madman
Super Moderator
Novel androgen therapies including selective androgen receptor modulators (2022)
Jungwoo Kang, Foundation Year 1 Doctor, Runzhi Chen, Medical student, Tharu Tharakan, Urology Registrar, Suks Minhas, Professor of Urology
Male hypogonadism is associated with reduced quality of life and the development of co-morbidities including obesity, diabetes mellitus, and dyslipidemia. The mainstay of treatment for male hypogonadism is testosterone replacement therapy (TRT). However, TRT has recognized side effects including impaired spermatogenesis and there are concerns regarding its use in men with concurrent cardiovascular disease. Thus, there has been an impetus to develop novel androgen therapies for treating male hypogonadism to mitigate the side effects of TRT. This review will discuss the benefits and adverse effects of TRT, and novel therapies including nasal testosterone, aromatase inhibitors, selective estrogen receptor modulators, and selective androgen receptor modulators.
Introduction
Male hypogonadism is a clinical syndrome resulting from hypoandrogenism, defined as testosterone deficiency. As such, the diagnosis of hypogonadism is based on the presence of both biochemical and clinical evidence of androgen deficiency. There are several definitions of hypogonadism in contemporary guidelines. The European Association of Urology (EAU) defines male hypogonadism as biochemical evidence of a consistently low testosterone level below 12 nmol/L measured on two separate occasions [1]. The Endocrine Society guidelines define low testosterone as a fasting morning serum testosterone value of less than 264 ng/dL (9.2 nmol/L) for non-obese, healthy young males [1,2].
With regards to the clinical sequelae of hypogonadism, there is a significant difference in symptomatology depending on the age of onset. Hypogonadism in the pubescent population may result in the absence of secondary sexual characteristics, leading to small testes, cryptorchidism, and sparse body/facial hair [1]. Androgen deficiency in older men is typically associated with decreased libido, erectile dysfunction, and systemic symptoms such as bone demineralization, cognitive dysfunction, and mood disturbance [1]. The prevalence of male hypogonadism has been reported to be between 2.1% and 12.8% in the European male population [3].
Hypogonadism can be classified into primary or secondary hypogonadism. Primary hypogonadism results from defects at the testicular level resulting in low testosterone and high gonadotropin levels. Secondary hypogonadism is caused by dysfunction in the pituitary or hypothalamic axis, resulting in low testosterone and gonadotrophin levels. There can also be a mixed presentation of primary and secondary hypogonadism, where the biochemical picture may change depending on which type of hypogonadism predominates [2]. Hypogonadism can be further classified by its etiology. Organic hypogonadism refers to dysfunction in the organs of the HPG axis due to a congenital defect or acquired damage. On the other hand, functional hypogonadism is the result of conditions that suppress gonadotrophin and testosterone production, which may be reversible on the resolution of the underlying cause. The classification and causes of hypogonadism are summarised in Table 1.
Within functional hypogonadism, there is an emerging concept of late-onset hypogonadism which is an age-dependent reduction in testosterone levels associated with comorbidities including metabolic syndrome (hypertension, dyslipidemia, diabetes mellitus, and obesity) [4]. This concept is supported by the Massachusetts Male Aging Study, a longitudinal study of 1709 males aged 40-69 years of age, which demonstrated that median testosterone levels were higher throughout the day in healthy men compared to men with metabolic syndrome. Further, the study suggests that age has a significant impact on hypogonadism, with prevalence increasing from 6.0% at baseline to 12.3% at follow-up (mean follow-up duration of 8.8 years), and incidence of hypogonadism significantly increasing with age [5]. Similarly, the European Male Aging Study (EMAS), a large multi-center cross-sectional study of 3219 men, reports that obesity (defined as body mass index 30 kg/m2 or waist circumference 102 cm) had the most substantial reductive effect on mean free testosterone levels [6]. It has been purported that obesity and metabolic syndrome may induce secondary hypogonadism through hypothalamic dysfunction of gonadotrophin-releasing hormone (GnRH) [8]. Hypothalamic dysfunction has been linked to excess adipose tissue-associated leptin resistance, insulin resistance, and increased aromatase activity resulting in increased conversion of testosterone into estradiol [9]. The exact mechanisms by which hypothalamic dysfunction occurs, however, require further elucidation.
As discussed above, there is emerging evidence that testosterone deficiency may contribute to the development of metabolic syndrome and other comorbidities. Murine studies have demonstrated that testosterone replacement in androgen-deficient mice prevented arterial fatty-streak formation and increased high-density lipoprotein (HDL) cholesterol levels [10]. Similarly, testosterone replacement in castrated rabbits led to reduced serum lipid and atherogenic lipoprotein levels and reduced aortic atherosclerosis [11]. A systematic review examining the systemic sequelae of androgen deprivation therapy in prostate cancer patients reported a greater risk of diabetes (hazard ratio (HR) 1.44, p < 0.001), coronary heart disease (HR 1.16, p < 0.001), myocardial infarction (HR 1.11, p ¼ 0.03), and sudden death (HR 1.16, p ¼ 0.04) when compared to conservative management or age-matched controls [12]. As such, it is thought that low testosterone levels are both a significant risk factor for metabolic syndrome and cardiovascular disease and may even be a biochemical marker for these conditions [13,14].
Although the exact mechanisms behind the protective role of testosterone remain unclear, it is postulated that testosterone may also mediate anti-inflammatory pathways. A prospective study of thirteen type 2 diabetic men with partial androgen deficiency reported a significant reduction in the expression of interleukin (IL)-1b, IL-6, and tumor necrosis factor (TNF)-a by leukocytes following therapeutic testosterone replacement therapy (p < 0.01) [15]. Testosterone therapy was also observed to increase serum IL-10 (anti-atherogenic) and reduce serum TNF-a and IL-1b in cohorts of hypogonadal males with cardiovascular disease [16,17]. Serum testosterone levels were also seen to have an inverse relationship to IL-1b in patients with coronary heart disease (p = 0.008) [18]. Thus, a reduction in testosterone levels may decrease systemic anti-inflammatory mechanisms and result in increased susceptibility to metabolic conditions with an inflammatory component, such as atherosclerosis and diabetes [13]. The anabolic effects of testosterone in developing muscle mass and reducing visceral fat may also mitigate cardiovascular risk and prevent insulin resistance [19]. Further research is needed to elucidate the biochemical and cellular mechanisms by which testosterone may reduce the risk of cardiovascular disease, metabolic syndrome, and diabetes mellitus.
*Testosterone replacement therapy: benefits, side effects, and contraindications
*Novel therapies for hypogonadism
There are two areas of clinical focus within the current literature on novel therapies for hypogonadism: novel forms of TRT delivery, such as nasal preparations, and non-TRT therapies, which include aromatase inhibitors, SERMs, and SARMs.
-Nasal testosterone
Nasal gel formulations of testosterone (TNG) were approved by the US Food and Drug Administration (FDA) for TRT in 2014. Natesto is a metered-dose pump applicator delivering 5.5 mg of testosterone per pump, with the recommended dosage of one pump per nostril repeated 2e3 times per day [41]. An advantage of nasal delivery of testosterone is that this formulation bypasses first-pass metabolism, enabling high bioavailability and the maximum concentration is achieved within 1h[48]. This transient rise and fall in testosterone, with post-dose testosterone levels rapidly returning to baseline, theoretically enables minimal disruption of the HPG axis and thus preservation of spermatogenesis whilst enabling appropriate testosterone replacement [49].
*These studies suggest that nasal TRT delivery may be an effective treatment for hypogonadism without causing significant systemic side effects. Post-trial surveys also suggest that nasal preparations of TRT are well-tolerated, with 68e74% of individuals in the phase III study and 67.2% in the MY-T trial preferring TNG over previous TRT regimens [48,53]. Notably, unlike other preparations of TRT, there is evidence that nasal TRT has a limited effect on the HPG axis and on hematocrit. In support of the latter, a retrospective cross-sectional analysis of 60 patients receiving either nasal or intramuscular TRT demonstrated intramuscular TRT increased hematocrit by 3.24% whilst no changes were observed in the TNG group [54].
*However, there are no RCTs comparing the benefits and adverse effects of TNG compared to established TRT regimens or placebo and thus trial results must be interpreted with caution. The long-term tolerability of TNG needs to be investigated as chronic nasal irritation and inflammation could lead to changes affecting TNG delivery through the nasal mucosa and also may be considered unacceptable to patients. Further, there is a paucity of longitudinal prospective data on the effect of TNG on spermatogenesis, hematocrit, bone density, lean body mass, and cardiovascular outcomes, especially in comparison to traditional TRT regimens. These parameters need to be fully assessed because TNG was observed to be associated with dyslipidaemic changes in the original phase III trial [48].
-Aromatase inhibitors
Aromatase inhibitors (AIs) inhibit the aromatase enzyme, responsible for converting testosterone to oestradiol, located within cells in adipose tissue, bone, brain, and other tissues [41]. Subsequently, there is a reduction in circulating oestradiol which attenuates the negative feedback effect on the hypothalamus and pituitary, leading to increased gonadotrophin release and a subsequent increase in testosterone production (Fig. 2). Examples of aromatase inhibitors include anastrozole and letrozole.
*The above literature suggests that AIs have the potential to increase testosterone levels and may improve semen parameters, although evidence on the spermatogenic effects of AI is overall lacking
*The ability to of AIs to maintain testosterone levels at levels similar to TRT, whilst maintaining and potentially augmenting HPG function and having limited systemic effects (e.g., on hematocrit), make AIs an attractive alternative option to TRT. However, there is a paucity of high-level evidence to support the use of AIs in improving hypogonadal symptoms such as libido, erectile dysfunction, fatigue, and mood disturbances. Moreover, further research is necessary to clearly elucidate the adverse effect profile of AIs, including long-term effects including lipid profile and BMD.
-Selective estrogen receptor modulators
Selective estrogen receptor modulators (SERMs), such as clomiphene, act as antagonists or agonists to the estrogen receptor, depending on its location. SERMs cause increased FSH and LH levels through disinhibition of the negative feedback loop of the HPG axis. SERMs tend to act as oestrogenic agonists in the bone and liver which enables them to preserve critical oestrogenic functions including bone health (Fig. 3) [67]. Since increased levels of gonadotrophins may promote testosterone production and spermatogenesis in individuals, SERMs have been investigated as a potential alternative to TRT for the treatment of male hypogonadism [67].
*As such, the current literature suggests that SERMs may be beneficial in treating hypogonadal men whilst preserving fertility. Moreover, there is data suggesting that SERMs do not adversely affect body composition and lipid profiles. The reported side effect profile of SERMs is minimal, with most adverse events (such as headache, nausea, vomiting, and gynaecomastia) being mild and dose-related [72]. The current evidence regarding clomiphene and enclomiphene is summarised in Table 3. Further RCTs with greater follow-up durations of over 12 months are needed to clarify the long-term clinical benefits for hypogonadal symptoms, fertility parameters, and safety profile. Future studies should also aim to elucidate which clinical and demographic factors may influence the treatment response of SERMs.
-Selective androgen receptor modulators
Selective androgen receptor modulators (SARMs) are a class of drugs that have been studied for over 20 years. To date, none have received approval from the FDA or the European Medicines Agency (EMA) for any therapeutic investigation. Like SERMs, they have variable actions as an agonist or antagonist in different tissues [36]. Whilst the exact mechanism of how SARMs achieve tissue specificity in full and partial agonism is unclear, it is postulated that SARMs have specific interactions with androgen receptors rather than selective distribution into certain tissues [73]. Hikichi et al. reported that even though the experimental SARM (TSAA-291) is bound to the same tissues and androgen receptors as dihydrotestosterone, it had reduced effects in the prostate tissue due to modulation by distinct cofactor recruitment to the androgen receptor which resulted in a different downstream cellular effect [74]. As such, SARMs may theoretically treat the physical symptoms associated with hypogonadism, such as decreased BMD and lean muscle mass, with a reduced side effect profile on increased PSA levels or LUTS [75]. For example, Enobosarm, the most well-studied SARM in humans to date, is thought to act as an agonist in the muscles, bones, and adipose tissue, whilst having limited effects on other androgen-responsive tissues such as the prostate and the seminal vesicles [76,77]. The chemical structures of SARMs undergoing human studies are annotated and compared to testosterone in Fig. 4
*Unfortunately, at present there are no studies that examine the efficacy of using SARMs in the context of hypogonadism in humans. This may be due to various factors, including difficulty in defining endpoints for objective evaluation of hypogonadism, safety concerns, and failure of SARMs to progress to clinical trial phases. Firstly, SARMs are more difficult to study in the context of hypogonadism, as serum testosterone measurements cannot be used as a biochemical marker of response. Within this context, there is currently no consensus on what constitutes biochemical markers of successful hypogonadism treatment [81]. Secondly, developing a SARM that does not increase prostate volume and hematocrit and reduce levels of HDL cholesterol has been challenging, all of which may have contributed to the limited investigation in hypogonadal males [82]. Finally, SARMs at present, including enobosarm, have not been able to demonstrate significant benefits in phase II or III trials, suggesting further work needs to be completed in the preclinical stages. Nonetheless, there are promising SARMs that may be suitable for further research, such as LY305, which has been demonstrated to result in no changes in hematocrit or HDL levels in phase I trials and is suggested to have significant anabolic action in the muscles and skeletal tissue whilst maintaining a weak agonist activity in androgenic tissues [82]. Ideally, research should be focused on the discovery of a SARM with isolated androgenic or anabolic effects, which could provide significant symptomatic benefit in not only hypogonadal men but also in cachectic patients where the anabolic effect would be significantly beneficial for muscle maintenance and growth.
Limitations of current evidence and future work
Whilst there is emerging evidence for the utility and need for novel androgen therapies for treating male hypogonadism, there is a need for high-level evidence for their use in the treatment of men with hypogonadism. With regards to SARMs, there are no studies that have investigated the effects of SARMs in hypogonadal men. More work is needed to elucidate the role of SARMs in treating male hypogonadism, in prospective clinical trials with a focus on symptomatic improvements including sexual dysfunction. The challenge here as with all studies of androgen therapies is defining specific endpoints and developing disease-specific PROMs (Patient-Reported Outcome Measures). However, it is likely that further research at pharmacological and preclinical levels is necessary to find a suitable SARM candidate for hypogonadism.
Other formulations of testosterone, such as TNG, may provide a suitable alternative for patients where traditional preparations of TRT are unsuitable. However, long-term studies investigating the tolerability of TNG due to the potential side effects of nasal irritation and inflammation with chronic use are needed. Such studies should also focus on determining the suitability of these novel therapies as an alternative in populations in which traditional TRT is contraindicated, for example in men with cardiovascular disease or raised hematocrit levels. This is especially pertinent given the reported dyslipidaemic changes associated with TNG in phase III trials, which may suggest that TNG is unsuitable for men with pre-existing cardiovascular conditions [48]. In men with active or treated prostate cancer, TNG may be a suitable alternative to systemic therapies and future work should monitor PSA changes with TNG administration. With regards to SERMs and AIs, further RCTs comparing SERMs to TRT are needed to elucidate the differences in symptomatic improvement, systemic effects, and safety profile. Overall, large-scale, prospective, randomized clinical trials which directly compare novel androgen therapies to traditional TRT are needed.
Furthermore, a critical limitation of the current evidence is the relatively short study durations. For example, most studies only report on a study period of 6 months. For instance, in studies investigating the effect of aromatase inhibitors, there was limited evidence for improving symptoms of hypogonadism. This may have been due to short follow-up durations, which may have limited the clinical outcomes for endocrinological changes. Long-term studies are also important for determining side effects, such as bone mineral density loss, and examining effects on morbidity and mortality, especially on cardiovascular events, diabetes, and androgen-driven cancer risk (e.g. prostate cancer). Considering that an increased prevalence of diabetes and cardiovascular events are seen in hypogonadism, and TRT has been shown to improve diabetic outcomes and reduce cardiovascular risk in hypogonadal males, novel non-testosterone treatments should ideally show similar benefits [12,22].
Summary
There is a need to treat male hypogonadism whilst avoiding the negative impact of TRT on spermatogenesis, hematocrit, and hepatic function, among others. There is data showing that nasal testosterone preparations may be a suitable alternative but further evidence is required to establish the optimal dosing regimen and the side effects profile. There are several randomized controlled trials investigating the use of AIs and SERMs in the context of hypogonadism and male infertility, but long-term effects on bone mineral density, cardiovascular risk, and prostate cancer risk remain unclear. There is a paucity of data for SARMs in male hypogonadism. Thus, whilst there are several potential novel treatments for male hypogonadism, a stronger evidence base is needed to support such treatments in clinical practice, especially due to lacking evidence in the form of longitudinal studies. The therapeutic potential, benefits, and negatives of each novel therapy for hypogonadism are summarised in Table 4.
Jungwoo Kang, Foundation Year 1 Doctor, Runzhi Chen, Medical student, Tharu Tharakan, Urology Registrar, Suks Minhas, Professor of Urology
Male hypogonadism is associated with reduced quality of life and the development of co-morbidities including obesity, diabetes mellitus, and dyslipidemia. The mainstay of treatment for male hypogonadism is testosterone replacement therapy (TRT). However, TRT has recognized side effects including impaired spermatogenesis and there are concerns regarding its use in men with concurrent cardiovascular disease. Thus, there has been an impetus to develop novel androgen therapies for treating male hypogonadism to mitigate the side effects of TRT. This review will discuss the benefits and adverse effects of TRT, and novel therapies including nasal testosterone, aromatase inhibitors, selective estrogen receptor modulators, and selective androgen receptor modulators.
Introduction
Male hypogonadism is a clinical syndrome resulting from hypoandrogenism, defined as testosterone deficiency. As such, the diagnosis of hypogonadism is based on the presence of both biochemical and clinical evidence of androgen deficiency. There are several definitions of hypogonadism in contemporary guidelines. The European Association of Urology (EAU) defines male hypogonadism as biochemical evidence of a consistently low testosterone level below 12 nmol/L measured on two separate occasions [1]. The Endocrine Society guidelines define low testosterone as a fasting morning serum testosterone value of less than 264 ng/dL (9.2 nmol/L) for non-obese, healthy young males [1,2].
With regards to the clinical sequelae of hypogonadism, there is a significant difference in symptomatology depending on the age of onset. Hypogonadism in the pubescent population may result in the absence of secondary sexual characteristics, leading to small testes, cryptorchidism, and sparse body/facial hair [1]. Androgen deficiency in older men is typically associated with decreased libido, erectile dysfunction, and systemic symptoms such as bone demineralization, cognitive dysfunction, and mood disturbance [1]. The prevalence of male hypogonadism has been reported to be between 2.1% and 12.8% in the European male population [3].
Hypogonadism can be classified into primary or secondary hypogonadism. Primary hypogonadism results from defects at the testicular level resulting in low testosterone and high gonadotropin levels. Secondary hypogonadism is caused by dysfunction in the pituitary or hypothalamic axis, resulting in low testosterone and gonadotrophin levels. There can also be a mixed presentation of primary and secondary hypogonadism, where the biochemical picture may change depending on which type of hypogonadism predominates [2]. Hypogonadism can be further classified by its etiology. Organic hypogonadism refers to dysfunction in the organs of the HPG axis due to a congenital defect or acquired damage. On the other hand, functional hypogonadism is the result of conditions that suppress gonadotrophin and testosterone production, which may be reversible on the resolution of the underlying cause. The classification and causes of hypogonadism are summarised in Table 1.
Within functional hypogonadism, there is an emerging concept of late-onset hypogonadism which is an age-dependent reduction in testosterone levels associated with comorbidities including metabolic syndrome (hypertension, dyslipidemia, diabetes mellitus, and obesity) [4]. This concept is supported by the Massachusetts Male Aging Study, a longitudinal study of 1709 males aged 40-69 years of age, which demonstrated that median testosterone levels were higher throughout the day in healthy men compared to men with metabolic syndrome. Further, the study suggests that age has a significant impact on hypogonadism, with prevalence increasing from 6.0% at baseline to 12.3% at follow-up (mean follow-up duration of 8.8 years), and incidence of hypogonadism significantly increasing with age [5]. Similarly, the European Male Aging Study (EMAS), a large multi-center cross-sectional study of 3219 men, reports that obesity (defined as body mass index 30 kg/m2 or waist circumference 102 cm) had the most substantial reductive effect on mean free testosterone levels [6]. It has been purported that obesity and metabolic syndrome may induce secondary hypogonadism through hypothalamic dysfunction of gonadotrophin-releasing hormone (GnRH) [8]. Hypothalamic dysfunction has been linked to excess adipose tissue-associated leptin resistance, insulin resistance, and increased aromatase activity resulting in increased conversion of testosterone into estradiol [9]. The exact mechanisms by which hypothalamic dysfunction occurs, however, require further elucidation.
As discussed above, there is emerging evidence that testosterone deficiency may contribute to the development of metabolic syndrome and other comorbidities. Murine studies have demonstrated that testosterone replacement in androgen-deficient mice prevented arterial fatty-streak formation and increased high-density lipoprotein (HDL) cholesterol levels [10]. Similarly, testosterone replacement in castrated rabbits led to reduced serum lipid and atherogenic lipoprotein levels and reduced aortic atherosclerosis [11]. A systematic review examining the systemic sequelae of androgen deprivation therapy in prostate cancer patients reported a greater risk of diabetes (hazard ratio (HR) 1.44, p < 0.001), coronary heart disease (HR 1.16, p < 0.001), myocardial infarction (HR 1.11, p ¼ 0.03), and sudden death (HR 1.16, p ¼ 0.04) when compared to conservative management or age-matched controls [12]. As such, it is thought that low testosterone levels are both a significant risk factor for metabolic syndrome and cardiovascular disease and may even be a biochemical marker for these conditions [13,14].
Although the exact mechanisms behind the protective role of testosterone remain unclear, it is postulated that testosterone may also mediate anti-inflammatory pathways. A prospective study of thirteen type 2 diabetic men with partial androgen deficiency reported a significant reduction in the expression of interleukin (IL)-1b, IL-6, and tumor necrosis factor (TNF)-a by leukocytes following therapeutic testosterone replacement therapy (p < 0.01) [15]. Testosterone therapy was also observed to increase serum IL-10 (anti-atherogenic) and reduce serum TNF-a and IL-1b in cohorts of hypogonadal males with cardiovascular disease [16,17]. Serum testosterone levels were also seen to have an inverse relationship to IL-1b in patients with coronary heart disease (p = 0.008) [18]. Thus, a reduction in testosterone levels may decrease systemic anti-inflammatory mechanisms and result in increased susceptibility to metabolic conditions with an inflammatory component, such as atherosclerosis and diabetes [13]. The anabolic effects of testosterone in developing muscle mass and reducing visceral fat may also mitigate cardiovascular risk and prevent insulin resistance [19]. Further research is needed to elucidate the biochemical and cellular mechanisms by which testosterone may reduce the risk of cardiovascular disease, metabolic syndrome, and diabetes mellitus.
*Testosterone replacement therapy: benefits, side effects, and contraindications
*Novel therapies for hypogonadism
There are two areas of clinical focus within the current literature on novel therapies for hypogonadism: novel forms of TRT delivery, such as nasal preparations, and non-TRT therapies, which include aromatase inhibitors, SERMs, and SARMs.
-Nasal testosterone
Nasal gel formulations of testosterone (TNG) were approved by the US Food and Drug Administration (FDA) for TRT in 2014. Natesto is a metered-dose pump applicator delivering 5.5 mg of testosterone per pump, with the recommended dosage of one pump per nostril repeated 2e3 times per day [41]. An advantage of nasal delivery of testosterone is that this formulation bypasses first-pass metabolism, enabling high bioavailability and the maximum concentration is achieved within 1h[48]. This transient rise and fall in testosterone, with post-dose testosterone levels rapidly returning to baseline, theoretically enables minimal disruption of the HPG axis and thus preservation of spermatogenesis whilst enabling appropriate testosterone replacement [49].
*These studies suggest that nasal TRT delivery may be an effective treatment for hypogonadism without causing significant systemic side effects. Post-trial surveys also suggest that nasal preparations of TRT are well-tolerated, with 68e74% of individuals in the phase III study and 67.2% in the MY-T trial preferring TNG over previous TRT regimens [48,53]. Notably, unlike other preparations of TRT, there is evidence that nasal TRT has a limited effect on the HPG axis and on hematocrit. In support of the latter, a retrospective cross-sectional analysis of 60 patients receiving either nasal or intramuscular TRT demonstrated intramuscular TRT increased hematocrit by 3.24% whilst no changes were observed in the TNG group [54].
*However, there are no RCTs comparing the benefits and adverse effects of TNG compared to established TRT regimens or placebo and thus trial results must be interpreted with caution. The long-term tolerability of TNG needs to be investigated as chronic nasal irritation and inflammation could lead to changes affecting TNG delivery through the nasal mucosa and also may be considered unacceptable to patients. Further, there is a paucity of longitudinal prospective data on the effect of TNG on spermatogenesis, hematocrit, bone density, lean body mass, and cardiovascular outcomes, especially in comparison to traditional TRT regimens. These parameters need to be fully assessed because TNG was observed to be associated with dyslipidaemic changes in the original phase III trial [48].
-Aromatase inhibitors
Aromatase inhibitors (AIs) inhibit the aromatase enzyme, responsible for converting testosterone to oestradiol, located within cells in adipose tissue, bone, brain, and other tissues [41]. Subsequently, there is a reduction in circulating oestradiol which attenuates the negative feedback effect on the hypothalamus and pituitary, leading to increased gonadotrophin release and a subsequent increase in testosterone production (Fig. 2). Examples of aromatase inhibitors include anastrozole and letrozole.
*The above literature suggests that AIs have the potential to increase testosterone levels and may improve semen parameters, although evidence on the spermatogenic effects of AI is overall lacking
*The ability to of AIs to maintain testosterone levels at levels similar to TRT, whilst maintaining and potentially augmenting HPG function and having limited systemic effects (e.g., on hematocrit), make AIs an attractive alternative option to TRT. However, there is a paucity of high-level evidence to support the use of AIs in improving hypogonadal symptoms such as libido, erectile dysfunction, fatigue, and mood disturbances. Moreover, further research is necessary to clearly elucidate the adverse effect profile of AIs, including long-term effects including lipid profile and BMD.
-Selective estrogen receptor modulators
Selective estrogen receptor modulators (SERMs), such as clomiphene, act as antagonists or agonists to the estrogen receptor, depending on its location. SERMs cause increased FSH and LH levels through disinhibition of the negative feedback loop of the HPG axis. SERMs tend to act as oestrogenic agonists in the bone and liver which enables them to preserve critical oestrogenic functions including bone health (Fig. 3) [67]. Since increased levels of gonadotrophins may promote testosterone production and spermatogenesis in individuals, SERMs have been investigated as a potential alternative to TRT for the treatment of male hypogonadism [67].
*As such, the current literature suggests that SERMs may be beneficial in treating hypogonadal men whilst preserving fertility. Moreover, there is data suggesting that SERMs do not adversely affect body composition and lipid profiles. The reported side effect profile of SERMs is minimal, with most adverse events (such as headache, nausea, vomiting, and gynaecomastia) being mild and dose-related [72]. The current evidence regarding clomiphene and enclomiphene is summarised in Table 3. Further RCTs with greater follow-up durations of over 12 months are needed to clarify the long-term clinical benefits for hypogonadal symptoms, fertility parameters, and safety profile. Future studies should also aim to elucidate which clinical and demographic factors may influence the treatment response of SERMs.
-Selective androgen receptor modulators
Selective androgen receptor modulators (SARMs) are a class of drugs that have been studied for over 20 years. To date, none have received approval from the FDA or the European Medicines Agency (EMA) for any therapeutic investigation. Like SERMs, they have variable actions as an agonist or antagonist in different tissues [36]. Whilst the exact mechanism of how SARMs achieve tissue specificity in full and partial agonism is unclear, it is postulated that SARMs have specific interactions with androgen receptors rather than selective distribution into certain tissues [73]. Hikichi et al. reported that even though the experimental SARM (TSAA-291) is bound to the same tissues and androgen receptors as dihydrotestosterone, it had reduced effects in the prostate tissue due to modulation by distinct cofactor recruitment to the androgen receptor which resulted in a different downstream cellular effect [74]. As such, SARMs may theoretically treat the physical symptoms associated with hypogonadism, such as decreased BMD and lean muscle mass, with a reduced side effect profile on increased PSA levels or LUTS [75]. For example, Enobosarm, the most well-studied SARM in humans to date, is thought to act as an agonist in the muscles, bones, and adipose tissue, whilst having limited effects on other androgen-responsive tissues such as the prostate and the seminal vesicles [76,77]. The chemical structures of SARMs undergoing human studies are annotated and compared to testosterone in Fig. 4
*Unfortunately, at present there are no studies that examine the efficacy of using SARMs in the context of hypogonadism in humans. This may be due to various factors, including difficulty in defining endpoints for objective evaluation of hypogonadism, safety concerns, and failure of SARMs to progress to clinical trial phases. Firstly, SARMs are more difficult to study in the context of hypogonadism, as serum testosterone measurements cannot be used as a biochemical marker of response. Within this context, there is currently no consensus on what constitutes biochemical markers of successful hypogonadism treatment [81]. Secondly, developing a SARM that does not increase prostate volume and hematocrit and reduce levels of HDL cholesterol has been challenging, all of which may have contributed to the limited investigation in hypogonadal males [82]. Finally, SARMs at present, including enobosarm, have not been able to demonstrate significant benefits in phase II or III trials, suggesting further work needs to be completed in the preclinical stages. Nonetheless, there are promising SARMs that may be suitable for further research, such as LY305, which has been demonstrated to result in no changes in hematocrit or HDL levels in phase I trials and is suggested to have significant anabolic action in the muscles and skeletal tissue whilst maintaining a weak agonist activity in androgenic tissues [82]. Ideally, research should be focused on the discovery of a SARM with isolated androgenic or anabolic effects, which could provide significant symptomatic benefit in not only hypogonadal men but also in cachectic patients where the anabolic effect would be significantly beneficial for muscle maintenance and growth.
Limitations of current evidence and future work
Whilst there is emerging evidence for the utility and need for novel androgen therapies for treating male hypogonadism, there is a need for high-level evidence for their use in the treatment of men with hypogonadism. With regards to SARMs, there are no studies that have investigated the effects of SARMs in hypogonadal men. More work is needed to elucidate the role of SARMs in treating male hypogonadism, in prospective clinical trials with a focus on symptomatic improvements including sexual dysfunction. The challenge here as with all studies of androgen therapies is defining specific endpoints and developing disease-specific PROMs (Patient-Reported Outcome Measures). However, it is likely that further research at pharmacological and preclinical levels is necessary to find a suitable SARM candidate for hypogonadism.
Other formulations of testosterone, such as TNG, may provide a suitable alternative for patients where traditional preparations of TRT are unsuitable. However, long-term studies investigating the tolerability of TNG due to the potential side effects of nasal irritation and inflammation with chronic use are needed. Such studies should also focus on determining the suitability of these novel therapies as an alternative in populations in which traditional TRT is contraindicated, for example in men with cardiovascular disease or raised hematocrit levels. This is especially pertinent given the reported dyslipidaemic changes associated with TNG in phase III trials, which may suggest that TNG is unsuitable for men with pre-existing cardiovascular conditions [48]. In men with active or treated prostate cancer, TNG may be a suitable alternative to systemic therapies and future work should monitor PSA changes with TNG administration. With regards to SERMs and AIs, further RCTs comparing SERMs to TRT are needed to elucidate the differences in symptomatic improvement, systemic effects, and safety profile. Overall, large-scale, prospective, randomized clinical trials which directly compare novel androgen therapies to traditional TRT are needed.
Furthermore, a critical limitation of the current evidence is the relatively short study durations. For example, most studies only report on a study period of 6 months. For instance, in studies investigating the effect of aromatase inhibitors, there was limited evidence for improving symptoms of hypogonadism. This may have been due to short follow-up durations, which may have limited the clinical outcomes for endocrinological changes. Long-term studies are also important for determining side effects, such as bone mineral density loss, and examining effects on morbidity and mortality, especially on cardiovascular events, diabetes, and androgen-driven cancer risk (e.g. prostate cancer). Considering that an increased prevalence of diabetes and cardiovascular events are seen in hypogonadism, and TRT has been shown to improve diabetic outcomes and reduce cardiovascular risk in hypogonadal males, novel non-testosterone treatments should ideally show similar benefits [12,22].
Summary
There is a need to treat male hypogonadism whilst avoiding the negative impact of TRT on spermatogenesis, hematocrit, and hepatic function, among others. There is data showing that nasal testosterone preparations may be a suitable alternative but further evidence is required to establish the optimal dosing regimen and the side effects profile. There are several randomized controlled trials investigating the use of AIs and SERMs in the context of hypogonadism and male infertility, but long-term effects on bone mineral density, cardiovascular risk, and prostate cancer risk remain unclear. There is a paucity of data for SARMs in male hypogonadism. Thus, whilst there are several potential novel treatments for male hypogonadism, a stronger evidence base is needed to support such treatments in clinical practice, especially due to lacking evidence in the form of longitudinal studies. The therapeutic potential, benefits, and negatives of each novel therapy for hypogonadism are summarised in Table 4.
