The ABC s and T s of Male Infertility

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1 The ABC s and T s of Male Infertility Men s Health Initiative of BC - Focus on Testosterone Ethan D. Grober, MD, MEd, FRCSC Assistant Professor University of Toronto Department of Surgery, Division of Urology Women s College Hospital & Mount Sinai Hospital

2 How to Treat Low T in Men Who Want to Preserve Fertility Men s Health Initiative of BC - Focus on Testosterone Ethan D. Grober, MD, MEd, FRCSC Assistant Professor University of Toronto Department of Surgery, Division of Urology Women s College Hospital & Mount Sinai Hospital

3 Disclosures Abbott speaker, consultant Paladin speaker, consultant, research support Lilly consultant Merck - consultant

4 Focus & Objectives 1) To review the role of T in male reproduction 2) To understand the impact of exogenous T administration on male fertility potential 3) To offer safe strategies to treat low T in men who wish to preserve fertility potential

5 Why is this Man So Miserable? How Can We Help Him?

6 Why is this Man So Miserable? How Can We Help Him? Exhausted at the end of a work day Increasing moody Can t maintain an erection Lost his mojo sex drive Wife wants a baby

7 Why is this Man So Miserable? How Can we Help Him? 42 y.o. healthy male, trying to have a baby for 2 years 34 y.o. healthy female partner, regular menses Symptoms Mild ED, difficulty maintaining erections Declining libido, sex at most 2/month Exhausted at the end of the work day Moody Feels out of shape Physical examination: normally virillized male, testis 16cc, firm bilaterally, Grade 3 left varicocele Semen analysis: Volume: 2.5cc, 10 million sperm/ml, 15% motile, 15% normal morphology Hormones: FSH 5, LH 4, total testosterone 8 (normal10-28 nmol/l) prolactin 18

8 Prevalence of Hypogonadal Symptoms among Infertile Men Infertile Males Fertile Controls 20-30% of infertile Hypogonadal Symptoms ( +ADAM) men have low levels of testosterone 38% 21% Zini et al. J Urol. 2005;174(5): Lombardo et al. J Endo Invest. 2005;28(3):51-5

9 The Testicles 1) Make Sperm 2) Make Testosterone

10 The Testicles

11 Testosterone and Male Reproduction T produced by the Leydig cells of testis & regulates spermatogenesis via an effect on Sertoli cells T levels in the testis are 100-fold greater than in the blood T regulates of growth factors and cytokines critical to spermatogenesis Development & maintenance of reproductive tissues (testis, epididymus, vas, seminal vesicles, prostate, penis ) Regulates sex drive, erections, orgasmic function

12 So Why Not Just Give This Poor Guy Testosterone?

13 Potential Adverse Effects of Testosterone Replacement Therapy Erythrocytosis (IM) Hepatotoxicity (oral) Lipid profile abnormalities (oral) Gynecomastia Infertility Fluid retention Sleep apnea CHF Acne/oily skin Hair loss from scalp Prostate growth (BPH) Prostate cancer growth? Adapted from the Endocrine Society Guidelines. July, 2006.

14 Exogenous testosterone administration has a CONTRACEPTIVE effect on men

15 Hypothalamus GnRH (-) Male Reproductive Hormonal Axis (-) Pituitary (-) LH FSH Estradiol Testicles Aromatase Exogenous Testosterone Testosterone X (Leydig Cells) Spermatogenesis (Sertoli Cells)

16 Exogenous testosterone administration has a CONTRACEPTIVE effect on men World Health Organization (1990) Contraceptive Efficacy of Testosterone in Normal Men 271 fertile men Weekly testosterone injections (200mg Enanthate) 65% azoospermic at 6 months Upon discontinuations of T 6 months to return to baseline 84% achieved concentrations > 20 million/ml Only 46% returned to baseline sperm concentrations

17 + High Testosterone Levels LH < 1 FSH < 1 No sperm

18 Exogenous testosterone administration has a CONTRACEPTIVE effect on men Other options?

19 Anti-Estrogens Clomiphene Citrate or Tamoxifen

20 Anti-Estrogens Clomiphene Citrate or Tamoxifen Estrogen (not testosterone) is the primary negative feedback inhibitor on the brain regulating T production Clomid: Anti-estrogen that competitively blocks estrogen receptors in the hypothalamus and pituitary Block the negative feedback of estrogen + GnRH, LH & FSH + T production from the Leydig cells of the testis

21 X Hypothalamus GnRH (+) Male Reproductive Hormonal Axis (-) X Pituitary (-) LH FSH Estradiol Aromatase Testicles Testosterone (Leydig Cells) Spermatogenesis (Sertoli Cells)

22 Anti-Estrogens Clomiphene Citrate or Tamoxifen Evidence: LH, FSH, total & free testosterone increase significantly with anti-estrogens 1-4 Improves hypogonadal symptoms (ED, libido, energy) 2,3 Reported benefits of clomid as an empiric therapy for male infertility 4,5 1. Shabsigh et al. J Sex Med 2005;2(5): Guay et al. Int J Impot Res 2003;15(3): Mulhall et al. AUA Taylor et al. SMS 2008 Toronto 5. Cochrane Database 2007

23 Anti-Estrogens Clomiphene Citrate or Tamoxifen Evidence: Works best in younger hypogonadal men Works best in men if low/normal LH & FSH Relatively cost effective ($80/month) vs. TRT Minimal side effects (acne, weight gain, gynecomastia) Starting dose: mg every other day x 3 months

24 Aromatase Inhibitors Arimidex or Testolactone

25 Hypothalamus Male Reproductive Hormonal Axis GnRH (-) (-) Estradiol Aromatase x Pituitary LH FSH Testicles Aromatase is a cytochrome p450 enzyme present in the testis, skin, liver, brain, and adipose tissue Testosterone (Leydig Cells) Spermatogenesis (Sertoli Cells)

26 Aromatase Inhibitors Arimidex (Anastrazole) or Testolactone Evidence: Infertile men have lower Testosterone (T) and higher Estrogen (E) levels vs. fertile controls Lower T/E ratios have been established as a treatable endocrinopaty among infertile men Raman et al. J Urol Pavlovich et al. J Urol. 2001

27 Aromatase Inhibitors Arimidex (Anastrazole) or Testolactone Evidence: Aromatase inhibitors reliably increase serum T levels Increasing T/E ratios ( T & E) with aromatase inhibitors has resulted in significant improvements in semen parameters While serum T increases >? Hypogonadal symptoms improve Arimidex (1mg daily), Testolactone ( mg daily) Raman et al. J Urol Pavlovich et al. J Urol. 2001

28 Gonadotrophins Human Chorionic Gonadotrophin (HCG)

29 Hypothalamus Male Reproductive Hormonal Axis GnRH (-) Pituitary (-) HCG LH FSH Estradiol Aromatase Testicles Testosterone (Leydig Cells) Spermatogenesis (Sertoli Cells)

30 Gonadotrophins: Human Chorionic Gonadotrophin (HCG) HCG purified LH (urine/synthetic) Efficacy established for the treatment of hypogonadotropic hypogonadal men Congenital: Kallmans Syndrome (anosmia) Acquired pituitary/hypothalamic disease (malignancy, trauma, surgery, radiation, infarct, infection) Idiopathic

31 Gonadotrophins: Human Chorionic Gonadotrophin (HCG) HCG: Increases serum T levels, initiates and maintains spermatogenesis, ameliorate hypogondal symptoms Used to kick start the reproductive axis among men with premature hypogonadism secondard to anabolic steroid abuse HMG or purified FSH may be needed to support spermatogenesis HCG: IU IM 2-3 x/week

32 Gonadotrophin Releasing Hormone (GnRH)?

33 Hypothalamus Male Reproductive Hormonal Axis (-) (-) GnRH Pituitary LH FSH Requires a functional pituitary $$$ Pump/injection Work no better than HCG/HMG/FSH Estradiol Aromatase Testicles Testosterone (Leydig Cells) Spermatogenesis (Sertoli Cells)

34 Hyperprolactinemia Dopamine Agonists: Cabergoline (Dostinex), Bromocriptine

35 Hyperprolactinemia - Dopamine Agonists: Cabergoline (Dostinex), Bromocriptine Prolactin is elevated in up to 12% of infertile men

36 Hyperprolactinemia - Dopamine Agonists: Cabergoline (Dostinex), Bromocriptine Prolactin is elevated in up to 12% of infertile men Pituitary adenomas (micro/macro) Hypothyroidism Liver/renal/chronic diseases Medications Stress response

37 (-) Hypothalamus GnRH Pituitary (-) Male Reproductive Hormonal Axis Prolactin (-) Estradiol Aromatase (-) LH FSH Testicles Clinical Consequences Oligospermia Hypogonadal Symptoms Testosterone (Leydig Cells) (-) Spermatogenesis (Sertoli Cells)

38 Hyperprolactinemia - Dopamine Agonists: Cabergoline (Dostinex), Bromocriptine 0.5 mg twice weekly mg daily Inhibits pituitary prolactin release

39 Hyperprolactinemia - Dopamine Agonists: Cabergoline (Dostinex), Bromocriptine Pituitary mico/macroadenoma & hyperprolactinemia Dopamine agonist De Rossa et al. Clin Endo. 2006;64: Ono et al. J Clin Edno Metab. 2008; epub Nomalize: Semen parameters Serum T levels Hypogonadal symptoms (ED, libido, fatigue)

40 Varicocelectomy: Varicoceles are a Established leading cause association of between male infertility varicoceles and low serum testosterone levels 15% of all males 40% infertile males Su et al. J Urol. 1995;154:

41 Varicocelectomy: Vein Improves semen parameters in 60-70% men Significantly increases serum T levels (30%) Artery Su et al. J Urol. 1995;154: Grober et al. Fertil Steril. 2004;82:

42 Targeted Symptomatic Treatment

43 Targeted Symptomatic Treatment

44 Targeted Symptomatic Treatment Sex Therapy

45 Sperm Cryopreservation Offer to all patients on exogenous TRT interested in future fertility!

46 Key Points Hypogonadal symptoms and low T are common among infertile men Testosterone is an essential mediator of normal spermatogenesis Hypogonadal symptoms (ED, low libido, depression) have a direct impact on relationships and successful conception Exogenous T administration adversely impacts male fertility potential Treatments should be aimed at supporting endogenous T production, decreasing hypogonadal symptoms without adversely impacting (potentially supporting) spermatogenesis

47

48 The ABC s and T s of Male Infertility Men s Health Initiative of BC - Focus on Testosterone Ethan D. Grober, MD, MEd, FRCSC Assistant Professor University of Toronto Department of Surgery, Division of Urology Women s College Hospital & Mount Sinai Hospital

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