Male Hypogonadism. Hypogonadism is characterised by impaired testicular function, which may affect spermatogenesis and/or testosterone synthesis.

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1 L APPROCCIO MEDICO AL PAZIENTE AZOOSPERMICO Marco Rossato Università degli Studi di Padova Dipartimento di Medicina - DIMED Clinica Medica 3 Direttore: prof. Roberto VETTOR Male Hypogonadism Hypogonadism is characterised by impaired testicular function, which may affect spermatogenesis and/or testosterone synthesis. The symptoms of hypogonadism depend on the degree of androgen deficiency and if the condition develops before or after pubertal development of the secondary sex characteristics. 1

2 Hormonal control of human reproduction Hormonal control of testicular function GnRH T( E 2 ) INHIBIN B LH FSH T = Testosterone LH = Leuteinizing Hormone (regulates T secretion) FSH = Follicle Stimulating Hormone (regulates seminiferous tubule function) GnRH = Gonadotropin Releasing Hormone (regulates LH & FSH secretion) INHIBIN B = from Sertoli cells feed-back on the pituitary to regulate FSH secretion 2

3 Male Hypogonadism Primary hypogonadism (testicular) (characterized by high levels of FSH and LH, and low levels of testosterone) Secondary hypogonadism (pituitary or hypothalamic) (characterized by low levels of FSH, LH and testosterone) Infectious orchitis: viral, granulomatous, bacterial Drugs: alkylating agents, alcohol, marijuana, antiandrogens, ketoconazole, spironolactone, histamine receptor antagonists Environmental toxins: dibromochloropropane, carbon disulfide, cadmium, lead, mercury, environmental estrogens and phytoestrogens Radiation exposure Hyperthermia Systemic illness Trauma or torsion Klinefelter s syndrome Pituitary and hypothalamic tumors: macroadenoma, craniopharyngioma, postsurgical resection Infiltrative disorders: sarcoidosis, histiocytosis, hemocromatosis tuberculosis, fungal infections Hormonal: hyperprolactinemia, androgen excess, estrogen excess, cortisol excess Drugs: opioids and psychotropic drugs, GnRH agonists or antagonists Nutritional deficiency Systemic illness Obesity The Problem of Azoospermia Infertility or subfertility affects 15% of couples, with a male factor contributing to the fertility problem in close to 50% of these couples. Of the men presenting for fertility investigation, up to 20% are found to be azoospermic 1% of all men % of infertile men History Physical Exam Hormones SemenAnalysis Obstructive (7-51%) Repair ICSI ICSI Non-obstructive (49-93%) PRE-TESTICULAR POST-TESTICULAR 3

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5 Guidelines on Male Infertility Conclusions concerning medical treatment MEDICAL TREATMENT IN MALE INFERTILITY 5

6 MEDICAL TREATMENT IN MALE INFERTILITY 1- Specific Therapy Endocrine Disorders Hypogonadotropic Hypogonadism Accounts for less than 1% of all cases of male infertility Gonadotropin replacement is the rational treatment and is the only clearly accepted and effective management of associated infertility Endocrinol Metab Clin North Am Hormonal control of testicular function GnRH T( E 2 ) INHIBIN B LH FSH T = Testosterone LH = Leuteinizing Hormone (regulates T secretion) FSH = Follicle Stimulating Hormone (regulates seminiferous tubule function) GnRH = Gonadotropin Releasing Hormone (regulates LH & FSH secretion) INHIBIN B = from Sertoli cells feed-back on the pituitary to regulate FSH secretion 6

7 Endocrine Disorders Normal male fertility: Adequate levels of intratesticular testosterone Adequate levels of follicle-stimulating hormone (FSH) FSH has been shown to initiate and maintain spermatogenesis Endocrine Disorders Gonadotropin replacement treatment hcg HP-FSH hmg mimics LH and FSH Purified FSH Pulsatile GnRH Normal Physiology Kallman Syndrome İnfrequent, a portable minipump, an inconvenient, costly practice 7

8 Endocrine Disorders Gonadotropin replacement in azoospermic male with HH: Initial management: hcg i.m. or s.c IU/twice a week (until adequate serum testosterone levels detected) concomitant treatment hmg ( IU 2-3 times/week) FSH ( IU 3 times/week) From 3 to 1-2 years of treatment Endocrine Disorders Androgens Exogenous testosterone therapy is detrimental for sperm production and has a contraceptive effect (role of intratesticular androgen concentrations). 8

9 Endocrine Disorders Gonadotropin Replacement Gonadotropins have proven highly effective in inducing fertility Eur J Endocrinol Sep;139(3): Int J Androl Oct;17(5):241-7 Int J Androl Aug;15(4):320-9 Predictive factors of gonodotropin replacement response The knowledge of the tubular status seems to be the only predictive parameter because in all patients FSH and inhibin B plasma levels were in the normal range 9

10 MEDICAL TREATMENT IN AZOOSPERMIA Empiric Hormonal Therapy A. Antiestrogens B. Aromatase inhibitors C. Alternative therapy 10

11 MEDICAL TREATMENT IN AZOOSPERMIA Gonadotropins registered indications 11

12 Gonadotropine in commercio in Italia - Classe A, nota 74, PT/PHT Attività Principio attivo Nome commerciale FSH r-α-follitropina Gonal F r-β-follitropina Puregon r-α-corifollitropina Elonva (No infertilità maschile) Urofollitropina Fostimon LH r-α-lutropina Luveris (No infertilità maschile) FSH + LH r-α-follitropina + r-α-lutropina Menotropina Pergoveris (No infertilità maschile) Menogon Meropur (No infertilità maschile) hcg r-α-coriogonadotropina Ovitrelle (No infertilità maschile) Gonadotropina corionica Gonasi Pregnyl Guidelines Strategie di trattamento dei diversi tipi di infertilità di coppia 12

13 RECOMMENDATIONS Medical treatment of the azoospermic male can only be advised in cases of hypogonadotrophic hypogonadism Medical treatment of male infertility can be more valuable in conjuction with sperm cryopreservation 13