madman
Super Moderator
Abstract
Purpose
To review the impact of testosterone and other androgenic-anabolic steroids (AASs) on male fertility, exploring potential drugs that can be used to preserve or restore male fertility upon AAS use or prior contact.
Methods
A review was performed to provide a unifying clinical link between drugs used to preserve or restore male fertility (ie, clomiphene citrate, human chorionic gonadotropin, selective estrogen receptor modulators, recombinant luteinizing and follicle-stimulating hormones, and human menopausal gonadotrophin) in the context of AAS-induced infertility and related aspects.
Findings
Human chorionic gonadotropin (125–500 IU every other day), clomiphene citrate (12.5–50 mg/d), recombinant luteinizing hormone (125–500 IU every other day), recombinant follicle-stimulating hormone (75–150IU 1–3×/wk), and human menopausal gonadotrophin (75–150 IU 1–3×/wk) are promising early pharmacologic approaches to avert AAS-induced male infertility. Additionally, a full partner assessment is crucial to the success of a couple planning to have children. The partner’s age and gynecopathies must be considered. Egg or sperm cryopreservation can also be alternatives for future fertility. Reinforcing AAS cessation is imperative to achieving better success in misusers.
Implications
The exponential increase in AAS misuse raises concerns about the impact on male fertility. This review suggests that gonadotropin analogs and selective androgen receptor modulators (clomiphene citrate) are viable approaches to early preserve or restore fertility in men on AAS use or with previous contact. However, proper standardization of doses and combinations is required and hence physicians should also be aware of patient's and partners’ fertility.
Introduction
Testosterone (T) and its 5-alpha-reduced metabolite, dihydrotestosterone (DHT), are the main androgens and play a crucial role in sexual differentiation, reproductive function, and behavior, acting on sexual and nonsexual organs (eg, brain, heart, bone, muscle mass, among others).1 In 1935, Butenandt and Hanisch, concomitantly with Ruzickaand Wettstein, were the pioneers in isolating androgens from urine and tests, affording the ensuing discussion in the clinical scenario.2,3 Initial androgen indications were created for T replacement therapy (TRT), cachexia, osteosarcopenia, and aplastic anemia thanks to the role of T in enhancing muscle protein synthesis, bone mineral density, and erythropoietic capacity.4–8 Currently, TRT is widely used as a means of improving the overall quality of life (mainly sexual function) in men with hypogonadism.9,10 Interestingly, TRT can exert these benefits without increasing the risk of cardiovascular events, while ameliorating cardiometabolic parameters can be expected.11,12
Despite the benefits of TRT, the abuse of anabolic steroids (AASs), that is, a drug class including not only T but also DHT (oxandrolone and stanozolol) and nandrolone, has been considered an epidemiological health concern.13 AAS misuse increases the risk of polycythemia, dyslipidemia, hypertension, left ventricular hypertrophy, and psychiatric disorders.14–17 Overall, the risk of mortality can be 3 times higher in AAS users (particularly those without medical indications) compared to non-users.18 Equally important, AAS misuse has grown as a major contributor to the high prevalence of infertility in young and middle-aged individuals and hence cannot be underestimated 19–21 AAS-induced infertility is a major concern especially for those planning to have children.22,23 Moreover, many AAS misusers become drug dependent due to fear of coping with unsuccessful T recovery and related side effects, mainly sexual dysfunction and altered body composition in virtue of muscle wasting and increased fat mass.24
Further skepticism is warranted in the management of AAS-induced infertility, especially to avoid the unsubstantiated use of nature-based interventions such as some herbal medicines and dietary supplements in severe cases.25–29 Instead, the focus must be on pharmacologic agents as first-line therapy to recover the hypothalamic–pituitary–testicular(HPT) axis. That said, a critical review to understand the prevalence of AAS-induced infertility and pharmacologic approaches to avert this condition is needed to aid clinical decision-making. Thus, we performed a review in an attempt to provide a more in-depth understanding of the impact of AAS misuse on male fertility, whereby proposals for early pharmacological approaches are further discussed.
*Definition of Male Infertility
*Impaired Sperm Analysis Induced by Supraphysiological Doses of Testosterone
High levels of intratesticular T secreted by Leydig cells are required for spermatogenesis.37 Infertility often occurs during and after AAS misuse due to negative feedback of androgens on the HPT axis,38 where high serum T levels reduce the secretion of gonadotropin release hormone by the hypothalamus and consequently decrease or even completely inhibit the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH).39,40
While serum T levels may be high in the bloodstream on T administration, the accompanied low LH and FSH levels decrease intratesticularT, which is needed for synthesis and maturation of sperm cells.41 In addition to the reduced intratesticular T production, low FSH levels can also reduce the testicular cell's capacity to uptake T, since FSH stimulates the production of androgen-binding protein, a protein responsible for sequestering T in the testis.42 Not surprisingly, only ∼18% of men with a history of AAS misuse have any morphologically normal sperm.41
*Beyond Testosterone: The Impact of Other AASs on Sperm Analysis
In addition to T misuse, other AASs contribute to the burden of impaired sperm parameters. However, there is a lack of RCTs focusing on the impact of particular AASs on sperm analysis other than T. Regardless of being T derivative (eg, methandienone and boldenone), DHT derivative (eg, oxandrolone, oxymetholone, and stanozolol), or 19-nortestosterone (eg, trenbolone and nandrolone), AASs seemingly inhibit the HPT axis proportionally to dose and time of use, causing severe inhibition of LH and FSH and thus impairing sperm parameters.7
Collectively, LH and FSH levels are expected to increase after AAS cessation, but low T levels and impaired sperm analysis can be observed even at 8 to 30 weeks of AAS withdrawal.13,45,56–58 At best, according to many reports, sperm quality tends to spontaneously normalize within 4 to 12 months after cessation of AAS misuse.23,59,60 Furthermore, fertility restoration has been reported even in situations of persistent azoospermia up to 5 years after the AAS cessation, however, the negative effect on sperm quality can persist for long periods in many patients and requires pharmacologic induction of spermatogenesis.13,61
*Illicit AAS Use for Performance in Athletes and Nonathlete Exercisers
The studies described in Table 1, well-designed and controlled long-term studies in athletes and nonathlete exercisers using higher doses of T and combinations with other AASs and performance-enhancing drugs are lacking, as this is unethical due to the plausibility of deleterious effects. At best, personalized pharmacologic approaches in an attempt to avert AAS-induced infertility in athletes of drug-free sports and nonathlete exercisers are proposed below.
Pharmacologic Approaches
Despite the miscellaneous benefits of TRT for men with hypogonadism, guidelines of the European Journal of Endocrinology and Endocrine Society contraindicate TRT for men with hypogonadism who desire fertility.19,21 Not surprisingly, TRT has been studied as a contraceptive method,43,44,72 although it cannot be considered as efficient and safe as condoms and vasectomy.73
Different pharmacologic regimens are described to avert AAS-induced male infertility, for example, selective estrogen receptor modulators (SERMs) such as clomiphene citrate and tamoxifen, human chorionic gonadotropin (hCG), human menopausal gonadotropin (hMG), and even recombinant FSH.39,74 Interestingly, recent studies have suggested the use of hCG during TRT for fertility maintenance.75–77
*SERMs
SERMs are a class of drugs that bind with high affinity to the estrogen-receptor and act as estrogen receptor agonists or antagonists depending on the tissue.78,79
Clomiphene citrate (38% zuclomiphene citrate plus 62% enclomiphene citrate) is the most widely drug used in the fertility field.80 As an estrogen agonistic, clomiphene citrate competes with estradiol(E2) for estrogen receptors in the hypothalamus and blocks the negative feedback of circulating E2 on the HPT axis, thereby increasing LH levels, endogenous T, and spermatogenesis.81,82 The dosing regimen used varies from 12.5 to 50 mg/d, with most studies using 12 to 25 mg/d.83–85 Doses higher than 50 mg/d apparently do not lead to a better response because zuclomiphene agonist effect can blunt the antagonist effect on the estrogen receptor responsible for increasing the positive feedback on the HPT axis.80
The benefits are not indisputable insofar as impaired semen analysis can be presented in some subjects on clomiphene. As reported by a systematic review including 384 sub-fertility men from 11 cohorts, 19%,21%, 17%, and 24% of clomiphene-treated subjects suffered from a decrease in sperm count, concentration, motility, and total motile sperm count, respectively.86 Moreover, after clomiphene discontinuation, deterioration in semen parameters did not recover in up to 17% of subjects.
The side effects of clomiphene seem to be mild and well-tolerated.The most common ones include headaches, dizziness, blurred vision, nausea, vomiting, gynecomastia, weight gain, hypertension, and even a paradoxical decrease in total T levels 86,87
*LH Receptor Agonists: hCG and Recombinant LH
Urinary hCG is obtained by collecting urine from early-stage pregnant women for medical use.88,89 Urine is filtered, concentrated, and purified using techniques such as ion exchange or affinity chromatography to extract the hCG hormone.88,89 hCG acts as an LH analog, with the added benefit of a longer half-life.89 By mimicking LH, hCG acts on Leydig cells by stimulating the production and release of intratesticularT.75,88,90
An RCT of healthy males using 200 mg of intramuscular T enanthate weekly to suppress intratesticular T found that low doses of hCG (125–500 IU every other day) for 3 weeks dose-dependently preserved intratesticular T, while the group using T alone had a 94% reduction intratesticular T production.76 In an observational study of men (n = 29) on TRT, combined hCG therapy (500 IU every other day) for approximately 1 year preserved semen analysis values and 9 patients were able to get their partners pregnant.77
Recombinant LH, a synthetic form of LH produced naturally in the pituitary gland, is another way to bind directly to LH receptors.91 Such a drug is produced using recombinant DNA technology, in which the DNA sequence that encodes the hormone is inserted into culture cells capable of producing large amounts of recombinant LH.91 Recombinant LH is used in fertility treatments to stimulate ovulation in women who do not ovulate normally.91 Recombinant LH is administered by subcutaneous injection and differs from urinary hCG in that it has greater potency in modulating LH receptors.91,92 To date, however, there are no RCTs using recombinant LH rather than urinary hCG to assess intratesticular T levels on TRT.92,93
The most common side effect of subcutaneous hCG and recombinant LH was local swelling at the injection site after injection, mild gynecomastia, acne, headache, restlessness, tiredness, swelling of the ankles and feet, and mood changes.94
*hMG
Human menopausal gonadotropin is a natural derivative of urine with action on LH and FSH receptors.95 The evolution of isolation and filtration methods has afforded a highly purified hMG with greater actions on the FSH receptor, reducing the number of inactive proteins present in less purified hMG.96 The FSH-like effect is important for providing indirect structural and metabolic support for spermatogenesis via FSH receptors on Sertoli cells, regulating structural genes involved in the organization of cell junctions and genes required for the metabolism and transport of regulatory and nutritional substances from Sertoli to germ cells.97,98 In the testes, endothelial FSH receptors mediate the FSH transport across the gonadal endothelial barrier.99,100 FSH also has a regulatory role in Sertoli cell number that is critical for maintaining spermatogenesis.100
Taken together, hMG therapy ranges from 75 to 150 IU once to 3 times a week and is commonly added to the fertility recovery protocol if the response to urinary hCG or recombinant LH alone fails to improve sperm count and quality satisfactorily.43,44,101 In men with AAS-induced infertility, that is, a hypogonadotropic hypogonadism pattern, combined therapy of hCG and hMG (1500–5000 IU for hCG and 75–150 IU for hMG, 3× weekly) for a median of 26 months (range 6–57) allowed 40% of patients (35 of 87) to achieve one or more pregnancies.102
As above-mentioned, studies assessing the effects of hMG in men have combined the therapy with other pharmacologic agents such as hCG. Case reports associate hMG administration with gynecomastia, dizziness, fainting, headache, loss of appetite, and irregular heartbeat.103 However, it is difficult to infer the side effects of a specific medication with the coexistence of other drugs. Correspondingly, hCG administration could be responsible for most of the effects such as gynecomastia, acne, and mood changes due to the rapid rise in T levels and subsequent fluctuations.94,95,103
*Recombinant FSH
Recombinant FSH, also known as follitropin alpha, is an alternative to hMG. The technology is based on the human FSH gene insertion into a host cell and purified from the culture medium, resulting in a highly-pure drug biologically identical to human FSH.104–106 However, its cost can be an obstacle for the patient and hence may be included later in the protocol in the absence of response to hCG and clomiphene.75
Considering its higher biological activity and cost, recombinant FSH administration at 75–150 IU 3 times weekly has become an option when LH agonists fail to improve sperm parameters.101 Research on recombinant FSH also combines treatment with LH analogs, making it challenging to specifically attribute isolated effects.88,102,107 Nevertheless, findings consistently indicate that elevated T levels are a causal factor.108 Recombinant FSH presents a similar profile to hMG, with studies describing mild reactions at the injection site and increases in red blood-cell count, hemoglobin, hematocrit, and creatinine levels.102
*Aromatase Inhibitors
Aromatase inhibitors are a class of drugs used in hormone therapy to treat hormone receptor-positive breast cancer, as well as certain conditions such as endometriosis and infertility.109 The primary function of aromatase inhibitors is to block the activity of aromatase, an enzyme responsible for converting androgens into estrogens, particularly E2.110 Anastrozole, and letrozole are 2 commonly used aromatase inhibitors that reversibly bind to the aromatase active site, thereby inhibiting its function.109
Recent studies have been conducted with letrozole in men with a T/E2 ratio lower than 10 and even with a normal T/E2 ratio, in which aromatase inhibitors appear to assist in the recovery of the HPT axis and improvement of sperm parameters.111–113 The use of letrozole in combination with hCG appears to favor a more significant improvement in semen analysis compared to using both substances individually.111 The proposed mechanism involves enhancing positive feedback and reducing negative feedback caused by the imbalance between T/E2.112,113
Common side effects of aromatase inhibitors may include hot flashes, joint pain, fatigue, and increased susceptibility to osteoporosis and fractures in women due to reduced estrogen levels.109 In males, hypoestrogenism can induce similar effects, particularly joint pain, and sexual dysfunction.114–116 Therefore, the administration of these medications should be exercised with caution to prevent the development of a hypoestrogenic state.114,117
*Proposed Dosing Regimens and Clinical Considerations
Taken together, the proposed pharmacologic regimens discussed here to avert AAS-induced male infertility, along with clinical considerations, are summarized in Figure 1.
*Behavioral Approach
The proposed interventions in the flowchart of Figure 1 consider the main factors associated with the male and couple´s fertility. The initial step toward successful treatment and recovery from AAS misuse must be a behavioral approach. This has been recognized by the guidelines for treating AAS misuse119; however, the way physicians deal with patients in the real-world scenario is far from ideal.119–121
In light of this, motivational interviewing (MI) can be a useful tool for AAS misusers who show signs of infertility awareness. MI is a person-centered strategy originating in the field of addiction that mixes components of cognitive-behavioral therapy and elements that encourage and strengthen the relationship between patient and professional to build trust.122–124 MI is the opposite of vertical care, in which the professional is the authority over the patient.122 This approach keeps the clinician closer to the patient, allowing greater patient motivation for change through reflections on life goals and values.122
*Pharmacologic Regimens
In addition to the behavioral approach, the pharmacologic approach is of crucial importance, and both should be implemented together. Pharmacologic protocols consist of LH analogs such as hCG with or without SERMs even before discontinuing AASs.39,101,102 Collectively, the pharmacologic approach can be useful for future success in achieving couples pregnancy, especially when considering the partner’s age, gynecological status, and the time to recovery of male spermatogenesis, whose severity of the latter depends on patients’ age and time of AAS misuse.125
The use of clomiphene is the starting point for restoring the HPTaxis and fertility in hypogonadotropic hypogonadism, particularly considering cost.126 The usual dose regimen varies from 12.5 to 25 mg/dor every other day.127 Conversely, its effectiveness seems to be limited concerning the duration of use and may even lead to a paradoxical worsening of the semen analysis.86,128 A plateau effect can occur within 3 to 6 months of use128; nevertheless, combining clomiphene citrate with an LH agonist or switching one for the other may overcome this potential desensitization due to the direct binding mechanism of an LH agonist as hCG.129
The dosing regimen of urinary hCG or recombinant LH, both at 125–500 IU every other day, can be prescribed early to improve sperm parameters. These drugs can be combined with clomiphene citrate or alone after screening for sperm analysis during follow-up.76,77
Combining hMG with recombinant FSH, both at 75–150 IU 1 to 3 times a week, is also conceivable in an attempt to enhance spermatogenesis recovery intra-AAS use or after cessation.23,39,75–77,101,102 If cost is not an issue, an early introduction of recombinant FSH may help a faster recovery given its direct effect on FSH receptors, but this strategy is not mandatory.130,131
Aromatase inhibitors can be combined with gonadotrophin analogs and SERMs since the rise in T levels by these drugs can increase E2 levels disproportionally due to negative feedback.132 Aromatase inhibitors may be used when the ratio of T (ng/dL) to E2 (pg/mL) falls above10.39,111,112,133 Anastrozole can reduce E2 levels by approximately70% to 80% at 1 mg per day.110,134,135 Letrozole at 2.5 mg per day can achieve a similar degree of E2 suppression, approximately 80% to 90%.109,110,112 In contrast, it is important to monitor E2 levels when taking aromatase inhibitors, as low E2 levels can cause problems such as sexual dysfunction.116 Lower doses must be considered if compounding medications are available.114,136
*Full Partner Assessment
*Complementary Laboratory Markers
*Cryopreservation
AAS Misuse
Practitioners must exercise empathetic skills in order not to judge AAS misusers, but is it crucial to reinforce AAS misuse as a potential concern that adds to others related to male infertility, as ceasing AAS misuse is a clinical barrier in the long term. The intervention can change the patient’s prognosis especially if it is done early and evaluates the partner’s status, which is often not approached earlier.
Ultimately, beyond fertility, concurrent nonpharmacologic approaches can be adopted to minimize muscle loss after discontinuing AASs, for example, high protein intake (∼1.6–2.2 g/kg/d),153,154 creatine supplementation (∼5 g/d),155 and a proper volume of resistancetraining.156,157
Conclusion
SERMs (clomiphene citrate), hCG, or recombinant LH agonists associated or not with hMG or recombinant FSH may be useful and effective approaches to early avert AAS-induced male infertility. Thus, dosing regimens can be personalized during AAS use or after cessation according to a series of factors beyond the reproductive wish time. Early assessment of partners’ fertility is essential to formulate individualized recommendations and increase success in conceiving in couples when this is a goal. Time is crucial and the partner component of fertility and/or cryopreservation of sperm and eggs must also be considered according to particular situations.
Purpose
To review the impact of testosterone and other androgenic-anabolic steroids (AASs) on male fertility, exploring potential drugs that can be used to preserve or restore male fertility upon AAS use or prior contact.
Methods
A review was performed to provide a unifying clinical link between drugs used to preserve or restore male fertility (ie, clomiphene citrate, human chorionic gonadotropin, selective estrogen receptor modulators, recombinant luteinizing and follicle-stimulating hormones, and human menopausal gonadotrophin) in the context of AAS-induced infertility and related aspects.
Findings
Human chorionic gonadotropin (125–500 IU every other day), clomiphene citrate (12.5–50 mg/d), recombinant luteinizing hormone (125–500 IU every other day), recombinant follicle-stimulating hormone (75–150IU 1–3×/wk), and human menopausal gonadotrophin (75–150 IU 1–3×/wk) are promising early pharmacologic approaches to avert AAS-induced male infertility. Additionally, a full partner assessment is crucial to the success of a couple planning to have children. The partner’s age and gynecopathies must be considered. Egg or sperm cryopreservation can also be alternatives for future fertility. Reinforcing AAS cessation is imperative to achieving better success in misusers.
Implications
The exponential increase in AAS misuse raises concerns about the impact on male fertility. This review suggests that gonadotropin analogs and selective androgen receptor modulators (clomiphene citrate) are viable approaches to early preserve or restore fertility in men on AAS use or with previous contact. However, proper standardization of doses and combinations is required and hence physicians should also be aware of patient's and partners’ fertility.
Introduction
Testosterone (T) and its 5-alpha-reduced metabolite, dihydrotestosterone (DHT), are the main androgens and play a crucial role in sexual differentiation, reproductive function, and behavior, acting on sexual and nonsexual organs (eg, brain, heart, bone, muscle mass, among others).1 In 1935, Butenandt and Hanisch, concomitantly with Ruzickaand Wettstein, were the pioneers in isolating androgens from urine and tests, affording the ensuing discussion in the clinical scenario.2,3 Initial androgen indications were created for T replacement therapy (TRT), cachexia, osteosarcopenia, and aplastic anemia thanks to the role of T in enhancing muscle protein synthesis, bone mineral density, and erythropoietic capacity.4–8 Currently, TRT is widely used as a means of improving the overall quality of life (mainly sexual function) in men with hypogonadism.9,10 Interestingly, TRT can exert these benefits without increasing the risk of cardiovascular events, while ameliorating cardiometabolic parameters can be expected.11,12
Despite the benefits of TRT, the abuse of anabolic steroids (AASs), that is, a drug class including not only T but also DHT (oxandrolone and stanozolol) and nandrolone, has been considered an epidemiological health concern.13 AAS misuse increases the risk of polycythemia, dyslipidemia, hypertension, left ventricular hypertrophy, and psychiatric disorders.14–17 Overall, the risk of mortality can be 3 times higher in AAS users (particularly those without medical indications) compared to non-users.18 Equally important, AAS misuse has grown as a major contributor to the high prevalence of infertility in young and middle-aged individuals and hence cannot be underestimated 19–21 AAS-induced infertility is a major concern especially for those planning to have children.22,23 Moreover, many AAS misusers become drug dependent due to fear of coping with unsuccessful T recovery and related side effects, mainly sexual dysfunction and altered body composition in virtue of muscle wasting and increased fat mass.24
Further skepticism is warranted in the management of AAS-induced infertility, especially to avoid the unsubstantiated use of nature-based interventions such as some herbal medicines and dietary supplements in severe cases.25–29 Instead, the focus must be on pharmacologic agents as first-line therapy to recover the hypothalamic–pituitary–testicular(HPT) axis. That said, a critical review to understand the prevalence of AAS-induced infertility and pharmacologic approaches to avert this condition is needed to aid clinical decision-making. Thus, we performed a review in an attempt to provide a more in-depth understanding of the impact of AAS misuse on male fertility, whereby proposals for early pharmacological approaches are further discussed.
*Definition of Male Infertility
*Impaired Sperm Analysis Induced by Supraphysiological Doses of Testosterone
High levels of intratesticular T secreted by Leydig cells are required for spermatogenesis.37 Infertility often occurs during and after AAS misuse due to negative feedback of androgens on the HPT axis,38 where high serum T levels reduce the secretion of gonadotropin release hormone by the hypothalamus and consequently decrease or even completely inhibit the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH).39,40
While serum T levels may be high in the bloodstream on T administration, the accompanied low LH and FSH levels decrease intratesticularT, which is needed for synthesis and maturation of sperm cells.41 In addition to the reduced intratesticular T production, low FSH levels can also reduce the testicular cell's capacity to uptake T, since FSH stimulates the production of androgen-binding protein, a protein responsible for sequestering T in the testis.42 Not surprisingly, only ∼18% of men with a history of AAS misuse have any morphologically normal sperm.41
*Beyond Testosterone: The Impact of Other AASs on Sperm Analysis
In addition to T misuse, other AASs contribute to the burden of impaired sperm parameters. However, there is a lack of RCTs focusing on the impact of particular AASs on sperm analysis other than T. Regardless of being T derivative (eg, methandienone and boldenone), DHT derivative (eg, oxandrolone, oxymetholone, and stanozolol), or 19-nortestosterone (eg, trenbolone and nandrolone), AASs seemingly inhibit the HPT axis proportionally to dose and time of use, causing severe inhibition of LH and FSH and thus impairing sperm parameters.7
Collectively, LH and FSH levels are expected to increase after AAS cessation, but low T levels and impaired sperm analysis can be observed even at 8 to 30 weeks of AAS withdrawal.13,45,56–58 At best, according to many reports, sperm quality tends to spontaneously normalize within 4 to 12 months after cessation of AAS misuse.23,59,60 Furthermore, fertility restoration has been reported even in situations of persistent azoospermia up to 5 years after the AAS cessation, however, the negative effect on sperm quality can persist for long periods in many patients and requires pharmacologic induction of spermatogenesis.13,61
*Illicit AAS Use for Performance in Athletes and Nonathlete Exercisers
The studies described in Table 1, well-designed and controlled long-term studies in athletes and nonathlete exercisers using higher doses of T and combinations with other AASs and performance-enhancing drugs are lacking, as this is unethical due to the plausibility of deleterious effects. At best, personalized pharmacologic approaches in an attempt to avert AAS-induced infertility in athletes of drug-free sports and nonathlete exercisers are proposed below.
Pharmacologic Approaches
Despite the miscellaneous benefits of TRT for men with hypogonadism, guidelines of the European Journal of Endocrinology and Endocrine Society contraindicate TRT for men with hypogonadism who desire fertility.19,21 Not surprisingly, TRT has been studied as a contraceptive method,43,44,72 although it cannot be considered as efficient and safe as condoms and vasectomy.73
Different pharmacologic regimens are described to avert AAS-induced male infertility, for example, selective estrogen receptor modulators (SERMs) such as clomiphene citrate and tamoxifen, human chorionic gonadotropin (hCG), human menopausal gonadotropin (hMG), and even recombinant FSH.39,74 Interestingly, recent studies have suggested the use of hCG during TRT for fertility maintenance.75–77
*SERMs
SERMs are a class of drugs that bind with high affinity to the estrogen-receptor and act as estrogen receptor agonists or antagonists depending on the tissue.78,79
Clomiphene citrate (38% zuclomiphene citrate plus 62% enclomiphene citrate) is the most widely drug used in the fertility field.80 As an estrogen agonistic, clomiphene citrate competes with estradiol(E2) for estrogen receptors in the hypothalamus and blocks the negative feedback of circulating E2 on the HPT axis, thereby increasing LH levels, endogenous T, and spermatogenesis.81,82 The dosing regimen used varies from 12.5 to 50 mg/d, with most studies using 12 to 25 mg/d.83–85 Doses higher than 50 mg/d apparently do not lead to a better response because zuclomiphene agonist effect can blunt the antagonist effect on the estrogen receptor responsible for increasing the positive feedback on the HPT axis.80
The benefits are not indisputable insofar as impaired semen analysis can be presented in some subjects on clomiphene. As reported by a systematic review including 384 sub-fertility men from 11 cohorts, 19%,21%, 17%, and 24% of clomiphene-treated subjects suffered from a decrease in sperm count, concentration, motility, and total motile sperm count, respectively.86 Moreover, after clomiphene discontinuation, deterioration in semen parameters did not recover in up to 17% of subjects.
The side effects of clomiphene seem to be mild and well-tolerated.The most common ones include headaches, dizziness, blurred vision, nausea, vomiting, gynecomastia, weight gain, hypertension, and even a paradoxical decrease in total T levels 86,87
*LH Receptor Agonists: hCG and Recombinant LH
Urinary hCG is obtained by collecting urine from early-stage pregnant women for medical use.88,89 Urine is filtered, concentrated, and purified using techniques such as ion exchange or affinity chromatography to extract the hCG hormone.88,89 hCG acts as an LH analog, with the added benefit of a longer half-life.89 By mimicking LH, hCG acts on Leydig cells by stimulating the production and release of intratesticularT.75,88,90
An RCT of healthy males using 200 mg of intramuscular T enanthate weekly to suppress intratesticular T found that low doses of hCG (125–500 IU every other day) for 3 weeks dose-dependently preserved intratesticular T, while the group using T alone had a 94% reduction intratesticular T production.76 In an observational study of men (n = 29) on TRT, combined hCG therapy (500 IU every other day) for approximately 1 year preserved semen analysis values and 9 patients were able to get their partners pregnant.77
Recombinant LH, a synthetic form of LH produced naturally in the pituitary gland, is another way to bind directly to LH receptors.91 Such a drug is produced using recombinant DNA technology, in which the DNA sequence that encodes the hormone is inserted into culture cells capable of producing large amounts of recombinant LH.91 Recombinant LH is used in fertility treatments to stimulate ovulation in women who do not ovulate normally.91 Recombinant LH is administered by subcutaneous injection and differs from urinary hCG in that it has greater potency in modulating LH receptors.91,92 To date, however, there are no RCTs using recombinant LH rather than urinary hCG to assess intratesticular T levels on TRT.92,93
The most common side effect of subcutaneous hCG and recombinant LH was local swelling at the injection site after injection, mild gynecomastia, acne, headache, restlessness, tiredness, swelling of the ankles and feet, and mood changes.94
*hMG
Human menopausal gonadotropin is a natural derivative of urine with action on LH and FSH receptors.95 The evolution of isolation and filtration methods has afforded a highly purified hMG with greater actions on the FSH receptor, reducing the number of inactive proteins present in less purified hMG.96 The FSH-like effect is important for providing indirect structural and metabolic support for spermatogenesis via FSH receptors on Sertoli cells, regulating structural genes involved in the organization of cell junctions and genes required for the metabolism and transport of regulatory and nutritional substances from Sertoli to germ cells.97,98 In the testes, endothelial FSH receptors mediate the FSH transport across the gonadal endothelial barrier.99,100 FSH also has a regulatory role in Sertoli cell number that is critical for maintaining spermatogenesis.100
Taken together, hMG therapy ranges from 75 to 150 IU once to 3 times a week and is commonly added to the fertility recovery protocol if the response to urinary hCG or recombinant LH alone fails to improve sperm count and quality satisfactorily.43,44,101 In men with AAS-induced infertility, that is, a hypogonadotropic hypogonadism pattern, combined therapy of hCG and hMG (1500–5000 IU for hCG and 75–150 IU for hMG, 3× weekly) for a median of 26 months (range 6–57) allowed 40% of patients (35 of 87) to achieve one or more pregnancies.102
As above-mentioned, studies assessing the effects of hMG in men have combined the therapy with other pharmacologic agents such as hCG. Case reports associate hMG administration with gynecomastia, dizziness, fainting, headache, loss of appetite, and irregular heartbeat.103 However, it is difficult to infer the side effects of a specific medication with the coexistence of other drugs. Correspondingly, hCG administration could be responsible for most of the effects such as gynecomastia, acne, and mood changes due to the rapid rise in T levels and subsequent fluctuations.94,95,103
*Recombinant FSH
Recombinant FSH, also known as follitropin alpha, is an alternative to hMG. The technology is based on the human FSH gene insertion into a host cell and purified from the culture medium, resulting in a highly-pure drug biologically identical to human FSH.104–106 However, its cost can be an obstacle for the patient and hence may be included later in the protocol in the absence of response to hCG and clomiphene.75
Considering its higher biological activity and cost, recombinant FSH administration at 75–150 IU 3 times weekly has become an option when LH agonists fail to improve sperm parameters.101 Research on recombinant FSH also combines treatment with LH analogs, making it challenging to specifically attribute isolated effects.88,102,107 Nevertheless, findings consistently indicate that elevated T levels are a causal factor.108 Recombinant FSH presents a similar profile to hMG, with studies describing mild reactions at the injection site and increases in red blood-cell count, hemoglobin, hematocrit, and creatinine levels.102
*Aromatase Inhibitors
Aromatase inhibitors are a class of drugs used in hormone therapy to treat hormone receptor-positive breast cancer, as well as certain conditions such as endometriosis and infertility.109 The primary function of aromatase inhibitors is to block the activity of aromatase, an enzyme responsible for converting androgens into estrogens, particularly E2.110 Anastrozole, and letrozole are 2 commonly used aromatase inhibitors that reversibly bind to the aromatase active site, thereby inhibiting its function.109
Recent studies have been conducted with letrozole in men with a T/E2 ratio lower than 10 and even with a normal T/E2 ratio, in which aromatase inhibitors appear to assist in the recovery of the HPT axis and improvement of sperm parameters.111–113 The use of letrozole in combination with hCG appears to favor a more significant improvement in semen analysis compared to using both substances individually.111 The proposed mechanism involves enhancing positive feedback and reducing negative feedback caused by the imbalance between T/E2.112,113
Common side effects of aromatase inhibitors may include hot flashes, joint pain, fatigue, and increased susceptibility to osteoporosis and fractures in women due to reduced estrogen levels.109 In males, hypoestrogenism can induce similar effects, particularly joint pain, and sexual dysfunction.114–116 Therefore, the administration of these medications should be exercised with caution to prevent the development of a hypoestrogenic state.114,117
*Proposed Dosing Regimens and Clinical Considerations
Taken together, the proposed pharmacologic regimens discussed here to avert AAS-induced male infertility, along with clinical considerations, are summarized in Figure 1.
*Behavioral Approach
The proposed interventions in the flowchart of Figure 1 consider the main factors associated with the male and couple´s fertility. The initial step toward successful treatment and recovery from AAS misuse must be a behavioral approach. This has been recognized by the guidelines for treating AAS misuse119; however, the way physicians deal with patients in the real-world scenario is far from ideal.119–121
In light of this, motivational interviewing (MI) can be a useful tool for AAS misusers who show signs of infertility awareness. MI is a person-centered strategy originating in the field of addiction that mixes components of cognitive-behavioral therapy and elements that encourage and strengthen the relationship between patient and professional to build trust.122–124 MI is the opposite of vertical care, in which the professional is the authority over the patient.122 This approach keeps the clinician closer to the patient, allowing greater patient motivation for change through reflections on life goals and values.122
*Pharmacologic Regimens
In addition to the behavioral approach, the pharmacologic approach is of crucial importance, and both should be implemented together. Pharmacologic protocols consist of LH analogs such as hCG with or without SERMs even before discontinuing AASs.39,101,102 Collectively, the pharmacologic approach can be useful for future success in achieving couples pregnancy, especially when considering the partner’s age, gynecological status, and the time to recovery of male spermatogenesis, whose severity of the latter depends on patients’ age and time of AAS misuse.125
The use of clomiphene is the starting point for restoring the HPTaxis and fertility in hypogonadotropic hypogonadism, particularly considering cost.126 The usual dose regimen varies from 12.5 to 25 mg/dor every other day.127 Conversely, its effectiveness seems to be limited concerning the duration of use and may even lead to a paradoxical worsening of the semen analysis.86,128 A plateau effect can occur within 3 to 6 months of use128; nevertheless, combining clomiphene citrate with an LH agonist or switching one for the other may overcome this potential desensitization due to the direct binding mechanism of an LH agonist as hCG.129
The dosing regimen of urinary hCG or recombinant LH, both at 125–500 IU every other day, can be prescribed early to improve sperm parameters. These drugs can be combined with clomiphene citrate or alone after screening for sperm analysis during follow-up.76,77
Combining hMG with recombinant FSH, both at 75–150 IU 1 to 3 times a week, is also conceivable in an attempt to enhance spermatogenesis recovery intra-AAS use or after cessation.23,39,75–77,101,102 If cost is not an issue, an early introduction of recombinant FSH may help a faster recovery given its direct effect on FSH receptors, but this strategy is not mandatory.130,131
Aromatase inhibitors can be combined with gonadotrophin analogs and SERMs since the rise in T levels by these drugs can increase E2 levels disproportionally due to negative feedback.132 Aromatase inhibitors may be used when the ratio of T (ng/dL) to E2 (pg/mL) falls above10.39,111,112,133 Anastrozole can reduce E2 levels by approximately70% to 80% at 1 mg per day.110,134,135 Letrozole at 2.5 mg per day can achieve a similar degree of E2 suppression, approximately 80% to 90%.109,110,112 In contrast, it is important to monitor E2 levels when taking aromatase inhibitors, as low E2 levels can cause problems such as sexual dysfunction.116 Lower doses must be considered if compounding medications are available.114,136
*Full Partner Assessment
*Complementary Laboratory Markers
*Cryopreservation
AAS Misuse
Practitioners must exercise empathetic skills in order not to judge AAS misusers, but is it crucial to reinforce AAS misuse as a potential concern that adds to others related to male infertility, as ceasing AAS misuse is a clinical barrier in the long term. The intervention can change the patient’s prognosis especially if it is done early and evaluates the partner’s status, which is often not approached earlier.
Ultimately, beyond fertility, concurrent nonpharmacologic approaches can be adopted to minimize muscle loss after discontinuing AASs, for example, high protein intake (∼1.6–2.2 g/kg/d),153,154 creatine supplementation (∼5 g/d),155 and a proper volume of resistancetraining.156,157
Conclusion
SERMs (clomiphene citrate), hCG, or recombinant LH agonists associated or not with hMG or recombinant FSH may be useful and effective approaches to early avert AAS-induced male infertility. Thus, dosing regimens can be personalized during AAS use or after cessation according to a series of factors beyond the reproductive wish time. Early assessment of partners’ fertility is essential to formulate individualized recommendations and increase success in conceiving in couples when this is a goal. Time is crucial and the partner component of fertility and/or cryopreservation of sperm and eggs must also be considered according to particular situations.
