Male Repro - Part III Flashcards
Answer D
Seminiferous tubules are bounded by a basal lamina, with columnar Sertoli cells extending from the basal lamina to the lumen. The Sertoli cells are connected by a continuous barrier of tight junctions, forming a functional boundary between the outer basal compartment and the inner luminal compartment of the tubule. These tight junctions form the blood-testis barrier (BTB), which controls the environment of the developing spermatids and prevents immune exposure.
Undifferentiated germ cells (spermatogonia) reside along the basal lamina, between the Sertoli cells, and outside the BTB. The spermatogonia are continually replenished by mitosis. During differentiation, spermatozoa pass through the barrier, which reforms behind them. Disruption to the BTB (eg, due to trauma or ischemia) can lead to formation of antisperm antibodies, which can impair fertility.
(Choice A) Leydig cells produce a high local concentration of testosterone, which diffuses into the nearby seminiferous tubules and facilitates spermatogenesis. However, the Leydig cells are outside the tubules and do not form the BTB.
(Choices B and C) Primary and secondary spermatocytes are postmeiotic cells derived from spermatogonia. They migrate between the Sertoli cells, inside the BTB, but are not found in a continuous layer and do not form the BTB.
(Choice E) The tunica albuginea of the testis is a thick connective tissue structure that forms the outer capsule of the testis within the scrotum. It supports the testis as a whole but does not separate individual seminiferous tubules or form the BTB between the inner tubule and the blood.
Educational objective:
The blood-testis barrier is formed by tight junctions between Sertoli cells in the seminiferous tubules and prevents immune exposure to the developing spermatids. During differentiation, spermatozoa pass through the barrier, which reforms behind them. Disruption to the blood-testis barrier can lead to formation of antisperm antibodies, which can impair fertility.
Answer D
Prostate cancer is testosterone-dependent and can be treated in most cases with surgical and/or pharmacologic androgen deprivation. Initial options include bilateral orchiectomy or a gonadotropin-releasing hormone (GnRH) agonist. Pulsatile release of GnRH from the hypothalamus stimulates secretion of LH from the anterior pituitary and leads to increased testosterone production. However, constant GnRH activity causes down-regulation of the GnRH receptors on pituitary gonadotrophin cells, which suppresses LH secretion. Therefore, long-acting GnRH agonists (eg, leuprolide) paradoxically cause a decrease in testicular Leydig cell stimulation (Choice B). The use of long-acting GnRH agonists can be associated with a transient rise in LH and testosterone levels following treatment initiation. As a result, antiandrogens are sometimes prescribed concurrently to limit the tumor-stimulating effects of this initial testosterone rise.
Flutamide is a nonsteroid agent that acts as a competitive testosterone receptor inhibitor. Prevention of androgen-receptor binding blocks the stimulatory effect of androgens on the primary tumor and metastases and leads to a reduction in their size (improving symptoms such as bone pain and urinary obstruction).
(Choice A) Aromatase inhibitors (eg, anastrozole) decrease the peripheral conversion of androgens to estrogen and are used in postmenopausal women with estrogen receptor-positive breast cancer. They do not lower androgen levels and are not used in the treatment of prostate cancer.
(Choice C) Finasteride decreases peripheral conversion of testosterone to dihydrotestosterone by inhibiting 5-α-reductase. It is used for treatment of benign prostatic hyperplasia and male-pattern baldness.
(Choice E) Ketoconazole is a weak antiandrogen that decreases synthesis of steroid hormones in the gonads and adrenals. Flutamide does not inhibit testosterone production by Leydig cells.
Educational objective:
Flutamide is a nonsteroid anti-androgen that acts as a competitive inhibitor of testosterone receptors. It is used in combination with long-acting gonadotropin-releasing hormone agonists for the treatment of prostate cancer.
Answer C
This patient has fever, dysuria, and prostatic tenderness, consistent with acute bacterial prostatitis (ABP). ABP is most commonly caused by reflux of urine and organisms from the bladder and urethra into the prostatic ducts, although it can occasionally be caused by direct inoculation (eg, prostate biopsy) or hematogenous seeding from remote infection (eg, endocarditis). The risk of developing ABP is greater in patients with diabetes mellitus, anatomic abnormalities (eg, strictures), or bladder catheterization.
As with other urinary tract infections, the most common organisms in ABP include enteric gram-negative bacilli, predominantly Escherichia coli, because of virulence factors (eg, adhesins on bacterial fimbriae) that allow it to adhere onto mucosal or urothelial cells. The other bacteria (also gram-negative bacilli) that commonly cause ABP include Proteus, Klebsiella, Pseudomonas.
(Choices A and E) Sexually transmitted organisms (eg, Chlamydia trachomatis, Neisseria gonorrhoeae) commonly cause urethritis and/or urogenital infections that can involve the prostate, but this typically occurs in younger, sexually active men (this patient is older and not sexually active).
(Choice B) Coccidioides infections most commonly cause community-acquired pneumonia in endemic areas (eg, California, Arizona), but they can also cause dermatologic (eg, erythema nodosum or multiforme) or rheumatologic (eg, arthralgias) manifestations.
(Choices D and H) Mycoplasma hominis and Ureaplasma urealyticum commonly colonize the genitourinary tract, but they have not been proven to be a significant cause of symptomatic genitourinary infections.
(Choice F) Gram-positive skin flora (eg, Staphylococcus aureus) most commonly cause skin and soft tissue infections. Although patients with S aureus bacteremia can develop localized infections throughout the body (eg, endocarditis, osteomyelitis, organ abscess), isolated ABP would be rare.
(Choice G) Coagulase-negative staphylococci (eg, S saprophyticus) are a common cause of acute cystitis in young women.
Educational objective:
Acute bacterial prostatitis is usually caused by reflux of urine and organisms from the bladder and urethra. The risk is greater in patients with anatomic abnormalities (eg, strictures) or bladder catheterization. Escherichia coli is the most common cause of acute bacterial prostatitis and other urinary tract infections because of adhesins on its fimbriae that promote adherence to urothelial or mucosal cells.
Answer D
The prostate is a walnut-sized gland that encases the urethra and vas deferens. It abuts the urinary bladder superiorly and the rectum posteriorly and is composed of 3 distinct zones:
The peripheral zone is largely glandular and is the site of >85% of prostate adenocarcinoma. Because this zone borders the rectum, patients with suspected prostate cancer generally undergo transrectal ultrasound–guided biopsy. In this procedure, transrectal ultrasound identifies the borders of the prostate and suspicious hypoechoic lesions; multiple core biopsies (usually 10-12) are then obtained from random locations within the apical and far-lateral prostate (peripheral zone). Because the distal urethra passes through only a small portion of the peripheral zone, prostate cancer does not typically present with urinary symptoms (eg, voiding difficulty, hematuria).
The central zone surrounds the ejaculatory duct. This zone is primarily composed of stroma elements; prostate cancer rarely develops in this area.
The transition zone surrounds the urethra. This is the primary site of benign prostatic hyperplasia. Because only 10% of prostate cancers arise in this region, cystoscopy approaches (via the urethra) are not typically used to sample the prostate for cancer (Choices A and B).
(Choice C) Fine-needle aspiration is not recommended for the diagnosis of prostate cancer because tissue architecture is lost during sampling. Transperineal core biopsies are occasionally used to diagnose prostate cancer in men who cannot tolerate the transrectal approach.
(Choice E) The diagnosis of prostate cancer requires multiple core biopsies to obtain adequate sampling of the prostate. A single biopsy would dramatically increase the risk of a false negative result. Furthermore, the central portion of the gland is less likely to develop prostate cancer than the peripheral portion.
Educational objective:
Most prostate cancer arises in the peripheral zone of the gland, which abuts the rectum. Therefore, prostate biopsies are primarily obtained via the transrectal approach; multiple random core samples of the prostate are typically taken. Because only a small part of the peripheral zone encases the distal urethra, patients with prostate cancer do not typically present with urinary symptoms.
Answer D
This patient is taking exogenous anabolic steroids (eg, testosterone, synthetic steroidal androgens). Anabolic steroids are utilized by athletes in an effort to increase lean body mass. Adverse effects associated with the excessive use of anabolic steroids include acne, gynecomastia, azoospermia, decreased testicular size and increased aggression. Hypertension, dyslipidemia, cholestatic hepatitis and hepatic failure may also occur.
Serum testosterone levels can be low in individuals taking only synthetic androgens (eg, trenbolone), but are often within the normal range or elevated due to exogenous testosterone intake. Although serum testosterone may appear adequate, lower than normal local testosterone levels in the seminiferous tubules lead to decreased spermatogenesis.
(Choice A) Kallmann syndrome is a cause of GnRH deficiency, which results in abnormally low production of sex hormones by the gonads. Affected males present with delayed puberty and an abnormally small penis in addition to other nonsexual findings such as anosmia, hearing loss, and cleft palate.
(Choice B) 5-alpha reductase deficiency results in an inability to convert testosterone to dihydrotestosterone in the peripheral tissues. Affected males are born with ambiguous genitalia. Following puberty, affected patients have normal or elevated levels of serum testosterone.
(Choice C) Klinefelter syndrome (XXY seminiferous tubule dysgenesis) is a common cause of male hypogonadism. Small, firm testes and a decreased serum testosterone level are characteristic. Patients may exhibit diminished secondary sexual characteristics.
(Choice E) Hyperprolactinemia causes hypogonadotropic hypogonadism by suppressing LH and FSH release thereby decreasing serum testosterone in affected males. Symptoms include diminished libido, impotence and oligospermia.
Educational objective:
Adverse effects associated with the use of excessive doses of anabolic steroids include acne, gynecomastia, azoospermia, decreased testicular size, and increased aggression. When measured, serum testosterone is typically normal or elevated. However, endogenous testosterone production and spermatogenesis are decreased.
Answer E
Klinefelter syndrome is most commonly caused by a meiotic nondisjunction event during parental gametogenesis that results in a 47,XXY karyotype. Variants include 46,XY/47,XXY mosaicism and 48,XXXY. In general, patients with higher numbers of X chromosomes are more likely to have more severe manifestations. The disorder is usually not diagnosed until puberty when the characteristic physical signs begin to develop. The major features are as follows:
Klinefelter syndrome causes primary testicular failure due to hyalinization and fibrosis of the seminiferous tubules. This results in small, firm testes and azoospermia (infertility). Leydig cell dysfunction also occurs and leads to testosterone deficiency. Gonadotropin (FSH, LH) levels are increased secondary to gonadal failure.
Testosterone deficiency results in development of a eunuchoid body habitus. Patients have tall stature and gynecomastia. Facial and body hair is sparse or absent and muscle mass is decreased.
Mild intellectual disability is seen in some patients, although the majority have normal intelligence. Psychosocial abnormalities (eg, lack of insight, poor judgment) are also common.
(Choice A) Arachnodactyly, scoliosis, and aortic root dilation are signs of Marfan syndrome, which occurs due to an inherited defect of the extracellular matrix protein fibrillin.
(Choice B) Macroorchidism, large jaw, and intellectual disability are seen in patients with fragile X syndrome, an X-linked disorder caused by mutations in the fragile X mental retardation 1 gene.
(Choice C) In females, loss of an X chromosome (45,XO karyotype) results in Turner syndrome, which presents with short stature, broad chest, and primary amenorrhea.
(Choice D) Prader-Willi syndrome is characterized by short stature, hypotonia, intellectual disability, and obesity. The most common cause is a microdeletion affecting the paternal chromosome 15q11-13 critical region.
Educational objective:
47,XXY is the most common genotype causing Klinefelter syndrome. Patients present with tall stature; small, firm testes; azoospermia; and gynecomastia. Mild intellectual disability is seen in some patients, and the severity generally increases with each additional X chromosome.
Answer B
This patient has undergone bilateral orchiectomy for testicular germ cell tumor. Bilateral orchiectomy is also performed for treatment of metastatic prostate cancer and as a component of gender-confirming surgery in transgender patients. With bilateral testicular loss or failure (eg, mumps orchitis), extragonadal androgen sources (eg, adrenals) are typically inadequate to replace the loss of testosterone, resulting in a hypogonadal state.
The prostate is dependent on the trophic effects of dihydrotestosterone (the primary active testosterone metabolite), which is derived from testosterone via 5-alpha-reductase activity in local tissues. Loss of the normal supply of testosterone leads to marked atrophy of the glandular component of the prostate. The effects on the prostate stroma are relatively less, but apoptosis may be seen in stromal cells, and the combined effect is a significant decrease in prostatic volume (Choice E). Other genitourinary and sexual effects of hypogonadism include erectile dysfunction, decreased ejaculate volume, and decreased libido.
(Choices A and C) Loss of testosterone leads to significant changes in body composition over time. Testosterone induces increased protein synthesis in myocytes, so hypogonadal patients typically experience a decrease in muscle mass/lean body weight. However, subcutaneous fat increases, and patients frequently experience a small net increase in total body weight.
(Choice D) Testosterone induces proliferation and differentiation of osteoblasts. If bilateral orchiectomy is performed after skeletal maturity, bone dimensions do not change, but trabecular bone density decreases (osteoporosis).
Educational objective:
Following bilateral orchiectomy, extragonadal androgen sources are inadequate to replace the loss of testosterone, causing a hypogonadal state. Loss of testosterone leads to changes in body composition, including decreased lean body weight, increased subcutaneous fat, and decreased bone density. Loss of testosterone also leads to a significant decrease in prostate volume.
Answer C
The presence of a pelvic fracture and inability to void despite the sensation of a full bladder is suggestive of urethral injury. Additional signs of urethral injury include the presence of blood at the urethral meatus and a high-riding, boggy prostate (caused by hematoma formation below the gland). If urethral injury is suspected, placement of a Foley catheter is contraindicated and should not be attempted as it can worsen the injury; a retrograde urethrogram should be performed first to assess urethral integrity.
Urethral injuries most commonly occur in men because of their longer urethral length and are divided into anterior and posterior urethral injuries. The posterior urethra is located above the bulb of the penis, and the anterior urethra lies within the bulb and the remainder of the corpus spongiosum. The posterior urethra is further divided into the prostatic and membranous segments; the anterior urethra is divided into bulbous and penile segments. In contrast to the prostatic and bulbous segments, the membranous segment is relatively unsupported by the adjacent tissues and is the weakest point of the posterior urethra. Trauma to the pelvis severe enough to cause fracture often results in disruption of the posterior urethra at the bulbomembranous junction.
(Choice A) Injury of the anterior bladder wall is common with pelvic fractures and is usually associated with extraperitoneal leakage of urine. Superior bladder wall ruptures often occur with abdominal trauma when the bladder is full and result in leakage of urine into the intraperitoneal cavity. This patient’s full bladder sensation and inability to pass a Foley catheter makes a urethral injury more likely.
(Choice B) The prostatic urethral segment is strengthened by the surrounding prostate tissue and thus is less likely to be damaged from a pelvic fracture.
(Choice D) Although the bulbous urethral segment is reinforced by the surrounding corpus spongiosum, it is susceptible to crushing injuries when the perineum is struck forcefully (ie, straddle injury). Common mechanisms include falling on the crossbar of a bicycle or the top of a fence.
(Choice E) The penile urethral segment is most commonly injured due to penetrating trauma or instrumentation.
Educational objective:
Injury to the posterior urethra is associated with pelvic fractures, and the anterior urethra is most commonly damaged in straddle injuries. Inability to void with a full bladder sensation, a high-riding boggy prostate, and blood at the urethral meatus are suggestive of urethral injury, particularly in the presence of a pelvic fracture. If urethral injury is suspected, placement of a Foley catheter is contraindicated.
Answer D
Sexual dysfunction is common in older individuals due to comorbid conditions, medication effects, and in women, menopausal changes. This patient is experiencing difficulty with sexual intercourse, and his hesitation in discussing it suggests that he feels awkward in bringing up the subject.
In counseling a patient on a potentially sensitive subject such as sexuality, the first objective is making the patient feel comfortable. The clinician should discuss the topic objectively, as with any other medical topic, and avoid giving the impression that the subject of sex is “dirty” or inappropriate. It is generally best to use the same terms the patient uses for bodily functions but otherwise avoid euphemisms. In this particular case, the clinician should begin the conversation by reassuring the patient that sexual dysfunction is common and is a perfectly appropriate subject of discussion between a patient and a physician.
(Choice A) The patient already appears to feel nervous discussing the subject of sexuality. This statement conveys empathy but reiterates and draws attention to his anxiety and may reinforce his feelings of awkwardness.
(Choices B and E) The patient takes a medication (ie, nitrates) that makes phosphodiesterase inhibitors (eg, sildenafil, sometimes referred to colloquially as “the blue pill”) contraindicated. Although the use of phosphodiesterase inhibitors is often complicated in patients with cardiovascular disease, age itself is not a contraindication.
(Choice C) Patients are unlikely to bring up a sensitive subject, such as sexuality, if they do not consider it important. This statement may make the patient feel even more uncomfortable in having to justify raising the concern.
Educational objective:
Sexual dysfunction is common in older individuals due to comorbid conditions, medication effects, and in women, menopausal changes. When counseling patients on sexuality, the clinician should attempt to make them feel comfortable and reassure them that sexual dysfunction is common and is an appropriate subject of discussion between a patient and a physician.
Answer C
Evaluation of sexual dysfunction requires ruling out medical conditions and substance use, as well as obtaining a history of psychosocial stressors, including stressors in the relationship itself. This patient has features of premature ejaculation, characterized by unwanted episodes of early ejaculation accompanied by a sense of lack of control. Although concern over the time to ejaculation is common, only an estimated 4% of men will meet diagnostic criteria (ejaculation within one minute of penetration, occurring most of the time for at least 6 months). The diagnostic criteria for premature ejaculation are based on ejaculation during partnered sexual activity, therefore a normal time to ejaculation during masturbation does not negate this diagnosis.
(Choice A) Erectile disorder is characterized by a persistent inability to attain or sustain an erection.
(Choice B) The symptom reported initially was a lack of sexual interest. However, on further questioning, it was found to be related to his embarrassment over premature ejaculation rather than to a pervasive lack of desire. It is common for men with premature ejaculation to develop anxiety and resultant aversion to sexual intercourse.
(Choice D) Medical conditions, including diabetes, that affect nerve function or blood flow to the pelvic tissue tend to result in erectile dysfunction rather than premature ejaculation. Medical conditions linked to premature ejaculation include prostatitis and thyroid disease.
(Choice E) Sexual dysfunction may occur in the context of psychiatric conditions, such as depression and anxiety. Apart from the distress secondary to his ejaculatory disorder, this patient reports no depressive symptoms.
(Choice F) Trazodone is a serotonin modulator used primarily for the treatment of insomnia. It may cause priapism (ie, persistent erection), but it does not cause premature ejaculation (nor does insulin).
Educational objective:
Premature ejaculation is characterized by recurrent episodes of early ejaculation accompanied by a sense of lack of control. Evaluation of any sexual disorder requires taking careful medical and substance use histories and assessing psychosocial stressors and comorbid psychiatric conditions.
A 66-year-old man comes to the office due to 2 episodes of hematuria over the past month. Digital rectal examination reveals an indurated prostate with no palpable nodules. An image from a transrectal prostate biopsy is shown in the exhibit. Which of the following is the most likely underlying cause of this patient’s symptoms?
A. Acute bacterial infection of the prostate
B. Benign hyperplasia of the prostatic stroma
C. Chronic bacterial inflammation of the prostate
D. Invasive carcinoma arising from the urethra
E. Neoplastic proliferation of prostate gland cells
Answer E
This older man with an indurated prostate has histopathologic evidence of crowded glands composed of atypical cells with large nuclei and prominent nucleoli, raising strong suspicion for prostate adenocarcinoma. Because most cases of prostate cancer arise in the periphery of the gland (peripheral zone) far from the prostatic portion of the urethra, patients do not typically present with urinary symptoms. However, a minority of cases occur in the portion of the gland (transition zone) that abuts the urethra, which can lead to hematuria and/or obstructive voiding manifestations.
Diagnostic evaluation begins with digital rectal examination; patients with prostate cancer often have an indurated (ie, abnormally firm), nontender gland with or without a nodule. An elevated prostate-specific antigen level adds supporting evidence. Confirmation is typically made by transrectal prostate biopsy, in which 10-12 random core biopsies of the gland are obtained. In contrast to normal prostatic cells, cancer cells typically display varying degrees of cellular atypia, including enlarged nuclei and prominent nucleoli, and commonly form crowded, infiltrative glands.
(Choices A and C) Acute prostatitis typically causes systemic symptoms (eg, fever, malaise), dysuria, and a tender, boggy prostate on digital rectal examination. Chronic prostatitis is generally marked by perineal pain and recurrent symptoms of urinary tract infection. Although patients can have hematuria with these conditions, biopsy would show inflammatory, not atypical glandular, cells.
(Choice B) Benign prostatic hyperplasia is common in older men. Hyperplasia of prostatic stroma in the area of the prostate that surrounds the urethra generally results in voiding symptoms (eg, hesitancy, dribbling, frequency). Hematuria may occasionally occur. Digital rectal examination generally reveals a symmetrically enlarged prostate with no nodules. Biopsy would show extensive stromal hyperplasia, not atypical glands.
(Choice D) Urothelial carcinoma from the bladder or urethra can occasionally invade the prostate. Although this cancer often causes hematuria, biopsy typically shows cancerous urothelial cells, not atypical glands. Furthermore, prostate cancer is a far more common cause of an indurated prostate than a urothelial tumor invading the prostate.
Educational objective:
Prostate adenocarcinoma is generally diagnosed with transrectal prostate biopsy, which often reveals atypical cells with enlarged nuclei and prominent nucleoli forming crowded, infiltrative glands.
Answer G
This patient’s clinical presentation is consistent with a congenital, communicating hydrocele, a collection of peritoneal fluid within the tunica vaginalis. During embryogenesis, the testis descends through the inguinal canal, drawing with it a diverticulum of peritoneum into the scrotum. This peritoneal tissue is known as the processus vaginalis. Normally, the communication between the processus vaginalis and the peritoneum is obliterated, and the tunica vaginalis is the remaining tissue overlying the testis and epididymis. A communicating hydrocele results when the processus vaginalis remains patent and allows peritoneal fluid to accumulate in the tunica vaginalis. This type of hydrocele is common in newborns and presents as a painless scrotal swelling that transilluminates.
(Choice A) The epididymis is a coiled tube posterior to the testicle that is responsible for the storage, maturation, and transportation of sperm. The caput, or head, of the epididymis is the superior-most aspect of the tube that stores sperm prior to maturation. Inflammation of the epididymis, or epididymitis, is classically associated with Gonorrhea and Chlamydia infection.
(Choices B, C, and D) The spermatic cord is a collection of structures that originate in the abdominal cavity and course downward toward the testes. It is covered by 3 layers: internal spermatic fascia, cremasteric fascia, and external spermatic fascia. The internal spermatic fascia immediately overlies the spermatic cord and is derived from the transversalis fascia. The cremasteric fascia arises from the internal oblique abdominal muscle. The external spermatic fascia is derived from the external oblique abdominal muscle. This is the outermost layer of the spermatic cord and lies deep to the dartos muscle and scrotal fascia.
(Choice E) The pampiniform plexus is a collection of veins within the spermatic cord. Distension of these veins leads to a varicocele and is clinically described as a palpable “bag of worms.”
(Choice F) The tunica albuginea is the fibrous tissue that immediately overlies the testicles (ie, beneath the tunica vaginalis) and the corpora cavernosa of the penis. In Peyronie disease, excess collagen formation within the tunica albuginea can cause significant pain and curvature of the penis.
Educational objective:
A communicating hydrocele results when serous fluid accumulates within the tunica vaginalis in the setting of a patent processus vaginalis. It presents as a painless swelling that transilluminates on examination.
Answer A
Androgen insensitivity syndrome is a disorder of sex development seen in genotypic males (XY) and characterized by a loss-of-function mutation of the androgen receptor gene on the X chromosome.
In utero, Leydig cells of the testes produce testosterone, which normally induces differentiation of precursor genital structures into male-specific genitalia by the following mechanisms:
Testosterone binds androgen receptors on the wolffian duct, which proliferates and develops into internal male genital ducts (eg, epididymis, vas deferens).
Testosterone is converted into dihydrotestosterone, which normally binds androgen receptors on the genital tubercle to promote differentiation into external male genitalia.
In patients with complete androgen insensitivity, there is appropriate testosterone and dihydrotestosterone production; however, without functional androgen receptors, patients do not develop internal male genital ducts or external male genitalia (Choice B). Instead, the absence of effective androgens leads to development of external female genitalia. In addition, appropriate production of antimüllerian hormone by testicular Sertoli cells leads to müllerian duct involution and suppression of internal female genital duct (eg, fallopian tubes, uterus) development.
Due to a typical female phenotype at birth, the diagnosis is usually made in adolescent girls with primary amenorrhea; this condition did not contribute to fetal demise in this case.
(Choices C and D) The combination of female internal genital ducts and ambiguous or external male genitalia may occur in a genotypic female (XX) with excess androgen exposure (eg, congenital adrenal hyperplasia).
(Choice E) Internal male genital ducts with external female genitalia occur in genotypic males (XY) with 5-alpha reductase deficiency. Testosterone can appropriately stimulate internal male genital duct development, but absence of conversion from testosterone to dihydrotestosterone results in the development of external female genitalia.
Educational objective:
Androgen insensitivity syndrome is caused by dysfunctional androgen receptors; genotypic males (XY) have testes but no external male genitalia or internal male genital ducts (eg, vas deferens) due to the lack of androgen effect during fetal development. Instead, external female genitalia develop, but antimüllerian hormone results in the absence of internal female genital ducts (eg, fallopian tubes) as well.
Answer C
This patient has gynecomastia and hypogonadal symptoms (eg, decreased libido, erectile dysfunction) after starting spironolactone, an aldosterone antagonist that acts as a potassium-sparing diuretic. In patients with heart failure, it reduces retention of sodium and water and attenuates the pathologic cardiac remodeling and deterioration in left ventricular function caused by local effects of aldosterone.
However, spironolactone also has broad antiandrogenic effects due to blockade of the androgen receptor and decreased testosterone production. Gynecomastia is abnormal growth of male breast tissue caused by an increase in the physiologic estrogen/androgen ratio and is a common adverse effect of spironolactone. Eplerenone, a more selective aldosterone antagonist, has fewer endocrine adverse effects and can be used in place of spironolactone.
(Choice A) Estrogens are metabolized primarily in the liver, largely by cytochrome P-450 enzymes. Patients with cirrhosis have diminished metabolism of estrogen, leading to gynecomastia and other signs of hyperestrogenism (eg, spider angiomas). However, spironolactone does not affect hepatic estrogen metabolism.
(Choice B) Continuous administration of GnRH agonists (eg, leuprolide), such as in patients with metastatic prostate cancer, suppresses the release of FSH and LH, which leads to lower testosterone levels. FSH and LH are also suppressed by starvation, leading to lower testosterone production and possible gynecomastia.
(Choice D) Sex hormone–producing adrenal tumors are rare neoplasms that can produce excessive quantities of androgens, estrogens (leading to gynecomastia), or both. Spironolactone decreases testicular production of testosterone, but adrenal estrogen production is not significantly increased.
(Choice E) Secretion of hCG by testicular germ cell tumors impairs testosterone production in testicular Leydig cells while increasing aromatase activity and conversion of androgens to estrogens; the increased estrogen/androgen ratio can cause gynecomastia.
Educational objective:
Spironolactone is an aldosterone antagonist commonly used to treat heart failure. It has significant antiandrogenic effects and can cause gynecomastia, decreased libido, and impotence. Eplerenone is a more selective aldosterone antagonist with fewer adverse effects.
Answer C
This patient had an undescended testis, or cryptorchidism. Embryologically, the testes originate within the abdomen and then migrate to the scrotum via the inguinal canal; cryptorchidism results when this process is disrupted. Undescended testes may be unilateral (more common) or bilateral and can lie anywhere along the path from the abdomen to the scrotum.
Complications of cryptorchidism include the following:
Infertility: Because the seminiferous tubules and Sertoli cells are temperature sensitive and prone to heat damage, the lower body temperature inside the scrotum is ideal for sperm production. Testicles located outside of the scrotum are at risk for atrophy and necrosis of the seminiferous tubules, resulting in reduced quality and quantity of sperm and decreased fertility. Orchiopexy (surgical fixation of the testes in the scrotum) before age 1 helps preserve fertility potential.
Malignancy: Patients with a history of cryptorchidism are at increased risk for a testicular germ cell tumor (eg, seminoma). Although orchiopexy decreases the rate of malignant transformation, the risk remains higher than that of the general population despite surgery. However, fixation of the testis in the scrotum does enable easier detection of testicular masses on examination.
(Choice A) Unlike the seminiferous tubules, the testosterone-producing Leydig cells are not sensitive to temperature, so testosterone levels and virilization are usually normal in patients with cryptorchidism.
(Choice B) Leydig cell tumors are rare, non–germ cell testicular tumors that are not associated with cryptorchidism.
(Choice D) Testicular torsion occurs more frequently in an undescended testicle compared to one in the normal scrotal position; however, the risk is minimal following surgical fixation of the testis.
(Choice E) A varicocele is typically a chronic, benign dilation of pampiniform plexus veins but can occur secondary to venous obstruction from an abdominal mass or thrombus. Undescended testes are not associated with varicoceles.
Educational objective:
Patients with undescended testicles are at increased risk for infertility (due to atrophy of temperature-sensitive Sertoli cells) and testicular germ cell tumors (eg, seminoma). Orchiopexy (surgical fixation of the testis in the scrotum) decreases, but does not eliminate, these risks.
Answer E
This older patient with urinary hesitancy and multiple bone lesions has biopsy evidence of well-differentiated adenocarcinoma, raising strong suspicion for metastatic prostate adenocarcinoma. Prostate cancer is the most common non-skin cancer in men; it has a predilection for metastases to bone due to tumor surface proteins that bind to pericytes and bone marrow stromal cells.
Prostate adenocarcinoma is generally an androgen-sensitive tumor. Because androgens in men are produced primarily in the testes, initial treatment for advanced disease usually involves medical or surgical orchiectomy to eliminate testicular production of androgens. However, androgens are also produced in the adrenal glands and tumor cells via the expression of 17-alpha-hydroxylase, a cytochrome P-450 enzyme that converts pregnenolone/progesterone into dehydroepiandrosterone (DHEA)/androstenedione. Because these extratesticular androgens can also drive tumor growth, patients with advanced disease and those with castration-resistant prostate cancer generally receive abiraterone, a medication that irreversibly inhibits 17-alpha-hydroxylase. This limits extratesticular androgen production, which slows the growth of the tumor.
(Choice A) Because prostate cancer is an androgen-sensitive tumor, activation of the androgen receptor would worsen the disease.
(Choice B) LH triggers Leydig cells in the testes to produce androgens. Therefore, activation of the LH receptor would worsen prostate cancer (increased androgen production). Medical orchiectomy involves the administration of GnRH analogues, which reduce LH levels by eliminating the pulsatile stimulation of pituitary gonadotrophs.
(Choice C) Estrogen receptor blockade is used in the treatment of estrogen-sensitive breast and endometrial cancer. Prostate cancer is driven by androgens such as testosterone and DHEA, not estrogen.
(Choice D) FSH induces spermatogenesis in men; LH is responsible for testicular androgen production. Therefore, blockade of FSH would not inhibit systemic androgen generation.
Educational objective:
Patients with advanced or castration-resistant prostate cancer are often treated with an 17-alpha-hydroxylase inhibitors (eg, abiraterone), which block the generation of androgens in the adrenal glands, testes, and tumor cells. This reduces systemic androgen levels, which limit prostate cancer growth.
Answer A
The precursors to male and female internal and external genital structures (gonads, Müllerian and Wolffian ducts) are initially undifferentiated. In patients with the SRY gene (eg, XY genotype), the undifferentiated gonads develop into testes, as seen in this patient. The testes produce:
Testosterone, which induces differentiation of the Wolffian duct into internal male genital ducts (eg, epididymis, vas deferens). Some testosterone is also converted to dihydrotestosterone (DHT), which stimulates external male genitalia development. Therefore, this patient with an epididymis, vas deferens, and penis has appropriate testosterone and DHT action (Choices C and E).
Antimüllerian hormone (AMH) induces Müllerian duct involution, suppressing internal female genital duct (eg, fallopian tubes, uterus) development. The presence of internal female structures in this patient indicates absent AMH.
AMH deficiency is a rare disorder of sex development in patients with an XY genotype that results in internal female genital ducts (lack of Müllerian duct involution) but normal external and internal male genital structures (due to androgens). Patients are at increased risk of cryptorchidism due to tethering of the testicle by Müllerian duct–derived structures during in utero descent from the abdomen to the scrotum; an associated inguinal hernia can also occur, as seen here.
(Choice B) Dehydroepiandrosterone is an adrenal androgen that is not involved in sex differentiation.
(Choice D) Because testosterone regulates LH production via negative feedback, a normal testosterone level (as expected in this patient with male anatomy) would result in a normal LH level.
Educational objective:
Antimüllerian hormone (AMH) is produced by the testes and stimulates Müllerian duct involution so internal female structures (eg, fallopian tubes, uterus) do not develop. The presence of these structures in a genotypic male suggests AMH deficiency.
Answer F
In general, the lymph drainage from a particular organ follows the path of the arterial supply to that site. During fetal development, the testes originate within the retroperitoneum and establish their arterial supply from the abdominal aorta. The testes subsequently descend through the inguinal canals into the scrotum, taking with them their arterial, venous, and lymphatic supplies. Thus, lymph from the testes drains through lymph channels directly back to the para-aortic (retroperitoneal) lymph nodes.
(Choice A) The superficial inguinal lymph nodes are located on the anterior thigh inferior to the inguinal ligament. These nodes drain nearly all cutaneous structures inferior to the umbilicus, including the external genitalia and the anus up to the pectinate line.
(Choice B) The deep inguinal nodes reside under the fascia lata on the medial side of the femoral vein. They receive afferents from the superficial inguinal nodes and deep lymphatic trunks along the femoral vessels. The lymphatics from the glans penis and clitoris also drain directly to these nodes.
(Choice C) The external iliac nodes drain the superficial and deep inguinal nodes and the deep lymphatics of the abdominal wall below the umbilicus.
(Choice D) The common iliac nodes are located alongside the common iliac artery and drain the internal and external iliac nodes.
(Choice E) The inferior mesenteric nodes drain the structures supplied with arterial blood by branches of the inferior mesenteric artery (eg, the left colic, sigmoid, and superior rectal arteries). Thus, these nodes drain the descending and sigmoid colon as well as the upper part of the rectum. Their efferents drain to pre-aortic nodes.
Educational objective:
Lymph from the testes drains through lymph channels directly back to the para-aortic lymph nodes. In contrast, lymph from the scrotum drains to the superficial inguinal lymph nodes.
