The genitourinary system encompasses 2 major organ systems, the reproductive and the urinary systems. Successful reproduction requires interaction between 2 sexually mature individuals. Xenobiotic exposures to either individual can have an adverse impact on fertility, which is the successful production of children, and fecundity, which is an individual’s or a couple’s capacity to produce children. The role of occupational and environmental exposures in the development of infertility is difficult to define.^12,42,88 Well-designed and conclusive epidemiologic studies are lacking because of the following factors: laboratory tests used to evaluate fertility are relatively unreliable, clinical endpoints are unclear, xenobiotic exposure is difficult to monitor, and indicators of biologic effects are imprecise. Although the negative impact of xenobiotics on fertility is often ignored, infertility evaluations are incomplete without a thorough xenobiotic exposure and occupational history. Differences in the toxicity of xenobiotics in individuals are sex related, age related, or both. Xenobiotic-related, primary infertility is the result of effects on the hypothalamic–pituitary–gonadal axis or a direct toxic effect on the gonads.⁷⁶ Fertility is also affected by exposures that cause abnormal sexual performance. Table 19–1 lists xenobiotics associated with infertility.

Aphrodisiacs are used to heighten sexual desire and to counteract sexual dysfunction. Humans have long sought the perfect aphrodisiac. However, of those tried, their effectiveness is variable, and toxic consequences occur commonly. Particularly popular are the various treatments for male sexual dysfunction, or erectile dysfunction.

Although many people search for a cure for impotence or infertility, others explore xenobiotics that can be used as abortifacients. Routes of administration used include oral, parenteral, and intravaginal, with an end result of pregnancy termination. However, many of these xenobiotics produce systemic toxic effects on the mother and a nonaborted fetus.

This chapter examines these issues, as well as the impact of xenobiotics on the urinary system, specifically, urinary retention and incontinence, and abnormalities detected in urine specimens. Renal (Chap. 27), reproductive (Chap. 31), and oncologic (Chap. 23) principles are discussed elsewhere in this text.

Male fertility is dependent on a normal reproductive system and normal sexual function. The male reproductive system is composed of the central nervous system (CNS) endocrine organs and the male gonads. The hypothalamus and the anterior pituitary gland form the CNS portion of the male reproductive system. Both organs begin low-level hormone secretion as early as in utero gestation. At puberty, the hypothalamus begins pulsatile secretion of gonadotropin-releasing hormone (GnRH). This stimulates the anterior pituitary gland to release follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in a similarly pulsatile fashion. The hormones exert their effects on the male target organs, inducing spermatogenesis and secondary body sexual characteristics.

Disruption of the normal function of any part of the system affects fertility. A number of xenobiotics adversely affect the male reproductive system and sexual function as shown in Fig. 19–1.

Spermatogenesis

Central to the male reproductive system is the process of spermatogenesis, which occurs in the testes. The bulk of the testes consist of seminiferous tubules with germinal spermatogonia and Sertoli cells. The remainder of the gonadal tissue is interstitium with blood vessels, lymphatics, supporting cells, and Leydig cells. Spermatogenesis begins with the maturation and differentiation of the germinal spermatogonia. The process is controlled by the secretion of GnRH from the hypothalamus, which in turn stimulates the pituitary to release FSH and LH. Follicle-stimulating hormone stimulates the development of Sertoli cells in the testes, which are responsible for the maturation of spermatids to spermatozoa. Luteinizing hormone promotes production of testosterone by Leydig cells. Testosterone concentrations must be maintained to ensure the formation of spermatids.²¹ Both FSH and testosterone are required for initiation of spermatogenesis, but testosterone alone is sufficient to maintain the process.

Testicular Xenobiotics

Xenobiotics can affect any part of the male reproductive tract, but invariably, the end result is decreased sperm production defined as oligospermia, or absent sperm production, azoospermia. In contrast to oogenesis in women, spermatogenesis is an ongoing process throughout life that is inhibited by decreases in FSH or LH or by Sertoli cell toxicity. Spermatogenic capacity is evaluated by semen analysis, including sperm count, motility, sperm morphology, and penetrating ability. Normal sperm count is greater than 40 million sperm/mL semen, and a count less than 20 million/mL is indicative of infertility.²¹ Decreased motility (asthenospermia) less than 40% of normal or abnormal morphology (teratospermia) of greater than 40% of the total number of sperm also indicates infertility.^21,102

Physiology of Erection

The penis is composed of 2 corpus cavernosa and a central corpus spongiosum. The internal pudendal arteries supply blood to the penis via 4 branches. Blood outflow is via multiple emissary veins draining into the dorsal vein of the penis and plexus of Santorini. Within the penis, the corpora cavernosa share vascular supply and drainage because of extensive arteriolar, arteriovenous, and sinusoidal anastomoses.¹²¹ Erection occurs when penile blood flow is greater than 20 to 50 mL/min, and tumescence is maintained with flow rates of 12 mL/min. The tunica albuginea limits the absolute size of erection.

In the flaccid state, sympathetic efferent nerves maintain arteriole constriction primarily through norepinephrine-induced α-adrenergic agonism. Whereas α-adrenergic receptor agonism in the erectile tissues decreases cyclic adenosine monophosphate (cAMP) to produce flaccidity, α-adrenergic antagonism can result in pathologic erection (priapism) as a consequence of parasympathetic dominance.¹²¹ Other endogenous vasoconstrictors, such as endothelin, prostaglandin F_2α (PGF_2α), and thromboxane A₂, play a role in maintaining corpus cavernosal smooth muscle tone in contraction, which results in a flaccid state.⁸³

Normal penile erection is a result of both neural and vascular effects. Psychogenic neural stimulation arising from the cerebral cortex inhibits norepinephrine release from thoracolumbar sympathetic pathways, stimulates nitric oxide (NO) and acetylcholine release from sacral parasympathetic tracts, and stimulates acetylcholine release from somatic pathways.⁸³ Reflex stimulation also occurs from the sacral spinal cord. The pudendal nerves supply the afferent limb and the nervi erigentes (pelvic splanchnic nerves) supply the efferent limb of the reflex arc.

The central impulses stimulate various neurotransmitters to be released by peripheral nerves in the penis. Nonadrenergic–noncholinergicnerves and endothelial cells produce NO, which is the principal neurotransmitter mediating erection.⁸⁵ Nitric oxide activates guanylate conversion of guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP). Increasing concentrations of cGMP act as a second messenger, mediating arteriolar and trabecular smooth muscle relaxation to enable increased cavernosal blood flow and penile erection.⁸³ Both cGMP and cAMP pathways mediate smooth muscle relaxation. Cholinergic nerves release acetylcholine, which stimulates endothelial cells via M₃ receptors to produce NO and prostaglandin E₂ (PGE₂). Prostaglandin E₂ and nerves containing vasoactive intestinal peptide (VIP) and calcitonin gene-related peptide (CGRP) increase cellular cAMP to potentiate smooth muscle relaxation.

Penile corpus cavernosal smooth muscle relaxation allows increased blood flow into the corpus cavernosal sinusoids. Expansion of the sinusoids compresses the venous outflow and enables penile erection (Fig. 19–2).

Male Sexual Dysfunction

The sexual response cycle is divided in 4 stages—sexual desire or libido, sexual arousal of the genitalia, orgasm, and resolution.⁹⁹ Dopamine, melanocortin, testosterone, and estrogen facilitate libido. Libido is decreased by xenobiotics that either block central dopaminergic or adrenergic pathways while xenobiotics that increase dopamine improve sexual function. Acetylcholine, NO, norepinephrine, melanocortin, testosterone, estrogen and dopamine mediate arousal. Sexual dysfunction is caused by xenobiotics that decrease testosterone production and by xenobiotics that produce dysphoria. Norepinephrine promotes orgasm and male ejaculation. Male sexual dysfunction can result from decreased libido, erectile dysfunction (impotence), and diminished ejaculation. Xenobiotics that increase prolactin decrease libido, and xenobiotics that increase serotonin decrease libido, arousal and orgasm.⁶⁴ Xenobiotics that affect spinal reflexes cause diminished ejaculation and erectile dysfunction.¹¹⁹

Approximately 30 million men in the United States have erectile dysfunction, with an increased prevalence in older men.⁵ Erectile dysfunction is defined as the inability to achieve or maintain an erection for a sufficiently long period of time to permit satisfactory sexual intercourse⁵ and is divided into the following classifications: psychogenic, vasculogenic, neurologic, endocrinologic, and xenobiotic-induced. Xenobiotic-induced erectile dysfunction is associated with the following classes of xenobiotics: antidepressants, antipsychotics, centrally and peripherally acting antihypertensives, CNS depressants, anticholinergics, exogenous hormones, antibiotics, and chemotherapeutics.^71,101,119 Treatment of this disorder is varied based on the etiology and includes vacuum-constriction devices, penile prostheses, vascular surgery, and medications that can be administered via the intracavernosal, transdermal, and oral routes.

Antihypertensives

Erectile dysfunction is reported as an adverse effect with many antihypertensives, and is caused, in part, by a decrease in hypogastric artery pressure, which impairs blood flow to the pelvis.¹¹⁹ Centrally acting α₂-adrenergic agonists treat hypertension by inhibiting sympathetic outflow from the brain but this in turn causes male sexual dysfunction.⁸⁹ Erectile dysfunction associated with thiazide diuretics are related to decreased vascular resistance, diverting blood from the penis.²² Spironolactone acts as an antiandrogen by inhibiting the binding of dihydrotestosterone to its receptors. Impotence related to use of β-adrenergic antagonists is caused by unopposed α-adrenergic–mediated vasoconstriction resulting in reduced penile blood flow and decreased testosterone and FSH concentrations.^30,37 Nebivolol has lower incidences of erectile dysfunction compared to other β-adrenergic antagonists, which is likely due to its ability to increase tissue nitric oxide leading to improved erectile function.²⁰ Calcium channel blockers, angiotensin-coverting enzyme (ACE) inhibitors, and angiotension receptor blockers have a neutral or beneficial effect on erectile function.³⁰ Angiotensin II vasoconstriction leads to erectile dysfunction, but ACE inhibitors and angiotension receptor blockers inhibit angiotensin II production in the corpus cavernosum.¹⁴

Ethanol

Ethanol is directly toxic to Leydig cells. Chronic ethanol abuse causes decreased libido and erectile dysfunction and is associated with testicular atrophy. In people with alcoholism, liver disease contributes to sexual dysfunction resulting from decreased testosterone and increased estrogen production or decreased breakdown. People with alcoholism develop autonomic neuropathies affecting penile nerves and subsequent erection. Men who drink heavily have more erectile dysfunction than episodic drinkers.¹¹⁸

Antidepressants and Antipsychotics

Individuals who take psychoactive medications therapeutically have varying degrees of sexual dysfunction related to their underlying disease and their medications. Antidepressant and antipsychotic inhibition of male sexual function is multifactorial and includes serotonin effects on 5HT₂ receptors, anticholinergic, antihistaminergic, α-adrenergic receptor antagonism, dopamine blockage, and increased prolactin.^63,64 Monoamine oxidase inhibitors (MAOIs), cyclic antidepressants (CAs), antipsychotics, and selective serotonin reuptake inhibitors (SSRIs) are associated with decreased libido and erectile dysfunction in men.³⁴ Thioridazine is associated with significantly lower LH and testosterone concentrations in men in comparison with other antipsychotics.²¹ Antidepressants such as bupropion, nefazodone, mirtazapine, and duloxetine have lower incidences of sexual dysfunction in comparison with other antidepressants.¹⁰³ Table 19–2 lists xenobiotics associated with sexual dysfunction.

Xenobiotics Used in the Treatment of Erectile Dysfunction

Intracavernosal and Intraurethral

Alprostadil (PGE₁) and papaverine are the most commonly used individual intracavernosal xenobiotics for erectile dysfunction, and combination therapies include alprostadil, papaverine, phentolamine, and atropine. Papaverine is a benzylisoquinoline alkaloid derived from the poppy plant Papaver somniferum. It exerts its effects through nonselective inhibition of phosphodiesterase (PDE), leading to increased cAMP and cGMP concentrations and subsequent cavernosal vasodilation.⁵⁵ Papaverine was used for the treatment of cardiac and cerebral ischemia but had limited efficacy. Presently, it is used as intracavernosal therapy for erectile dysfunction alone or in conjunction with phentolamine. Systemic adverse effects include dizziness, nausea, vomiting, hepatotoxicity, metabolic acidosis with elevated lactate concentration with oral administration, and cardiac dysrhythmias with intravenous use. Intracavernosal administration is associated with penile fibrosis, which is related to the frequency and duration of administration, although fibrosis also occurs with limited use.⁶⁵ More concerning is the development of priapism with papaverine use.

Alprostadil is a nonspecific agonist of PG receptors resulting in increased concentrations of intracavernosal cAMP, cavernosal smooth muscle relaxation, and penile erection.⁵⁵ It is effective via intracavernosal administration as monotherapy. Other preparations include an intraurethral preparation, which is less effective, and a topical gel formulation.⁵² Penile fibrosis occurs, but the incidence is lower compared with papaverine. Other adverse effects include penile pain, secondary to its effects as a nonspecific PG receptor agonist, and priapism.

Phentolamine is a competitive α-adrenergic antagonist at both α₁ and α₂ receptors in cavernosal smooth muscle. Although this increases arterial blood flow and produces erection, it is not effective as a sole therapeutic.⁵⁵ It is usually combined with papaverine, alprostadil, or atropine as 2, 3 or 4 xenobiotic mixtures. Penile fibrosis, prolonged erection, and priapism are also more common with these xenobiotic combinations.⁵⁵

Oral

Since the development of the PDE-5 inhibitors, oral therapy has replaced intracavernosal injections as the mainstay for treatment of erectile dysfunction. Sildenafil was the first drug developed followed by vardenafil, tadalafil, and avanafil in the United States and lodenafil, mirodenafil, and udenafil in other parts of the world. These medications share a mechanism of action but differ in their pharmacokinetics. Phosphodiesterase-5 inhibitors increase NO-induced cGMP concentrations by preventing PDE breakdown of cGMP, enhancing NO-induced vasodilation to promote penile vascular relaxation and erection.¹⁸

Sildenafil and vardenafil have similar times to peak concentration, ranging from 30 minutes to 2 hours. Avanafil has a shorter time to peak concentration (30–45 minutes) and tadalafil has a longer time to peak concentration (30 minutes to 6 hours).⁶² The PDE-5 inhibitors have large volumes of distribution ranging from 63 L for tadalfil up to 208 L for vardenafil.⁶² Elimination half-life is similar for avanafil, sildenafil, and vardenafil (4–5 hours), and tadalafil is longest at 17.5 hours.⁶² Serum concentrations of sildenafil and vardenafil are increased in patients older than 65 years, hepatic dysfunction (Child Pugh A and B), severe kidney disease (creatinine clearance <30 mL/min).²⁸ Age, hepatic dysfunction, and kidney disease do not affect serum concentrations of avanafil or tadalfil.⁶² Phosphodiesterase-5 inhibitors are metabolized primarily by the CYP3A4 pathway, with some minor metabolic activity via the CYP2C pathway for sildenafil, tadalafil, and vardenafil.⁶² Strong CYP3A4 inhibitors like erythromycin, ketoconazole, cimetidine, protease inhibitors (indinavir, ritonavir, saquinavir), and grapefruit juice will increase PDE-5 inhibitor concentrations.⁵⁴ Inducers of CYP3A4 like rifampin, phenobarbital, phenytoin, and carbamazepine can decrease PDE-5 inhibitor concentrations.⁷⁹

The most common adverse effects of the PDE-5 inhibitors are headache, flushing, dyspepsia, and rhinitis, which are related to PDE-1 inhibitory effects in the brain, myocardium, and vascular smooth muscle.⁷⁹ Blurred vision, increased light perception, and transient blue-green tinged vision are also reported and are related to the weak PDE-6 inhibition of sildenafil in the retina.⁵¹ Vardenafil and tadalafil are associated with infrequent abnormal vision, including blurred and abnormal color vision.⁵³ Back pain and myalgia with PDE-5 inhibitor use is postulated to be from PDE-11 inhibition.⁷⁹

More serious adverse effects of PDE-5 inhibitors include myocardial infarction, when used alone or with nitrates; subaortic obstruction; stroke; transient ischemic attack; priapism; and hearing loss.^{10,43,58,78,104,110} Phosphodiesterase-5 inhibitors are associated with adverse bleeding events, including epistaxis, variceal bleeding, intracranial hemorrhages, and aortic dissection. The FDA updated the labeling of the PDE-5 inhibitors, warning of possible vision loss after reported cases of nonarteritic ischemic optic neuropathy associated with PDE-5 inhibitor use.^6,16,43

When taken alone, the vasodilatory effects of PDE-5 inhibitors cause a modest decrease in systemic blood pressure. However, because of their mechanism of action via cGMP inhibition and vascular vasodilation, PDE-5 inhibitors can have synergistic interactions with the vasodilatory effects of nitrates, resulting in profound hypotension.^18,59 A study of healthy male volunteers taking sildenafil demonstrated significantly less tolerance to a nitroglycerin infusion in comparison with those who took placebo.¹¹⁶ Because of this interaction, patients with acute myocardial ischemic syndromes using PDE-5 inhibitors should avoid taking organic nitrates as well.²⁸ α₁-Adrenergic antagonists are also contraindicated with concomitant PDE-5 inhibitor use because of increased hypotensive effects.⁵⁹ Hypotension occurred in patients using vardenafil in combination with terazosin and tamsulosin⁵⁹ and in patients using tadalafil with doxazosin.⁶⁰ However, patients using tadalafil with tamsulosin did not develop hypotension.⁶⁰

Sublingual apomorphine effects erection through activation of central dopaminergic pathways, most likely D₂ receptors in the paraventricular nucleus of the hypothalamus.⁵⁶ It reaches maximum serum concentrations within 40 to 60 minutes after sublingual administration and is metabolized hepatically with a half-life of 2 to 3 hours.⁹ Common adverse effects are nausea, vomiting, headache, dizziness, and syncope. Unlike the PDE-5 inhibitors, apomorphine is not associated with hypotension when used with antihypertensives, such as nitrates.

Priapism is defined as prolonged involuntary erection unassociated with sexual stimulation. Subtypes of priapism are ischemic (characterized by low cavernosal blood flow), nonischemic (characterized by increased arterial flow), and stuttering (recurrent ischemic priapism).⁸² It most commonly occurs during the third and fourth decades of life and is caused by inflow of blood to the penis in excess of outflow. The corpora cavernosa become firm and the corpus spongiosum flaccid. Intracavernosal pressures exceed arterial systolic pressure, resulting in cell death. Priapism occurs from an imbalance in neural stimuli, interference with venous outflow or as a result of xenobiotic-induced inhibition of penile detumescence. α-Adrenergic antagonists prevent constriction of blood vessels supplying erectile tissue, resulting in priapism.⁸² One in 10,000 patients taking trazodone develops priapism, which is thought to be related to its α-adrenergic antagonist effects.⁹⁸ Xenobiotics associated with priapism are listed in Table 19–3.

The goal in the treatment of priapism is detumescence with retention of potency. Initial therapy includes sedation with benzodiazepines, analgesia with opioids, ice packs, treatment of underlying systemic diseases such as sickle cell disease, and early urologic consultation. In ischemic priapism, aspiration with or without 9% NaCl solution irrigation of the corpora cavernosa is effective in 24% to 36% of cases, and adding intracavernosal injection of sympathomimetic agents increases priapism resolution to 43% to 81%.⁸² The American Urology Association guidelines recommend phenylephrine (100–500 mcg/mL solution) injection into the corpora cavernosa at a dosage of 0.5 to 1 mL every 3 to 5 minutes up to 1 hour.⁸² Oral xenobiotics are not recommended for ischemic priapism but oral terbutaline (5–10 mg) was effective for PGE₁-induced prolonged erections.^70,82,95 Intracavernosal methylene blue has been used successfully as an alternative to intracavernosal sympathomimetics.⁷⁴ If the above measures fail, an operative venous shunt placement is often required.²³