Anabolic Steroids and Male Infertility

Nelson Vergel

Thread starter #1
AU - Fronczak, Carolyn M.
AU - Kim, Edward D.
AU - Barqawi, Al B.
TI - The Insults of Illicit Drug Use on Male Fertility
JO - Journal of Andrology
VL - 33

Anabolic-Androgenic Steroids

AAS are cholesterol derivatives of testosterone with effects that are both anabolic and androgenic to build lean muscle and enhance masculinization (Kopera, 1985; Bhasin et al, 1996; Sheffield-Moore and Urban, 2004; Pope and Brower, 2009). Popular types of AAS are oral oxandrolone (Oxandrin), oral methandienone (Dianabol), injectable stanozolol (Winstrol-V), injectable nandrolone decanoate (Deca-Durabolin), and injectable boldenone undecylenate (Equipoise). Stereotypically, the AAS user is a weightlifter or competitive athlete who combines intensive power lifting with AAS in supraphysiologic doses to enhance performance. Professional and amateur athletic associations are intolerant of the use of performance-enhancing substances and subscribe to antidoping organizations, such as the US Anti-Doping Agency or the World Anti-Doping Agency (WADA), or have their own guidelines and protocols to prevent doping, as does the National Collegiate Athletic Association. These antidoping regulations deter the use of performance-enhancing drugs by athletes. However, at the same time, these regulations have pushed the design of sophisticated doping compounds undetectable by current laboratory testing techniques (Kayser et al, 2007). It should be emphasized that testosterone, which is available as a prescription medication as well as illicitly, is an AAS (WADA, 2011). Testosterone (T) coupled with epitestosterone (E) have been abused together to disguise T/E ratios in athletic antidoping systems (Saudan et al, 2006). Elevated T/E ratios have been recognized as a marker of AAS use in athletes. In addition to the athletes who currently are able to dope undetected, the use of performance-enhancing drugs by the general public is a concern, because the typical user of AAS is a “regular Joe” who desires a leaner, more muscular physique so he can emulate the media-perpetuated image of masculinity and fitness (Buckley et al, 1988; Parkinson and Evans, 2006; Cohen et al, 2007).

In 2001, the annual prevalence rate of AAS use in high school boys was estimated to be between 8% and 12% but has since declined to an annual prevalence rate of 3% (Johnson et al, 1989; Kanayama et al, 2009b). In males ages 19–30 years, the annual prevalence rate was 0.7% (Table 1; Johnston et al, 2009). However, the lifetime prevalence of AAS use in males is estimated to be between 3.0% and 4.2%, and of concern are case reports of individuals taking AAS who develop depressive withdrawal symptoms after discontinuing AAS, and may develop AAS dependence as a result. Although AAS dependence needs further study, possible hypotheses include psychologic dependence due to body image disorders such as “muscle dysmorphia” (Pope et al, 1997), and physiological dependence similar to opioid dependence, in which AAS potentiates central endogenous opioid activity and withdrawal decreases endogenous opioids, leading to an acute hyperadrenergic syndrome (Kashkin and Kleber, 1989). Support for the similarity of AAS dependence to opioid dependence is limited in the literature. There are case reports indicating that AAS users are at risk for developing opioid abuse (Tennant et al, 1988). Kanayama et al (2009b) examined 5 naturalistic-type studies published between 1991 and 2005 that recruited AAS users from gymnasiums or the Internet and attempted to diagnose AAS dependence using the Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria of the American Psychiatric Association for substance dependence. They found that 30% of these study participants met DSM-IV criteria for noncyclic dependence, with an average age of onset of dependence in the late 20s (Johnson et al, 1989; Johnston et al, 2009; Kanayama et al, 2009a; Kanayama et al, 2009b). Kanayama et al (2009a) suggest that there are likely hundreds of thousands of men in their 30s and 40s who began use in high school and are currently dependent on AAS. Many more are likely to experience clinically significant side effects of AAS on fertility (Tennant et al, 1988; Kanayama et al, 2009a).

The understanding of how AAS affects spermatogenesis is complicated by several factors. The method used to obtain information is usually through naturalistic study design, with recruitment of AAS users from gymnasiums or the Internet. This method of recruiting users has inherent selection biases because some users may be more or less likely to disclose their abuse, as well as information bias if users choose to not disclose their use, side effects, and concurrent medications. Many abusers concurrently take antiestrogens, aromatase inhibitors, and human chorionic gonadotropin (hCG) to counteract the adverse effects of AAS and perhaps avert the detection of their use (Kanayama et al, 2009a).

Even though AAS are Schedule III drugs, they are easy to order over the Internet and easy to self-administer (Duchaine, 1981;Phillips, 1991). There is an extreme variability in the types, doses, combinations, and dosing schedules of AAS. Because a direct dose response relationship between AAS and muscle growth exists (Bhasin et al, 1996,2001), it is estimated that AAS users often take 600–5000 mg of AAS per week (Parrott et al, 1994;Pope and Katz, 1994;Wilson-Fearon and Parrott, 1999; Fudala et al, 2003; Parkinson and Evans, 2006). These doses are supraphysiologic in that they are 50–100 times greater than the 40- to 50-mg weekly production of testosterone by normal male testes (Reyes-Fuentes and Veldhuis, 1993).

Not only do the combinations and types of AAS vary widely, the administration and dosing schedules are just as variable. Typically, two or more types of AAS are taken simultaneously in blocks of 8–16 weeks, and doses are increased and then decreased over the course of the active block, termed “stacking,” “cycling,” and “pyramiding,” respectively (Lukas, 1993;Pope and Katz, 1994;Kanayama et al, 2003). The goal is to maximize both receptor binding and effect, avoid plateauing, avoid tolerance, and minimize the withdrawal symptoms of fatigue, loss of libido, and depressed mood.

Male fertility requires active spermatogenesis, which depends on Leydig cells secreting high levels of endogenous intratesticular testosterone. However, supraphysiologic levels of exogenous AAS actually exert negative feedback on the hypothalamic-pituitary-testicular axis and subsequently reduce FSH, LH, and intratesticular testosterone concentration. These hormonal changes can lead to azoospermia, oligospermia, testicular atrophy, hypogonadotropic hypogonadism, and an increased percentage of morphologically abnormal sperm with amorphous spermatozoa and defects in the head and center pieces (Table 6;Schurmeyer et al, 1984;Torres-Calleja et al, 2001;Bonetti et al, 2008).

Usually, spermatogenesis recovers spontaneously within 4–6 months after cessation of AAS (Knuth et al, 1989), timing that is similar to the recovery of spermatogenesis after the use of pharmacologic levels of testosterone for male contraception (Liu et al, 2006). However, recovery has been reported to take up to 3 years or longer (Schurmeyer et al, 1984; Turek et al, 1995; Menon, 2003). Reasons for the extended recovery time are not yet known but are likely due to the wide variety of combinations and types of AAS. Various clinical treatments have been prescribed to reestablish fertility (Gazvani et al, 1997). Human chorionic gonadotropin can induce spermatogenesis (Martikainen et al, 1986; Gill, 1998). Tamoxifen, an estrogen receptor blocker, when combined with hCG may alter gonadotropin secretion and improve spermatogenesis, as well as possibly stimulate endogenous testosterone production (Damber et al, 1989). Clomiphene citrate, a nonsteroidal antiestrogen most often used to initiate ovulation in women, has also been applied in a short course to stimulate normal sex hormone secretion in males by producing a gonadotropin surge (Guay et al, 1995; Tan and Vasudevan, 2003).

Although the combination of hCG and AAS can maintain spermatogenesis, there can also be a transient impairment on semen quality with abnormal and hypokinetic spermatozoa (Karila et al, 2004). Many users of AAS are concurrent abusers of hCG, antiestrogens, and aromatase inhibitors in order to counteract the hypogonadotropic hypogonadism and gynecomastia side effects of AAS, and to disguise and prevent detection of AAS abuse (Karila et al, 2004; Basaria, 2010). Human chorionic gonadotropin and antiestrogens are on WADA's 2009 list of prohibited androgens and androgen modulators. By stimulating endogenous testosterone production and preventing testicular atrophy, hCG and clomiphene are concurrently abused by AAS users to avoid detection of exogenous testosterone (Kicman et al, 1990; Hoffman et al, 2009).

It is difficult to study AAS use and its side effects because of the variable dosing as well as the prevalence of selection and information biases in research design, because most AAS users are recruited from gymnasiums or through the Internet. Clinicians can look for increased libido, virilization, and bulk muscle with atrophic testes as signs of AAS use, but counseling patients can be difficult. Many are fearful to disclose their use of illegal substances and subsequently do not report side effects (Lloyd et al, 1996; Cohen et al, 2007). Pope et al (2004) interviewed 80 weightlifters, 54% of whom were current AAS users. Although 50% of those using AAS respected physicians with regard to their general medical knowledge, they did not regard the knowledge of the physician regarding AAS as any more reliable than that of their friends, Internet sites, or suppliers of AAS (Pope et al, 2004). Importantly, 56% of the users had never revealed their AAS use to a physician. Confounding variables such as premorbid attributes of AAS users or concomitant use of other substances also likely influence observed associations in the literature (Kanayama et al, 2009a). Furthermore, many drug abusers use multiple illicit medications. These medications are used because of their perceived desired effects and to prevent adverse effects caused by the primary abused drug or drugs. This makes interpretation of the literature complicated and often misclassifies adverse effects to one drug that may in fact be due to a coadministered illicit agent.