Infertility: inability to achieve pregnancy after 1 year of regular unprotected intercourse 

• Evaluate male after 12 mo, or after 6 mo if female is > 35 yo
• Male infertility present in 50%
• Affects 8-15% of couples: 50% female only, 20% male only, 30% male + female

Classification:

• Primary/secondary (i.e. fathered prior pregnancy)
• Location of abnormality
• Pre-testicular
• Hypogonadotropic hypogonadism (eg Kallman's)
• Prolactinoma
• Testicular
• Varicocele (most common)
• Hypergonadotropic hypogonadism (eg Klinefelter's)
• Sertoli cell only syndrome (germ cell aplasia)
• Gonadotoxins, genetic, immotile cilia, testis infection
• Cryptorchidism
• Post-testicular
• Ejaculatory duct obstruction (EDO), vasectomy, CBAVD
• Ejaculatory disorder
• Hypospadias, improper coital technique
• Sperm parameters
• Normospermia, azoo (no sperm in ejaculate x 2 centrifuged semen samples), oligo ([sperm] < 15-20 million/ml), astheno (< 40-50% of sperm are mobile), terato (abnormal morphology), aspermia (semen volume = 0 ml)
• Obstructive/non-obstructive
• Obstructive - 2/2 ejaculatory duct obstruction: surgery, GU trauma/infxn, CF, CBAVD (congenital bilateral absence of the vas)
• Non-obstructive - 2/2 impaired spermatogenesis: hypogonadism, gonadal toxins, testicular torsion, mumps orchitis

Genetic causes

• CFTR - chr 7, a/w CF (100%), CBAVD (70%) (almost all with CF also have CBAVD)
• **hide**Also test intron 8, a/w decreased CFTR mRNA
• Y chromosome microdeletions - impaired spermatogenesis; in 10-15% of men with azoospermia
• Testicular sperm extraction successful in AZFc deletion (67%), but not AZFa/b (0% have sperm) (AZF = azoospermia factor regions)
• Chromosomal - in 6% of infertile men. e.g. Klinefelter's (XXY, 66% of karyotype abnormalities)
• Klinefelter's infertility 2/2 sclerosis of seminiferous tubules - can still have normal sperm on biopsy (about 50%). A/w breast cancer, extragonadal germ cell tumor
• Kallmann's  - hypogonadotropic hypogonadism
• Thalassemia, sickle cell also a/w infertility
• Young's syndrome - obstructive azoospermia (abnormal cilia and thick epididymal secretions), chronic sinusitis, bronchiectasis
• ADPKD can have cysts in testis/epididymis/SV leading to obstruction

Spermatogenesis

• Spermatogenesis occurs in seminiferous tubules (Sertoli cells)
• **hide**Takes 75 days total; 12 days for sperm transit within epididymis
• Requires FSH, high intraluminal testosterone level, Sertoli cells tight junctions (blood-testis barrier; protect from immune system), temperature 34°C
• **hide**Mitosis: spermatogonia (2n) → spermatocytes (2n)
• **hide**Meiosis: 1° spermatocyte (2n) → 2° spermatocyte (2n) → spermatid (1n)
• **hide**Spermiogenesis: spermatid -> sperm (spermatozoa)
• Sperm travels from seminiferous tubules → rete testis → efferent ducts → epididymis (caput → cauda; acquire motility and mature) (stored until ejaculation)
• Epididymis is most proximal site with motile sperm capable of fertilization

Embryology

• Sex determinatin - SRY gene on short arm of Y chromosome
• LH  → Leydig cells → T → internal genitalia
• DHT → external genitalia
• FSH  →  Sertoli cells → MIS → prevent Mullerian duct from developing uterus
• Sertoli cells  →  inhibin B  →  inhibit FSH
• 3 surges in T - neonatal (12-18 wks), 2 months, puberty

Male initial screening: reproductive history and semen analysis

History

• Coital frequency and timing
• Duration of infertility; prior fertility
• Childhood illnesses, developmental history
• **hide**Mumps orchitis (post-puberty only, damages seminiferous tubules and Leydig cells)
• Systemic medical illness
• Diabetes a/w ED
• Thyroid disorder a/w pituitary imbalance
• Upper resp. disease a/w cystic fibrosis (a/w CBAVD), Kartagener's (immotile cilia), Young's syndrome (thick epididymal secretions)
• **hide**Other: cirrhosis, myotonic dystrophy
• Previous surgery
• Vasectomy/reversal, inguinal hernia, orchiectomy/pexy, prostate surgery, RPLND, etc. can damage vas deferens
• Medications/allergies
• Sexual history (including STDs)
• Epididymitis, orchitis, prostatitis
• Exposure to gonadal toxins
• Environmental - heavy metals, agricultural chemicals, cigarette smoke
• Chemical - abx, drugs, anti-androgen medications, chemo, genital radiation
• Hyperthermia - hot tub, sauna, febrile illness (may impair spermatogenesis x 3 mo), varicocele
• Cycling > 5 hrs/wk can affect blood flow and sperm count

Physical exam

• Penis/meatus (hypospadias → semen is not directed properly)
• Testes (seminiferous tubules comprise most of testes volume) - normal size ~ 20 cc/4.5 cm
• Vasa and epididymides
• Absence of the vas diagnosed on exam
• Unilateral vasal agenesis - should have renal ultrasound (25% a/w ipsi renal agenesis)
• Bilateral vasal agenesis - test for CFTR mutation (CF/CBAVD); renal agenesis is rare with CFTR mutation (indication for renal US if mutation is absent)
• Varicocele
• Right sided varicocele may indicate renal mass - consider imaging
• 2° sex characteristics, evidence of endocrine dysfunction (e.g. gynecomastia)

Semen analysis 

• 2 samples, 1 mo apart
• Very high variance in semen quality so get > 1 sample
• Pre-test abstinence x 2-5d; at least 3 mo after febrile illness or extreme physical stress
• Store at body temperature, analyze within 1 hr
• **hide**Centrifuge (≥ 3000g x 15 min) and look at pellet to diagnose azoospermia
• Low volume < 1.0 ml - rule out retrograde ejaculation with post-ejaculatory UA (unless hypogonadism/CBAVD)
• **hide**Centrifuge 300g x 10 min, look at 400x
• Presented as volume / concentration / motility / morphology (eg 2.1 mL/13M/32%/2%)

• Varicocele shows "stress pattern" of decreased concentration, motility, and morphology
• *morphology cut-offs vary by lab/criteria. If this is the only abnormality, don't really need to worry about it

Endocrine evaluation (for abnormal semen parameters esp. sperm < 10 x 10⁶ / ml, impaired sexual function or clinical findings suggestive of endocrinopathy)

• **hide**Draw hormones in morning before 10 AM
• Minimum evaluation: Testosterone and FH
• Low testosterone: reflex to total/free testosterone, prolactin, LH
• FSH > 2x normal: primary testicular failure
• LH → Leydig cells → T
• FSH → Sertoli cells → sperm
• Prolactin → ?↑ LH receptors

Karyotype/Y chromosome testing - offer to men with NOA or severe oligospermia < 5-10 x 10⁶ / ml

CFTR testing - if absent vas deferens (or idiopathic ductal obstruction), test both patient and partner

Other work-up:

TRUS - work up ejaculatory duct obstruction (EDO) in men with low ej. vol, low sperm count, palpable vasa

• Symptoms suggesting ejaculatory duct obstruction: hematospermia, painful ejaculation, low volume ejaculate, infertility (may have hx of infections or trauma)
• Semen analysis in EDO: low volume, thin watery consistency, low fructose, pH < 7.0, oligo/azoospermia
• **hide**Normal SV < 1.5 cm anterior-posterior. Other abnormal findings: dilated ejaculatory ducts > 2.3 mm diameter, calcifications, midline cystic structures in prostate
• **hide**Can perform SV aspiration within 24 hr of ejaculation - if SV still contains sperm (> 3/hpf), EDO probably present
• Risks of ejaculatory duct resection - epididymoorchitis (reflux of urine), go home w catheter. Use cut not coag

**hide**Scrotal ultrasound - indicated for ambiguous/inadequate/suspicious scrotal exam. (Non-palpable varicoceles found on US do not impair fertility)

**hide**Specialized semen/sperm tests:

• **hide**Semen fructose - fructose produced by SVs; normal ≥ 13 umol
• **hide**Semen WBCs - > 1 million/ml → evaluate for GU infxn; needs special assay to differentiate WBC from immature germ cell
• **hide**Anti-sperm antibodies - indicated for abnormal post-coital test e.g. "shaking sperm", agglutination, impaired mobility with normal concentration, unexplained fertility. Test for IgG and IgA, not IgM. Use immunobaed test or mixed antiblobulin reaction (MAR).
• **hide**Sperm viability - use eosin/trypan blue dye or hypo-osmotic swelling test (HOS) to assess cell membrane (live sperm do not stain and do undergo tail swelling)
• **hide**Post-coital test - intercourse immediately before ovulation, then look at cervical mucus; normal sperm is hypermobile. Test not standardized; poor timing most common cause of abnormal test. "Shaking sperm" indicates anti-sperm antibodies
• **hide**Limited utility: sperm penetration test with zona free hamster oocyte (may predict IVF success), acrosome reaction assay, sperm DNA integrity tests (eg fragmentation), semen reactive oxygen species test

General recommendations

• Avoid smoking/alcohol/drugs
• Avoid hyperthermia (hot tubs)
• Coital technique: avoid most lubricants (impairs sperm motility); optimal frequency q2d starting 2d before ovulation (sperm survives 2 days in cervical mucus), avoid spermicides/contraceptives
• Healthy lifestyle - exercise, diet, multivitamin

Medical therapy 

• Hypogonadotropic hypogonadism:
• GnRH/gonadotropin replacement (hCG/hMG)
• Anti-estrogens (e.g. clomiphene/Clomid) may increase testosterone
• **hide**12.5-25 mg PO qd vs 50 mg qod
• Recheck semen analysis at 3 mo, 9 mo; can stop if no improvement
• Aromatase inhibitor - empiric therapy for idiopathic oligospermia with testosterone/estrogen ratios of < 10 (normal 20:1)
• **hide**testolactone 50-100 mg PO BID, anastrazole 1 mg PO daily, for 4-5 months. Check LFTs with anastrazole
• FSH replacement (Follistim) - $$$
• Testosterone replacement worsens fertility - lowers LH, decreases intratesticular androgens, and impairs spermatogenesis
• Hyperprolactinemia - cabergoline vs surgical resection
• Klinefelter's - do microTESE
• Can switch flomax to alfuzosin (less ejaculatory dysfunction)
• Pseudoephedrine/imipramine can help with retrograde ejaculation

Surgical therapy

• Vasectomy reversal
• Varicocelectomy
• Correct hypospadias, Peyronie's
• EDO - ejaculatory duct dilation, or transurethral resection (TURED)
• If only one pregnancy desired or if female infertility contributing, may choose assisted reproduction instead of surgical repair

Assisted reproduction

• e.g. intrauterine insemination (IUI), IVF
• Sperm retrieval
• Normal - masturbation
• **hide**Retrograde ejaculation - bladder wash (should alkalinize the urine first)
• **hide**Spinal cord injury above T10 - penile vibratory stimulation (PVS), stimulates sympathetic T10-L2 and parasympathetic S2-S4
• **hide**RPLND or failed PVS - electroejaculation
• **hide**EDO - SV aspiration
• **hide**Vasectomy - vas aspiration during vasectomy reversal
• **hide**Obstructive azoospermia - epididymal sperm retrieval (PESA percutaneous, MESA microsurgical (yields more sperm))
• Non-obstructive azoospermia - testicular sperm retreival (TESA percutaneous, TESE biopsy extraction)

Success rates