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

Evaluation and Management of NEvaluation and Management of Nonobstructive Azoospermiaonobstructive Azoospermia

Sang Kon Lee, M.D.

College of Medicine, Hallym University

Causes of AzoospermiaCauses of Azoospermia

Pretesticular failure

Testicualr failure

Post-testicular failure

Pretesticular failurePretesticular failure

– Genetic abnormality Kallmann’s syndrome Prader-Willi syndrome Cerebral ataxia with HH

– Idiopathic HH– Isolated LH deficeincy – Isolated FSH deficiency– Prolactin excess

Testicular failureTesticular 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

EvaluationEvaluation

History– Infertility : duration, pregnancy– Developmental– Medical, surgical– Sexual– Family

Physical exam. Semen analysis Endocrine test

Childhood and Developemental 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 historyMedical historyMedical history

– Systemic illness: hepatic, renal failure– Gonadotoxins

sulfasalazine, cimetidine, nitrofuratoin, chemotherapeutic, anabolic androgen

Thermal injury Smoking, alcohol,marijuana

Surgical history– Herniorrhaphy, badder neck, orchiectomy, r

etroperitoneal surgery

Physical examinationPhysical examination

General appearanceGynecomastiaAxillary, pubic hairTestis volume, consistency Epididymis indurationVaricoceleDigital rectal examination

Semen analysisSemen analysis

At least 2 times analysisSecretory azoospermia

– Pellet inspected after centrifugation at 1,500-2,000 rpm for 10min

If ejaculatory vol < 1ml– Postejaculatory urine should be examined

Ultrasound examinationUltrasound 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 DxHormonal status in clinical Dx

Clinical status

FSH LH T

Germ cell aplagia

↑ Normal Normal

Testicualr failure

↑ Normal or ↓

HH ↓ ↓ ↓

↑

Indication of testicular biopsyIndication 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 biopsyInterpretation of testis biopsy

Severe hypospermatogenesisSetoli cell only syndromeMaturation arrest

– Spermatocyte stage– Spermatid stage

Tubular and peritubular sclerosis

DNA flowcytometryDNA flowcytometry

Advantage– Rapid, objective, quantitative– reproducible

Disadvantage– Inability of distinguishment between specifi

c type of 1N cells (spermatozoa and spermatid)

Normal spermatogenesis Hypospermatogenesis

Maturation arrest Sertoli cell only syndrome

Genetic evaluation of NOAGenetic 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 NOAGenetic 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)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.

Management of NOA (II)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

Management of NOA(III)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 R

eprod)

– ROSI MA spermatid stage

Genetic risk of ICSIGenetic 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 Secondary NOA Case 1.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 Secondary NOA Case 2.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

ConclusionConclusion

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.