MALE INFERTILITY

DR. PREKSHA JAINDR. BHAVANA KUMARE

INFERTILITY: Failure to conceive within one or

more years of regular unprotected coitus.

PRIMARY INFERTILITY: Patients who have never conceived

SECONDARY INFERTILITY : Previous pregnancies but failure to conceive subsequently

Definitions

1. Prevalence 2. Spermatogenesis3. Hormonal regulation4. Aging & Fertility5. ADAM6. Causes7. Semen Analysis8. Evaluation9. Treatment

CONTENTS

It is sole cause in 20% of infertile couple Contributing factor in 20-40% couples Female infertility in 40-55%

PREVALENCE

74 days from spermatocyte stage Transport 12-21 days

SPERMATOGENESIS

200-300 million/day

LH

FSH

LEYDIG

SERTOLI

TESTOSTERONE

ABP

LH receptor

5-10mg/day

ESTRADIOL

BRAIN

HORMONE REGULATION

INHIBIN B

Semen volume 0.03ml/yr Total Motility -0.7%/yr Morphologically normal sperm proportion

decreases. Pregnancy rates >50yrs are 23-38% Causes Male factors contribute less to age related

decline in fertility

AGING & FERTILITY

PREGNANCY OUTCOMES: Point mutations Birth defects & congenital diseases Autosomal Dominant Schizophrenia & autism X-linked disease (grandfather effect) Spontaneous abortions

AGING & FERTILITY

Androgen deficiency in aging male Serum Total & free testosterone levels Decrease in SHBG so Free levels decrease more than

Total Hypogonadal men : Total Ts <300-325 ng/dl Free Ts <5ng/dl Andropause

Evaluation by morning levels of Total serum ts, Free ts index (FTI= total/SHBG) for amount of bioavailable ts.

Secondary hypogonadism : When LH normal or low levels. MRI & PRL done to rule out Hth or Pituitary mass.

ADAM

TREATMENT: • When Total Testosterone levels < 200ng/dL• Side effect- fluid retention, gynecomastia,

sleep apnea, malignant prostatic disease, cvd.• Parenteral (75 gm/wk)• Pellets (225 mg every 4-6 mth)• Gel (5 g/d)• Patches

ADAM

1. IDIOPATHIC (40-50%)

2. HYPOTHALAMIC & PITUITARY DISORDERS (1-2%)

• Idiopathic isolated gonadotropin deficiency(M/C)• Kallmann syndrome• Single gene mutations• Hth & pit tumors• Infilterative diseases• Hyperprolactinemia• Drugs• Critical illness • Chronic systemic illness• Infections• Obesity

CAUSES

2. PRIMARY GONADAL DISORDERS (30-40%)

• Klinefelter syndrome• Y chromosome deletions• Single gene mutations • Cryptorchidism • Varicoceles• Infection(mumps orchitis)• Drugs • Radiation • Gonadotoxins• Chronic illness

CAUSES

3. SPERM TRANSPORT DISORDERS (10-20%)

• Epididymal obstruction or dysfunction• Hypospadias • CBAVD• Infections• Vasectomy, herniorraphy• Kartagener syndrome• Young syndrome• Ejaculatory dysfunction

CAUSES

Kallman syndromeGnRH deficiency +

HYPOTHALAMIC PITUITARY DISORDERS

Red-green blindnessAnosmia

Cleft palateNeurosensory hearing

loss

Synkinesis

Renal anomalies

Klinefelter syndrome:

47XXY and other forms & no. of CAG repeats• Small firm testes• FSH & LH Ts • Cryptorchidism • Long arms & legs• Psychosocial abnormalities• Pulmonary diseases• Mediastinal germ cell tumors, breast cancer

PRIMARY GONADAL DISORDERS

Y chromosome deletions: 20% men with

infertility• Severe oligospermia & azoospermia• Genetic counselling offered before ICSI, as

these deletions are transmitted to sons.

Single gene mutations & polymorphism: No. of CAG repeats inversely proportional to sperm concentration & fertility

PRIMARY GONADAL DISORDERS

Cryptorchidism: Failure of testicular descent. An androgen dependent process. FSH levels raised. LH normal Risk of tumors

Varicoceles: Dilatation of pampiniform plexus of spermatic veins.

More common on left side. No causal relationship with infertility

Radiation: 0.015 Gy (15 rads) supress spermatogenesis > 6 Gy permanent azoospermia

PRIMARY GONADAL DISORDERS

Epididymal dysfunction: Intrauterine

exposure to DES. Causes isolated asthenospermia

CBAVD: Congenital bilateral absence of the vas deferens related to CFTR gene mutations. 1-2% of infertile men

Kartagener syndrome: Recurrent sinus infection, bronchiectasis, situs inversus, male infertility.

SPERM TRANSPORT DISORDERS

Goals are to Identify-• Specific cause & correct it• Individuals who can be offered IUI & ART• Individuals with genetic abnormality that may

affect offspring conceived by ART• Adoption & donor sperm options for those who

are not candidate for ART• Underlying Medical condition

MALE INFERTILITY EVALUATION

Time to start evaluation : When pregnancy fails to occur after 1

yr of regular unprotected intercourse. Earlier evaluation for men with any obvious infertility factor.

HISTORY: • Duration of infertility & previous fertility• Coital frequency & sexual dysfunction• h/o previous evaluation & t/t• Childhood illness • Previous surgical & medical illness• Past episodes of STI• Exposure to gonadotoxins & heat• Medications & allergies• Occupation & addictions

MALE INFERTILITY EVALUATION

PHYSICAL EXAMINATION:• Examination of penis, location of urethral

meatus• Palpation of testes & size• Presence & consistency of vas & epididymis• Sec sexual characteristics, habitus, hair &

breast development• Digital rectal examination

MALE INFERTILITY EVALUATION

Collection method: After a defined period of

abstinence of 2-3 days. Semen may be collected in a clean container

by masturbation or via intercourse using silastic condom that does not contain spermicidal agents.

Sample should be examined within an hour of collection.

If abnormal, repeat it after 4 weeks.

SEMEN ANALYSIS

Volume 1.5-5 ml pH >7.2 Viscosity < 3 (scale 0-4) Sperm concentration >20 million/ml Total sperm number >40million/ejaculate Percent motility > 50% Forward progression >2 (scale 0-4) Normal morphology >50%, >30%, >14% Round cells < 5 million/ml Sperm agglutination <2 (scale 0-3)

Normal Reference Values (WHO)

Volume 1.5 ml (1.4 – 1.7) Sperm concentration 15 million/ml (12 - 16) Total sperm number 39 million/ejac (33-46) Total motility 40% (38 - 42) Progressive motility 32% (31 - 34) Normal morphology 4% (3 - 4) Vitality 58% (55 - 63)

To assess prognosis for achieving pregnancies with their partner

Lower Reference Limits

Alkaline & fructose CBAVD – acidic pH B/l ejaculatory duct block – acidic & neither

fructose or sperm Post ejaculatory urinalysis - Retrograde

ejaculation

Ejaculate volume & pH

Azoospermia : Complete absence of sperm on std

microscopic examination in ejaculate. • 1-3% male population, 10-15% male infertility• To confirm diagnosis semen is centrifuged & pellet

examined• Obstructive• Non Obstructive- Primary & secondary testicular

failure. Candidate for IVF (TESE)

Oligospermia : sperm density < 20 million/ml. Severe when < 5 million/ml

Total sperm count – semen volume* sperm conc

Sperm Concentration & Total Sperm Count

% of total sperm exhibiting any motion

Total motile sperm count = total sperm count & % of progressively motile sperm

Asthenospermia : Poor sperm motility. Suggests anti sperm antibodies, genital tract infections, partial obstruction of ejaculatory duct, varicoceles, vasectomy reversal, prolonged abstinence

Motility, Total motile count, Total motile count & Vitality

Viable non-motile sperm- Kartagener

syndrome

Vitality test- to differentiate viable non motile sperm from dead sperm for ICSI

Motility, Total motile count, Total motile count & Vitality

Teratospermia : > 70% abnormal morphology. Varicocele, primary & sec testicular failure

Necrospermia : dead sperm

Sperm Morphology

> 5million/ml round cells (round spermatid,

spermatocytes) Leucocytospermia > 1million leucocytes/ml.

Semen culture for Mycoplasma, ureaplasma, Chlamydia.

Rounds cells & leukocytospermia

To evaluate attachment to zona pellucida,

penetration of the oocyte, release of acrosomal enzymes.

Sperm autoantibodies (PCT) Sperm penetration assay Human Zona Binding Assay Computer Assisted Sperm Analysis Acrosome reaction Biochemical test Sperm Chromatin Structure & DNA

SPECIALIZED TEST

Indications: • Abnormal semen analysis• Sexual dysfunction• Specific endocrinopathy

Tests :• Sr. FSH• Total testosterone• Sr. Free Testosterone• LH• PRL, TSH• Serum estradiol

Endocrine Evaluation

Disorder FSH LH Free Ts

Hypogonadotropic hypogonadism

low low low

Abnormal spermatogenesis N/high N N

Testicular Failure High High N/low

Physical examination TRUS (transrectal usg for duct obstruction) Transscrotal Usg Renal Scan Testis Biopsy in azoospermic men Vasogram

Urologic evaluation

Y chromosome deletions Chromosomal anomalies CFTR gene mutations (CABVD)

Genetic Evaluation

Hypogonadotropic Hypogonadism:• Hyperprolactinoma- Dopamine agonists • Cong hypogonadotropic hypogonadism- hCG or

exogenous testosterone• Adult onset hypogonadotropin hypogonadism- hCG

2000-5000 IU 3 times per week. Start alone with hCG (as LH) as1. hCG stimulate Leydig cells to produce testosterone2. hCG alone can stimulate spermatogenesis3. Annual costs lower than hMG (both FSH & LH)Sr. Ts every 1-2 mth for 1st 3-4 mth level 400-900 ng/dl

MEDICAL TREATMENT

• Non-responders - hCG & hMG or pure FSH

(75-100 IU 3 times weekly)

• Hypogonadotropin hypogonadism unrelated to cause- Portable programmable pulsatile infusion pump s/c.

Eugonadotropin HypogonadismSevere oligospermiaLow Sr. testosteroneT/t by aromatase inhibitor (Testolactone 50-100 mg BD Anastrazole 1 mg OD)

Hypergonadotropic HypogonadismInsemination with donor sperm IVF with ICSI with preliminary genetic evaluation

Erectile dysfunctionSildenafil- 25-100mg 1hr before intercourse

Retrograde Ejaculation- • Sympathomimetics, pseudoephidrine, ephedrine• IVF & IUI & ICSI

Leucocytospermia-• Antibiotics (doxycycline, erythromycin,

cotrimoxazole)

Idiopathic Male Infertility-• Androgen therapy• Exogenous FSH • Clomiphene citrate (25 mg)/Tamoxifen (20 mg)

Indications :• Oligospermia, • Asthenospermia, • Premature or retrograde ejaculation, • Sperm autoantibodies & cervical factors,• Unexplained infertility• Sex selection in genetic & chromosomal anomalies • Hypospadias• HIV positive

Advantages :1. Overcome limitation of decreased sperm density or motility. Better than

Cervical insemination2. With washed sperm concentrate delivers more no. of sperms3. IUI yields better results than cervical insemination.

ARTIFICIAL INSEMINATION

Types: 1. IUI2. Intracervical3. Pericervical & Vaginal4. DIPI (Direct intraperitoneal insemination)

ARTIFICIAL INSEMINATION

Cycle fecundity 3-10% infertile partner sperm 9-30% donor sperm Processed motile sperm count at least 1 million

Best results when no. of TOTAL MOTILE SPERMS > 10 million

Success rates • Highest > 14% sperm have normal morphology • Intermediate 4-14%• Poor <4% (advised IVF & ICSI)

INTRAUTERINE INSEMINATION

INDICATIONS :1. Azoospermia2. Immunological factors not correctable3. Genetic disease in husband

Donor Sperm

1. Vasovasostomy & vasoepididymostomy- In

vasectomized men 2. Transurethral resection of the ejaculatory

ducts- in men with Ejaculatory duct obstruction (1-5% of infertile men)

3. Varicocele repair- In men with varicoceles (20-45% of infertile men)

4. Orchipexy – In cryptorchidism5. Vibratory stimulation & Electroejaculation

– In neurological dysfunctions

SURGICAL TREATMENT

Assisted Reproductive Techniques

IVF-ET – In vitro fertilization & embryo transfer GIFT – Gamete intra fallopian transfer ZIFT – Zygote intra fallopian transfer POST – Peritoneal oocyte & sperm transfer TET – Tubal embryo transfer zone SUZI – Subzonal insemination ICSI – Intracytoplasmic sperm injection AH – Assisted Hatching IVM – In vitro maturation of oocyte PGD – Preimplantation genetic diagnosis

1. NON OBSTRUCTIVE AZOOSPERMIA: TESE – Testicular sperm extraction Micro-TESE – Microdissection testicular sperm

extraction

2. OBSTRUCTIVE AZOOSPERMIA : MESA – Microsurgical Epididymal Sperm Aspiration PESA – Percutaneous epididymal sperm aspiration

Sperm Retrieval Techniques

Sperm may be cryopreserved for future use or,

if timed to coincide with oocyte retrieval, can be immediately used for ICSI.

1. Conventional TESE2. Fine Needle Aspiration/Testicular Mapping3. Microdissection TESE

Genetic Screening for TESE Candidates Y Microdeletion Testing Cytogenetic Analysis

Sperm Retrieval

Best Technique for Sperm Retrieval

Non obstructive azoospermia (NOA) defines men

with testicular failure who have severely deficient sperm production with no sperm in the ejaculate.

10% of infertile men On testicular biopsy, hypospermatogenesis,

maturation arrest, or Sertoli cell-only pattern (germinal cell aplasia).

Genetic causes- Klinefelter syndrome (KS) and XX-male syndrome.

Acquired- Testicular failure secondary to cryptorchidism or systemic chemotherapy.

Micro-testicular Sperm Extraction

An area of the tunicaalbuginea is incised andmicrodissected

ICSI