Evaluation and Management of Nonobstructive Azoospermia

1. Evaluation and Management of Nonobstructive Azoospermia Sang Kon Lee, M.D. College of Medicine, Hallym University

2. Causes of Azoospermia • Pretesticular failure • Testicualr failure • Post-testicular failure

3. Pretesticular failure • Genetic abnormality • Kallmann’s syndrome • Prader-Willi syndrome • Cerebral ataxia with HH • Idiopathic HH • Isolated LH deficeincy • Isolated FSH deficiency • Prolactin excess

4. Testicular failure • Genetic abnormality • Klinfelter’s syndrome: nonmosaic, mosaic • XYY syndrome • 46 XX male syndrome • Yq AZF gene deletion • Varicocele • Bilateral anorchism, cryptorchidism • Sertoli cell only syndrome • Gonadotoxin : drug, radiation, chemical • Orchitis

5. Evaluation • History • Infertility : duration, pregnancy • Developmental • Medical, surgical • Sexual • Family • Physical exam. • Semen analysis • Endocrine test

6. Childhood and Developemental • Crytorchidism, testicualr torsion, • Mumps orchitis • Herniorrhaphy • Onset of puberty • Secondary sexual development • Onset axillary, pubic hair, start of shaving • Onset of masturbation

7. Medical history • Medical history • Systemic illness: hepatic, renal failure • Gonadotoxins • sulfasalazine, cimetidine, nitrofuratoin, chemotherapeutic, anabolic androgen • Thermal injury • Smoking, alcohol,marijuana • Surgical history • Herniorrhaphy, badder neck, orchiectomy, retroperitoneal surgery

8. Physical examination • General appearance • Gynecomastia • Axillary, pubic hair • Testis volume, consistency • Epididymis induration • Varicocele • Digital rectal examination

10. Semen analysis • At least 2 times analysis • Secretory azoospermia • Pellet inspected after centrifugation at 1,500-2,000 rpm for 10min • If ejaculatory vol < 1ml • Postejaculatory urine should be examined

11. Ultrasound examination • Scrotal US • Testis volume • Varicocele • Testis tumor • Transrectal US • Low volume azoospermia without absence of testicular atrophy • Palpable abnormality on DRE

12. Volume(cc) = length x width x AP depth x 0.52

16. Hormonal status in clinical Dx ↑

17. Indication of testicular biopsy • Dignostic • DDX of ductal obstruction and testicular failure • Identification of mature sperm for ICSI • Identification of malignancy • Therapeutic • Harvesting of sperm for ICSI

18. Interpretation of testis biopsy • Severe hypospermatogenesis • Setoli cell only syndrome • Maturation arrest • Spermatocyte stage • Spermatid stage • Tubular and peritubular sclerosis

19. DNA flowcytometry • Advantage • Rapid, objective, quantitative • reproducible • Disadvantage • Inability of distinguishment between specific type of 1N cells (spermatozoa and spermatid)

20. Normal spermatogenesis Hypospermatogenesis Maturation arrest Sertoli cell only syndrome

21. Genetic evaluation of NOA • Sex chromosomal disorder • Klinfelter’s syndrome(1/500) :15% of NOA • XYY male(1/1,000), XX male(1/20,000) • Yq deletion : 10-20% of NOA • X-linked : • Kallamann’s syndrome • Androgen receptor deficiency • Kennedy syndrome (spinal-bulabar muscular atrophy) • Autosomal defect • Prader-Willi syndrome • Androgen synthesis deficiency

22. Genetic evaluation of NOA • Indication • NOA with clinical abnormality • Hypogonadism, anosmia, mental retardation • For genetic counselling • All couples with male infertility prior to ICSI • Chromosomal abnormalities in 12% of men and 6% of women in 150 couples prior to ICSI (Mau, 1997 , Hum Reprod) • Research purpose • Normal phynotype except infertility

23. Management of NOA (I) • Hypogonadotropic hypogonadism • Treatment • Initial 1,000-2,500 IU HCG (x2/wk) followed by 75-150 IU HMG (x3/wk) (Finkel,1987) • Combination of HCG and HMG(Yong ,1997) • GnRH sc or pulsatile infusion (Kliesch,1994) • LHRH pulsatile treatment (Shargil,1987) • Outcome • IHH after puberty showed better results. • Sperm count increase in 3-6mos.

24. Management of NOA (II) • Varicocelectomy • Mehan DJ (1976, Fertil Steril) Of 10 azoo men, 2 with varicocele results in pregnency • Matthews G, et al (1998, Fertil Steril) Of 22 with azoo, sperm recovery rate is 55% • Kim ED, et al (1999, J Urol) Of 28 men, 12(43%): mean post-op sperm count 1.2x106 /ml Indication: severe hypospermatogenesis, MA spermatid stage

25. Management of NOA(III) • ICSI • Ejaculatoy sperm: • less invasive,cost effective • HH, varicocele, mosaic Klinfelter’s synd. • TESE • Presence of spermatozoa in SCO, MA • Nonmosaic Klinfelter’s syndrome (Bourne,1997 , Hum Reprod) • ROSI • MA spermatid stage

26. Genetic risk of ICSI • Congenital anomaly : • Autosomal abberation: <2% Y chromosomal abberation: 13% • not results in major anomaly other than infertility • Sex chromosomal abnormality • Higher in ICSI than natural pregnancy • 1%: 47XXY, XXX, 45X, etc (Liebaers,1995) • Major malformation in Turner • Infertility obligate in Klinfelter’s synd • No major congenital handicaps • No increased rate of mental retardation

27. Secondary NOA Case 1. M/31: infertility for 18 mos • History • 4 yrs PTV impregnated hx • Allergic rhinitis for 12 yrs • Antiallergic administered for 3-4 mos. every year • During medication, anorexia, 5-6 kg wt loss • Noticed testis atrophy 3 yrs PTV • Study • Both testis 8cc • S/A: azoospermia • FSH 18.5 IU/ml T 2.5 ng/ml, 46,XY • Testis biopsy : MA spermatocytic stage

29. Secondary NOA Case 2. M/30: infertility for 6 yrs • History • 2yrs PTV necrospermia • 10 mos PTV spontaneous abortion • Worked in Rayon manufacture industry for 11 yrs • Study • Both testis 12 cc • S/A: azoospermia, • FSH 13.0 mIU/ml, T 9.4 ng/ml • Testis bopsy: Spermatocytic MA

31. Conclusion • NOA may be a local presentation of systemic illnesses. • A complete careful evaluation is important for identification of etiology of male infertility which may open new approaches regarding prevention and treatment.