Medical Therapy in Male Infertility9th Royan Int. Congress

G. Pourmand, MDUrology Research Center,

Medical Sciences/University of Tehran Aug. 2008

Causes of Male Infertility

PRETESTICULAR

1. Hypothalamic Disease s1. Gonadotropin deficiency (Kallmann Syndrome)2. Isolated LH deficiency (Fertile eunuch) 3. Isolated FSH deficiency4. Congenital Hypogonadotropic Syndrome

2. Pituitary Diseases• Pituitary Insufficiency (tumors, infiltrative processes,

operation, radiation, deposits)• Hyperprolactinemia • Exogenous or Endogenous hormones (Estrogen-

Androgen excess, Glucocorticoid excess, hyper- and hypothyroidism)

• Growth hormone deficiency

Causes of Male Infertility

TESTICULAR1. Chromosomal Causes

• Klinefelter Syndrome • XX Sex Reversal• XYY Syndrome

• Noonas Syndrome (Male Turner Syndrome)• Myotonic dystrophy • Vanishing Testis Syndrome• Sertoli-cell-only Syndrome

Germ cell aplasia

Causes of Male InfertilityTESTICULAR (Cont.)

1. Y Chromosome Microdeletions (DAZ)2. Gonadotoxins

Radiation, Drugs3. Systemic Disease

1. Renal Failure, Liver Cirrhosis, Sickle Cell Disease4. Defective Androgen Activity

1. 5a-reductase deficiency, androgen receptor deficiency5. Testis Injury

Orchitis, Torsion, Trauma• Cryptorchidism• Varicocele• Idiopathic

Causes of Male Infertility

POST-TESTICULAR

1. Reproductive Tract Obstruction

1. CONGENITAL BLOCKAGES Cystic fibrosis1. Young syndrome2. Idiopathic epidiymal obstruction3. Adult polycystic kidney disease4. Ejaculatory duct Obstruction

2. ACQUIRED BLOCKAGES1. Vasectomy2. Groin and hernia surgery3. Bacterial infections

3. FUNCTIONAL BLOCKAGES Sympathetic nerve injury

Pharmacologic

Causes of Male Infertility

POSTTESTICULAR (Cont.)

1.Disorders of Sperm Function or Motility Immotile Cilia Syndromes1.Maturation defects2.Immunologic infertility3.Infection

2.Disorders of Coitus Impotence Hypospadias Timing & Frequency

Reproductive Hazards in the Workplace

TYPE OF EXPOSUREOBSERVED EFFECTS

DecreasedSperm Count

AbnormalMorphology

Altered Sperm

Trasnfer

AlteredHormones/Sexual

Performance

Lead + + + +Dibromchloropropane +Carbaryl(Sevin®) +Ethlyene bromide + + +Plastic production (Sterene and acetone) +Ethylene glycol monoethyl ether +Welding + +Mercury vapor +Heat + +Military radar +Radiation (Chernobyl) + + + +Carbon disulfide +(From Carbone D, Thomas AJ: Medical therapy – Specific. AUA Postgraudate Course, 92nd Annual Meeting of the AUA, New Orleans, LA, April 1997)

(AUA, 1999)

Drug-induced Infertility

SUPPRESSION OF HPG AXIS

DIRECT GONADOTOXICITY

IMPAIRED FERTILIZATION

Anabolic steroids Ketoconazole Calcium channel blockers

Cimetidine Sulfasaralazine Colchicine

DES Valproic acid Nitrofurantoin

Cyclosporine Sprironolactone Minocycline

Phenothiazine Allopurinol

Chronic Conditions Associated with Male Infertility

Diagnosis Percent of Infertility

Mechanism

Spinal cord injuryUremiaChronic liver diseaseSickle cell anemiaMyotonic dystrophyCystic fibrosis

95>50>50>508090

Elevated scrotal temperatureHypogonadismHypogonadismHypogonadismTesticular atrophyAbsence of vasa

Treatment of Male Infertility

1. Medical Therapy

2. Surgical Therapy VaricocelectomyVasovasostomy VasoepididymostomyTUR of ejaculatory ductobstruction

3. Assisted ReproductionTherapy (ART)

Sperm processing, IUI, IVF

4. Artificial Insemination of Donor (AID)

Algorithm for the workup of isolated abnormalities in semen parameters

Predominance of Single Abnormal Parameters

Motility/ Forward progression

TRUS

Antibody testEndocrine evaluation

Positive

Semen processing

Negative

High(>1ml)Low(<1ml)

Viscosity: hyperviscous

Morphology: rare transient

Density: Oligospermia <20×106ml/cc

volume

Endocrine evaluation

VaricoceleSperm washing

Sperm washing: AIH

Infection

ART

Steroids

retry

AIH, ART

VaricocelecotomyAppropriate treatment

Collection error

Abnormality of sex glands

AIH

Mechanical

None of above

ED obstruction

Retrograde ejaculation Urine centrifugaton

Specific therapy

TURED

Specific or empirical medical therapy

Specific or empirical medical therapy

Empirical medical therapy

Specific therapy

Evaluation of Oligospermic MenNormal serum testosterone, LH, FSH

Oligospermic Azoospermic

VaricoceleNo varicoceleIdiopathic oligospermia

Varicocelectomy

Moderate & Severe oligospermiaMild oligospermia

ICSI-IVF AID adoption

Intrauterine insemination(after “swim-up” or Percoll)

failed

* ; Empirical therapy

*

* *

*

Evaluation of Azoospermic MenNormal serum testosterone, LH, FSH

Oligospermic Azoospermic

Post ejaculation urine specimen

Assess ejaculatory process by Hx and P/E

Sperm absent

Evidence for retrograde ejaculation

Sperm presentSemem fructose

Re-exam Vas

No evidence for retrograde ejaculation

Retrograde ejaculation

Neurologic exam

negative positive

Congenital absence of seminal vesicle

Exploration, vasogram and/or Testicular biopsy

Obstruction of ductal system

absent present

Obstruction of ED

Testicular failureTRUS

Johnsen score10 Full spermatogenesis

9 Many late spermatids, sloughing

8 Few late spermatids

7 No late spermatids, many early spermatids

6 Few early spermatids, arrest of spermatogenesis at the spermatid stage

5 No spermatids, many spermatocytes

4 No spermatids, few spermatocytes, Arrest of spermatogenesis

3 Spermatogonia only

2 No germ cells, Sertoli cells only

1 No seminiferous epithelial cells

Johnsen score

• 113 Patients with male infertility

Mean Score

Normal testesModerate hypospermatogenesisAcquired hypopituitarismSevere hypospermatogenesisSertoli cell-only syndromeKlinefelter’s syndrome

9.387.806.095.322.0

1.25

(Johnsen,1970)

Medical Therapy

1.According to causes• Specific Medical Therapy • Non-specific (Empirical Medical Therapy)

II. According to drugs• Hormonal therapy• Non-hormonal therapy

Criteria for Post-therapeutic Success

• Duration : 3~6 months, at least one full spermatogenic cycle• Parameter : Semen analysis & hormonal assay

Volume >2.0ml

pH >7.2

Sperm concentration >20×106/ml

Total sperm count >40×106/ejaculate

Motility >50% (grade a+b) or >25% (grade a)

Morphology >15% by strict criteria

Viability >75%

WBC <1×106/ml

WHO criteria of normal semen, 1999

Specific Medical Therapy

1.Adaptation symptoms 1.Endocrine Disorder2.Pyospermia3.Immunologic Infertility with Antisperm Ab 4.Retrograde Ejaculation

• Success rate: Above 70~80%, relatively high therapeutic success rate

Endocrine disorders : Causes

1. Hypogonadotropic hypogonadism– Hyperprolactinemia– Congenital adrenal hyperplasia– Anabolic steroid abuse– Thyroid dysfunction– Hypergonadotropic hypogonadism & Testicular

dysfunction– Androgen receptor, short CAG repeat sequence– Hyperestrogenemia

Endocrine disorder

1. Hypogonadotropic hypogonadism◈ Cause

Congenital Prader-Willi syndrome (Obesity, motor weakness and mental retardation and

small eextremities) Laurence-Moon-Bardet-Biedle syndrome (Retinitis pigmentosa, polydactylism and memory loss) Kallman’s syndrome (Adolescence delay and absence of olfactory sense)

Aquired Radiation treatment Hypophysis adenoma

Endocrine disorder

1. Hypogonadotropic hypogonadism

GnRH

Nasal Spray Buserelin

Gonadotrophin

hCG r-FSH hMG

◈ Treatment

Endocrine disorder

2. Hyperprolactinemia◈ Cause

Idiopathic Pitituary tumor Hypothyroidism Epilepsy Medication: phenothiazine, tricyclic antidepressant

◈ Diagnosis serum prolactin CT, MR of sella

◈ Treatment : bromocriptine

Endocrine disorder

3. Congenital Adrenal Hyperplasia

◈ Cause 21-hydroxylase→ Decreased cortisol Secretion → ACTH Increased level

◈ Diagnosis : Serum 17-hydroxyprogesterone Urine pregnanetriol ◈ Treatment : fluorocortisone, 0.05~0.3mg/day

Endocrine disorder

4. Anabolic steroid abuseAnabolic steroid abuse

Hypogonadotropic Hypogonadism

Anabolic steroid stop

If not normalized

· hCG 2,000 IU IM

Spermatogenesis promotion

hCG 3,000 IU IM

· Tamoxifen 10mg 2×/day

Normalized < 3month

· recombinant FSH 75~150 IU

H-P-G axis negative feedback mechanism

Endocrine disorder

5. Hypothyroidism

◈ Not recommended for screening test in asymptomatic pt.

◈ Treatment: Thyroid hormone pill (Levothyroxine sodium, T4) once a day, preferably in the morning.Initial dose: 25 mcg qd, p.o., Maintenance : 100~400 mcg/day

Endocrine disorder

6. Hypogonadism & testicular dysfunctionSerum testosterone↓ & gonadotrophin normal or ↑

Testosterone (T), Estradiol (E2) measurment

T(ng/dl) / E2(pg/dl)ratio > 10

T(ng/dl) / E2(pg/dl) ratio < 10

Measuring serum testosterone & estradiol (E2) after 1 mnth of treatment

• Antiestrogen : clomiphene citrate 25mg qd tamoxifen 10mg bid • hCG 2,000 IU 3×/wk

Aromatase inhibitor

Recheck every 3 month

Endocrine disorder7. Hyperestrogenemia

Inhibition of conversion of androgen to estrogen

◈ Use

Brand name Dose

Testolactone Teslac® (Bristol-Meyers Squibb) 50mg~100gm/day

Anastrozole Arimidex® (AstraZeneca) 1mg /day

Letrozole Femara® (Novartis) 2.5mg/day

◈ Treatment : Aromatase inhibitor

◈ Diagnosis: 1. Serum E2 > 50pg/dl2. T (ng/dl) / E2 (pg/dl) ratio < 10

Endocrine disorder8. Androgen receptor, short CAG repeat sequence

◈ Cause Androgen receptor, Short CAG-repeat sequence

◈ Treatmento High dose testosterone o Antiestrogen

Pyospermia, LeukocytospermiaUrethritis (most common)

ProstatitisEpididymitisSeminal vesiculitis

Leukocyte ↑

ROS↑*

Sperm motility ↓ & fertility ↓

Causative or Empirical Antibiotics

Diagnosis: * Semen analysis* Endtz test* Pap smear* Giemsa stain* Peroxidase stain* IHC stain(monoclonal Ab)Diagnosis (WHO) : leukocyte in sperm >1×106/ml

* ROS ; Reactive Oxygen Species

Pyospermia Treatment

Chlamydiae trachomatis :Doxycycline 100mg, bid 10days orCiprofloxacin 400mg, bid 10days orTetracycline 500mg, bid 10days

Neisseria gonorrhea : Ceftriaxone 250mg, i.m. qd 후Doxycycline 10mg, bid 10days

Alternative treatmentIf, hypersensitive to cephalosporinSpectinomycin 2g, i.m.If, hypersensitive to tetracyclineErythromycin 500mg, qid 10days

Unknown CauseCiprofloxacin, trimethoprim-sulfamethoxazole, bid 2~12wk

Detection test for Antisperm Ab

(WHO guidelines ; Normal<10%)

SpermMAR test

(WHO guidelines ; Normal<20%)

Indirect Immunobead Test, IBT(×400)

Antisperm Antibody

Infertility with antisperm antibody

Corticosteroid or immunosuppression

After 3month

Antisperm antibody and semen analysis

Sperm washing, IUI or ICSI

Improvement* No improvement*

Pregnancy Ratio : prednisolone 6~50% cyclosporine 33%

*; Combined empirical medical therapy

Antisperm Antibody

Corticosteroid • prednisolone 60~90mg/day in 5~7day prednisolone 20mg p.o. week 1~3 or10mg p.o. week 4

• prednisolone 20~40mg/day

Immunosuppression • cyclosporine 5~10mg/day in 6 months

◈ Treatment

Retrograde Ejaculation

Anatomic

Y-V plastyOpen prostatectomyTransurethral resectionof prostate Transurethral incisionof bladder neck

Neurologic

Retroperitoneal LN dissectionDMPharmacologicPelvic surgerySpinal cord injuryIdiopathic

◈ Cause

Retrograde Ejaculation ◈ Treatment

Medication

ephedrine 25~50mg qid × 2wk

pseudoephedrine 60mg qid × 2wk

phenylpropanolamine 75mg bid × 2wk

imipramine 25mg tid × 2wk

Anejaculation

◈ Cause :

• Psychological anejaculation (anorgasmic) • Physical (organic) anejaculation

◈ Treatment Treatment depends on the cause and includes

psychosexual counseling, drugs such as ephedrine and imipramine, vibrator therapy and electroejaculation.