serum hormone values significantly (p<0.01) increased for FSH (3.4 mIU/mL), LH (2.7 mIU/mL), TT (250.0 ng/dL), FT (5.2 ng/dL), SHBG (5.2nmoI/L) and E ( 1.9 ng/dL). Patients with a baseline FSH of 2 mIU/mL had no change in sperm density( -13.1±32.0 million/mL) or total motile count (-20.6 ± 45.5 million). Men with an initial FSH>2 (n=32) had a mean change in density of +1.68±7.46 million/mL and demonstrateda significant improvement in total motile sperm (+3.4±13.96 million). There were no significant differences between the serum hormone levels in men with baseline FSH levels of 2 or >2 mIU/mL.Conclusions: Infertile men exhibit significant increases in serum hormone levels with CC. Those with FSH >2 mIU/mL had improved sperm density and motility relative to men with FSH 2mIU/mL. FSH prior to initiating CC therapy may be a useful predictor of improvement in semen parameters.

Infertility, Male; Clomiphene Citrate; Idiopathic Infertility; Hypogonadism, Male

1. Louis, J.F., Thoma, M. E., Sorensen, D. N. et al: The prevalence of couple infertility in the United States from a male perspective: evidence from a nationally representative sample. Andrology, 1: 741, 2013.

2. Thonneau, P.,Marchand, S., Tallec, A. et al: Incidence and main causes of infertility in a resident population (1,850,000) of three French regions (1988-1989). Hum Reprod, 6: 811, 1991

3. Ferlin, A., Raicu, F., Gatta, V. et al: Male infertility: role of genetic background. Reprod Biomed Online, 14: 734, 2007

4. Kovac, J.R., Pastuszak, A.W., Lamb, D. J.: The use of genomics, proteomics, and metobolomics in identifying biomarkers of male infertility. Fertil Steril, 99: 998, 2013

5. Ko, E. Y., Siddiqi, K., Brannigan, R. E. et al: Empirical medical therapy for idiopathic male infertility: a survey of the American Urological Association. J Urol, 187:973, 2012

6. Liu, P. Y. Handelsman, D. J.: The present and future state of hormonal treatment for male infertility. Hum Reprod Update, 9: 9, 2003

7. Foss, G. L., Tindall, V. R., Birkett, J. P.: The treatment of subfertile men with clomiphene citrate. J Reprod Fertil, 32: 167, 1973

8. Ghanem, H., Shaeer, O., El-Segini, A.: Combination clomiphene citrate and antioxidant therapy for idiopathic male infertility: a randomized controlled trial. Fertil Steril, 93: 2232, 2010

9. Matsumiya, K., Kitamura, M., Kishikawa, H. et al: A prospective comparative trial of a gonadotropin-releasing hormone analogue with clomiphene citrate for the treatment of oligoasthenozoospermia. Int. J Urol, 5: 361, 1998

10. Mellinger, R.C., Thompson, R.J.: The effect of clomiphene citrate in male fertility. Fertil Steril, 17:94, 1966

11. Ronnberg, L.: The effect of clomiphene citrate on different sperm parameters and serum hormone levels in preselected infertile men: a controlled double-blind cross-over study. Int J Androl, 3: 479, 1980

12. Willets, A.E., Corbo, J.M., Brown, J. N: Clomiphene for treatment of idiopathic male infertility. Reprod Sci, 20: 739, 2013

13. A double-blind trial of clomiphene citrate for the treatment of idiopathic male infertility. World Health Organization. Int J. Androl, 15: 299, 1992

14. Vandekerckhove, P., Lilford, R., Vail., A. et al: Clomiphene or tamoxifen for idiopathic oligo/asthenospermia. Cochrane Database Syst Rev: CD000151, 2000

15. Katz, D.J., Nabulsi, O., Tal, R. et al: Outcomes of clominphene citrate treatment in young hypogonadal men. BJU Int, 110: 573, 2012

16. Moskovic, D.J., Katz, D.J., Akhavan, A. et al: Clomiphene citrate is safe and effective for long-term management of hypogonadism. BJU Int, 110: 1524, 2012

17. Bardin, C. W., Ross, G.T., Lipsett, M. B.: Site of action of clomiphene citrate in men: a study of the pituitary-Leydig cell axis. J Clin Endocrinol Metab, 27: 1558, 1967

18. Vandekerckhove, P., Lilford, R., Vail, A et al: WITHDRAWN: Clomiphene or tamoxifen for idiopathic olig/asthenospermia. Cochrane Database Sys Rev: CD000151, 1996

19. Willets, A.E., Corbo, J.M., J.N.: Clomiphene for the treatment of male infertility. Reprod Sci, 2012

20. Boyle, K.: Nonsurgical treatment of male infertility: empiric therapy. In: Infertility in the Male, Fourth ed. Edited by L. Lipshultz, Howards, S., Neiderberger, C.: Cambridge, UK: Cambridge University Press pp. 438-453, 2009

21. Chua, M.E., Escusa, K. G., Luna, S. et al: Revisiting oestrogen antagonists (clomiphene or tamoxifen) as medical empiric therapy for idiopathic male infertility: a met-analysis. Andrology, 1: 749, 2013

22. Hendriks, D. J., Mol, B.W., Bancsi, L. F. et al: The clomiphene citrate challenge test for the prediction of poor ovarian response and nonpregnancy in patients undergoing in vitro fertilization: a systematic review. Fertil Steril, 86: 807, 2006