21: Genitourinary Principles

The genitourinary system encompasses two major organ systems, the reproductive and the urinary systems. Successful reproduction requires interaction between two 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.^14,41,95,99 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 and occupational history. Differences in the toxicity of xenobiotics in individuals may be sex or age related (or both). Xenobiotic-related, primary infertility may be the result of effects on the hypothalamic–pituitary–gonadal axis or a direct toxic effect on the gonads.⁸² Fertility is also affected by exposures that cause abnormal sexual performance. Table 21–1 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. 28), reproductive (Chap. 31), and carcinogenic 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 normal function of any part of the system affects fertility. A number of xenobiotics can adversely affect the male reproductive system and sexual function as shown in Fig. 21–1

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 stimulates the pituitary to release FSH and LH. FSH stimulates the development of Sertoli cells in the testes, which are responsible for the maturation of spermatids to spermatozoa. LH promotes production of testosterone by Leydig cells. Testosterone concentrations must be maintained to assure the formation of spermatids.²⁴ 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 can be 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.²⁴ 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.^24,108

Physiology of Erection.

The penis is composed of two corpus cavernosa and a central corpus spongiosum. The internal pudendal arteries supply blood to the penis via four 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.¹²⁸ When penile blood flow is greater than 20 to 50 mL/min, erection occurs. Maintenance of tumescence occurs 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.¹²⁸ Other 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.⁹⁰

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.⁹⁰ Reflex stimulation can also occur from the sacral spinal cord. The afferent limb of the reflex arc is supplied by the pudendal nerves and the efferent limb by the nervi erigentes (pelvic splanchnic nerves).

The central impulses stimulate various neurotransmitters to be released by peripheral nerves in the penis. Nonadrenergic–noncholinergic nerves and endothelial cells produce NO, which is the principal neurotransmitter mediating erection. NO activates guanylate cyclase 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.⁹⁰ 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). PGE₂ 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. 21–2).

Sexual Dysfunction

Male sexual dysfunction can result from decreased libido (sexual desire), impotence, diminished ejaculation, and erectile dysfunction. Dopamine, norepinephrine, oxytocin, and adrenocorticotrophic hormone (ACTH) are central neurotransmitters and hormones that facilitate sexual function. Serotonin, prolactin, endogenous opioids, and GABA (γ-aminobutyric acid) inhibit sexual function centrally.³ Libido can be decreased by xenobiotics that block central dopaminergic or adrenergic pathways or by xenobiotics that increase serotonin or prolactin concentrations. Conversely, xenobiotics that increase dopamine can improve sexual function. Sexual dysfunction can also be caused by xenobiotics that decrease testosterone production and by xenobiotics that produce dysphoria. Xenobiotics that affect spinal reflexes can cause diminished ejaculation and erectile dysfunction.¹²⁶

Approximately 30 million men in the United States have erectile dysfunction, with an increased prevalence in older men.⁶ Erectile dysfunction is defined as the inability to achieve or maintain an erection for a sufficiently long period of time to permit satisfactory sexual intercourse⁶ and is divided into the following classifications: psychogenic, vasculogenic, neurologic, endocrinologic, and xenobiotic induced. Xenobiotic-induced erectile dysfunction is associated with the following categories of xenobiotics: antidepressants, antipsychotics, centrally and peripherally acting antihypertensives, CNS depressants, anticholinergics, exogenous hormones, antibiotics, and antineoplastics.^76,107,126 Treatment of this disorder is varied 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 all antihypertensives and may be caused, in part, by a decrease in hypogastric artery pressure, which impairs blood flow to the pelvis.¹²⁶ Methyldopa and clonidine both are centrally acting α₂-adrenergic agonists that inhibit sympathetic outflow from the brain. Sexual dysfunction is reported in 26% of patients receiving methyldopa and in 24% of patients receiving clonidine.^18,93 Erectile dysfunction associated with thiazide diuretics may be related to decreased vascular resistance, diverting blood from the penis.²⁵ Spironolactone acts as an antiandrogen by inhibiting the binding of dihydrotestosterone to its receptors. Impotence related to use of β-adrenergic antagonists is well documented^5,59,122 and may be caused by unopposed α-adrenergic–mediated vasoconstriction resulting in reduced penile blood flow.

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 can have autonomic neuropathies affecting penile nerves and subsequent erection. Heavy drinkers have more erectile dysfunction than episodic drinkers.¹²⁵

Antidepressants and Antipsychotics.

Individuals who take antipsychotics therapeutically have varying degrees of sexual dysfunction related to their underlying disease and their medications. All psychoactive medications are associated with sexual dysfunction to some degree. Monoamine oxidase inhibitors (MAOIs), cyclic antidepressants (CAs), antipsychotics, and selective serotonin reuptake inhibitors (SSRIs) are associated with decreased libido and erectile dysfunction in men.³⁵ Thioridazine is associated with significantly lower LH and testosterone concentrations in men in comparison with other antipsychotics.²⁴ Antidepressants such as bupropion, nefazodone, mirtazapine, and duloxetine have lower incidences of sexual dysfunction in comparison with other antidepressants.¹⁰⁹Table 21–2 lists xenobiotics associated with sexual dysfunction.

Xenobiotics Used in the Treatment of Erectile Dysfunction

Intracavernosal Agents.

The three most commonly used intracavernosal agents used for erectile dysfunction are papaverine, PGE₁, and phentolamine. 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. 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 usually a dose-related phenomenon, although fibrosis can also occur with limited use.³⁷ More concerning is the development of priapism with papaverine use.

Prostaglandin E₁ (Alprostadil) is a nonspecific agonist of PG receptors resulting in increased concentrations of intracavernosal cAMP, cavernosal smooth muscle relaxation, and penile erection. It is effective via intracavernosal administration as monotherapy. Other preparations include an intraurethral preparation, which is less effective, and a topical gel formulation.⁵⁶ Penile fibrosis can occur, 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. It effects erection by inhibiting the normal resting adrenergic tone in cavernosal smooth muscle, thus allowing increased arterial blood flow and erection. Intracavernosal use can cause hypotension, reflex tachycardia, nasal congestion, and gastrointestinal (GI) upset. Penile fibrosis and priapism are also reported.

Oral Agents.

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 and tadalafil. These medications share a mechanism of action but differ in their pharmacokinetics. PDE-5 inhibitors increase NO-induced cGMP concentrations by preventing PDE breakdown of cGMP, enhancing NO-induced vasodilation to promote penile vascular relaxation and erection.²³

After oral administration, sildenafil is rapidly absorbed with a bioavailability of 40% and a median peak serum concentration of 60 minutes. Its mean volume of distribution is 105 L, and its elimination half-life is 3 to 5 hours. Metabolism is primarily by the CYP3A4 pathway with some minor metabolic activity via the CYP2C9 pathway. Serum concentrations of sildenafil are increased in patients older than 65 years as well as those with hepatic dysfunction or severe kidney disease (creatinine clearance <30 mL/min) and when used with CYP3A4 inhibitors (macrolide antibiotics, cimetidine, antifungal agents, protease inhibitors).³¹

Vardenafil has more selective inhibition of PDE-5 and less inhibition of PDE-6 compared with sildenafil. After oral administration, it has a 14% bioavailability, a volume of distribution of 208 L, a median peak serum concentration of 60 minutes and an elimination half-life of 4 to 5 hours. The CYP3A4 pathway is the primary hepatic metabolic pathway with minor contributions from CYP3A5 and CYP2C9 isoenzymes.^17,20 The primary metabolite, M1, has PDE-5 inhibitory activity but is four times less potent than vardenafil.²⁰ As with sildenafil, vardenafil concentrations are increased in patients older than 65 years, and those with hepatic dysfunction or severe kidney disease (creatinine clearance <30 mL/min) and when used with CYP3A4 inhibitors (macrolide antibiotics, cimetidine, antifungal agents, protease inhibitors).⁶⁴

Tadalafil has a median peak serum concentration of 2 hours and a mean elimination half-life of 17.5 hours. It is predominantly metabolized by CYP3A4 isoenzymes. Unlike sildenafil and vardenafil, serum concentrations are not affected by age, hepatic dysfunction, kidney disease, or CYP3A4 inhibitors. However, the Food and Drug Administration (FDA) has issued recommendations to decrease the dosage of all PDE-5 inhibitors if used in conjunction with atazanavir.⁷

The most common adverse effects of the PDE-5 inhibitors are headache, flushing, dyspepsia, and rhinitis, which are related to PDE-5 inhibitory effects on extracavernosal tissue.⁵⁵ 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.⁵⁵ Vardenafil and tadalafil are associated with infrequent abnormal vision, including blurred and abnormal color vision.⁵⁷

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.^{12,44,63,84,110,114} PDE-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 (NAION) associated with PDE-5 inhibitor use.^9,21,44

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.^23,65 A study of healthy male volunteers taking sildenafil demonstrated significantly less tolerance to a nitroglycerin infusion in comparison with placebo.¹²³ Because of this interaction, patients with acute myocardial ischemic syndromes using PDE-5 inhibitors should avoid taking organic nitrates as well.³¹α₁-Adrenergic antagonists are also contraindicated with concomitant PDE-5 inhibitor use because of increased hypotensive effects.⁶⁵ Hypotension occurred in patients using vardenafil in combination with terazosin and tamsulosin⁶⁵ and in patients using tadalafil with doxazosin.⁶⁶ However, patients using tadalafil with tamsulosin did not develop hypotension.⁶⁶

Yohimbine, an indole alkylamine alkaloid from the West African yohimbe tree (Corynanthe yohimbe), is an α₂-adrenergic antagonist with cholinergic activity used to treat erectile dysfunction and postural hypotension associated with anticholinergic drugs.⁷³ It is structurally similar to reserpine. Other names for yohimbine include Aphrodyne, corynine, hydroaergotocin, quebrachine, and the street name “yo-yo.”⁷⁴ Its use in the treatment of impotence is based on the theory that erection is linked to cholinergic stimulation and α₂ antagonism, resulting in an increase inflow and decrease outflow of blood to the penis. Although the agent Aphrodex, which contained 5 mg of yohimbine, 5 mg methyltestosterone, and 5 mg strychnine, improved performance in men with erectile failure,⁷⁷ its distribution was halted in 1973 because of safety concerns.¹⁰⁵

Yohimbine can be obtained by prescription, but extracts are also available in “health food” products marketed as “vitalizing agents for men and women.”³⁹ Yohimbine can also be extracted from the Rauwolfia root.⁴⁹ The “therapeutic” dose is 2 to 6 mg three times daily. The drug is rapidly absorbed, with peak serum concentrations occurring in 45 to 60 minutes. The half-life is 36 minutes, and clearance is by hepatic metabolism without renal excretion.⁹⁶ Maximum pharmacologic effects occur 1 to 2 hours after ingestion, and effects persist for 3 to 4 hours.⁷⁴

Because the erectile process involves various neurotransmitters, a single xenobiotic would be expected to only have a partial effect. In a ­double-blind study of 100 men with erectile failure treated with 18 mg/d of yohimbine, 42.6% of the treatment group and 27.6% of the placebo group reported some improvement in erectile function, which was not statistically significant.⁸⁹ Another study that compared a higher dose of yohimbine and ­placebo in 82 elderly men showed a statistically significant improvement with treatment.¹¹⁶

Adverse effects can occur with relatively low doses of yohimbine. Tachycardia, hypertension, mydriasis, diaphoresis, lacrimation, salivation, nausea, vomiting, and flushing can occur after intravenous administration.⁶⁰ Ten milligrams of yohimbine can elicit manic symptoms in patients with bipolar disorder,¹⁰² and 15 mg/d is associated with bronchospasm⁶⁸ and a lupuslike syndrome.¹⁰⁶ A 16 year-old woman who ingested 250 mg of yohimbine powder, purchased for its purported aphrodisiac activity, developed an acute dissociative reaction with weakness, paresthesias, headache, nausea, palpitations, and chest pain. She also developed tachycardia, tachypnea, diaphoresis, tremors, and a rash. Her symptoms resolved after 36 hours without treatment.⁷⁴ Another report describes a 62 year-old man who ingested 200 mg of yohimbine and developed tachycardia, hypertension, and a brief period of anxiety that resolved without treatment.⁴⁹ Symptomatic patients who ingest yohimbine should receive activated charcoal and should be observed until asymptomatic. Clonidine has been recommended for treatment of yohimbine’s central and peripheral effects.⁷⁴β-Adrenergic antagonists may attenuate some of the peripheral toxicity but may also result in unopposed α₁-adrenergic activity and worsening of hypertension and should be avoided. Benzodiazepine administration may be sufficient for the treatment of agitation and sympathomimetic effects related to yohimbine.

Sublingual apomorphine effects erection through activation of central dopaminergic pathways, most likely D₂ receptors in the paraventricular nucleus of the hypothalamus.⁵⁸ 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.¹¹ Common adverse effects are nausea, vomiting, headache, dizziness, and syncope. Unlike the PDE-5 inhibitors, apomorphine is not associated with hypotension when used with antihypertensive, such as nitrates.

Priapism.

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).⁸⁷ 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 can exceed arterial systolic pressure, resulting in cell death. Priapism can occur from an imbalance in neural stimuli or 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.¹²⁸ One in 10,000 patients taking trazodone develops priapism, which is thought to be related to its α-adrenergic antagonist effects.¹⁰⁵ Priapism can result from the injection of papaverine for the treatment of impotence.⁸⁷ Other xenobiotics associated with xenobiotic-induced priapism include prazosin, labetalol, guanethidine, hydralazine, phenothiazines, androgens, anticoagulants, ethanol, marijuana, and cantharidin^62,128 (Table 21–3).

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. Aspiration with or without 9% NaCl solution irrigation of the corpora cavernosa may be effective. If priapism occurs secondary to α₁-adrenergic antagonism, an α₁-adrenergic agonist (100–500 μg/mL phenylephrine solution) can be instilled into the corpora cavernosa at a dosage of 0.5 to 1 mL every 3 to 5 minutes up to 1 hour.⁸⁷ Oral terbutaline (5–10 mg) was effective for PGE₁-induced prolonged erections.^75,103 For ischemic priapism symptoms greater than 4 hours, the American Urological Association guidelines do not recommend oral sympathomimetics.⁸⁷ Intracavernosal methylene blue has been used successfully as an alternative to intracavernosal sympathomimetics.⁸⁰ If the above measures fail, an operative venous shunt placement may be required.^117,128

The female reproductive system consists of the female gonadal organs and the respective hormonal system (Fig. 21–3). Fertility encompasses the reproductive system, the process of oocyte fertilization, and gestation. Female infertility may result from changes in hormone concentrations, direct toxicity to the ovum, interference with the transport of the ovum, or inhibition of implantation of the ovum in the uterus. Women usually notice reproductive abnormalities more quickly than men because menses may be affected, although infertility may occur while normal menses persists. Evaluation of female fertility is more difficult because of the complexity of the systems involved and the inaccessibility of the female germ cell, but it is feasible and involves investigations of the anatomy and hormonal concentrations. The following is a discussion of oogenesis, xenobiotics that disrupt oogenesis, and xenobiotics that affect early embryo gestation.

Oogenesis

In contrast to men, women have a limited number of reproductive cells (ovarian follicles). Follicles are most numerous while a fetus is in utero, with the number decreasing to approximately 2 million at birth. By the time a woman reaches puberty, the majority of follicles have degenerated, leaving 300,000 to 400,000 ova, of which approximately 400 will eventually produce mature ova during a woman’s reproductive years. In contrast, men produce millions of spermatozoa each day. The process of oogenesis requires secretion of GnRH from the hypothalamus, resulting in production of LH and FSH from the pituitary, which are required for ovarian follicle maturation.²⁴ FSH induces early maturation by stimulating granulosa and thecal cell proliferation and estrogen production. LH is required for ovulation and for the formation of the corpus luteum. The corpus luteum continues estrogen production and produces progesterone, which stimulates the uterus to develop an endometrium receptive to any fertilized ovum. Successful ovulation requires not only hormone secretion but also appropriate cyclic secretion.

Female Sexual Dysfunction

The National Health and Social Life Survey found that 43% of women in the United States (in comparison with 31% of men) reported having sexual dysfunction.⁶⁹ In 1999, a consensus panel of the American Foundation for Urologic Disease modified the four categories of female sexual dysfunction in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision to include the following: (1) sexual desire disorders, which include hypoactive sexual desire disorder and sexual aversion disorder; (2) sexual arousal disorder; (3) orgasmic disorder; and (4) sexual pain disorders, which include dyspareunia, vaginismus, and noncoital sexual pain disorder.^2,15 The organic etiologies of female sexual dysfunction parallel those of male sexual and erectile dysfunction: vascular, neurologic, muscular, psychogenic, endocrinologic, and xenobiotic-induced causes.¹⁹ The medications implicated in female sexual dysfunction are similar to those mentioned earlier that decrease male fertility with antihypertensives; antidepressants, especially SSRIs; and antipsychotics as the most frequent causes.⁴⁵

Treatments for xenobiotic-induced female sexual dysfunction include decreasing medication dosages, switching to alternate medications with less adverse effects on sexual function such as bupropion and nefazodone, temporary cessation of the medication (drug holiday), or adding another medication to stimulate sexual function. Bupropion alone was as effective as fluoxetine for the treatment of depression but with less sexual ­dysfunction,³⁶ and when used in conjunction with SSRIs, bupropion improved sexual function compared with SSRIs alone.^30,34 Sildenafil was successful for treating spinal cord–induced¹¹³ and antidepressant-induced sexual dysfunction,⁹⁴ but larger trials had mixed results with sildenafil for sexual arousal disorder.^16,27 Sublingual apomorphine improved sexual function in women with hypoactive sexual disorder.²⁶

The majority of medical therapy for female sexual dysfunction is centered on hormonal manipulation, both estrogen and androgen supplementation. Estrogen replacement therapy is available in oral, dermal, vaginal ring, and topical cream formulations alone or in combination with progesterone.¹²¹ Estrogen therapy is associated with a higher incidence of coronary disease, breast cancer, stroke, and venous thromboembolism. Androgen therapy includes testosterone, which is available in oral, dermal, and topical preparations, and dehydroepiandrosterone.⁸ Adverse effects are weight gain, increased cholesterol concentrations, and androgenization.

Abortifacients.

An abortifacient is defined as a xenobiotic that affects early embryonic gestation to induce abortion. Xenobiotics may act by flushing the zygote from the fallopian tube, blocking the uterine horn inhibiting implantation, inducing fetal resorption, or producing oxytocinlike activity that results in uterine irritation and contraction. Abortifacients may also indirectly affect pregnancy by altering hormonal concentrations through placental inhibition of human chorionic gonadotropin or progesterone production or through interference with progesterone receptors.

The toxic effects of abortifacients are varied. Many produce GI symptoms such as abdominal pain, nausea, and vomiting. Abdominal pain may be related to the oxytocic uterine effects associated with misoprostol and mifepristone, cytotoxic effects on the GI mucosa associated with methotrexate, leading to stomatitis and ulcers or hepatoxicity associated with pennyroyal oil.³² Mifepristone inhibits implantation or has abortive effects that can cause severe vaginal bleeding. Other toxic effects are not necessarily related to their abortive mechanisms but due to the specific xenobiotic. Plant-derived abortifacients such as Aristolochia can cause nephrotoxicity, dong quai can cause photosensitivity, blue cohosh can cause seizure, and quinine can cause cardiac dysrhythmias.⁹² Congenital abnormalities of the scalp and skull defects, cranial nerve palsies, and limb defects such as talipes equinovarus are also reported with misoprostol use that did not terminate pregnancy³² (Table 21–4).

In a US poison center study, five of 43 pregnant women who intentionally overdosed used known abortifacients, including quinine, misoprostol, methylergonovine, and oral contraceptives. Four of these patients developed vaginal bleeding and cramping, but no short-term (1–3 days) fetal demise was reported.¹⁰¹ The use of abortifacients is more common in underdeveloped countries and in people without access to safer methods for termination or prevention of pregnancy.

Toxicity of Aphrodisiacs

Aphrodisiacs heighten sexual desire, pleasure, or performance and include xenobiotics from the plant, animal, and mineral kingdoms.³⁸ The search for an effective aphrodisiac has continued for thousands of years. Ancient fertility cults used Datura, belladonna, and henbane as aphrodisiacs. Yohimbine has been used by African cultures to enhance sexual prowess, and ­mandrake was used in medieval Europe. A small sampling of other xenobiotics recommended as aphrodisiacs include oysters, live beetles, vitamin E, ginseng, ­saffron, horny goat weed, and tongkat ali. Because there are few measurable objective parameters, research in this area is lacking. Most published studies evaluating aphrodisiacs have been conducted in animals, and little information is available in humans. Toxicity can result from the aphrodisiac or adulterants¹³ (Table 21–5).

Dopamine, NO, oxytocin, and ACTH facilitate sexual behavior. Dopamine stimulates the forebrain and midbrain and leads to an increase in sexual response and arousal. In animals, dopamine agonists, such as apomorphine and quinpirole, have proerectile effects through stimulation of dopamine pathways, increasing NO in the paraventricular nucleus in the hypothalamus, and releasing oxytocin.⁹⁰ Other preparations tested for the treatment of impotence include bromocriptine,^1,22 nitroglycerin,⁹¹ zinc,¹⁰ oxytocin,⁷² and LH.⁷¹ Endogenous opioids, GABA, and norepinephrine are associated with decreased sexual behavior. Serotonin is generally inhibitory to sexual function, but the effects are dependent on the receptor subclass. Whereas 5-HT_1A receptor stimulation inhibits erection but facilitates ejaculation in rats, 5-HT_2C receptors facilitate male sexual behavior.⁹⁰ Various serotonergic drugs, including trazodone, nefazodone, bupropion, and clomipramine, are reported to improve sexual dysfunction.^105,127

Urinary System

The urinary system is composed of the kidneys, ureters, bladder, and urethra (Chap. 28). Many xenobiotics are concentrated by the kidneys and eliminated in the urine. The following discusses the effect of xenobiotics on the bladder and urine.

Bladder Anatomy and Physiology.

The bladder is a hollow, muscular reservoir composed of two parts—the body and the neck—and normally stores up to 350 to 450 mL of urine in adults. A smooth muscle, the detrusor muscle, makes up the bulk of the body and contracts during urination. Urine from the ureters enters the bladder at the uppermost part of the trigone, an area in the posterior wall of the bladder, and leaves via the neck and the posterior urethra. Surrounding the neck and posterior urethra is smooth muscle interlaced with elastic tissue to form the internal sphincter. Sympathetic innervation from the lumbar spinal cord to the internal sphincter maintains smooth muscle contraction. Distal to the internal sphincter is an area with voluntary skeletal muscle that forms the external sphincter and is innervated by somatic pudendal nerves.

The nerve supply and neurophysiology of urination involve interplay among lumbar sympathetic nerves, sacral parasympathetic nerves, and sacral somatic nerves. Fig. 21–4 illustrates the physiology of micturition. With bladder filling, norepinephrine is released by sympathetic postganglionic fibers. α-Adrenergic receptors predominate in the internal sphincter and the bladder neck, and β-adrenergic receptors supply the detrusor wall of the bladder. Stimulation of α-adrenergic receptors results in internal sphincter contraction and increased bladder outlet resistance, and stimulation of β-adrenergic receptors leads to detrusor relaxation and bladder filling.¹¹⁹ In micturition, parasympathetic pre- and postganglionic fibers release acetylcholine to M₂ and M₃ muscarinic receptors in the detrusor muscle. Stimulation of M₃ receptors is responsible for detrusor muscle contraction and bladder emptying.³⁰ Conversely, anticholinergics prevent bladder emptying and result in urinary retention.^{28,29,33,48,53,88}

Urinary Abnormalities.

Urinary incontinence is common in elderly adults. As age increases, bladder size decreases, resulting in more frequent emptying. Early detrusor contraction, even with low bladder volumes, occurs more commonly in elderly adults, causing a sense of urgency. There are many etiologies for urinary incontinence, including various xenobiotic exposures (Fig. 21–5). General or regional anesthesia, bladder instrumentation, and medications may produce bladder atony, leading to ­incontinence.³³ Functional incontinence can also result from use of any medication that causes impaired cognition or decreased mobility as recognized with the use of sedative–hypnotics and opioids.³³ Xenobiotics used in the treatment of urinary incontinence include the anticholinergics darifenacin, fesoterodine oxybutynin, solifenacin, tolterodine, trospium chloride, imipramine, botulinum toxin A, and venlafaxine. Venlafaxine is a serotonin and norepinephrine reuptake inhibitor that acts centrally at the sacral cord pudendal motor nucleus to stimulate urethral rhabdosphincter contraction.⁴² Urinary retention can be obstructive, neurogenic, psychogenic, or pharmacologic in origin. Medications associated with urinary retention include sympathomimetics, anticholinergics, antidysrhythmics (quinidine, procainamide, disopyramide), antidepressants, antipsychotics, hormonal agents (progesterone, estrogen, testosterone), and muscle relaxants.^33,48 In men older than 50 years, benign prostatic hyperplasia is the most common cause of bladder outlet obstruction, leading to decreased urinary output and urinary retention. Treatment of benign prostatic hyperplasia consists of 5α-reductase inhibitors and α-adrenergic antagonists. 5α-Reductase inhibitors (finasteride, dutasteride) block the conversion of testosterone to dihydrotestosterone to decrease prostate volume.⁸³α₁-Adrenergic antagonists (doxazosin, terazosin, alfuzosin, tamsulosin) decrease urethral α-adrenergic ­contraction.⁵⁰Table 21–6 lists xenobiotics associated with urinary retention and incontinence.

Abnormalities in Urinalysis.

Abnormalities of the urinalysis are often useful in identifying xenobiotic exposures. Crystalluria is a common finding and may be normal, but the presence of crystals may aid in diagnosis. Crystal formation is dependent on supersaturation of the urine and changes in the urine temperature or pH. The most common crystals are calcium oxalate, uric acid, and phosphate. However, crystals of various xenobiotics alone or in combination with other crystals may be seen in ingestions.⁴⁶ The urinalysis in patients who ingest ethylene glycol may reveal calcium oxalate or hippurate crystals in 50% of cases. Calcium oxalate crystals are monohydrates (prism or needlelike) or dihydrates (envelope shaped). Hippurate crystals are needle shaped.⁹⁷ Birefringent single or conglomerates of hexagonal crystals are noted after massive primidone poisoning and result from precipitation of primidone in the urine.¹¹⁸ Crystalluria may be present with therapeutic doses of salicylate, phenacetin, sulfonamide, and quinolones. Oral sodium phosphate preparations for bowel cleansing have caused calcium phosphate calcifications leading to acute phosphate nephropathy.⁷⁸ After large exposures, crystals can be seen with methotrexate, amoxicillin, cephalexin, ampicillin, and indinavir (Table 21–7).

Urine color is dependent on several factors, including pH, concentration, natural pigments, and length of time exposed to air. Normal urine specimens should be clear and yellow in coloration. Whereas dilute urine secondary to diuretic use, diabetes mellitus, diabetes insipidus, or simply hydration can appear colorless, concentrated urine is usually orange. Fluorescein, found in some antifreeze products, can be detected by illumination of the urine with a Wood lamp, although this diagnostic test has poor sensitivity and specificity.¹²⁰ One study used urine samples from a group of unpoisoned children and three urine samples with added sodium fluorescein to examine physicians’ ability to detect urinary fluorescence with a Wood lamp against a fluorometer. The fluorometer reported fluorescence in 100% of the urine samples, but the physicians reported fluorescence in 70% to 80% of the samples.⁹⁸ Urinary fluorescence, even when present, is not useful as a diagnostic test. Table 21–8 lists other causes of colored urine.

There are multiple causes of hematuria⁷⁹ (Table 21–9). It can occur with xenobiotic-induced interstitial nephritis, a condition distinguished by fever, rash, eosinophilia, eosinophiluria, azotemia, and oliguria.⁴⁰ Hemorrhagic cystitis is a more frequent cause of hematuria and is associated with a number of xenobiotics. The clinical presentation of hemorrhagic cystitis includes hematuria, dysuria, and urinary frequency. Criteria for diagnosis of hemorrhagic cystitis10 include a history of gross hematuria, laboratory findings, of microscopic hematuria (>3 red blood cells/high-power field), platelet count above 50,000/mm³, and a negative urine culture result.¹⁰⁴ When in doubt, the diagnosis may be confirmed by cystoscopy, which reveals an inflamed, hyperemic, and sometimes ulcerated bladder mucosa.

Cyclophosphamide-related hemorrhagic cystitis was first described in 1959⁸⁶ and is the best-documented type of xenobiotic-induced hemorrhagic cystitis.⁵¹ As many as 46% of patients receiving cyclophosphamide develop hemorrhagic cystitis.^43,61,67,70 Acrolein, the causative xenobiotic, is a metabolite of cyclophosphamide that damages the urothelium when excreted (Chap. 52).^101,115 Cyclophosphamide- and ifosfamide-induced hemorrhagic cystitis may be prevented with mesna therapy.⁴

An outbreak of hemorrhagic cystitis occurred in workers in a packaging plant after exposure to chlordimeform, a formamidine insecticide used to control mites and insects on cotton. Nine workers developed abdominal pain, dysuria, urgency, and hematuria, with biopsy-proven hemorrhagic cystitis.⁴⁷ Eight young adults developed painful hematuria after consuming “bootleg” methaqualone. The cause was orthotoluidine, a compound used in the synthesis of methaqualone, and the symptoms occurred within 6 hours of ingestion.⁵⁴ Chronic ketamine and methoxetamine abuse is associated with the development of hemorrhagic ulcerative cystitis.¹¹¹ Rare cases of hemorrhagic cystitis have also been described with ticarcillin,⁸¹ nafcillin, penicillin G, carbenicillin, piperacillin, isoniazid, indomethacin, tiaprofenic acid, and busulphan.^52,85,112

Treatment for other causes of hemorrhagic cystitis includes bladder irrigation with saline, alum, PGs, silver nitrate, formalin, and phenol. Systemic therapy include estrogens, vasopressin, aminocaproic acid, and hyperbaric oxygen.¹²⁴ These therapies may have inherent adverse effects as well. Aluminum toxicity has been reported with alum bladder irrigation for hemorrhagic cystitis in patients with kidney failure.¹⁰⁰

• Xenobiotics decrease fertility and fecundity by decreasing FSH and LH centrally or altering sperm production in men and altering ovarian function in women.

• Xenobiotics can cause sexual dysfunction by decreasing libido in men and women, increasing prolactin, decreasing dopamine, or causing erectile dysfunction in men.

• Therapies for male erectile dysfunction can lead to priapism.

• Abortifacients usually prevent embryo implantation or induce uterine contractions leading to increased vaginal bleeding and abdominal pain.

• Xenobiotics can alter bladder function to cause urinary retention or incontinence as well as changing the characteristics of urine in terms of color, hematuria, or crystal formation.

References