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

Causes of Azoospermia Pretesticular failure Testicualr failure Post-testicular failure

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

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

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

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

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

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

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

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

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

Hormonal status in clinical Dx Clinical status FSHLHT Germ cell aplagia ↑Normal Testicualr failure ↑Normal or ↓ HH↓↓↓ ↑

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

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

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

Normal spermatogenesisHypospermatogenesis Maturation arrestSertoli cell only syndrome

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

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

Management of NOA (I) Hypogonadotropic hypogonadism – Treatment Initial 1,000-2,500 IU HCG (x2/wk) followed by 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.

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 1.2x10 6 /ml Indication: severe hypospermatogenesis, MA spermatid stage

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

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

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

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

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.