Medical School · Year 2 · Reproductive · includes a quiz and discussion video

Lecture 2: Male Reproductive Disorders

Unit 2.4: Reproductive System

Learning Objectives

By the end of this lecture, students will be able to:

1. Describe the causes and evaluation of male hypogonadism
2. Explain erectile dysfunction pathophysiology and treatment
3. Describe benign prostatic hyperplasia and its management
4. Explain the diagnosis and management of prostate cancer
5. Describe testicular disorders including masses and torsion
6. Explain male infertility causes and evaluation

Lecture Outline

I. Male Hypogonadism - Overview

Male hypogonadism is a clinical syndrome resulting from insufficient testosterone production and/or defective spermatogenesis. This condition profoundly affects quality of life, sexual function, bone health, and metabolic status. Understanding the classification and causes of hypogonadism enables appropriate diagnostic evaluation and targeted treatment.

The definition and epidemiology of hypogonadism establish its clinical importance. Hypogonadism is defined as failure of the testes to produce adequate testosterone and/or viable sperm. Prevalence increases substantially with age, affecting approximately 20% of men over 60 years and 50% of men over 80 years. However, many cases go undiagnosed because symptoms such as fatigue, decreased libido, erectile dysfunction, and reduced muscle mass are often attributed to normal aging or other conditions.

Classification of hypogonadism is based on the anatomic site of dysfunction and guides both diagnosis and treatment. Primary hypogonadism (hypergonadotropic hypogonadism) results from testicular failure. The pituitary responds appropriately to low testosterone by increasing LH and FSH secretion, resulting in elevated gonadotropins. Secondary hypogonadism (hypogonadotropic hypogonadism) results from hypothalamic or pituitary dysfunction. LH and FSH are inappropriately low or normal despite low testosterone, indicating failure of the hypothalamic-pituitary signaling.

Primary hypogonadism causes include both congenital and acquired conditions. Klinefelter syndrome (47,XXY) is the most common congenital cause, affecting approximately 1 in 500-1000 males. Cryptorchidism (undescended testes), if uncorrected, causes progressive testicular damage from the elevated temperature. Acquired causes include orchitis (particularly mumps orchitis in post-pubertal males), testicular trauma, radiation therapy, and chemotherapy with alkylating agents. Systemic conditions causing primary hypogonadism include hemochromatosis (iron deposition in the testes) and cirrhosis (both from impaired testosterone synthesis and increased estrogen production).

Secondary hypogonadism causes also span congenital and acquired conditions. Kallmann syndrome is a congenital condition caused by failure of GnRH neuron migration, resulting in isolated hypogonadotropic hypogonadism combined with anosmia. Other congenital syndromes include Prader-Willi and septo-optic dysplasia. Acquired causes include pituitary tumors (particularly prolactinomas, which suppress GnRH), pituitary surgery, radiation, and infiltrative diseases. Functional secondary hypogonadism, increasingly recognized, results from obesity (which increases aromatization of testosterone to estrogen), chronic opioid use, glucocorticoid therapy, critical illness, and severe caloric restriction.

<image>Panel A: HPG axis diagram showing primary hypogonadism at testicular level with elevated LH/FSH arrows versus secondary hypogonadism at hypothalamic-pituitary level with low/normal LH/FSH. Panel B: Primary causes including Klinefelter syndrome with 47,XXY karyotype, cryptorchidism, mumps orchitis, testicular trauma, radiation/chemotherapy, hemochromatosis, and cirrhosis. Panel C: Secondary causes including Kallmann syndrome with olfactory bulb hypoplasia, pituitary tumors, prolactinoma, and functional causes such as obesity and opioids. Panel D: Laboratory diagnostic flowchart showing low testosterone leading to LH/FSH measurement, with high values indicating primary and low/normal values indicating secondary hypogonadism.</image>

II. Specific Hypogonadal Conditions

Several genetic and acquired conditions cause hypogonadism with distinctive clinical features. Recognizing these syndromes enables early diagnosis, appropriate genetic counseling, and targeted management.

Klinefelter syndrome (47,XXY) is the most common chromosomal cause of hypogonadism and infertility in males. The additional X chromosome results from nondisjunction during meiosis and occurs in approximately 1 in 500-1000 male births. Most cases involve 47,XXY, though mosaicism (47,XXY/46,XY) occurs in approximately 10% and results in milder phenotypes. The testes are characteristically small and firm due to progressive fibrosis and hyalinization of the seminiferous tubules, typically measuring less than 4 mL in adults. The phenotype is variable but often includes tall stature with eunuchoid proportions (long limbs relative to trunk due to delayed epiphyseal fusion), gynecomastia (from increased estrogen-to-androgen ratio), reduced facial and body hair, and learning difficulties (particularly verbal processing). Virtually all patients with classic Klinefelter syndrome are azoospermic and infertile, though rare sperm may be retrievable from testicular tissue in some mosaic cases. Laboratory findings show elevated LH and FSH (reflecting primary testicular failure) and low to low-normal testosterone. Treatment consists of lifelong testosterone replacement, which improves bone density, muscle mass, libido, and quality of life but does not restore fertility.

Kallmann syndrome is a congenital condition characterized by isolated hypogonadotropic hypogonadism combined with anosmia or hyposmia (absent or reduced sense of smell). The underlying defect is failure of GnRH-secreting neurons to migrate from the olfactory placode to the hypothalamus during embryonic development. Because the olfactory nerve develops from the same embryonic region, olfactory bulbs are hypoplastic or absent. Several genes have been implicated, including KAL1 (X-linked, encoding anosmin-1), FGFR1, and others. Patients present with delayed or absent puberty and anosmia (which patients often do not notice or report). Associated features may include cleft lip/palate, renal agenesis, synkinesia (mirror movements), and hearing loss. Laboratory findings show low testosterone with low or normal LH and FSH. MRI may reveal absent olfactory bulbs or sulci. Treatment aims to induce puberty and restore fertility: testosterone replacement achieves virilization, but pulsatile GnRH or gonadotropin therapy (hCG + FSH) is required to induce spermatogenesis if fertility is desired.

Androgen insensitivity syndrome (AIS) results from mutations in the androgen receptor gene on the X chromosome. Affected individuals have 46,XY karyotype and functional testes that produce normal or elevated testosterone levels, but tissues cannot respond to androgens. Complete AIS produces phenotypically female individuals with female external genitalia, breast development at puberty (from aromatization of testosterone to estrogen), absence of pubic and axillary hair (which are androgen-dependent), a blind-ending vagina, and absent uterus and fallopian tubes (because Müllerian-inhibiting substance/AMH is produced normally by Sertoli cells). The testes are typically located in the inguinal canal or labia. Partial AIS produces varying degrees of genital ambiguity. Laboratory findings include elevated testosterone and LH (due to loss of negative feedback from androgen resistance). Management includes gonadectomy (to prevent malignancy in undescended testes), estrogen replacement, and psychological support. Gender identity is typically female in complete AIS.

Age-related testosterone decline (sometimes called late-onset hypogonadism or andropause) affects a significant proportion of older men. Unlike menopause, which is a discrete event, the decline in testosterone is gradual, averaging 1-2% per year after age 30. Many older men with low testosterone levels are asymptomatic, and the clinical significance of age-related decline remains debated. Contributing factors include obesity (which increases aromatization to estrogen and suppresses gonadotropin secretion), chronic illness, and medications. Diagnosis requires both consistent symptoms (fatigue, decreased libido, erectile dysfunction) and confirmed low testosterone on two morning measurements (typically <300 ng/dL). Treatment is controversial and should be individualized, balancing potential benefits against risks of testosterone therapy in older men.

<image>Panel A: Klinefelter syndrome showing 47,XXY karyotype diagram with characteristic phenotype including tall stature, eunuchoid proportions, small firm testes, gynecomastia, and sparse body hair. Panel B: Klinefelter laboratory findings with high LH/FSH, low testosterone, and azoospermia. Panel C: Kallmann syndrome illustrating failed GnRH neuron migration from olfactory placode during embryonic development, MRI showing absent olfactory bulbs, and clinical features of anosmia and delayed puberty. Panel D: Androgen insensitivity syndrome with 46,XY karyotype showing androgen receptor mutation, phenotypic female appearance with absent uterus and blind vagina, and tissue resistance mechanism despite high testosterone.</image>

III. Hypogonadism - Diagnosis and Treatment

The diagnosis of hypogonadism requires correlation of clinical features with laboratory confirmation. Treatment with testosterone replacement therapy significantly improves symptoms and quality of life but carries risks that must be monitored.

Clinical features of hypogonadism reflect testosterone's multiple physiologic roles. Sexual symptoms include decreased libido (often the earliest symptom), erectile dysfunction, decreased frequency of morning erections, and reduced sexual satisfaction. Physical changes include decreased muscle mass and strength, increased body fat (particularly abdominal), gynecomastia, decreased facial and body hair, and decreased testicular volume. Energy and mood symptoms include fatigue, decreased motivation, depressed mood, and difficulty concentrating. Bone effects include decreased bone mineral density, which increases fracture risk. Fertility-related findings include decreased sperm production and infertility. In prepubertal hypogonadism, failure to develop secondary sex characteristics and eunuchoid body proportions (due to delayed epiphyseal fusion) are characteristic.

Laboratory evaluation follows a systematic approach. Initial testing should include a morning total testosterone, drawn between 8-10 AM when levels are highest (testosterone follows a circadian rhythm with higher morning levels). If the initial testosterone is low (generally <300 ng/dL), it should be confirmed with a repeat measurement on a different day. Free or bioavailable testosterone should be measured if SHBG is suspected to be abnormal (obesity, aging, liver disease, thyroid disease). LH and FSH levels distinguish primary from secondary hypogonadism: elevated levels indicate primary testicular failure, while low or normal levels indicate hypothalamic-pituitary dysfunction. Prolactin should be measured to exclude prolactinoma as a cause of secondary hypogonadism. Additional testing includes complete blood count (baseline before testosterone therapy), PSA (prostate cancer screening), lipid profile, glucose, and bone density if osteoporosis is suspected. For secondary hypogonadism, pituitary MRI and additional pituitary function testing may be indicated.

Testosterone replacement options vary in administration route, pharmacokinetics, and convenience. Intramuscular injections of testosterone cypionate or enanthate are given every 1-2 weeks; they produce supraphysiologic peaks followed by troughs, which some patients notice as cyclical symptom fluctuations. Transdermal gels (applied daily to shoulders, arms, or abdomen) provide more stable levels but carry risk of transfer to partners or children through skin contact. Transdermal patches are applied daily and provide steady levels but may cause skin irritation. Nasal gel is applied two to three times daily. Subcutaneous testosterone pellets are implanted every 3-6 months and provide stable levels with infrequent dosing. Oral testosterone undecanoate is a newer option that avoids first-pass hepatic metabolism (which limits traditional oral androgens). The choice depends on patient preference, cost, insurance coverage, and individual response.

Monitoring during testosterone therapy ensures efficacy and safety. Testosterone levels should be measured at 3-6 months after initiation, with dose adjustments to achieve mid-normal levels. Hematocrit must be monitored because testosterone stimulates erythropoiesis; polycythemia (hematocrit >54%) increases thrombotic risk and requires dose reduction or phlebotomy. PSA should be measured at baseline and monitored periodically; testosterone therapy is contraindicated in patients with known or suspected prostate cancer. Bone density may be assessed after 1-2 years of therapy in patients with osteoporosis. Ongoing symptom assessment confirms therapeutic benefit.

Contraindications to testosterone therapy must be recognized. Testosterone is absolutely contraindicated in known prostate cancer or breast cancer (both are hormone-sensitive malignancies). Severe benign prostatic hyperplasia with urinary obstruction may worsen with testosterone. Baseline hematocrit greater than 50% increases the risk of polycythemia. Untreated obstructive sleep apnea may be exacerbated. Crucially, testosterone replacement suppresses gonadotropin secretion and consequently spermatogenesis; men desiring fertility should not receive testosterone and instead should be treated with gonadotropin therapy (hCG ± FSH) or clomiphene citrate to stimulate endogenous testosterone production while preserving fertility.

<image>Panel A: Symptoms checklist organized by category including sexual symptoms of low libido and ED, physical changes of muscle loss, fat gain, and gynecomastia, energy/mood symptoms of fatigue and depression, and bone/fertility effects. Panel B: Laboratory evaluation algorithm showing morning testosterone measurement, repeat confirmation if low, then LH/FSH to classify as primary or secondary, with additional testing for prolactin, CBC, and PSA. Panel C: Treatment options comparison table showing IM injections, gels, patches, pellets, and oral formulations with dosing frequency and advantages/disadvantages for each. Panel D: Monitoring schedule showing testosterone levels, hematocrit, and PSA at 3-6 months then annually, plus contraindications including prostate cancer, desire for fertility, polycythemia, and sleep apnea.</image>

IV. Erectile Dysfunction

Erectile dysfunction (ED) is the persistent inability to achieve or maintain an erection sufficient for satisfactory sexual intercourse. Beyond its impact on quality of life and relationships, ED often serves as an early marker of underlying vascular disease. Understanding its pathophysiology guides both diagnosis and treatment selection.

Definition and epidemiology establish ED as a common condition with significant health implications. ED affects approximately 40% of men by age 40, with prevalence increasing to approximately 70% by age 70. The condition has psychogenic and organic components that often coexist. Organic ED typically develops gradually and is present in all circumstances, while psychogenic ED often has sudden onset and is situational (present with a partner but not during masturbation or morning erections). The presence of nocturnal erections suggests intact neurovascular mechanisms and a psychogenic component.

Causes of ED are multifactorial and often overlap. Vascular disease is the most common organic cause, reflecting the fact that erection is fundamentally a vascular event requiring arterial inflow and venous restriction. Atherosclerosis, diabetes mellitus (which causes both vascular and neurologic damage), and hypertension impair the vascular mechanisms of erection. Because the penile arteries are smaller than coronary and cerebral vessels, ED often precedes symptomatic coronary artery disease by 3-5 years—making ED an important warning sign for cardiovascular risk. Neurologic causes include diabetic neuropathy (affecting autonomic fibers), spinal cord injury, multiple sclerosis, and pelvic surgery or radiation that damages the cavernous nerves. Endocrine causes include hypogonadism (low testosterone decreases libido and may impair the NO signaling necessary for erection), hyperprolactinemia, and thyroid disorders. Medications causing ED include beta-blockers, thiazide diuretics, SSRIs and other antidepressants, antiandrogens, and some antipsychotics. Psychogenic causes include performance anxiety, depression, relationship stress, and prior negative sexual experiences. Structural abnormalities such as Peyronie disease (fibrous plaques in the tunica albuginea causing penile curvature) can mechanically impair erection.

Evaluation of ED begins with a thorough history and focused physical examination. History should assess the onset (gradual vs. sudden), duration, presence of morning erections (preserved in psychogenic ED), situational factors, relationship quality, and associated symptoms (libido, ejaculatory function). A complete medication list is essential. Cardiovascular risk factors should be assessed, as ED may herald coronary disease. Physical examination includes assessment of secondary sex characteristics (for hypogonadism), genital examination (testicular size, penile abnormalities), peripheral pulses, and neurologic examination. Laboratory testing should include testosterone level (morning), glucose or HbA1c, and lipid profile. Specialized testing such as penile Doppler ultrasound (to assess arterial inflow and venous leak) is reserved for cases where the results would change management, such as young men considering vascular surgery.

Treatment of ED follows a stepwise approach. Lifestyle modifications—weight loss, exercise, smoking cessation, and optimization of cardiovascular risk factors—provide modest benefit and address underlying disease. Phosphodiesterase type 5 (PDE5) inhibitors are first-line pharmacotherapy. These drugs inhibit the degradation of cGMP, prolonging and enhancing the erectile response to sexual stimulation. Available agents include sildenafil (Viagra; 4-6 hour duration, should be taken on an empty stomach), tadalafil (Cialis; 36-hour duration, enabling a daily dosing option), vardenafil (Levitra; 4-6 hours), and avanafil (Stendra; faster onset). All require sexual stimulation to be effective. The critical contraindication is concurrent nitrate use (nitroglycerin, isosorbide); the combination causes severe, potentially fatal hypotension. Second-line therapies for PDE5 inhibitor failures include intracavernosal injection of alprostadil (prostaglandin E1), which induces erection within minutes regardless of sexual stimulation, and vacuum erection devices, which draw blood into the penis using negative pressure and maintain erection with a constricting ring. Intraurethral alprostadil (MUSE) is an alternative to injection. Penile prosthesis implantation is a surgical option for refractory cases, with high patient satisfaction rates despite its irreversibility. For psychogenic ED, psychotherapy or sex therapy addresses underlying psychological factors.

<image>Panel A: Pathophysiology comparison showing normal erection mechanism with arterial inflow, sinusoidal relaxation, and venous occlusion versus dysfunction at each level including arterial insufficiency, impaired relaxation, and venous leak. Panel B: Causes categorized as vascular (atherosclerosis, diabetes, hypertension with ED preceding CAD by 3-5 years), neurologic (diabetic neuropathy, spinal injury, pelvic surgery), endocrine (hypogonadism, hyperprolactinemia), medications, and psychogenic. Panel C: First-line treatment with PDE5 inhibitors comparison table showing sildenafil, tadalafil, vardenafil, and avanafil with duration times and nitrate contraindication warning. Panel D: Treatment algorithm progression from lifestyle modification through PDE5 inhibitors to second-line options of intracavernosal injection and vacuum device, then penile prosthesis.</image>

V. Benign Prostatic Hyperplasia (BPH)

Benign prostatic hyperplasia (BPH) is a histologic diagnosis referring to non-malignant proliferation of prostatic tissue, predominantly in the transition zone surrounding the urethra. The resulting enlargement can obstruct urinary flow, producing the symptom complex known as lower urinary tract symptoms (LUTS).

Epidemiology and pathophysiology establish BPH as nearly universal in aging men. Histologic BPH (microscopic evidence of hyperplasia) is present in 50% of men by age 60 and 90% by age 85. However, only about half of those with histologic BPH develop clinically significant symptoms. Risk factors include advancing age, family history, obesity, and metabolic syndrome. BPH is androgen-dependent; castrated or severely hypogonadal men do not develop BPH, and 5α-reductase inhibitors that block DHT production cause prostatic regression.

The pathophysiology of BPH involves both static and dynamic components. The prostate is divided into zones: the peripheral zone (70% of glandular tissue, site of most prostate cancers), central zone (25%, surrounding the ejaculatory ducts), and transition zone (5% of normal prostate, but the site of BPH development). Transition zone hyperplasia involves both stromal (smooth muscle and connective tissue) and epithelial proliferation. The static component refers to mechanical obstruction from physical enlargement of the gland compressing the prostatic urethra. The dynamic component refers to increased smooth muscle tone in the prostate and bladder neck, mediated by α₁-adrenergic receptors; this explains why α-blockers provide rapid symptomatic relief. Dihydrotestosterone (DHT), converted from testosterone by 5α-reductase, is the primary androgen driving prostatic growth.

Clinical features of BPH are collectively termed lower urinary tract symptoms (LUTS). Storage (irritative) symptoms result from detrusor instability and include urinary frequency, urgency, nocturia, and urge incontinence. Voiding (obstructive) symptoms result from urethral obstruction and include hesitancy, weak stream, intermittency, straining to void, prolonged voiding, and sensation of incomplete emptying. Post-void dribbling is common. The International Prostate Symptom Score (IPSS) is a validated questionnaire (0-35 points) that quantifies symptom severity: mild (0-7), moderate (8-19), or severe (20-35). Complications of untreated BPH include acute urinary retention (painful inability to void), chronic urinary retention with overflow incontinence, urinary tract infections, bladder stones, and rarely, obstructive nephropathy.

Evaluation of BPH begins with history and symptom assessment using the IPSS. Digital rectal examination (DRE) assesses prostate size (though size correlates poorly with symptom severity), consistency, and nodularity (which raises concern for cancer). Urinalysis screens for infection and hematuria. Serum PSA is typically measured, though its role in screening for prostate cancer is controversial; PSA is elevated in BPH as well as prostate cancer, and 5α-reductase inhibitors reduce PSA by approximately 50%. Post-void residual (PVR) volume, measured by ultrasound or catheterization, assesses bladder emptying; significant residual (>200 mL) suggests obstruction.

Treatment of BPH is guided by symptom severity. Watchful waiting is appropriate for mild symptoms (IPSS <8) that do not significantly affect quality of life; many patients remain stable or improve spontaneously. Medical therapy is first-line for bothersome moderate to severe symptoms. Alpha-adrenergic blockers (tamsulosin, alfuzosin, silodosin, doxazosin, terazosin) relax prostatic smooth muscle, providing rapid symptomatic relief within days. Side effects include orthostatic hypotension, dizziness, and retrograde ejaculation. 5α-reductase inhibitors (finasteride, dutasteride) block conversion of testosterone to DHT, causing gradual prostatic shrinkage (15-25% reduction over 6-12 months). They are most effective for larger prostates (>40 mL) and reduce the risk of acute urinary retention and need for surgery. They also reduce PSA by approximately 50%, which must be accounted for when interpreting PSA levels. Combination therapy (α-blocker plus 5ARI) is more effective than either alone for men with larger prostates and moderate to severe symptoms. Tadalafil (a PDE5 inhibitor) is approved for BPH/LUTS and may be particularly useful in men with concomitant ED. Surgical intervention is indicated for refractory symptoms, recurrent urinary retention, or complications. Transurethral resection of the prostate (TURP) is the gold standard, though various minimally invasive alternatives (laser prostatectomy, prostatic urethral lift/UroLift, water vapor therapy) are available. Open prostatectomy is reserved for very large glands.

<image>Panel A: Prostatic anatomy cross-section showing transition zone as site of BPH with enlargement, peripheral zone as site of cancer, and prostatic urethra compression. Panel B: Pathophysiology illustrating static component of mechanical compression and dynamic component of alpha-1-mediated smooth muscle tone, with DHT-driven epithelial and stromal proliferation. Panel C: LUTS categorized as storage symptoms (frequency, urgency, nocturia) and voiding symptoms (hesitancy, weak stream, incomplete emptying). Panel D: Treatment algorithm by severity showing watchful waiting for IPSS less than 8, medical therapy with alpha-blockers for rapid relief and 5-alpha-reductase inhibitors for larger prostates, combination therapy, and surgical options including TURP and minimally invasive procedures.</image>

VI. Prostate Cancer

Prostate cancer is the most common non-cutaneous malignancy in men and the second leading cause of cancer death in men. Understanding its epidemiology, screening controversies, diagnosis, and treatment options is essential for appropriate patient counseling and management.

Epidemiology and risk factors define the population at risk. Prostate cancer is rare before age 50, with incidence increasing dramatically with age. Lifetime risk of diagnosis is approximately 1 in 8. However, autopsy studies show microscopic prostate cancer in 30% of men over 50 and more than 70% of men over 80, indicating that most prostate cancers are indolent and would never cause clinical symptoms. This discrepancy underlies the screening controversy. Major risk factors include advancing age, family history (first-degree relative with prostate cancer doubles the risk), African American ancestry (2-3 times higher incidence and mortality), and possibly dietary factors (high animal fat intake). Most prostate cancers arise in the peripheral zone (70%), which is palpable on digital rectal examination, in contrast to BPH, which arises in the transition zone.

Screening for prostate cancer remains controversial. PSA (prostate-specific antigen) is a serine protease produced by prostatic epithelium that is elevated in prostate cancer but also in BPH, prostatitis, and after prostatic manipulation. A threshold of 4 ng/mL has traditionally been used, though there is no clear cutoff that reliably distinguishes cancer from non-cancerous conditions. Digital rectal examination can detect palpable abnormalities (nodules, asymmetry, induration). Screening reduces prostate cancer mortality but at significant cost: many men are diagnosed with indolent cancers that would never have caused harm, leading to overtreatment and its associated morbidity (urinary incontinence, erectile dysfunction). Current guidelines recommend shared decision-making with informed patients aged 55-69, considering individual risk factors and preferences.

Refinements in PSA interpretation help address its limitations. PSA velocity (rate of PSA rise over time; >0.75 ng/mL/year is concerning) and PSA density (PSA divided by prostate volume; higher density more concerning) provide additional information. Free PSA (the percentage of PSA not bound to proteins) is lower in cancer than in BPH; a low free PSA percentage suggests higher cancer risk. 5α-reductase inhibitors reduce PSA by approximately 50%, so measured PSA should be doubled in men taking these medications.

Diagnosis of prostate cancer requires tissue confirmation. Biopsy is indicated for elevated PSA or abnormal DRE. Multiparametric MRI of the prostate is increasingly used before biopsy to identify suspicious lesions (reported using PI-RADS scoring) and guide targeted biopsy. Traditional systematic transrectal ultrasound-guided biopsy takes 10-12 cores from various prostate regions. MRI-fusion biopsy combines MRI-identified targets with systematic sampling. Transperineal biopsy approaches reduce infection risk compared to transrectal routes.

Gleason grading assesses cancer aggressiveness based on histological architecture. The Gleason score is the sum of the two most prevalent patterns (each graded 1-5). Gleason 6 (3+3) represents low-grade cancer with excellent prognosis. Gleason 7 (3+4) is favorable intermediate-risk; Gleason 7 (4+3) is unfavorable intermediate-risk (the primary pattern being more significant). Gleason 8-10 represents high-grade cancer with worse prognosis. The newer Grade Group system (1-5) is increasingly used for clearer risk stratification.

Treatment options depend on cancer stage, grade, patient age, comorbidities, and preferences. Active surveillance is appropriate for low-risk localized cancer (Gleason 6, low PSA, limited tumor volume) in patients with reasonable life expectancy; the cancer is monitored with periodic PSA, examination, and repeat biopsies, with treatment initiated if progression occurs. This approach avoids overtreatment of indolent cancers. Definitive local treatment with curative intent includes radical prostatectomy (surgical removal, offering potential cure with risks of urinary incontinence and erectile dysfunction) and radiation therapy (external beam or brachytherapy). For intermediate and high-risk localized disease, radiation is often combined with androgen deprivation therapy (ADT). Advanced and metastatic disease is treated primarily with ADT, which may be combined with chemotherapy or newer hormonal agents.

Androgen deprivation therapy (ADT) is the cornerstone of treatment for advanced prostate cancer, leveraging the androgen dependence of prostate cancer cells. GnRH agonists (leuprolide, goserelin) initially cause a testosterone surge ("flare") before suppressing the HPG axis through receptor downregulation. Anti-androgens (flutamide, bicalutamide) are given initially to block the flare effect. GnRH antagonists (degarelix) suppress testosterone without causing a flare. Bilateral orchiectomy achieves permanent surgical castration. Newer agents for castration-resistant prostate cancer include abiraterone (inhibits androgen synthesis), enzalutamide and apalutamide (androgen receptor antagonists), and chemotherapy with docetaxel or cabazitaxel.

<image>Panel A: Anatomic location showing peripheral zone as site of 70% of cancers that is palpable on DRE versus transition zone as site of BPH with cross-sectional anatomy. Panel B: Screening with PSA showing factors affecting levels including cancer, BPH, prostatitis, manipulation, and 5ARI effect, plus free PSA percentage interpretation and MRI-fusion biopsy technique. Panel C: Gleason grading illustrated with patterns 1-5 showing corresponding Grade Groups and prognosis. Panel D: Treatment by stage including active surveillance criteria for low-risk disease, radical prostatectomy versus radiation for localized disease, and ADT for advanced disease with GnRH agonists showing flare effect, antagonists, and newer agents.</image>

VII. Testicular Disorders

Testicular masses and other scrotal abnormalities require systematic evaluation to distinguish benign from malignant conditions. Testicular cancer, though relatively rare, is the most common solid malignancy in young men and is highly curable when diagnosed appropriately.

The approach to testicular masses follows key principles. The critical first distinction is whether a mass is intratesticular or extratesticular. Intratesticular masses should be considered malignant until proven otherwise. Extratesticular masses are usually benign (hydrocele, epididymal cyst, spermatocele). Transillumination is helpful: fluid-filled structures (hydroceles) transmit light, while solid tumors do not. Scrotal ultrasound is the primary imaging modality and should be obtained promptly for any palpable testicular mass. A solid intratesticular mass on ultrasound requires further workup for malignancy.

Testicular cancer epidemiology and risk factors define the at-risk population. Testicular cancer is the most common solid tumor in men aged 15-35, though it accounts for only about 1% of all male cancers. Germ cell tumors comprise 95% of testicular cancers, with the remainder being sex cord-stromal tumors and lymphoma (more common in older men). Risk factors include cryptorchidism (undescended testis, which increases risk 3-8 fold even after surgical correction), personal history of testicular cancer (increases risk in the contralateral testis), family history, and infertility or testicular dysgenesis syndromes. Most patients present with a painless testicular mass noticed incidentally or during self-examination; approximately 10% present with pain (from hemorrhage or infarction within the tumor).

Germ cell tumors are classified as seminoma or non-seminomatous germ cell tumors (NSGCT). Seminoma is the most common single type (40-50% of germ cell tumors), typically occurs in men 30-40 years old, and has excellent prognosis due to high sensitivity to radiation and chemotherapy. Pure seminoma does not produce AFP (alpha-fetoprotein). Non-seminomatous germ cell tumors include embryonal carcinoma (aggressive), yolk sac tumor (most common in children, produces AFP), choriocarcinoma (highly aggressive, produces hCG, hematogenously metastatic), teratoma (contains tissues from all three germ layers), and mixed germ cell tumors (approximately 40% of testicular cancers).

Tumor markers are essential for diagnosis, staging, and monitoring. Alpha-fetoprotein (AFP) is produced by yolk sac tumor and embryonal carcinoma; it is not elevated in pure seminoma, so an elevated AFP excludes pure seminoma regardless of histology. Beta-hCG is produced by choriocarcinoma (markedly elevated) and approximately 10% of seminomas (mildly elevated). Lactate dehydrogenase (LDH) is a non-specific marker correlating with tumor burden.

Treatment of testicular cancer begins with radical inguinal orchiectomy—surgical removal of the testis through an inguinal incision (not transscrotal, to avoid violating scrotal lymphatic drainage). This provides both diagnosis and initial treatment. Further management depends on histology and staging. For seminoma, options include active surveillance (for stage I), radiation therapy (historically standard, now less common), or chemotherapy for more advanced disease. For non-seminomatous tumors, options include surveillance, retroperitoneal lymph node dissection (RPLND), and chemotherapy with bleomycin, etoposide, and cisplatin (BEP regimen) for advanced disease. Overall cure rates exceed 90%, making testicular cancer one of the most curable solid tumors.

<image>Panel A: Approach to testicular mass with decision tree starting with location (intratesticular versus extratesticular), transillumination (solid versus cystic), and ultrasound findings. Panel B: Germ cell tumor classification showing seminoma with characteristics, age, and radiosensitivity, and NSGCT types including embryonal, yolk sac, choriocarcinoma, and teratoma with typical marker patterns. Panel C: Tumor markers table showing AFP elevated in yolk sac and embryonal but not seminoma, beta-hCG elevated in choriocarcinoma and some seminomas, and LDH as non-specific tumor burden marker. Panel D: Treatment showing radical inguinal orchiectomy approach with subsequent options based on histology and stage including surveillance, RPLND, and BEP chemotherapy, with overall greater than 90% cure rate.</image>

VIII. Testicular Torsion and Other Conditions

Acute scrotal conditions require rapid differentiation between surgical emergencies and conditions manageable with medical therapy. Testicular torsion is a urologic emergency where timely diagnosis and treatment determines whether the testis can be salvaged.

Testicular torsion is the twisting of the spermatic cord, resulting in obstruction of venous outflow and subsequently arterial inflow, leading to testicular ischemia and infarction if not corrected. There are two peak incidence periods: the neonatal period (usually prenatal torsion with non-salvageable testis at birth) and adolescence (12-18 years), with the "bell-clapper" deformity (abnormally high attachment of the tunica vaginalis, allowing the testis to rotate freely) being the predisposing anatomic factor in adolescents.

Clinical presentation of testicular torsion is characteristic. Patients present with sudden onset of severe testicular or scrotal pain, often awakening from sleep. Associated symptoms include nausea and vomiting (from testicular innervation from the T10 level). Physical examination findings include a high-riding testis (elevated compared to the contralateral side due to shortening of the twisted cord), horizontal lie (the affected testis lies transversely rather than vertically), and absence of the cremasteric reflex (normally, stroking the inner thigh causes ipsilateral testicular elevation—this reflex is lost in torsion). The scrotum becomes edematous and erythematous as ischemia progresses. Pain is not relieved by elevation (in contrast to epididymitis).

Diagnosis of testicular torsion is clinical—imaging should not delay surgical exploration when clinical suspicion is high. Color Doppler ultrasound can demonstrate absent or decreased blood flow to the affected testis, but a normal ultrasound does not exclude torsion, and the test should not delay surgery when clinical findings are convincing.

Treatment is emergency surgical exploration and detorsion. The salvage rate depends on duration of ischemia: approximately 90% if surgery occurs within 6 hours, dropping to approximately 50% at 12 hours, and essentially 0% after 24 hours. At surgery, the testis is detorsed, assessed for viability, and fixed to the scrotum (orchiopexy) if viable, or removed (orchiectomy) if non-viable. Because the bell-clapper deformity is often bilateral, prophylactic orchiopexy of the contralateral testis is routinely performed to prevent future torsion.

Epididymitis is inflammation of the epididymis, typically caused by bacterial infection. In sexually active young men, Chlamydia trachomatis and Neisseria gonorrhoeae are the most common pathogens. In older men or men with urinary tract abnormalities, urinary pathogens (E. coli and other Enterobacteriaceae) predominate. Presentation is gradual onset of scrotal pain and swelling, in contrast to the sudden onset of torsion. Dysuria may be present. Physical examination reveals a tender, swollen epididymis (initially posterior to the testis, but swelling may obscure landmarks). Prehn sign (relief of pain with scrotal elevation) is classically positive in epididymitis but unreliable for distinguishing from torsion. Urinalysis may show pyuria. The cremasteric reflex is typically preserved. Treatment is antibiotics based on the likely pathogens: for suspected STI, ceftriaxone plus doxycycline; for suspected urinary pathogens, fluoroquinolones or trimethoprim-sulfamethoxazole.

Hydrocele is a collection of serous fluid within the tunica vaginalis surrounding the testis. In children, it often results from a patent processus vaginalis (communicating hydrocele, which fluctuates in size). In adults, it may be idiopathic or reactive (secondary to infection, trauma, or tumor). Presentation is painless scrotal swelling that transilluminates. Treatment is observation if asymptomatic, or surgical repair (hydrocelectomy) if symptomatic.

Varicocele is dilatation of the pampiniform venous plexus draining the testis. It is far more common on the left side (90%) due to the left testicular vein draining into the left renal vein at a right angle, while the right testicular vein drains directly into the IVC. On examination, the scrotum has a "bag of worms" feel, particularly while standing and with Valsalva maneuver (which increases venous pressure). A new right-sided varicocele in an older man, or a varicocele that does not decompress when supine, raises concern for renal vein or IVC obstruction (such as by a renal tumor). Varicoceles may impair fertility through increased testicular temperature and other mechanisms. Treatment is surgical ligation or embolization if symptomatic or if associated with infertility and abnormal semen parameters.

<image>Panel A: Testicular torsion showing twisted spermatic cord anatomy with vascular compromise, clinical findings of high-riding testis, horizontal lie, absent cremasteric reflex, and sudden onset, with time-dependent salvage rates of 90% at 6 hours declining thereafter. Panel B: Torsion treatment with emergency surgical detorsion and bilateral orchiopexy. Panel C: Epididymitis contrasted showing gradual onset, tender posterior epididymis, positive Prehn sign, preserved cremasteric reflex, with treatment by age/risk including STI pathogens in young men and urinary pathogens in older men. Panel D: Hydrocele showing transilluminating fluid collection with communicating versus non-communicating types, and varicocele showing bag of worms appearance with left-side predominance due to venous anatomy and fertility implications.</image>

IX. Male Infertility

Male infertility affects 7% of men and contributes to approximately 30-40% of infertility cases in couples. Evaluation and treatment require understanding of the causes and systematic assessment using semen analysis as the cornerstone of investigation.

Definition and epidemiology establish the clinical framework. Infertility is defined as failure to conceive after 12 months of regular unprotected intercourse. Both partners should be evaluated simultaneously, as multiple factors often contribute. Male factor infertility may be the sole cause in 20% of infertile couples and a contributing factor in an additional 20-30%.

Causes of male infertility are classified by the anatomic site of dysfunction. Pre-testicular causes involve defective gonadotropin stimulation of the testes, as seen in hypogonadotropic hypogonadism (Kallmann syndrome, pituitary tumors, hyperprolactinemia, exogenous testosterone use). These are potentially treatable with gonadotropin replacement. Testicular causes involve intrinsic testicular failure and include varicocele (the most common correctable cause, present in 35-40% of infertile men), cryptorchidism, genetic abnormalities (Klinefelter syndrome, Y chromosome microdeletions, CFTR mutations), prior orchitis, testicular trauma or torsion, and gonadotoxic exposures (chemotherapy, radiation). Post-testicular causes involve obstruction of the reproductive tract or ejaculatory dysfunction and include vasectomy, congenital bilateral absence of the vas deferens (CBAVD, associated with CFTR mutations—these men are carriers or have atypical cystic fibrosis), ejaculatory duct obstruction, and retrograde ejaculation. Idiopathic causes account for 30-40% of cases despite thorough evaluation.

Semen analysis is the fundamental diagnostic test. Proper collection requires 2-5 days of abstinence (shorter or longer intervals affect results), collection by masturbation into a sterile container, and analysis within one hour of collection. Because semen quality varies, at least two samples obtained at least one week apart should be analyzed. WHO reference values (5th edition) define lower limits of normal: volume ≥1.5 mL, concentration ≥15 million/mL, total count ≥39 million per ejaculate, progressive motility ≥32%, total motility ≥40%, and normal morphology ≥4% by strict criteria. Terminology for abnormalities includes oligozoospermia (low concentration), asthenozoospermia (poor motility), teratozoospermia (abnormal morphology), oligoasthenoteratozoospermia (OAT, all three abnormalities), and azoospermia (no sperm in ejaculate).

Azoospermia requires further workup to distinguish obstructive from non-obstructive causes. Obstructive azoospermia results from blockage in the reproductive tract despite normal spermatogenesis. FSH levels are typically normal (because Sertoli cell function is intact). Testicular volume is normal. Causes include prior vasectomy, CBAVD, and epididymal or ejaculatory duct obstruction. Non-obstructive azoospermia results from primary testicular failure with absent or severely impaired spermatogenesis. FSH is elevated (reflecting loss of inhibin B feedback). Testicular volume is often reduced. Causes include Klinefelter syndrome, Y chromosome microdeletions, and prior gonadotoxic exposure. Genetic testing (karyotype, Y microdeletion analysis, CFTR mutation) is indicated for azoospermic men to identify genetic causes and provide appropriate counseling.

Treatment options depend on the underlying cause. For hypogonadotropic hypogonadism, gonadotropin therapy (hCG to stimulate testosterone, FSH to stimulate spermatogenesis) or pulsatile GnRH can restore fertility—in contrast, exogenous testosterone suppresses spermatogenesis and is contraindicated. For varicocele, surgical repair improves semen parameters in many men and may improve natural conception rates or outcomes with assisted reproduction. For obstructive azoospermia, surgical correction (vasectomy reversal, ejaculatory duct resection) or sperm retrieval directly from the epididymis (MESA) or testis (TESE) for use in IVF is possible. For non-obstructive azoospermia, micro-TESE (microsurgical testicular sperm extraction) may retrieve sperm in up to 50% of cases for use with ICSI. For unexplained or refractory male factor infertility, assisted reproduction with intrauterine insemination (IUI) or in vitro fertilization with intracytoplasmic sperm injection (ICSI) may achieve pregnancy.

<image>Panel A: Causes classified by anatomic level showing pre-testicular with hypogonadotropic hypogonadism diagram of suppressed HPG axis treatable with gonadotropins, and testicular causes with varicocele as most common correctable cause, genetic causes, and gonadotoxic exposure. Panel B: Post-testicular causes including obstruction, CBAVD with CFTR association, and ejaculatory dysfunction. Panel C: Semen analysis showing reference values table for volume, concentration, motility, and morphology, with terminology for abnormalities including oligozoospermia, asthenozoospermia, teratozoospermia, and azoospermia, distinguishing obstructive from non-obstructive azoospermia. Panel D: Treatment options showing gonadotropins for hypogonadotropic cases, varicocele repair, sperm retrieval techniques including MESA, TESE, and micro-TESE, and ART options of IUI and IVF-ICSI.</image>

X. Gynecomastia

Gynecomastia is the benign proliferation of male breast glandular tissue, resulting from an imbalance in the estrogen-to-androgen ratio. This common condition has both physiologic and pathologic causes and requires appropriate evaluation to exclude underlying disease.

Definition and epidemiology establish gynecomastia as common and often benign. Gynecomastia must be distinguished from pseudogynecomastia (lipomastia), which is fat deposition without glandular proliferation, common in obese men. True gynecomastia is palpable as firm, rubbery tissue beneath the nipple-areolar complex, while pseudogynecomastia feels soft and fatty without a discrete glandular component. The prevalence of gynecomastia has been estimated at 30-65% in various studies, depending on the population and definition used.

The mechanism underlying gynecomastia is an altered estrogen-to-androgen ratio at the breast tissue level. Estrogen stimulates breast glandular proliferation, while androgens inhibit it. Gynecomastia develops when estrogen action predominates, whether from increased estrogen production, decreased androgen production or action, or altered balance between the two.

Physiologic gynecomastia occurs at three life stages. Neonatal gynecomastia affects 60-90% of newborns due to transplacental passage of maternal estrogens; it resolves spontaneously within weeks. Pubertal gynecomastia affects up to 65% of adolescent boys, typically appearing between ages 10-14 when estrogen levels rise before testosterone reaches adult levels. It is usually bilateral and resolves within 1-2 years in most cases. Senescent gynecomastia occurs in older men due to declining testosterone production and increased peripheral aromatization of androgens to estrogens (particularly in adipose tissue).

Pathologic causes of gynecomastia require investigation. Increased estrogen states include estrogen-secreting tumors (testicular Sertoli cell tumors, Leydig cell tumors, adrenal tumors), hCG-secreting tumors (testicular choriocarcinoma, extragonadal germ cell tumors, some lung cancers) that stimulate testicular estrogen production, liver disease (increased aromatase activity and decreased estrogen metabolism), obesity (increased peripheral aromatization in adipose tissue), and hyperthyroidism (increased SHBG binding testosterone more than estrogen, raising free estrogen ratio). Decreased androgen states include primary hypogonadism (Klinefelter syndrome), secondary hypogonadism, and androgen insensitivity syndrome. Medications are a major cause: spironolactone (blocks androgen receptor), ketoconazole (inhibits testosterone synthesis), cimetidine (has anti-androgen effects), anabolic steroids (aromatization to estrogens), anti-androgens used for prostate cancer (bicalutamide, enzalutamide), digoxin, and marijuana.

Evaluation begins with history focusing on duration, symptoms (tenderness suggests recent onset and active glandular proliferation), medications, substance use, and symptoms of underlying disease. Physical examination should distinguish true gynecomastia from pseudogynecomastia, assess for tenderness, evaluate testicular size and masses, and look for stigmata of liver disease or thyroid dysfunction. Laboratory evaluation includes testosterone, LH, FSH, estradiol, hCG, liver function tests, and thyroid function tests. If hCG is elevated, testicular ultrasound and consideration of extragonadal germ cell tumors are indicated.

Treatment depends on the cause and duration. Observation is appropriate for physiologic gynecomastia (pubertal, mild senescent) and recent-onset asymptomatic cases. Discontinuation of offending medications should be considered. Medical therapy may be tried for painful or progressive gynecomastia of recent onset (<12 months): tamoxifen (selective estrogen receptor modulator) is most commonly used, though evidence is limited; aromatase inhibitors are occasionally used. Surgical treatment (reduction mammoplasty) is indicated for persistent, symptomatic, or cosmetically distressing gynecomastia, particularly if present for more than 12 months (when fibrosis has developed and medical therapy is unlikely to help).

<image>Panel A: Anatomy and examination showing cross-sectional comparison of true gynecomastia with palpable firm glandular disc versus pseudogynecomastia with diffuse fatty tissue. Panel B: Causes categorized as physiologic (neonatal, pubertal with age range and natural history, senescent), increased estrogen (tumors, liver disease, obesity, hyperthyroidism), and decreased androgen (hypogonadism, AIS). Panel C: Medication causes including spironolactone, ketoconazole, cimetidine, anabolic steroids, and marijuana. Panel D: Evaluation algorithm showing history and physical examination to distinguish true from pseudogynecomastia, laboratory panel with testosterone, LH, FSH, estradiol, hCG, LFTs, and TFTs, and treatment options by duration and severity including observation, discontinuing offending drugs, tamoxifen, and surgery.</image>

Summary

Male hypogonadism is classified as primary (elevated LH/FSH indicating testicular failure) or secondary (low/normal LH/FSH indicating hypothalamic-pituitary dysfunction). Klinefelter syndrome (47,XXY) is the most common genetic cause. Testosterone replacement improves symptoms but is contraindicated in those desiring fertility.

Erectile dysfunction is primarily vascular in etiology and often heralds cardiovascular disease. PDE5 inhibitors are first-line therapy but are contraindicated with nitrates.

BPH develops in the transition zone and causes lower urinary tract symptoms. Alpha-blockers provide rapid relief; 5α-reductase inhibitors shrink the prostate over months.

Prostate cancer arises in the peripheral zone. PSA screening is controversial due to detection of indolent cancers. Treatment options range from active surveillance to radical prostatectomy, radiation, and androgen deprivation therapy.

Testicular cancer is the most common solid tumor in young men. Germ cell tumors (seminoma and non-seminoma) predominate. Radical inguinal orchiectomy is both diagnostic and therapeutic. Cure rates exceed 90%.

Testicular torsion is a surgical emergency; salvage rates decline dramatically after 6 hours.

Key Terms

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