Complex Infertile Cases approach and management

1. Complex Infertile Cases approach and management Dr. Anmar Nassir, FRCS(C) Canadian board in General Urology Fellowship in Andrology (U of Ottawa) Fellowship in EndoUrology and Laparoscopy (McMaster Univ) Assisstent Prof Umm Al-Qura Consultant Urology King Khalid National Guard Hospital

2. The hypothalamo-pituitary-gonadal axis provides pulsatile secretion of GnRH • GnRH pulses are released every 90 to 120 minutes • LH and FSH release from the pituitary to stimulate spermatogenesis and testosterone production. • Diurnal variation of testosterone results in higher morning levels of testosterone

3. Pituitary-Gonadal Axis • LH • Activate testicular T production from Leydig cells • Feed back inhibition by testosterone • FSH • Stimulate Sertoli cells & spermatogonial membranes • The major stimulator of seminiferous tubule growth during development • Feed back inhibition by inhibin from Sertoli cells

5. The seminiferous tubules have a combined length of approximately 250 meters. • The rete testis coalesces to form the 6 to 12 ductuli efferentes, • They carry testicular fluid and spermatozoa into the caput epididymis.

7. The scrotal temperature is is 2°C to 4°C below rectal temperature due to counter-current mechanism • Testosterone will initiate and maintain spermatogenesis • Sperm fertility maturation, achieved at the level of the distal corpus or proximal cauda epididymis.

9. Patterns of tail movement in human epididymal spermatozoa. A, The pattern shown by spermatozoa taken from proximal regions of the epididymis is characterized by a high-amplitude, low-frequency beat producing little forward movement. B, In contrast, tail movement in a large proportion of spermatozoa from the cauda epididymis is characterized by low-amplitude, rapid beats that result in forward progression.

10. The oval sperm head consists principally of • a nucleus that contains highly compacted chromatin material • an acrosome that contains the enzymes required for penetration of the outer vestments of the egg.

11. ▪ The middle piece of the spermatozoon consists of • helically arranged mitochondria surrounding • outer dense fibers • 9 + 2 microtubular structure of the sperm axoneme. ▪ The sperm tail has outer dense fibers, rich in disulfide bonds, • provide the rigidity necessary for progressive motility.

12. Sperm fertility maturation in the human epididymis. Sperm fertilizing ability was assessed using zona pellucida-free hamster eggs and by changes in motility, which increases in the distal regions of the human epididymis.

13. The process of spermatogenesis and spermiogenesis takes approximately 64 days in humans and results in a haploid germ cell that acquires natural ability to fertilize oocytes during epididymal transport. • Spermatogenesis is an androgen-dependent process that optimally occurs with very high intratesticular levels of testosterone . • Spermatozoa exiting the testis are immotile and have limited capacity to fertilize an oocyte unless assisted reproductive techniques are applied. • After epididymal transit (that takes 2 to 11 days), sperm are typically motile and capable of fertilization without assistance. • Immediately before emission, spermatozoa are rapidly and efficiently transported to the ejaculatory ducts from the distal epididymis. • Spermatozoal function does not stop at the time of fertilization; • sperm-derived spindles even drive embryo development.

15. Physiology • Epididymis: • Maturation • Transport • Storage • Vas: • Transfer of sperm • Seminal vesicles (The main bulk of the ejaculate): • Secretory products: e.g. • fructose, prostaglandin, clotting factors • Ejaculation • Coagulation of semen • Prostate: • Liquifaction • Zn: antibacterial & sperm stabilization Seminal vesicles  1.5 to 2.0 mL. Prostate  0.5 mL, Cowper's glands  0.1 to 0.2 mL,

16. Before the ejaculation of the major portion of the ejaculate, a small amount of fluid from the glands of Littre and the bulbourethral glands is secreted. • This is followed by a low viscosity opalescent fluid from the prostate containing a few sperm. • The principal portion of the ejaculate contains the highest concentration of sperm, along with secretions from the testis, epididymis, and vas deferens, as well as some prostatic and seminal vesicle fluids. • The last fraction of the ejaculate consists of seminal vesicle secretions. • The majority of ejaculated sperm come from the distal epididymis, with a small contribution from the ampulla of the vas.

18. The chance of a normal couple conceiving is estimated to be • 20% to 25% per month, • 75% by 6 months • 90% by 1 year. • Fertility rates are at their peak in men and women at age 24. • Studies of couples of unknown fertility status that are attempting to conceive within 1 year, • 15% of couples are unable to do so. • 20% of cases of infertility are due entirely to a male factor, • 30% to 40% of cases involving both male and female factors. • male factor is present in one half of infertile couples.

19. Of infertile couples without treatment, • 25% to 35% will conceive at some time by intercourse alone • 23% will conceive within the first 2 years, • 10% will do so within 2 more years. (pregnancy rate of 1% to 3% per month ) • Infertility is often not considered to exist until after 12 months of attempted conception, • With the advancing age of infertile couples, it is not recommend deferring an initial evaluation. A basic, simple, cost-effective evaluation of both the male and female partners should be initiated at the time of presentation.

21. Evaluation ofInfertile patient

22. Infertility History

23. Impairing Spermatogenesis • Medications: • nitrofurantoin , • cimetidine , • sulfasalazine , • Anabolic steroid • Substances: • cocaine • marijuana • Nicotine • pesticides

24. Many of the genes that affect male reproduction, including the androgen receptor gene, are located on the X chromosome. • Therefore, family history should focus on the phenotype of the maternal uncles

25. Pregnancy rates in normal fertile couples are 20% to 25% per cycle compared with 1% to 3% in infertile couples. • A thorough medical and reproductive history should be obtained on all men presenting with infertility. • The female partner should be questioned about key aspects of her fertility evaluation.

26. Abnormalities in the woman are involved in approximately 75% of infertile couples. • 30% Ovulatory disorders • 25% fallopian tube abnormalities • 4% endometriosis • 4% cervical mucus abnormalities • 4% hyperprolactinemia • Conception rates drop more rapidly in the 35- to 39-year-old age group.

27. Physical Exam

29. This may be performed using calipers, an orchidometer, or sonography. • The normal adult testis is • greater than 4 × 3 cm in its greatest dimensions or • greater than 20 mL in volume for whites and African Americans. • Asian men normally have smaller testes.

30. Laboratory Assessment • Semen analysis X2 • Quantitation of leukocytes in semen • Lab: Baseline, gluc. , U/A • Hormonal assay FSH, LH, Prol, TSH, • Other tests: Antisperm antibodies: semen or blood Advanced sperm fertility tests

31. Semen • The WHO (1999) defines the following reference values:

35. rigid criteria

36. Small volume ejaculates may be produced in patients with • obstruction of the ejaculatory ducts, • retrograde ejaculation, • sympathetic denervation, • androgen deficiency • drug therapy, • absence of the vas deferens • absence of seminal vesicles, • bladder neck surgery.

37. Hormonal Evaluation • Although male reproductive function is critically dependent on endocrinologic control, less than 3% of infertile men have a primary hormonal etiology • endocrine abnormalities are rarely present when the sperm concentration is greater than 10 million/mL

38. Hormonal Evaluation

39. Most prolactin-secreting tumors in men are macroadenomas (tumors greater than 1 cm) • Prolactin levels in these patients are typically higher than 50 ng/mL, and both gonadotropin and serum testosterone levels are depressed. • In infertile patients • Mild elevations of prolactin (<50 ng/mL) are more frequently discovered, • Their clinical significance is questionable. • Imaging often fails to identify a tumor in these patients, • They often have normal gonadotropin and testosterone levels.

40. Potential causes for mild prolactin elevation include • stress, • renal failure, • medications, • chest wall irritation, • thyroid dysfunction. • Treatment of isolated mild hyperprolactinemia doesn’t improve spermatogenesis. • pituitary tumor should be ruled out.

41. DIAGNOSTIC ALGORITHMS BASED ON THE INITIAL EVALUATION

43. Azo

45. Patients with small (atrophic) testes have either primary or secondary testicular failure. Serum hormone testing including testosterone , LH, FSH, and prolactin is done to differentiate between the two as well as to identify both functioning and nonfunctioning pituitary tumors. Patients with small testesand FSH concentrations greater than two to three times normal have severe germ cell failure, and the prognosis for natural conception is poor. A testicular biopsy should only be performed in these patients if testicular sperm retrieval combined with IVF is being considered, and this is often performed in conjunction with egg retrieval in the spouse.

46. Patients with azoospermia due to testicular failure should be offered genetic testing to rule out chromosomal abnormalities such as Klinefelter's syndrome and microdeletions of the Y chromosome. Patients with secondary testicular failure may be treated with hormone therapy, whereas primary testicular failure is almost always irreversible.

47. Oligo • Oligospermiarefers to sperm densities of less than 20 million sperm/mL. Isolated oligospermia with normal motility and morphology parameters is uncommon. • In cases with less than 10 million sperm/mL, testosterone and FSH levels should be determined.

48. Asthenospermia • Defects in sperm movement (asthenospermia) refer to low levels of motility or forward progression, or both. Spermatozoal structural defects, prolonged abstinence periods, genital tract infection, antisperm antibodies, partial ductal obstruction, varicoceles, and idiopathic causes may beresponsible for these cases

50. Complete absence of sperm motility or cases with motilities less than 5% to 10% should be evaluated by a sperm viability assay. Necrospermia exists when the nonmotile sperm are not viable. The finding of a high fraction of viable sperm in the presence of low or absent sperm motility suggests an ultrastructural abnormality, such as that found in primary ciliary dyskinesia (PCD, formerly called immotile cilia syndrome) and Kartagener's syndrome (PCD associated with situs inversus).