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Normal Physiology

Normal sperm development

• Spermatogenesis: occurs in spermatic tubules, mitosis (spermatogonia to spermatocytes), meiosis x2 (primary spermatocytes to secondary spermatocytes to spermatids), spermiogenesis (spermatids to spermatozoa)
• Maturation: occurs in epididymis, acquire mobility and capacity to fertilize, completed at epididymal tail (stored here)
• Capacitation: activation of sperm's ability to fertilize egg, only occurs in female genital tract
• Hypermobility: increased mobility occurs after capacitation (only in female genital tract)
• Acrosome reaction: head of sperm releases enzymes to dissolve the outer layer of ovum

Normal male ejaculation

• Controlled by spinal ejaculatory center (T12-L2)
• Emission: sympathetic mediated, bladder neck contraction, release of fluid into posterior urethra (stimulates urethral-muscle reflex)
• Expulsion: activated by urethral-muscle reflex, contraction of bulbospongiosus/ischiocavernosus, mediated by pudendal nerve

Infertility Workup

Timing

• Wait 1yr before starting workup, 6mo if woman > 35yo
• 75% can achieve pregnancy within 6mo trying, 85% within 12mo, 90% within 2yr
• 30% male infertility will be identified as idiopathic
• Both partners need to undergo workup
• Consider if 2+ pregnancy losses or failed artificial reproduction cycles

History

• Prior pregnancies and childbirth: some men may have had prior children
• Ejaculate frequency: semen parameters peak after 1-2 days, then decline - no benefit in abstaining for long periods to "build up" semen
• Intercourse: timing, frequency
• Comorbidities: higher risk of infertility with HTN, HLD, obesity, DM, hypo/hyperthyroidism
• No association with infertility: caffeine, cell phones

Medical Causes

• TICS: Toxins, Infections/inflammation, Childhood history, Sexual history
• Neurologic: DM, SCI, and MS all affect normal ejaculation
• Cancer: can negatively affect sperm parameters even prior to treatment, testis cancer has even greater effect
• Hyperthermia: cryptorchidism, heated seats, and laptop heat should be avoided
• Infections: can cause strictures, prostatitis, testis failure, pre-pubertal mumps does not affect fertility, wait 3mo after febrile illness to check semenalysis
• Medical risk factors: liver failure, DM, thyroid disorders
• Hydrocele: increased prevalence in infertile patients but unclear cause and unclear benefit to performing hydrocelectomy
• Kartagener syndrome: nonmotile cilia prevent sperm motility, also have bronchiectasis, sinusitis, situs inversus, diagnose with evaluation of axoneme
• Young syndrome: thick epididymal secretions obstruct the vas, may also have bronchiectasis and sinusitis
• Cystic fibrosis: absent vas, bronchiectasis, sinusitis, pancreatic disease, evaluate with CFTR panel
• Congenital bilateral absence of vas deferens (CBAVD): isolated absence of vas (no URI symptoms)

Surgical Causes

• RPLND: results in retrograde ejaculation
• Hernia repair: can obstruct vas deferens or testicular blood supply, 1-2% vs 0.3% pediatric vs adult repair
• Pediatric inguinal surgery: testis atrophy develops in 0.3%
• Torsion: oligospermia (36-39%), antisperm antibodies (11%)
• Cryptorchidism: paternity rates 96% (unilateral) and 70% (bilateral), orchiopexy recommended before 10yo

Medication Causes

• Endocrine modulators: antiandrogens, spironolactone, HAART, steroids, estrogens, cimetidine, finasteride, allopurinol
• 5ARi: questionable effect on semen parameters, can consider stopping
• Anabolic steroids: inhibits LH, withdrawal can take months/years to reverse
• Illicit drugs: marijuana may decrease tesosterone, alcohol converts T to E, tobacco may affect sperm parameters, cocaine has questionable effects
• Antipsychotics: antidopamine effect leads to elevated prolactin
• Opioids: suppress LH at the hypothalamic level
• Chemotherapy: can lead to DNA damage at 2yrs after administration, mainly platinum-based, alkylating agents, antimetabolites, vinca alkaloids, topoisomerase inhibitors
• Antibiotics: tetracycline can be directly spermatotoxic, nitrofurantoin may have negative temporary effect
• Sulfasalazine: leads to oligoasthenospermai, can switch to mesalazine
• Environmental/Occupational exposure: heavy metals, pesticides, hyperthermia

Physical Exam

• Secondary sexual characteristics: pubic hair, gynecomastia, arm span > 5cm height
• Obesity: increased aromatase conversion to estradiol
• Genital exam: location/size of testes, presence of varicocele, palpable vas deferens, abnormal urethral appearance
• DRE: optional, SVs not normally palpable

Lab Evaluation

Semenalysis

• Highly variable, check minimum 2 separated by 2-4 weeks
• Abstain from ejaculation for 24hrs (not more) to provide optimal sample
• Volume: consider workup if < 1.0-1.5mL
• Density: oligospermia (< 13.5million/mL) and cryptozoospermia (so few it's hard to measure)
• Total #: volume x density (normal > 39mil)
• Motility: asthenospermia (normal > 32%)
• Morphology: teratospermia (overabundance of abnormal forms), globospermia (lacking acrosomes) normal > 4%
• Vitality: necrospermia (large number nonliving sperm), normal > 58%
• Antisperm antibodies: due to injury of blood/testis barrier, suspect if sperm agglutination or decreased motility, seen in vasectomy, testis trauma, orchitis, cryptorchidism, testis cancer, varicocele
• Pyospermia: > 1million/mL, may cause injury secondary to reactive oxygen species, Pap smear will differentiate WBCs from immature germ cells
• Fructose level: > 13umol/ejaculate, low levels may indicated ejaculatory duct obstruction

Hormonal labs

• Indications: not required for every patient, obtain if concern for impaired libido, erectile dysfunction, oligozoospermia, azoospermia, atrophic testes, or abnormal physical exam
• Testosterone: normal > 280-300, 55+% should be bioavailable (check albumin + SHBG), peaks in the morning
• LH/FSH: sertoli dysfunction indicated by elevated FSH, testicular dysfunction indicated by elevated LH
• Estrogen: T/E ratio < 10 may indicate testicular dysfunction
• Prolactin: consider testing if infertility associated with visual field changes, headaches, or ED, repeat if elevated level (large variation)
• Hypergonadotropic hypogonadism: elevated LH/FSH with low T, indicates testicular dysfunction
• Hypogonadotropic hypogonadism: low LH/FSH/T, indicates pituitary dysfunction
• Solitary testis: may demonstrate normal semen parameters and testosterone level but relatively higher level of FSH/LH than would be considered normal due to pituitary response

Azoospermia

• Obstructive: likely cause in 96% of patients with FSH < 7.6 and testis > 4.6cm
• Nonobstructive: likely cause in 89% of patients with FSH > 7.6 and testis < 4.6cm
• Biopsy: not indicated for initial workup, consider if indeterminate findings