madman
Super Moderator
Primum non nocere. As physicians, our goal is to treat illnesses and alleviate suffering; however, in doing so, we can generate new problems in a game of medical whack-a-mole. For some patients, certain consequences or side effects are tolerable, while others may believe they have no alternative. For a male patient with infertility, a thorough history is imperative to elucidate whether the patient has been or is currently being exposed to medications that will harm libido, spermatogenesis, ejaculation, or the hypothalamic-pituitary–testosterone axis. This article will review the most common medications causing iatrogenic male infertility as well as options to minimize or even reverse their impact.
Assessing and treating an infertile male patient requires an intimate understanding of the tangled web of hormones, psychology, anatomy, sexual function, and how they come together to produce and deliver healthy sperm. Attempts to separate these systems are futile. For the purposes of this article, therapies that impact one often affects all. In this Views and Reviews article, we discuss the commonly prescribed classes of medications and the impact they have on fertility and sexual and hormonal function. Table 1 provides an overview of these medications and their impact on male reproductive health.
*CHEMOTHERAPY AND RADIATION
Traditional chemotherapy and radiation therapies target rapidly dividing cells, thus damaging nonmalignant cells in addition to cancer cells. For both modalities, damage to spermatogenesis and the likelihood of recovery is dependent on the dose received and the age of the patient (2, 3). The testis is one of the most radiosensitive organs, with the more immature cells being the most susceptible to radiation injury. Severe oligospermia may result in radiation doses >0.8 gray, and azoospermia occurs at radiation doses exceeding 2.0 gray. Sperm counts can progressively recover, but this may take up to 2 years after 1 gray and 5 years or more with >2.0 gray (4, 5). Fractionated radiation causes greater delays in spermatogenic recovery, with lower total doses of fractionated radiation causing azoospermia (5). Adult Leydig cells appear to be more resistant to radiation, with literature reporting doses of more than 20 gray to produce hypogonadism (6).
*ANDROGEN DEPRIVATION THERAPY
Androgen deprivation therapy (ADT) is most commonly used as adjunctive therapy for prostate cancer but now has broadened applications in gender affirmation and recurrent priapism. Gonadotropin-releasing hormone (GnRH) agonists and antagonists suppress the normally pulsatile release of GnRH, inducing a hypogonadotropic hypogonadism state. The intended goal of hormonal castration for oncologic control additionally results in several side effects, including fatigue, difficulty concentrating, increased fat and decreased muscle mass, and a range of sexual dysfunction. The rate of erectile dysfunction is estimated to be up to 90% in men on ADT for prostate cancer. In addition, patients may experience loss of libido, anorgasmia, and a decrease in penile and testicular size (16). Antiandrogens block binding at the androgen receptor and typically result in less severe sexual dysfunction (17). Thus, antiandrogens are typically favored over GnRH agonists/antagonists for stuttering priapism (18).
*5-ALPHA REDUCTASE INHIBITORS
Five-alpha reductase inhibitors (5ARIs) competitively inhibit 5-alpha reductase, an enzyme that converts testosterone to dihydrotestosterone. Finasteride is a type 2 selective 5ARI, targeting genital tissues, while dutasteride works on type 1 and 2 5-alpha reductases, which are present throughout the body (29).
Perhaps more alarming are the reports of ongoing sexual dysfunction despite cessation of 5ARI therapy. As Dr. Abdulmaged Traish discussed in his recent Views and Reviews article, post finasteride syndrome may include persistent erectile dysfunction, delayed orgasm or anorgasmia, loss of penile sensitivity, anhedonia, difficulty concentrating, and loss of muscle mass (32). A retrospective chart review of 11,909 men with 5ARI exposure and no history of sexual dysfunction found that 1.4% developed persistent ED, lasting at least 3 months after stopping the 5ARI. The investigators identified 26 significant predictors for persistent erectile dysfunction, of which 5ARI exposure was the third most accurate predictor (33).
*SELECTIVE SEROTONIN RECEPTOR INHIBITORS
One in 8 Americans has used a selective serotonin receptor inhibitor (SSRI) in the past 10 years (35). Indicated for the treatment of depression and anxiety, SSRIs are known to cause sexual dysfunction in up to 80% of patients. Symptoms of SSRI-induced sexual dysfunction include poor libido, erectile dysfunction, delayed ejaculation, anejaculation, anorgasmia, and even genital paresthesia (35, 36). The sexual side effect profile of SSRIs is so profound that SSRIs are even used off-label to treat premature ejaculation (37).
The main neurotransmitters involved in SSRI-induced sexual dysfunction are serotonin, acetylcholine, noradrenaline, and dopamine (38). The higher concentrations of serotonin depress dopamine and noradrenaline, resulting in poor sexual function and arousal. Selective serotonin receptor inhibitors have been shown to decrease nitric oxide and exhibit anticholinergic effects, further contributing to erectile dysfunction (39). In addition, selective serotonin receptor inhibitors may impact the hypothalamic-pituitary–testis axis, resulting in lower serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and ultimately testosterone (38). Compared with normal controls, the subjects taking SSRIs had significantly lower serum levels of LH, FSH, and testosterone and a poorer response to GnRH challenges than healthy controls without a history of SSRI use.
*OPIOIDS
Opioids have long been used for pain management, but opioid misuse, overprescribing, and unauthorized distribution have resulted in over 6% of Americans suffering from some form of opioid abuse (47). Chronic opioid use results in the inhibition of the hypothalamus-pituitary–gonad axis, resulting in hypogonadotropic hypogonadism and hyperprolactinemia.
*EXOGENOUS TESTOSTERONE
Exogenous testosterone is the best-studied form of male contraceptive. Although it does not uniformly induce azoospermia when administered to an average man, exogenous testosterone suppresses the pituitary secretion of LH and FSH. The subsequent decrease in testosterone concentrations within the testicle deprives the fuel for normal spermatogenesis (52).
Unfortunately, several hypogonadal men do not receive appropriate fertility counseling before starting testosterone therapy. Even among American Urological Association members, 25% of urologists reported prescribing testosterone as a male infertility treatment (53). Furthermore, several patients do not realize that up to 20% of legally sold sports nutrition supplements in the United States contain synthetic anabolic–androgenic steroids, which additionally act to suppress the hypothalamus-pituitary–gonad axis (54).
Once exogenous testosterone is discontinued, the timeline to spermatogenesis recovery is uncertain. In a pooled analysis of 30 studies, Liu et al. (55) found the likelihood of regaining a sperm density of R20 million/mL to be 67% at 6 months, 90% at 12 months, and 100% at 24 months. To help patients avoid a ‘‘crash’’ after ceasing testosterone therapy and to promote spermatogenesis recovery, combination therapy of human chorionic gonadotropin 3,000 IU every other day and a selective estrogen receptor modulator, anastrozole, or recombinant FSH has been proposed. Wenker et al (56) reported spermatogenesis recovery at an average of 4.6 months using this regimen, with a mean first sperm density of 22.6 million/mL. Recombinant FSH at 75–150 IU 3 times per week may be added to this regimen should an adequate recovery of spermatogenesis not occur after 6 months of therapy (54, 56).
*There is a new alternative to exogenous testosterone. Natesto (Acerus Biopharma, Mississauga, Canada) is a 4.5% testosterone gel, administered as a 125-mL dose, 3 times per day, via an intranasal pump. With a half-life ranging from 10 to 100 minutes, the testosterone levels return to near baseline in between administrations (57). Short-acting testosterone has been shown to minimally disrupt the pituitary axis and preserve spermatogenesis. In 60 men, only 1 became azoospermic at 3 months of Natesto therapy, and 3 developed severe oligospermia (sperm density < 1 million/mL). With average testosterone levels rising from 231 to 616 ng/dL at 3 months and 652 ng/dL at 6 months, Natesto may strike the Goldilocks compromise between eugonadism and fertility maintenance (58).
In conclusion, male infertility is a complex crossroads of sexual function, sperm production and retrievability, and hormonal control. Although perhaps not central to the patient’s survival, it is a significant component of quality of life and, therefore, cannot be overlooked. The evaluation of the male partner requires communication with other prescribing physicians to consider dose adjustments and medication substitutions, additions, or cancelations. In addition, male infertility specialists should continue to work closely with oncology teams to ensure that patients are provided the opportunity for fertility preservation before spermatotoxic chemoradiation regimens. Finally, more research is needed to treat patients suffering from post finasteride and post-SSRI syndromes.
Assessing and treating an infertile male patient requires an intimate understanding of the tangled web of hormones, psychology, anatomy, sexual function, and how they come together to produce and deliver healthy sperm. Attempts to separate these systems are futile. For the purposes of this article, therapies that impact one often affects all. In this Views and Reviews article, we discuss the commonly prescribed classes of medications and the impact they have on fertility and sexual and hormonal function. Table 1 provides an overview of these medications and their impact on male reproductive health.
*CHEMOTHERAPY AND RADIATION
Traditional chemotherapy and radiation therapies target rapidly dividing cells, thus damaging nonmalignant cells in addition to cancer cells. For both modalities, damage to spermatogenesis and the likelihood of recovery is dependent on the dose received and the age of the patient (2, 3). The testis is one of the most radiosensitive organs, with the more immature cells being the most susceptible to radiation injury. Severe oligospermia may result in radiation doses >0.8 gray, and azoospermia occurs at radiation doses exceeding 2.0 gray. Sperm counts can progressively recover, but this may take up to 2 years after 1 gray and 5 years or more with >2.0 gray (4, 5). Fractionated radiation causes greater delays in spermatogenic recovery, with lower total doses of fractionated radiation causing azoospermia (5). Adult Leydig cells appear to be more resistant to radiation, with literature reporting doses of more than 20 gray to produce hypogonadism (6).
*ANDROGEN DEPRIVATION THERAPY
Androgen deprivation therapy (ADT) is most commonly used as adjunctive therapy for prostate cancer but now has broadened applications in gender affirmation and recurrent priapism. Gonadotropin-releasing hormone (GnRH) agonists and antagonists suppress the normally pulsatile release of GnRH, inducing a hypogonadotropic hypogonadism state. The intended goal of hormonal castration for oncologic control additionally results in several side effects, including fatigue, difficulty concentrating, increased fat and decreased muscle mass, and a range of sexual dysfunction. The rate of erectile dysfunction is estimated to be up to 90% in men on ADT for prostate cancer. In addition, patients may experience loss of libido, anorgasmia, and a decrease in penile and testicular size (16). Antiandrogens block binding at the androgen receptor and typically result in less severe sexual dysfunction (17). Thus, antiandrogens are typically favored over GnRH agonists/antagonists for stuttering priapism (18).
*5-ALPHA REDUCTASE INHIBITORS
Five-alpha reductase inhibitors (5ARIs) competitively inhibit 5-alpha reductase, an enzyme that converts testosterone to dihydrotestosterone. Finasteride is a type 2 selective 5ARI, targeting genital tissues, while dutasteride works on type 1 and 2 5-alpha reductases, which are present throughout the body (29).
Perhaps more alarming are the reports of ongoing sexual dysfunction despite cessation of 5ARI therapy. As Dr. Abdulmaged Traish discussed in his recent Views and Reviews article, post finasteride syndrome may include persistent erectile dysfunction, delayed orgasm or anorgasmia, loss of penile sensitivity, anhedonia, difficulty concentrating, and loss of muscle mass (32). A retrospective chart review of 11,909 men with 5ARI exposure and no history of sexual dysfunction found that 1.4% developed persistent ED, lasting at least 3 months after stopping the 5ARI. The investigators identified 26 significant predictors for persistent erectile dysfunction, of which 5ARI exposure was the third most accurate predictor (33).
*SELECTIVE SEROTONIN RECEPTOR INHIBITORS
One in 8 Americans has used a selective serotonin receptor inhibitor (SSRI) in the past 10 years (35). Indicated for the treatment of depression and anxiety, SSRIs are known to cause sexual dysfunction in up to 80% of patients. Symptoms of SSRI-induced sexual dysfunction include poor libido, erectile dysfunction, delayed ejaculation, anejaculation, anorgasmia, and even genital paresthesia (35, 36). The sexual side effect profile of SSRIs is so profound that SSRIs are even used off-label to treat premature ejaculation (37).
The main neurotransmitters involved in SSRI-induced sexual dysfunction are serotonin, acetylcholine, noradrenaline, and dopamine (38). The higher concentrations of serotonin depress dopamine and noradrenaline, resulting in poor sexual function and arousal. Selective serotonin receptor inhibitors have been shown to decrease nitric oxide and exhibit anticholinergic effects, further contributing to erectile dysfunction (39). In addition, selective serotonin receptor inhibitors may impact the hypothalamic-pituitary–testis axis, resulting in lower serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and ultimately testosterone (38). Compared with normal controls, the subjects taking SSRIs had significantly lower serum levels of LH, FSH, and testosterone and a poorer response to GnRH challenges than healthy controls without a history of SSRI use.
*OPIOIDS
Opioids have long been used for pain management, but opioid misuse, overprescribing, and unauthorized distribution have resulted in over 6% of Americans suffering from some form of opioid abuse (47). Chronic opioid use results in the inhibition of the hypothalamus-pituitary–gonad axis, resulting in hypogonadotropic hypogonadism and hyperprolactinemia.
*EXOGENOUS TESTOSTERONE
Exogenous testosterone is the best-studied form of male contraceptive. Although it does not uniformly induce azoospermia when administered to an average man, exogenous testosterone suppresses the pituitary secretion of LH and FSH. The subsequent decrease in testosterone concentrations within the testicle deprives the fuel for normal spermatogenesis (52).
Unfortunately, several hypogonadal men do not receive appropriate fertility counseling before starting testosterone therapy. Even among American Urological Association members, 25% of urologists reported prescribing testosterone as a male infertility treatment (53). Furthermore, several patients do not realize that up to 20% of legally sold sports nutrition supplements in the United States contain synthetic anabolic–androgenic steroids, which additionally act to suppress the hypothalamus-pituitary–gonad axis (54).
Once exogenous testosterone is discontinued, the timeline to spermatogenesis recovery is uncertain. In a pooled analysis of 30 studies, Liu et al. (55) found the likelihood of regaining a sperm density of R20 million/mL to be 67% at 6 months, 90% at 12 months, and 100% at 24 months. To help patients avoid a ‘‘crash’’ after ceasing testosterone therapy and to promote spermatogenesis recovery, combination therapy of human chorionic gonadotropin 3,000 IU every other day and a selective estrogen receptor modulator, anastrozole, or recombinant FSH has been proposed. Wenker et al (56) reported spermatogenesis recovery at an average of 4.6 months using this regimen, with a mean first sperm density of 22.6 million/mL. Recombinant FSH at 75–150 IU 3 times per week may be added to this regimen should an adequate recovery of spermatogenesis not occur after 6 months of therapy (54, 56).
*There is a new alternative to exogenous testosterone. Natesto (Acerus Biopharma, Mississauga, Canada) is a 4.5% testosterone gel, administered as a 125-mL dose, 3 times per day, via an intranasal pump. With a half-life ranging from 10 to 100 minutes, the testosterone levels return to near baseline in between administrations (57). Short-acting testosterone has been shown to minimally disrupt the pituitary axis and preserve spermatogenesis. In 60 men, only 1 became azoospermic at 3 months of Natesto therapy, and 3 developed severe oligospermia (sperm density < 1 million/mL). With average testosterone levels rising from 231 to 616 ng/dL at 3 months and 652 ng/dL at 6 months, Natesto may strike the Goldilocks compromise between eugonadism and fertility maintenance (58).
In conclusion, male infertility is a complex crossroads of sexual function, sperm production and retrievability, and hormonal control. Although perhaps not central to the patient’s survival, it is a significant component of quality of life and, therefore, cannot be overlooked. The evaluation of the male partner requires communication with other prescribing physicians to consider dose adjustments and medication substitutions, additions, or cancelations. In addition, male infertility specialists should continue to work closely with oncology teams to ensure that patients are provided the opportunity for fertility preservation before spermatotoxic chemoradiation regimens. Finally, more research is needed to treat patients suffering from post finasteride and post-SSRI syndromes.
