Subscribe to RSS
DOI: 10.1055/s-0029-1202303
Endocrinology of Male Infertility: Evaluation and Treatment
Publication History
Publication Date:
26 February 2009 (online)
ABSTRACT
A normal functioning reproductive endocrine system is a prerequisite for normal male fertility. Any disruption of the delicately coordinated interaction between the components of the hypothalamic-pituitary-testicular axis may lead to hypogonadism and/or infertility. The goal of the clinical evaluation is to determine if the patient has an abnormality of testosterone production or action, the etiology of the abnormality, and if hormone therapy will correct the infertility. Based on a careful history, physical examination, and evaluation of the hormones of the reproductive axis, the physician will ascertain if the patient's hypogonadism is (1) prepubertal or postpubertal in onset; (2) the result of an abnormality in the hypothalamic-pituitary axis, the testes, or the androgen receptor; or (3) associated with another underlying medical condition. This information will place the patient into one of four diagnostic categories: hypogonadotropic hypogonadism, testicular failure, 5α-reductase deficiency, or androgen resistance. Within each category are disorders with identifiable pathogenic mechanisms. Recent studies have added to these lists and have provided insights into the molecular basis and inheritance patterns of several of these endocrinopathies.
KEYWORDS
Male infertility - hypogonadism - testosterone - luteinizing hormone - follicle-stimulating hormone
REFERENCES
-
1 Sokol R Z, Swerdloff R S.
Endocrine evaluation . In: Lipshultz LI, Howards ST Infertility in the Male. Third ed. St. Louis, MO; Mosby-Year Book 1997: 10-18 - 2 Bilezikjian L M, Blountal A L, Leal A M, Donaldson C J, Fischer W H, Vale W W. Autocrine/paracrine regulation of pituitary function by activin, inhibin, and follistatin. Mol Cell Endocrinol. 2004; 225 29-36
- 3 Gillam M P, Molitch M E, Lombardi G, Colao A. Advances in the treatment of prolactinomas. Endocr Rev. 2006; 27 485-534
- 4 Wilson J D, Griffin J E, Russell D W. Steroid 5α-reductase 2 deficiency. Endocr Rev. 1993; 14 577-593
- 5 Hughes I A. Mini-review: sex differentiation. Endocrinology. 2001; 142 3281-3287
- 6 Longcope C, Sato K, McKay C, Horton R. Aromatization by splanchnic tissue in men. J Clin Endocrinol Metab. 1984; 58 1089-1093
- 7 Ismail A A, Barth J H. Endocrinology of gynecomastia. Ann Clin Biochem. 2001; 38 596-607
- 8 Petersen C, Soder O. The Sertoli cell – a hormonal target and ‘super’ nurse for germ cells that determines testicular size. Horm Res. 2006; 66 153-161
- 9 Holsberger D R, Cooke P S. Understanding the role of thyroid hormone in Sertoli cell development: a mechanistic hypothesis. Cell Tissue Res. 2005; 322 133-140
- 10 de Kretser D M, Buzzard J J, Okuma Y et al.. The role of activin, follistatin and inhibin in testicular physiology. Mol Cell Endocrinol. 2004; 225 57-64
- 11 Kolb B A, Stanczyk F Z, Sokol R Z. Serum inhibin B levels in males with gonadal dysfunction. Fertil Steril. 2000; 74 234-238
- 12 Tong S, Wallace E M, Burger H G. Inhibins and activins: clinical advances in reproductive medicine. Clin Endocrinol (Oxf). 2003; 58 115-127
- 13 Jarow J P, Zirkin B R. The androgen microenvironment of the human testis and hormonal control of spermatogenesis. Ann N Y Acad Sci. 2005; 1061 208-220
- 14 Bain J, Langevin R, D'Costa M, Sanders R M, Hucker S. Serum pituitary and steroid hormone levels in the adult male: one value is as good as the mean of three. Fertil Steril. 1988; 49 123-126
- 15 Vermeulen A, Verdonck L, Kaufman J M. A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab. 1999; 84 3666-3672
- 16 Wang C, Catlin D H, Demers L M, Starcevic B, Swerdloff R S. Measurement of total serum testosterone in adult men: comparison of current laboratory methods versus liquid chromoatography-tandem mass spectrometry. J Clin Endocrinol Metab. 2004; 89 534-543
- 17 Handelsman D J. Update in andrology. J Clin Endocrinol Metab. 2007; 92 4505-4511
- 18 Rosner W, Auchus R J, Azziz R, Sluss P M, Raff H. Position statement: utility, limitations, and pitfalls in measuring testosterone: an Endocrine Society position statement. J Clin Endocrinol Metab. 2007; 92 405-413
- 19 Carruthers M. Androgen Deficiency in the Adult Male: Causes, Diagnosis and Treatment. London, England; Taylor & Francis 2004
- 20 Harman S M, Metter E J, Tobin J D, Pearson J, Blackman M R. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. J Clin Endocrinol Metab. 2001; 86 724-731
- 21 Melmed S. Update in pituitary disease. J Clin Endocrinol Metab. 2008; 93 331-338
- 22 Trarbach E B, Baptista M TM, Garmes H M, Hackel C. Molecular analysis of KAL-1, GnRH-R, NELF and EBF2 genes in a series of Kallmann syndrome and normosmic hypogonadotropic hypogonadism patients. J Endocrinol. 2005; 187 361-368
- 23 Bhagavath B, Podolsky R H, Ozata M et al.. Clinical and molecular characterization of a large sample of patients with hypogonadotropic hypogonadism. Fertil Steril. 2006; 85 706-713
- 24 Nachtigall L B, Boepple P A, Pralong F P, Crowley Jr W F. Adult-onset idiopathic hypogonadotropic hypogonadism – a treatable form of male infertility. N Engl J Med. 1997; 336 410-415
- 25 Goldstone A P, Beales P L. Genetic obesity syndromes. Front Horm Res. 2008; 36 37-60
- 26 Giltay J C, Deege M, Blankenstein R A, Kastrop P MM, Wijmenga C, Lock T TWT. Apparent primary follicle-stimulating hormone deficiency is a rare cause of treatable male infertility. Fertil Steril. 2004; 81 693-696
- 27 Bunin G R, Surawicz T S, Witman P A, Preston-Martin S, Davis F, Bruner J M. The descriptive epidemiology of craniopharyngioma. J Neurosurg. 1998; 89 547-551
- 28 Karavitaki N, Cudlip S, Adams C B, Wass J A. Craniopharyngiomas. Endocr Rev. 2006; 27 371-397
- 29 Murialdo G, Tamagno G. Endocrine aspects of neurosarcoidosis. J Endocrinol Invest. 2002; 25 650-662
- 30 Courtney C H, Atkinson A B. Lewis ASCommentStCommentEndCommentBody . All patients with ‘idiopathic’ hypopituitarism should be screened for hemochromatosis. Pituitary. 2008; , February 13 (Epub ahead of print)
- 31 Bayrak A, Saadat P, Mor E, Chong L, Paulson R J, Sokol R Z. Pituitary imaging is indicated for the evaluation of hyperprolactinemia. Fertil Steril. 2005; 84 181-185
- 32 Saeger W, Lüdecke D K, Buchfelder M, Fahlbusch R, Quabbe H J, Petersenn S. Pathohistological classification of pituitary tumors: 10 years of experience with the German Pituitary Tumor Registry. Eur J Endocrinol. 2007; 156 203-216
- 33 Schneider H J, Kreitschmann-Andermahr I, Ghigo E, Stalla G K, Agha A. Hypothalamopituitary dysfunction following traumatic brain injury and aneurysmal subarachnoid hemorrhage: a systematic review. JAMA. 2007; 298 1429-1438
- 34 Maiya B, Newcombe V, Nortje J et al.. Magnetic resonance imaging changes in the pituitary gland following acute traumatic brain injury. Intensive Care Med. 2008; 34 468-475
- 35 Spratt D I, Cox P, Orav J, Moloney J, Bigos T. Reproductive axis suppression in acute illness is related to disease severity. J Clin Endocrinol Metab. 1993; 76 1548-1554
- 36 Ding E L, Song Y, Malik V S, Li S. Sex differences of endogenous sex hormones and risk of type 2 diabetes: a systematic review and meta-analysis. JAMA. 2006; 295 1288-1299
- 37 Goodman-Gruen D, Barrett-Connor E. Sex differences in the association of endogenous sex hormone levels and glucose tolerance status in older men and women. Diabetes Care. 2000; 23 912-918
- 38 Hammoud A O, Gibson M, Peterson C M, Hamilton B D, Carrell D T. Obesity and male reproductive potential. J Androl. 2006; 27 619-626
- 39 Catlin D H, Cowan D A, de la Torre R et al.. Urinary testosterone (T) to epitestosterone (E) ratios by GC/MS. I. Initial comparison of uncorrected T/E in six international laboratories. J Mass Spectrom. 1996; 31 397-402
- 40 Stikkelbroeck N M, Otten B J, Pasic A et al.. High prevalence of testicular adrenal rest tumors, impaired spermatogenesis, and Leydig cell failure in adolescent and adult males with congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2001; 86 5721-5728
- 41 Ghazi A A, Hadayegh F, Khakpour G, Azizi F, Melby J C. Bilateral testicular enlargement due to adrenal remnant in a patient with C11 hydroxylase deficiency congenital adrenal hyperplasia. J Endocrinol Invest. 2003; 26 84-87
- 42 Bojesen A, Juul S, Gravholt C H. Prenatal and postnatal prevalence of Klinefelter syndrome: a national registry study. J Clin Endocrinol Metab. 2003; 88 622-626
- 43 Simpson J L, de la Cruz F, Swerdloff R S et al.. Klinefelter syndrome: expanding the phenotype and identifying new research directions. Genet Med. 2003; 5 460-468
- 44 Thomas N S, Hassold T J. Aberrant recombination and the origin of Klinefelter syndrome. Hum Reprod Update. 2003; 9 309-317
- 45 Lanfranco F, Kamischke A, Zitzmann M, Nieschlag E. Klinefelter's syndrome. Lancet. 2004; 364 273-283
- 46 Kamischke A, Baumgardt A, Horst J, Nieschlag E. Clinical and diagnostic features of patients with suspected Klinefelter syndrome. J Androl. 2003; 24 41-48
- 47 Vernaeve V, Staessen C, Verheyen G, Van Steirteghem A, Devroey P, Tournaye H. Can biological or clinical parameters predict testicular sperm recovery in 47,XXY Klinefelter's syndrome patients?. Hum Reprod. 2004; 19 1135-1139
- 48 Bojesen A, Juul S, Birkebaek N H, Gravholt C H. Morbidity in Klinefelter syndrome: a Danish register study based on hospital discharge diagnoses. J Clin Endocrinol Metab. 2006; 91 1254-1260
- 49 Swerdlow A J, Hermon C, Jacobs P A et al.. Mortality and cancer incidence in persons with numerical sex chromosome abnormalities: a cohort study. Ann Hum Genet. 2001; 65 177-188
- 50 Geschwind D H, Boone K B, Miller B L, Swerdloff R S. Neurobehavioral phenotype of Klinefelter syndrome. Ment Retard Dev Disabil Res Rev. 2000; 6 107-116
- 51 Ross J L, Roeltgen D P, Stefanatos G et al.. Cognitive and motor development during childhood in boys with Klinefelter syndrome. Am J Med Genet A. 2008; 146A 708-719
- 52 Hasle H, Mellemgaard A, Nielsen J, Hansen J. Cancer incidence in men with Klinefelter syndrome. Br J Cancer. 1995; 71 416-420
- 53 Hultborn R, Hanson C, Köpf I, Verbiené I, Warnhammar E, Weimarck A. Prevalence of Klinefelter's syndrome in male breast cancer patients. Anticancer Res. 1997; 17 4293-4297
- 54 Lue Y, Jentsch J D, Wang C et al.. XXY mice exhibit gonadal and behavioral phenotypes similar to Klinefelter syndrome. Endocrinology. 2005; 146 4148-4154
- 55 Meschede D, Horst J. The molecular genetics of male infertility. Mol Hum Reprod. 1997; 3 419-430
-
56 Cilento B G, Atala A.
Cryptorchidism, testicular torsion, and torsion of testicular appendages . In: Kandeel FR Male Reproductive Dysfunction: Pathophysiology and Treatment. New York, NY, and London, England; Informa Healthcare 2007: 161-171 - 57 Hauser R, Sokol R. Science linking environmental contaminant exposures with fertility and reproductive health impacts in the adult male. Fertil Steril. 2008; 89(Suppl 1) e59-e65
- 58 Marchetti F, Wyrobek A J. Mechanisms and consequences of paternally-transmitted chromosomal abnormalities. Birth Defects Res C Embryo Today. 2005; 75 112-129
- 59 Dowsing A T, Yong E L, Clark M, McLachlan R I, de Kretser D M, Trounson A O. Linkage between male infertility and trinucleotide repeat expansion in the androgen-receptor gene. Lancet. 1999; 354 640-643
- 60 Griffin J E. Androgen resistance – the clinical and molecular spectrum. N Engl J Med. 1992; 326 611-618
- 61 Davis-Dao C A, Tuazon E D, Sokol R Z, Cortessis V K. J Clin Endocrinol Metab. 2007; 92 4319-4326
- 62 Finkel D M, Phillips J L, Snyder P J. Stimulation of spermatogenesis by gonadotropins in men with hypogonadotropic hypogonadism. N Engl J Med. 1985; 313 651-655
-
63 Sokol R Z.
Male factor infertility . In: Lobo RA, Mishell DR Jr, Paulson RJ, Shoupe D Infertility, Contraception, and Reproductive Endocrinology. Fourth ed. Malden, MA; Blackwell Science 1997: 547-566 - 64 Bouloux P M, Nieschlag E, Burger H G et al.. Induction of spermatogenesis by recombinant follicle-stimulating hormone (puregon) in hypogonadotropic azoospermic men who failed to respond to human chorionic gonadotropin alone. J Androl. 2003; 24 604-611
- 65 Bouloux P, Warne D W, Loumaye E, Study F SH. Group in Men's Infertility. Efficacy and safety of recombinant human follicle-stimulating hormone in men with isolated hypogonadotropic hypogonadism. Fertil Steril. 2002; 77 270-273
- 66 Attia A M, Al-Inany H G, Proctor M L. Gonadotrophins for idiopathic male factor subfertility. Cochrane Database Syst Rev. 2006; 1 CD005071
- 67 Fukagai T, Kurosawa K, Sudo N et al.. Bilateral testicular tumors in an infertile man previously treated with follicle-stimulating hormones. Urology. 2005; 65 592.e16-592.e18
- 68 Liu P Y, Handelsman D J. The present and future state of hormonal treatment for male infertility. Hum Reprod Update. 2003; 9 9-23
- 69 Liu P Y, Turner L, Rushford D, McDonald J, Baker H W, Conway A J. Efficacy and safety of recombinant human follicle stimulating hormone (Gonal-F) with urinary human chorionic gonadotrophin for induction of spermatogenesis and fertility in gonadotrophin-deficient men. Hum Reprod. 1999; 14 1540-1545
- 70 Sokol R Z, McClure R D, Peterson M, Swerdloff R S. Gonadotropin therapy failure secondary to human chorionic gonadotropin-induced antibodies. J Clin Endocrinol Metab. 1981; 52 929-932
- 71 Whitten S J, Nangia A K, Kolettis P N. Select patients with hypogonadotropic hypogonadism may respond to treatment with clomiphene citrate. Fertil Steril. 2006; 86 1664-1668
- 72 Hoffman A R, Crowley Jr W F. Induction of puberty in men by long-term pulsatile administration of low-dose gonadotropin-releasing hormone. N Engl J Med. 1982; 307 1237-1241
- 73 Kliesch S, Behre H M, Nieschlag E. High efficacy of gonadotropin or pulsatile gonadotropin-releasing hormone treatment in hypogonadotropic hypogonadal men. Eur J Endocrinol. 1994; 131 347-354
- 74 Skarin G, Nillius S J, Wibell L, Wide L. Chronic pulsatile low dose GnRH therapy for induction of testosterone production and spermatogenesis in a man with secondary hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 1982; 55 723-726
- 75 Hammar M, Berg A A. Long term androgen replacement therapy does not preclude gonadotrophin-induced improvement on spermatogenesis. Scand J Urol Nephrol. 1990; 24 17-19
- 76 Ley S B, Leonard J M. Male hypogonadotropic hypogonadism. Factors influencing response to human chorionic gonadotropin and human menopausal gonadotropin, including prior endogenous androgens. J Clin Endocrinol Metab. 1985; 61 746-752
- 77 Schiff J D, Palermo G D, Veeck L L, Goldstein M, Rosenwaks Z, Schlegel P N. Success of testicular sperm injection and intracytoplasmic sperm injection in men with Klinefelter syndrome. J Clin Endocrinol Metab. 2005; 90 6263-6267
- 78 Zitzmann M, Nordhoff V, von Schönfeld V et al.. Elevated follicle-stimulating hormone levels and the chances for azoospermic men to become fathers after retrieval of elongated spermatids from cryopreserved testicular tissue. Fertil Steril. 2006; 86 339-347
- 79 Foresta C, Bettella A, Garolla A, Ambrosini G, Ferlin A. Treatment of male idiopathic infertility with recombinant human follicle-stimulating hormone: a prospective, controlled, randomized clinical study. Fertil Steril. 2005; 84 654-661
- 80 Hauser R, Temple-Smith P D, Southwick G J, de Kretser D. Fertility in cases of hypergonadotropic azoospermia. Fertil Steril. 1995; 63 631-636
- 81 Pavlovich C P, King P, Goldstein M, Schlegel P N. Evidence of a treatable endocrinopathy in infertile men. J Urol. 2001; 165 837-841
- 82 Raman J D, Schlegel P N. Aromatase inhibitors for male infertility. J Urol. 2002; 167 624-629
- 83 Sokol R Z, Palacios A, Campfield L A, Saul C, Swerdloff R S. Comparison of the kinetics of injectable testosterone in eugonadal and hypogonadal men. Fertil Steril. 1982; 37 425-430
- 84 Meikle A W, Arver S, Dobs A S, Sanders S W, Rajaram L, Mazer N A. Pharmacokinetics and metabolism of a permeation-enhanced testosterone transdermal system in hypogonadal men: influence of application site – a clinical research center study. J Clin Endocrinol Metab. 1996; 81 1832-1840
- 85 Swerdloff R S, Wang C, Cunningham G et al.. Long-term pharmacokinetics of transdermal testosterone gel in hypogonadal men. J Clin Endocrinol Metab. 2000; 85 4500-4510
Rebecca Z SokolM.D. M.P.H.
Women's and Children's Hospital, 1240 North Mission Road
Room 8K3, Los Angeles, CA 90033
Email: rsokol@usc.edu