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
Schematic of the male reproductive axis and sites of xenobiotic effects. CNS = central nervous system; DBCP = dibromochloropropane; FSH = follicle-stimulating hormone; GnRH = gonadotropin-releasing hormone; LH = luteinizing hormone.
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.
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
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 F2α(PGF2α), 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).
Schematic of the erection and xenobiotics that cause sexual dysfunction. ACH = acetylcholine; cAMP = cyclic adenosine monophosphate; cGMP = cyclic guanosine monophosphate; MAOI = monoamine oxidase inhibitor; NANC = nonadrenergic-noncholinergic; NE = norepinephrine; NO = nitric oxide; PDE = phosphodiesterase; VIP = vasoactive intestinal peptide; SSRI = selective serotonin reuptake inhibitor.
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.
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 documented5,59,122 and may be caused by unopposed α-adrenergic–mediated vasoconstriction resulting in reduced penile blood flow.
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.
TABLE 21–2.Xenobiotics Associated with Sexual Dysfunction (Particularly Diminished Libido and Impotence) ||Download (.pdf) TABLE 21–2. Xenobiotics Associated with Sexual Dysfunction (Particularly Diminished Libido and Impotence)
|α1-Adrenergic antagonists ||Digoxin |
|α2-Adrenergic agonists ||Diuretics |
|β-Adrenergic antagonistsa ||Ethanol |
|Amphetamines ||Gonadotropin-releasing hormone agonistsa |
|Anabolic steroids ||Ketoconazole |
|Antiandrogensa ||Lead |
|Anticholinergicsa ||Lithium |
|Anticonvulsants ||Methotrexate |
|Antiestrogens ||Methyldopa |
|Benzodiazepines ||Monamine oxidase inhibitorsa |
|Calcium channel blockers ||Opioids |
|Chemotherapeutics ||Oral contraceptives |
|Cimetidine ||Phenothiazines |
|Clonidine ||Selective serotonin reuptake inhibitors |
|Cocaine ||Spironolactone |
|Cyclic antidepressants ||Thiazides |
Xenobiotics Used in the Treatment of Erectile Dysfunction
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.
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 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 cantharidin62,128 (Table 21–3).
TABLE 21–3.Xenobiotics Associated with Priapism
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