Male Reproductive Disorders F23 D2L.ppt.pdf

Male Reproductive Disorders Beth Zerr, PharmD BCACP 11/14/23 Outline • Development of male and female phenotypic fetuses • Normal structure and function • Pathophysiology of BPH • Pathophysiology of Infertility Abbreviations SHBG – sex-hormone binding globulin BPH – benign prostatic hyperplasia...

Male Reproductive Disorders Beth Zerr, PharmD BCACP 11/14/23 Outline • Development of male and female phenotypic fetuses • Normal structure and function • Pathophysiology of BPH • Pathophysiology of Infertility Abbreviations SHBG – sex-hormone binding globulin BPH – benign prostatic hyperplasia T – testosterone E – estrogen DHT – dihydrotestosterone FSH – follicle stimulating hormone LH – luteinizing hormone GnRH – gonadotropin releasing hormone LUTS – lower urinary tract symptoms Differentiation of male and female reproductive organs Male • Wolffian duct • Sertoli cells – anti-Mullerian hormone • Leydig cells – testosterone • DHT Female • Mullerian duct • Absence of anti-Mullerian hormone, testosterone and DHT Citation: Disorders of the Female Reproductive Tract, Hammer GD, McPhee SJ. Pathophysiology of Disease: An Introduction to Clinical Medicine, 8e; 2019. Available at: https://accesspharmacy.mhmedical.com/content.aspx?bookid=2468&sectionid=198224594 Accessed: April 17, 2019 Copyright © 2019 McGraw-Hill Education. All rights reserved Differentiation of male and female reproductive organs Male • Wolffian duct • Sertoli cells – anti-Mullerian hormone • Leydig cells – testosterone • DHT Female • Mullerian duct • Absence of anti-Mullerian hormone, testosterone and DHT Citation: Chapter 9 Reproductive Physiology, kibble JD. The Big Picture Physiology: Medical Course & Step 1 Review, 2e; 2020. Available at: https://accessmedicine.mhmedical.com/ViewLarge.aspx?figid=24554 4542&gbosContainerID=0&gbosid=0&groupID=0&sectionId=245544 538&multimediaId=undefined Accessed: April 12, 2021 Copyright © 2021 McGraw-Hill Education. All rights reserved Patient Case Sarah is a 25 yo pharmacy tech. She is 8 weeks pregnant. She is filling a finasteride prescription. Finasteride works to inhibit the conversion of testosterone to dihydrotestosterone (DHT) in the body. What is the potential risk to Sarah and/or her fetus if she is exposed to this drug? Patient Case Sarah is a 25 yo pharmacy tech. She is 8 weeks pregnant. She is filling a finasteride prescription. Finasteride works to inhibit the conversion of testosterone to dihydrotestosterone (DHT) in the body. What is the potential risk to Sarah and/or her fetus if she is exposed to this drug? What is the effect of androgen exposure on a female fetus? Androgen deficiency on a male fetus? Outline • Development of male and female phenotypic fetuses • Males – Wolffian duct (anti-Mullerian hormone), DHT • Females – Mullerian duct • Normal structure and function • Pathophysiology of BPH • Pathophysiology of Infertility Summary • Leydig cells → intratubular connective tissue → make testosterone • Sertoli cells → tubular compartment → spermatogenesis • Blood-testis barrier Anatomy of the male reproductive system (left) and the duct system of the testis (right). (Redrawn, with permission, from Barrett KE et al. Ganong’s Review of Medical Physiology, 25th ed. McGraw-Hill, 2016.) Citation: Disorders of the Male Reproductive Tract, Hammer GD, McPhee SJ. Pathophysiology of Disease: An Introduction to Clinical Medicine, 8e; 2019. Available at: https://accesspharmacy.mhmedical.com/content.aspx?bookid=2468&sectionid=198224783 Accessed: April 05, 2019 Copyright © 2019 McGraw-Hill Education. All rights reserved Clinical question • Approximately 2-5% of all full-term male infants, and 30% of premature infants are born with cryptorchidism (undescended testicles). • Most descend spontaneously, leaving approximately 1% of male infants with cryptorchidism at age 1. • Decreased fertility is a potential sequelae of cryptorchidism – why? Testosterone formation and metabolism DHT Copyrights apply Testosterone formation and metabolism 5-α-reductase type I and II – liver and skin 5-α-reductase type II – reproductive tissues Copyrights apply Testosterone and SHBG • Sex hormone-binding globulin (SHBG) • Majority of circulating T is bound to SHBG • 2% loosely bound to albumin or unbound – ‘free testosterone level’ if SHBG then biologically active T What can increase SHBG? • Advanced age • Estrogen • Untreated hypERthyroidism What can decrease SHBG? • Obesity • Androgen administration • Untreated hypOthyroidism Copyrights apply Leisegang K, et al. Obesity and male infertility: Mechanisms and management. Andrologia, May 12 2020, 53(1):e:13167. Androgen action • Development of male characteristics in developing fetus • HPA gonadotropin secretion • Sexual maturation and function • Development of secondary sexual characteristics • Closure of long-bone epiphyses • Increased muscle mass and bone density, decreased fat • Spermatogenesis • Increasing and maintenance of erythropoiesis and hematocrit Mechanism of androgen action. (DHT, dihydrotestosterone; Rc, cytoplasmic receptor, which becomes the nuclear receptor, Rn, in the nucleus; T, testosterone.) (Redrawn, with permission, from Gardner DG et al. Greenspan’s Basic and Clinical Endocrinology, 10th ed. McGraw-Hill, 2017.) Citation: Disorders of the Male Reproductive Tract, Hammer GD, McPhee SJ. Pathophysiology of Disease: An Introduction to Clinical Medicine, 8e; 2019. Available at: https://accesspharmacy.mhmedical.com/content.aspx?bookid=2468&sectionid=198224783 Accessed: April 05, 2019 Copyright © 2019 McGraw-Hill Education. All rights reserved Tubular compartment and spermatogenesis Germ cell spermatogonia spermatocytes spermatids spermatozoa Key points • • • • Blood Testes - Barrier Spermatogenesis FSH and LH High levels of intratesticular testosterone needed • Transport Schematic section of testis. (Redrawn, with permission, from Barrett KE et al. Ganong’s Review of Medical Physiology, 25th ed. McGraw-Hill, 2016.) Citation: Disorders of the Male Reproductive Tract, Hammer GD, McPhee SJ. Pathophysiology of Disease: An Introduction to Clinical Medicine, 8e; 2019. Available at: https://accesspharmacy.mhmedical.com/content.aspx?bookid=2468&sectionid=198224783 Accessed: April 05, 2019 Copyright © 2019 McGraw-Hill Education. All rights reserved Anatomy of the male reproductive system (left) and the duct system of the testis (right). (Redrawn, with permission, from Barrett KE et al. Ganong’s Review of Medical Physiology, 25th ed. McGraw-Hill, 2016.) Citation: Disorders of the Male Reproductive Tract, Hammer GD, McPhee SJ. Pathophysiology of Disease: An Introduction to Clinical Medicine, 8e; 2019. Available at: https://accesspharmacy.mhmedical.com/content.aspx?bookid=2468&sectionid=198224783 Accessed: April 05, 2019 Copyright © 2019 McGraw-Hill Education. All rights reserved Hypothalamic-Pituitary-Gonadal axis Summary • Hypothalamus releases GnRH • Pituitary releases FSH and LH • FSH acts on Sertoli cells in the testes stimulating spermatogenesis and inhibin • LH acts on Leydig cells in testes stimulating T formation • Inhibin provides the main negative feedback action on FHS release • Both FSH and intratesticular T concentration are needed for spermatogenesis Endocrine control of the male reproductive system. (ABP, androgen-binding protein; DHT, dihydrotestosterone; E2, estradiol; GnRH, gonadotropinreleasing hormone; T, testosterone.) (Redrawn and modified, with permission, from Gardner DG et al. Greenspan’s Basic and Clinical Endocrinology, 10th ed. McGraw-Hill, 2017.) Citation: Disorders of the Male Reproductive Tract, Hammer GD, McPhee SJ. Pathophysiology of Disease: An Introduction to Clinical Medicine, 8e; 2019. Available at: https://accesspharmacy.mhmedical.com/content.aspx?bookid=2468&sectionid=198224783 Accessed: April 05, 2019 Copyright © 2019 McGraw-Hill Education. All rights reserved Hypothalamic-Pituitary-Gonadal axis What if? • • • • • • Damaged seminiferous tubules Damaged Leydig cells Elevated estradiol Fasting / anorexia Chronic illness Meds • Chronic opioids • Corticosteroids • 2nd gen antipsychotics Endocrine control of the male reproductive system. (ABP, androgen-binding protein; DHT, dihydrotestosterone; E2, estradiol; GnRH, gonadotropinreleasing hormone; T, testosterone.) (Redrawn and modified, with permission, from Gardner DG et al. Greenspan’s Basic and Clinical Endocrinology, 10th ed. McGraw-Hill, 2017.) Citation: Disorders of the Male Reproductive Tract, Hammer GD, McPhee SJ. Pathophysiology of Disease: An Introduction to Clinical Medicine, 8e; 2019. Available at: https://accesspharmacy.mhmedical.com/content.aspx?bookid=2468&sectionid=198224783 Accessed: April 05, 2019 Copyright © 2019 McGraw-Hill Education. All rights reserved Summary • Development of male and female phenotypic fetuses • Normal structure and function – Hypothalamic – pituitary – gonadal axis – Testes • Interstitial, Leydig cells, LH, testosterone • Tubular, Sertoli cells, FSH (LH), sperm – Androgen action • Pathophysiology of BPH • Pathophysiology of Infertility Patient Case Frank is a 64-year-old male who presents to his PCP with complaints of urinary urgency and slow urine stream. He has been experiencing these symptoms for a couple years, but they seem to be getting worse. Is he suffering from BPH? Benign Prostatic Hyperplasia BPH • LUTS • Obstructive/voiding symptoms • Decreased stream • Weak flow • Hesitancy • Incomplete/storage voiding • Irritative/storage symptoms • Urgency / frequency • nocturia • Enlarged prostate Citation: Disorders of the Male Reproductive Tract, Hammer GD, McPhee SJ. Pathophysiology of Disease: An Introduction to Clinical Medicine, 8e; 2019. Available at: https://accesspharmacy.mhmedical.com/content.aspx?bookid=2468&sectionid=198224783 Accessed: April 05, 2019 Copyright © 2019 McGraw-Hill Education. All rights reserved Copyrights apply Androgen action on prostatic stromal (muscle) and epithelial (gland) cells Citation: Disorders of the Male Reproductive Tract, Hammer GD, McPhee SJ. Pathophysiology of Disease: An Introduction to Clinical Medicine, 8e; 2019. Available at: https://accesspharmacy.mhmedical.com/content.aspx?bookid=2468&sectionid=198224783 Accessed: April 05, 2019 Copyright © 2019 McGraw-Hill Education. All rights reserved Medication therapy for BPH Alpha1 receptor blockers 5 alpha reductase inhibitors Citation: Disorders of the Male Reproductive Tract, Hammer GD, McPhee SJ. Pathophysiology of Disease: An Introduction to Clinical Medicine, 8e; 2019. Available at: https://accesspharmacy.mhmedical.com/content.aspx?bookid=2468&sectionid=198224783 Accessed: April 05, 2019 Copyright © 2019 McGraw-Hill Education. All rights reserved Androgen deprivation as treatment for BPH What other actions in the body would be expected with complete androgen suppression? Endocrine control of the male reproductive system. (ABP, androgen-binding protein; DHT, dihydrotestosterone; E2, estradiol; GnRH, gonadotropinreleasing hormone; T, testosterone.) (Redrawn and modified, with permission, from Gardner DG et al. Greenspan’s Basic and Clinical Endocrinology, 10th ed. McGraw-Hill, 2017.) Citation: Disorders of the Male Reproductive Tract, Hammer GD, McPhee SJ. Pathophysiology of Disease: An Introduction to Clinical Medicine, 8e; 2019. Available at: https://accesspharmacy.mhmedical.com/content.aspx?bookid=2468&sectionid=198224783 Accessed: April 05, 2019 Copyright © 2019 McGraw-Hill Education. All rights reserved True anti-androgens (GnRH agonists or androgen receptor blockers) vs. 5 alpha reductase inhibitors • • • • Which lowers DHT? Which lowers T? Which lowers LH? Clinical effects? Citation: Disorders of the Male Reproductive Tract, Hammer GD, McPhee SJ. Pathophysiology of Disease: An Introduction to Clinical Medicine, 8e; 2019. Available at: https://accesspharmacy.mhmedical.com/content.aspx?bookid=2468&sectionid=198224783 Accessed: April 05, 2019 Copyright © 2019 McGraw-Hill Education. All rights reserved Management algorithm for benign prostatic hyperplasia (BPH). Citation: Chapter 67. Benign Prostatic Hyperplasia, DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. Pharmacotherapy: A Pathophysiologic Approach, 9e; 2014. Available at: https://accesspharmacy.mhmedical.com/ViewLarge.aspx?figid=45319778&gbosContainerID=0&gbosid=0&groupID=0 Accessed: April 07, 2019 Copyright © 2019 McGraw-Hill Education. All rights reserved Dutasteride – 5 alpha reductase inhibitor Tamsulosin – alpha blocker Copyrights apply Summary • Development of male and female phenotypic fetuses • Normal structure and function – Testes • Interstitial, Leydig cells, LH, testosterone • Tubular, Sertoli cells, FSH (LH), sperm – Hormone movement and action – Hypothalamic – pituitary – gonadal axis • Pathophysiology of BPH – Age + Androgens = BPH – Stromal (smooth muscle) and epithelial (glandular) components – Alpha blockers, 5-alpha reductase inhibitors and total androgen deprivation therapy (GnRH agonists and androgen receptor blockers) • Pathophysiology of Infertility Infertility • • • • What is required for conception? Definition Male vs female Pre-testicular, testicular and post-testicular Signal Problem Production Problem Secondary hypogonadism Primary hypogonadism Transport Problem Infertility – Pretesticular Secondary Hypogonadism • Decreased or absent GnRH → and/or decreased FSH/LH → decreased T production and spermatogenesis Signal Problem Infertility – Pretesticular Secondary hypogonadism 1. Genetic abnormalities 2. Suppression of gonadotrophs • • • • • • • • Hyperprolactinemia GnRH analogs Corticosteroids Opioids DM Obesity Thyroid disorder Anabolic steroid use 3. Damage to gonadotrophs • Tumors • Infection • Trauma Signal Problem Infertility - Testicular Primary Hypogonadism • Direct effects on testes inhibit spermatogenesis – Normal or elevated GnRH → normal or elevated FSH/LH – Decreased T production and spermatogenesis Production Problem Infertility - Testicular Primary Hypogonadism • • • • • • • • • • Varicocele Genetic abnormality Cryptorchidism Toxins Cigarette smoking Temperature Chemo/radiation Infections Torsion of spermatic cord Testicular trauma Production Problem Infertility – Transport Post-testicular Problem • Ductal obstruction – Congenital or acquired – Epididymitis • Congenital bilateral absence of the vas deferens (CBAVD) • Ejaculatory duct obstruction • Immunologic infertility • Disorders of ejaculation – Diabetes - via neuropathy – Vascular disease – Medications – alpha blockers, antipsychotics, antidepressants Infertility evaluation • Medical history • Physical history • Semen analysis Approach to the diagnosis of male infertility. (ART, assisted reproductive technologies; FSH, follicle-stimulating hormone; LH, luteinizing hormone; PRL, prolactin; TSH, thyroid-stimulating hormone.) (Redrawn, with permission, from Gardner DG et al. Greenspan’s Basic and Clinical Endocrinology, 9th ed. McGraw-Hill, 2011.) Citation: Disorders of the Male Reproductive Tract, Hammer GD, McPhee SJ. Pathophysiology of Disease: An Introduction to Clinical Medicine, 8e; 2019. Available at: https://accesspharmacy.mhmedical.com/content.aspx?bookid=2468&sectionid=198224783 Accessed: April 05, 2019 Copyright © 2019 McGraw-Hill Education. All rights reserved Summary • Development of male and female phenotypic fetuses – Males – Wolffian duct – anti-Mullerian hormone, DHT – Females – Mullerian duct • Normal structure and function – Testes • Interstitial, Leydig cells, LH, testosterone • Tubular, Sertoli cells, FSH (LH), sperm – Hormone movement and action – Hypothalamic – pituitary – gonadal axis • Pathophysiology of BPH – Age + Androgens = BPH – Stromal (smooth muscle) and epithelial (glandular) components – Alpha blockers, 5-alpha reductase inhibitors and total androgen deprivation therapy (GnRH agonists and androgen receptor blockers) • Pathophysiology of Infertility – Pre-testicular, testicular, post-testicular • Definitions and examples in red Questions? Email Dr. Zerr at [email protected]