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Workup

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

Timing the workup

• 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

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

Labs

• Not required for every patient
• Lab indications: 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

Diagnosing Infertility

Diagnoses (by semenalysis finding)

Semenalysis finding	Further workup	Interpreting findings
Azoospermia (absent sperm)	Semenalysis	Low volume + acidic pH indicates obstruction
	Testis size	Cutoff testis axis 4.6cm determines whether obstruction present
	Vas deferens	Absence indicates obstruction
	FSH	Cutoff 7.6IU/L determines whether obstruction present
	Karyotype + Y Microdeletion (if elevated FSH or testicular atrophy)	Kleinfelter and Y deletions are most common causes of non-obstructive azoospermia
	TRUS (if normal T and vas, obstruction suspected)	Confirm ejaculatory duct obstruction
Low volume	History	Caused by DM, SCI, RPLND
	Post-ejaculate urinalysis	Confirms sperm ending up in bladder
Round cells > 1mil/mL	Special stains	Differentiate pyospermia from germ cells
Sperm agglutination	Antisperm antibody testing	ICSI may be indicated for ASA instead of IUI
Poor sperm mobility	Viability testing	Assess whether nonmotile sperm can be used for ICSI

Adjunct Tests

Test	Indication	If positive:
Post-ejaculate urinalysis	Low-volume ejaculate	Sperm retrieval
Karyotype	Nonoobstructive azoospermia	microTESE (for Kleinfelter)
	Repeat pregnancy loss	Sperm aneuploidy - ICSI, adoption, donor sperm
Y microdeletion	Nonobstructive azoospermia	Adoption (AZFa/AZFb) or ICSI (AZFc)
Transrectal US	Obstructive azoospermia + low volume/pH + normal T + palpable vas	TURED
CFTR gene panel	Absent vas deferens	Test female partner TESE
Sperm DNA fragmentation	Repeat IVF failure Repeat pregnancy loss	TESE + ICSI
Antisperm antibody testing	Concern for obstruction, azoospermia, agglutination	Recommend ICSI Do not order if already planning ICSI
Scrotal US	Assess for varicocele in difficult scrotum (obese, high + tight)	Discuss clinical relevance of US varicocele
Abdominal imaging	Assess for malignant cause of new or nonreducible large right varicocele
Renal US	Assess for renal absence if vas absent unilaterally (26-75%) or bilaterally (10%)

Diagnoses (by cause):

Infertility Grouping	Diagnosis	Findings	Treatment
Gonadotropin Dysfunction	Kallman syndrome	Hypogonadotropic hypogonadism Anosmia	HCG + FSH, GnRH pump
	Incomplete hypoandrogenism	Increased LH Decreased T	Clomiphene/Tamoxifen Anostrozole/Letrozole
	Pituitary tumors	Elevated prolactin MR imaging if prolactin elevated (> 50ug/L)	Bromocriptine/Cabergoline Transsphenoidal surgery
	Exogenous suppression	Specific hx steroids or other drugs	Stop offening agent(s)
Testicular dysfunction	Kleinfelter (XXY)	azoospermia (92%) + small testes + hypergonadotropins mosaic in 10-20%	microTESE + IVF/ICSI
	Leydig cell (steroidogenic) dysfunction	Elevated LH Decreased T	microTESE + IVF/ICSI
	Y Microdeletions	azoospermia (AZFa/AZFb)	Adoption, donor sperm
		oligospermia (AZFc)	microTESE + IVF/ICSI
	Antisperm antibodies	secondary to blood/testis barrier breakdown	IVF/ICSI
	Varicocele	Physical exam	Surgical repair
	DNA Fragmentation	Assess after repeat IVF failure	TESE + ICSI
Transportation Dysfunction	Absence of Vas Deferens	Physical exam findings History renal agenesis	TESE + IVF
	Congenital Bilateral Absence of the Vas Deferens (CBAVD)	CFTR mutation	CFTR screen panel TESE + IVF
	Hypospadias Epispadias	Physical exam findings	Intrauterine insemination
	Ejaculatory duct obstruction	Azoospermia + Hypovolemia TRUS findings (SV > 15mm AP, ED > 2.3mm)	TURED
	Retrograde ejaculation	Azoospermia + Hypovolemia Sperm on post-ejaculate urinalysis	Sperm retrieval (alkalinize with bicarb) Sympathomimetic agents (25% success)
	Anejaculation	Neurologic history Prior RPLND	Penile vibratory device Electroejaculation

Azoospermia

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

Treatments

Medications

Class	Medication	Dose	Indication	Side effects
Gonadotropin agonist	Human Chorionic Gonadotropin (HCG)	1500-5000 IU 2-3x weekly Titrate up to 10K IU/week Titrate to T level	Hypogonadotropic hypogonadism	Nausea (12%) Breast enlargement/tenderness (1-10%) Headache (34%) Injection discomfort (1-10%)
	Human Menopausal Gonadotropin (HMG)	75-150 IU 2-3x weekly
Selective estrogen receptor modulator	Clomiphene citrate	25mg QD or 50mg EOD Titrate to max 100mg QD Titrate to T level		Headache (1%) Blurred vision (2%) Flushing (10%) Breast discomfort (2%) Nausea (2%) Impaired libido Gynecomastia (rare)
Aromatase inhibitor	Anostrozole	1mg daily	Hypergonadotropic hypogonadism (Kleinfelter syndrome)	Nausea (11-19%) Headache (9-10%) Hot flashes (12-26%) Chest discomfort (2-12%)
	Lestrozole	2.5mg daily
Dopamine agonist	Cabergoline	0.25mg 2x weekly Titrate up to 1mg Titrate per prolactin levels	Prolactin-secreting pituitary tumor	Headache (26%) Dizziness (15-17%) Nausea (27-29%) Constipation (7-10%)
a-agonist	Pseudoephedrine	60mg PO QID	Retrograde ejaculation	restlessness Nausea/vomiting Weakness Headache Nervousness Dizziness Palpitations

Varicoceles

• Prevalence: 15% all men, 40% subfertile men, more comon on L side, most common cause of infertility
• Grading scale (1-3): palpable with Valsalva only, palpable standing without Valsalva, visible on exam)
• Surgery recommended: palpable varicocele, infertility, and abnormal semen parameters
• Sugery maybe recommended: palpable varicocele and associated testis pain (may not improve/resolve), adolescent with varicocele + small testis (reverses testicular atrophy but may not prevent infertility)
• Surgery not recommended: non-clinically significant varicocele, even if scrotal/testis pain, non-obstructive azoospermia
• Success: pain improves in 50-90%, semen parameters improve in 70%, rates based on surgeon experience/technique, microsurgical has 1% recurrence rate and 0.4% hydrocele rate
• Varicocelectomy side effects: hematoma, hydrocele, edema, recurrence, atrophy, infection

Ejaculatory stimulation

• Penile vibratory stimulation: vibrator stimulates ejaculation in anejaculatory men, ejaculation reflex pathway must be intact, usually does not work in RPLND or SCI patients
• Electroejaculation: electrical current applied via transrectal probe, usually induces retrograde ejaculation (remove sperm from bladder), does not require ejaculation reflex, requires anesthesia (very painful)

Surgical treatment

Class	Procedure	Indications	Description	Side effects
Azoospermia diagnosis	Testis aspiration	Confirm obstructive (vs nonobstructive) azoospermia	Insert biopsy needle (thru skin or skin incision) and aspirate to assess for sperm	Hematoma, hematocele, spermatocele, hydrocele
	Testis biopsy		Incise tunica albuginea, extrude tubules and remove, close incision	Low risk bleeding
Sperm retrieval	Tes(TESE)	Obstructive azoospermia	Obtain sperm via opening testis or epididymis and removing tubules	Bleeding, postop pain
	microTESE	Nonobstructive azoospermia	Obtain sperm via assessing and extracting microtubules
	Epididymal sperm extraction	Obstructive azoospermia with epididymal dilation	Obtain sperm via assessing and extracting microtubules
Improve sperm delivery	Vas reversal	Obstructive azoospermia (after vasectomy)	Obtain sperm via assessing and extracting microtubules	Hematoma (0.3%), granulomas (5%), delayed failure (5%), can consider TESE instead
	Transurethral resection of ejaculatory ducts (TURED)	Obstructive azoospermia (ejaculatory ducts)	Resect ducts to remove obstruction, can transrectally inject dye to improve identification	Restenosis, pain, epididymoorchitis (chemical/infectious), retention, incontinence, hematuria
Assisted reproductive technology	Intrauterine insemination (IUI)	Normal sperm but unable to reach egg naturally, oligospermia (5-8mil)	Inject collected/concentrated sperm into uterus (via cervix) to allow natural fertilization of egg	Minimal risks
	In vitro fertilization (IVF)	Sperm unable to reach egg, oligospermia (< 5mil)	Sperm placed in proximity to egg, natural fertilization, embryos placed within uterus for implantation	Risks of egg stimulation/retrieval Multifetal pregnancy
	Intracytoplasmic sperm injection (ICSI)	Sperm unable to fertilize egg, oligospermia (< 5mil)	Sperm directly injected into egg, embryos placed within uterus for implantation	Risks of egg stimulation/retrieval 4x risk for sex chromosome abnormalities Congenital malformations (slight increased risk) Spontaneous abortion/ectopic pregnancy