**1.5.8 Medications and male reproductive toxicity**

There are a variety of prescription medications that can lead to male infertility, often temporary but sometimes permanent. Arthritis medication, depression drugs, high blood pressure medication, drugs for digestive problems as well as antibiotics and cancer drugs are just a few of the medications that can lead to interferences with sperm production, sexual function and ejaculation (Nudell et al., 2002). Here is a look at some of the common medications and drugs that can cause a man to experience fertility problems.

### **1.5.8.1 Antihypertensive**

486 Toxicity and Drug Testing

rats results in abnormalities of androgen-regulated sexual differentiation similar to those induced by flutamide, e.g. reduced anogenital distance, nipple retention, hypospadias, undescended testes and small or absent accessory glands (Gray et al., 2001). Studies have tried to define the 'sensitive window' for exposure to vinclozolin, and have determined that administration to pregnant rats during gestational day (GD) 14–19 induced reproductive tract malformations, with treatment over GD16–17 causing the most severe malformations (Wolf et al., 2000). This illustrates that the whole period of male reproductive tract

Linuron is a urea-based herbicide which acts as a weak androgen receptor antagonist in vitro and in vivo, and disrupts androgen-dependent male reproductive tract development after gestational exposure (Gray et al., 2001). When administered to pregnant rats (GD 14– 18; 100 mg/ kg/day) the male pups displayed a reduced anogenital distance and retention of areolas (Gray et al., 1999). Linuron failed to induce either hypospadias or undescended testes, suggesting that linuron affects testosterone-but not DHT-mediated development,

It is beyond the scope of this review to provide a detailed review of the literature on cigarette smoking and semen quality. However, PAH (polycyclic aromatic hydrocarbons), the major carcinogenic components of cigarette smoke (Vine, 1996), were found to activate aryl hydrocarbon receptor (AhR), suggesting that tobacco smoke may represent a chemical mixture with endocrine disrupting activity. There is extensive evidence demonstrating that exposure to tobacco smoke is associated with reduced semen quality (Vine, 1996). An inverse dose-dependent relationship between smoking and semen volume, total sperm count, and percent motile sperm was reported following a large cross-sectional study of 2542 healthy Danish men. Sperm concentration was 19% lower in heavy smokers compared to non-smokers. Serum LH and testosterone were positively correlated with smoking (Ramlau-Hansen et al., 2007). The incidence of bilateral cryptorchidism in a sample of cryptorchid Danish boys was increased in children of smoking mothers. Testicular biopsies from boys exposed in utero/neonatal to tobacco smoke demonstrated a decreased number of spermatogonia and gonocytes per tubule cross section (Thorup et al., 2006). Similarly, a large cross-sectional European study of 889 Danish men, 221 men from Norway, 313 Lithuanian men, and 190 men from Estonia reported reductions of sperm concentrations by 20% in sons exposed to prenatal tobacco smoke (Jensen et al., 2004), while a separate study described an inverse dose-dependent association between sperm concentration and prenatal tobacco exposure, measured in adult sons of 522 Danish women (Jensen et al., 2005). The association between impaired semen quality and smoking is fairly well established (Vine, 1996). Although epidemiological studies of male reproductive function were designed to avoid the confounding effects of smoking, by limiting samples to non-smokers or segmenting samples according to smoking status, the interaction effects of tobacco smoke, alcohol, and other lifestyle factors are often not considered. An important study by Robbins et al.,(1997) did investigate the interactions of caffeine, alcohol, and cigarette smoking on sperm aneuploidy, determining that incidence of sperm abnormalities decreased after

differentiation is sensitive to the effects of anti-androgens.

though how this occurs is not known (McIntyre et al., 2002).

controlling for age and other lifestyle factors.

**1.5.6.2 Linuron** 

**1.5.7 Tobacco smoke** 

Although most men who are treated for hypertension are older, the recent focus on the importance of blood pressure control has led to greater numbers of younger patients on antihypertensives. Many of these medications are commonly associated with erectile dysfunction but most do not directly affect fertility. One exception is spironolactone, which acts as an anti-androgen and has been associated with impaired semen quality. Calcium channel blockers (e.g. nifedipine) have been reported to cause reversible functional defects in sperm, impairing their ability to fertilize eggs without affecting sperm production or standard semen analysis parameters; however, not all investigators report these types of effects. Diuretics can affect function by decreasing penile blood flow, and beta-blockers may affect libido and erectile function (Benoff et al., 1994).

### **1.5.8.2 Hormones**

Diethylstilbestrol (DES) was given to pregnant women in the 1950s, and reports of epididymal cysts and cryptorchidism (undescended testes) in males with prenatal DES exposure have raised concerns about fertility; however, follow-up studies on adult men with prenatal DES exposure have revealed no adverse effects on fertility (Wilcox et al., 1995). Exogenous androgens are well known to induce hypogonadotropic hypogonadism. This may be induced directly by testosterone supplementation or by use of synthetic anabolic steroids, leading to azoospermia. This hypogonadism is usually reversible but may take 3 to 6 months, and some patients do not recover pituitary function. It is important to remember that testosterone replacement therapy in younger men may lead to infertility. Dehydroepiandrosterone (DHEA) is a natural steroid prohormone precursor of androsterone, testosterone, and estrogen. DHEA is commonly taken and easily available over the counter. Antiandrogens and estrogens can adversely affect fertility by altering the HPG axis or decreasing libido or erectile function, while progesterones act by decreasing libido or erectile function (Nudell et al., 2002).

#### **1.5.8.3 Antiandrogens**

Finasteride and dutasteride are antiandrogens that act by inhibiting 5-alpha-reductase. Finasteride has also been used to treat male-pattern baldness. These drugs increase the risk of low ejaculate volumes and libido, as well as cause erectile and ejaculatory dysfunction; however, men taking low doses of finasteride for hair loss have shown no changes in semen parameters (Overstreet et al., 1999).

### **1.5.8.4 Antibiotics**

Many antibiotics have been reported to exert adverse effects on male fertility; however, there are few human data on the majority of these medications. High doses of nitrofurantoin have been reported to cause early maturation arrest at the primary spermatocyte stage but

Environmental Toxicants Induced

Common environmental

(Mainly cadmium, Lead

Volatile organic compounds (Toluene, benzene and

DBP = di(n)butylphthalate DiBP =di(iso)butylphthalate

Toxicants

Heavy Metals

and arsenic)

xylene)

Phthalates

Male Reproductive Disorders: Identification and Mechanism of Action 489

impaired fertility in rats, there are no human data available (Nudell et al., 2002). Epilepsy has been associated with decreased testosterone levels and increased estrogen levels leading to reductions in libido and to erectile dysfunction. Medications used to treat epilepsy (eg, valproate, oxcarbazepine, and carbamazepine) may worsen hormonal abnormalities and

Heavy marijuana use has been associated with gynecomastia, decreased serum testosterone levels, decreased sperm concentration, and pyospermia (white cells in the semen indicating possible infection) (Close et al., 1990). Patients experience variable sensitivity to marijuana,

Oligospermia (abnormally low sperm concentration in the ejaculate) and defects in sperm morphology and motility have been reported in users of cocaine. Opiates have also been shown to decrease libido and erectile function through induction of hypogonadotropic hypogonadism. This also is important to note when prescribing opioids for pain. Chronic opioid use whether, oral or intrathecal, may lead to sexual dysfunction (Bracken et al., 1990). Cumulative evidence suggests that cigarette smoking may have a deleterious effect on male fertility by reducing sperm production, motility, and morphology. Cigarette smoking may also lead to development of pyospermia, decreased sperm penetration, and hormonal alterations (Nudell et al., 2002; Close et al., 1990). Long-term abuse of alcohol has detrimental effects in the HPG axis. Alcoholics exhibit significant decreases in semen volume, sperm count, motility, and number of morphologically normal sperm. They also show signs of pyospermia. Alcohol in excess can thus exert profound deleterious effects on all aspects of the male reproductive system. However, there is no evidence that moderate

have been associated with some sperm morphologic defects (Isojarvi et al., 2004).

**1.5.9 Recreational and illicit substances and male reproductive toxicity** 

alcohol intake impairs male fertility (Nudell et al., 2002; Close et al., 1990).

**The examples of few chemicals which are reported to disrupt the sex hormones and/or damage the male in animal studies are summarized below (Woodruff et al., 2008).** 

> Population exposed to cadmium and lead via contaminations found in drinking water and food, while occupational exposure takes place during mining or manufacturing of batteries and pigments or industrial activities such as smelting and refining

metals and municipal waste

Mostly occupational exposure in

Phthalates are a group of chemicals used to impart flexibility to plastic polyvinyl chloride (PVC) products as

incineration.

industrial workers.

Common uses and routes of exposure The effects on male

reproductive system

a. Testicular toxicity b. Low sperm count and motility and density. c. Reduce male fertility d. Foetal toxicity and malformation of male

a. Testicular toxicity b. Low sperm count and motility and density. c. Reduce male fertility

a. Testicular toxicity b. Reduce anogenital distance, hypospadias and

organs.

and it may take 2 to 3 months for symptoms to improve.

the more common short-term low-dose therapy is not likely detrimental. While in vitro data on erythromycin, tetracycline, and gentamycin suggest the potential for adverse effects on fertility, documentation of an in vivo effect in humans is lacking (Hargreaves et al., 1998). Sulfasalazine, used in the treatment of ulcerative colitis, is well known to cause defects in human sperm concentration and motility. Aminoglycosides, type of antibiotics is generally used for serious bacterial infections, like TB, and are administered under medical supervision. Aminoglycosides can negatively impact sperm production while neomycin has been shown to reduce both sperm count and motility. Macrolides, in addition to being used to treat chlamydia and Legionnaires disease, macrolides are similar to penicillin and can be used in place of it in people with a penicillin allergy. Macrolides research has mainly focused on animals, where it has been found that the antibiotic can decrease sperm motility as well as kill off sperm. It is believed that the antibiotic produces similar results in humans (Schlegel et al., 1991).
