madman
Super Moderator
Abstract
Testosterone replacement therapy is an important treatment option for men with low testosterone and symptomatic hypogonadism. Various formulations of exogenous testosterone replacement therapy exist, including oral, buccal, intramuscular, transdermal, subdermal, and nasal preparations. However, exogenous testosterone replacement therapy is a double-edged sword, posing risks to fertility due to negative feedback mechanisms on the hypothalamic-pituitary-gonadal (HPG) axis, which is the main regulator of testosterone production and spermatogenesis in males. Alternative pharmacologic therapies are being used to increase endogenous testosterone levels while attempting to preserve the fertility and function of the HPG axis. These include selective estrogen receptor modulators, gonadotropins, and aromatase inhibitors. This review focuses on overviewing and comparing the currently available methods of exogenous testosterone replacement therapy, alternative treatments to increasing endogenous testosterone, and novel treatments that are currently under investigation to normalize testosterone levels while preserving the function of the HPG axis. In conclusion, reports suggest that, though Testosterone replacement therapy is an important way to restore testosterone levels and reduce symptoms associated with low testosterone, it is often difficult to decide which treatment to select for patients with testosterone deficiency. Several factors need to be considered to decide on optimal therapy options for the patient which include but are not limited to safety, efficacy, cost-effectiveness, dosing flexibility, and side effects. Alternative approaches that aim to improve endogenous testosterone production and preserve fertility are promising but still are at their initial stages of development. Ultimately, patient-centered decision making is paramount to appropriate treatment selection.
Essential points:
*The manuscript reviews the available methods of exogenous testosterone replacement therapy which are but not limited to oral, buccal, intramuscular, transdermal, subdermal, and nasal, respectively.
*The manuscript reviews the alternative therapies to increase endogenous testosterone replacement which includes but not limited to Selective estrogen receptor modulators, gonadotropins, and Aromatase inhibitors, respectively.
*Furthermore, the review highlights Investigational therapies to increase endogenous testosterone such as Selective androgen receptor modulators and Leydig stem cell transplantation, respectively.
*Moreover, the review compares the core impacts of these therapy options on hormone levels and modulation of the HPG axis.
Introduction
Testosterone, a steroid hormone, is the primary androgen in males and is essential for various biologic processes, including reproductive and sexual function, metabolism, body composition, and cognition (1-3). Male hypogonadism, also known as testosterone deficiency (TD), is defined as having one or more symptoms attributable to low circulating levels of testosterone (serum total testosterone <300 ng/dL) (1, 4, 5). Symptoms of TD include decreased libido, erectile dysfunction, decrease in muscle mass and strength, decrease in bone mass, anemia, increase in central body fat, and impaired memory, mood, concentration, and sleep (6, 7).
TD increases with age, with approximately a 1% annual decrease in free testosterone levels after age 30 (6, 7). However, the exact prevalence is unclear due to the varying testosterone level thresholds and non-standardized methodology used in measuring prevalence in population-based studies (5, 8, 9). The pathophysiology of hypogonadism can be characterized into two types: primary (hypergonadotropic hypogonadism) and secondary (hypogonadotropic hypogonadism). Primary hypogonadism is a TD due to a testicular abnormality impairing testosterone production; for example, Klinefelter syndrome, testicular tumors, infection, trauma, impaired Leydig cell function, or those caused by certain medications (2). Secondary hypogonadism is a TD due to a hypothalamic or pituitary abnormality that disrupts stimuli to the testes essential for testosterone production (i.e., luteinizing hormone (LH) and follicle-stimulating hormone (FSH)); for example, hypothalamic or pituitary lesions, GnRH deficiency, or hyperprolactinemia (2). Another important etiology of hypogonadism is late-onset hypogonadism, an age-related (i.e., >40 years) decline in testosterone accompanied by clinical symptoms that are often associated with obesity, diabetes, and other chronic health conditions (7, 10-12).
Several treatments are currently available to reestablish testosterone levels and improve TD symptoms. This review addresses the various forms of exogenous testosterone replacement therapy along with their individual benefits and risks. It also delves into alternative and investigational therapies for TD that aim to mitigate the undesired effects of male infertility and hypothalamic-pituitary-gonadal axis disruption by increasing endogenous testosterone (Table 1).
Available methods of exogenous testosterone replacement therapy
The full spectrum of testosterone action in the body can only be achieved if testosterone is aromatized to estradiol and 5 alpha-reductase to dihydrotestosterone (DHT) (13). Testosterone is generally successful when taken orally and is absorbed well in the intestine, but at times it can be so rapidly metabolized by the liver that it is sometimes ineffective via this route (14). Due to this, a variety of preparations have been developed including oral, buccal, intramuscular, transdermal, subdermal, and nasal preparations. This section includes examples of each preparation and details about their administration, advantages, and disadvantages. These details are summarized in Table 2.
*Oral
*Buccal
*Intramuscular
*Transdermal
*Subdermal
*Nasal
Impact of external testosterone supplementation on the HPG axis
Endogenous testosterone production is stimulated by LH secretion from the pituitary leading to Leydig cell activation. The testosterone produced by LH stimulation participates in a negative feedback axis that regulates pituitary LH synthesis. Thus, when exogenous testosterone is administered, LH is suppressed from the pituitary resulting in decreased endogenous hormone production and markedly reduced endogenous intratesticular testosterone. The decreased intratesticular testosterone results in low stimulation of spermatogenesis which may cause male infertility (36). Therefore, it is apparent that exogenous testosterone functions as a contraceptive by suppressing LH synthesis and subsequently may lead to markedly reduced sperm counts in nearly all men (37)
Alternative therapies to increase endogenous testosterone replacement
Selecting appropriate dosing regimens and formulations of testosterone have been shown to have a lower suppressive capacity on the HPG axis. Additionally, appropriate hormonal monitoring before and during TRT can prevent HPG axis suppression and preserve spermatogenesis (45). However, in addition to these safeguards, there are several alternative therapeutic approaches to raise endogenous testosterone levels other than supplementing exogenous forms of the hormone (44) (Table 3). These include selective estrogen receptor modulators (SERMs), gonadotropins, and aromatase inhibitors that can successfully restore the concentration of testosterone in serum and within the testis as well as preserve fertility (39, 44, 45). Although none of these have been approved by the US Food and Drug Administration (FDA) for the treatment of patients with hypogonadism or infertility, they are commonly used off-label by male fertility specialists. However, a paradoxical decline in the quality of semen and complications related to estrogen level change can be rare unintended effects of these medications (39).
*Selective estrogen receptor modulators
*Gonadotropins
*Aromatase inhibitors
Investigational therapies to increase endogenous testosterone
*Selective androgen receptor modulators
*Leydig stem cell transplantation
Conclusion
There has been a dramatic surge in the use of testosterone replacement therapy (TRT) over the past 2 decades (39, 76, 77). With numerous formulations continually being developed, patients and clinicians have many options to choose from with various factors to consider such as efficacy, cost-effectiveness, convenience, safety, and dosing flexibility (78). From 2000 to 2014, an average of 2.6 new transdermal TRT drugs was approved each year (76). Rao et al. (2017) performed a retrospective cross-sectional analysis assessing trends in TRT use from 2003 to 2013 and found a fourfold increase in TRT use in men ages 18-45, compared with a threefold increase in use in men ages 56-64 (39). However, despite the rise in exogenous TRT, there are concerns about long-term consequences of continued use such as gynecomastia, erythrocytosis, sleep apnea, and the potential risks of heart attack, which cannot be ignored. Therefore, large prospective multiethnic cohort studies are necessary for better clarifying both risk and hazard ratios of TRT (79).
Alternative treatments, including synthetic gonadotropins, selective estrogen receptor modulators (SERMs), and aromatase inhibitors, are being used off-label to raise serum and intratesticular testosterone levels while preserving fertility (39, 80). However, these may have unintended side effects, including a decline in semen quality and consequences for bone mineral density and libido due to changes in estrogen levels (80). Thus, there is a need to develop different approaches to restoring testosterone levels in patients that can both reduce negative side effects and preserve the HPG axis and fertility. The future of TRT in men desiring to preserve fertility is moving towards the stimulation of endogenous testosterone production by manipulating LSCs. Novel therapeutic approaches of transplanting LSCs in the various animal model testis have shown great promise in this endeavor (73, 74). Arora et al. (2019) was the first study of its kind to show successful ALC differentiation, increased testosterone production, and preservation of the HPG axis with subcutaneous autograft of LSCs in hypogonadal mice (75). Further in vivo studies are needed to assess the efficacy, safety, and clinical applicability of LSC transplant in practice.
Testosterone replacement therapy is an important treatment option for men with low testosterone and symptomatic hypogonadism. Various formulations of exogenous testosterone replacement therapy exist, including oral, buccal, intramuscular, transdermal, subdermal, and nasal preparations. However, exogenous testosterone replacement therapy is a double-edged sword, posing risks to fertility due to negative feedback mechanisms on the hypothalamic-pituitary-gonadal (HPG) axis, which is the main regulator of testosterone production and spermatogenesis in males. Alternative pharmacologic therapies are being used to increase endogenous testosterone levels while attempting to preserve the fertility and function of the HPG axis. These include selective estrogen receptor modulators, gonadotropins, and aromatase inhibitors. This review focuses on overviewing and comparing the currently available methods of exogenous testosterone replacement therapy, alternative treatments to increasing endogenous testosterone, and novel treatments that are currently under investigation to normalize testosterone levels while preserving the function of the HPG axis. In conclusion, reports suggest that, though Testosterone replacement therapy is an important way to restore testosterone levels and reduce symptoms associated with low testosterone, it is often difficult to decide which treatment to select for patients with testosterone deficiency. Several factors need to be considered to decide on optimal therapy options for the patient which include but are not limited to safety, efficacy, cost-effectiveness, dosing flexibility, and side effects. Alternative approaches that aim to improve endogenous testosterone production and preserve fertility are promising but still are at their initial stages of development. Ultimately, patient-centered decision making is paramount to appropriate treatment selection.
Essential points:
*The manuscript reviews the available methods of exogenous testosterone replacement therapy which are but not limited to oral, buccal, intramuscular, transdermal, subdermal, and nasal, respectively.
*The manuscript reviews the alternative therapies to increase endogenous testosterone replacement which includes but not limited to Selective estrogen receptor modulators, gonadotropins, and Aromatase inhibitors, respectively.
*Furthermore, the review highlights Investigational therapies to increase endogenous testosterone such as Selective androgen receptor modulators and Leydig stem cell transplantation, respectively.
*Moreover, the review compares the core impacts of these therapy options on hormone levels and modulation of the HPG axis.
Introduction
Testosterone, a steroid hormone, is the primary androgen in males and is essential for various biologic processes, including reproductive and sexual function, metabolism, body composition, and cognition (1-3). Male hypogonadism, also known as testosterone deficiency (TD), is defined as having one or more symptoms attributable to low circulating levels of testosterone (serum total testosterone <300 ng/dL) (1, 4, 5). Symptoms of TD include decreased libido, erectile dysfunction, decrease in muscle mass and strength, decrease in bone mass, anemia, increase in central body fat, and impaired memory, mood, concentration, and sleep (6, 7).
TD increases with age, with approximately a 1% annual decrease in free testosterone levels after age 30 (6, 7). However, the exact prevalence is unclear due to the varying testosterone level thresholds and non-standardized methodology used in measuring prevalence in population-based studies (5, 8, 9). The pathophysiology of hypogonadism can be characterized into two types: primary (hypergonadotropic hypogonadism) and secondary (hypogonadotropic hypogonadism). Primary hypogonadism is a TD due to a testicular abnormality impairing testosterone production; for example, Klinefelter syndrome, testicular tumors, infection, trauma, impaired Leydig cell function, or those caused by certain medications (2). Secondary hypogonadism is a TD due to a hypothalamic or pituitary abnormality that disrupts stimuli to the testes essential for testosterone production (i.e., luteinizing hormone (LH) and follicle-stimulating hormone (FSH)); for example, hypothalamic or pituitary lesions, GnRH deficiency, or hyperprolactinemia (2). Another important etiology of hypogonadism is late-onset hypogonadism, an age-related (i.e., >40 years) decline in testosterone accompanied by clinical symptoms that are often associated with obesity, diabetes, and other chronic health conditions (7, 10-12).
Several treatments are currently available to reestablish testosterone levels and improve TD symptoms. This review addresses the various forms of exogenous testosterone replacement therapy along with their individual benefits and risks. It also delves into alternative and investigational therapies for TD that aim to mitigate the undesired effects of male infertility and hypothalamic-pituitary-gonadal axis disruption by increasing endogenous testosterone (Table 1).
Available methods of exogenous testosterone replacement therapy
The full spectrum of testosterone action in the body can only be achieved if testosterone is aromatized to estradiol and 5 alpha-reductase to dihydrotestosterone (DHT) (13). Testosterone is generally successful when taken orally and is absorbed well in the intestine, but at times it can be so rapidly metabolized by the liver that it is sometimes ineffective via this route (14). Due to this, a variety of preparations have been developed including oral, buccal, intramuscular, transdermal, subdermal, and nasal preparations. This section includes examples of each preparation and details about their administration, advantages, and disadvantages. These details are summarized in Table 2.
*Oral
*Buccal
*Intramuscular
*Transdermal
*Subdermal
*Nasal
Impact of external testosterone supplementation on the HPG axis
Endogenous testosterone production is stimulated by LH secretion from the pituitary leading to Leydig cell activation. The testosterone produced by LH stimulation participates in a negative feedback axis that regulates pituitary LH synthesis. Thus, when exogenous testosterone is administered, LH is suppressed from the pituitary resulting in decreased endogenous hormone production and markedly reduced endogenous intratesticular testosterone. The decreased intratesticular testosterone results in low stimulation of spermatogenesis which may cause male infertility (36). Therefore, it is apparent that exogenous testosterone functions as a contraceptive by suppressing LH synthesis and subsequently may lead to markedly reduced sperm counts in nearly all men (37)
Alternative therapies to increase endogenous testosterone replacement
Selecting appropriate dosing regimens and formulations of testosterone have been shown to have a lower suppressive capacity on the HPG axis. Additionally, appropriate hormonal monitoring before and during TRT can prevent HPG axis suppression and preserve spermatogenesis (45). However, in addition to these safeguards, there are several alternative therapeutic approaches to raise endogenous testosterone levels other than supplementing exogenous forms of the hormone (44) (Table 3). These include selective estrogen receptor modulators (SERMs), gonadotropins, and aromatase inhibitors that can successfully restore the concentration of testosterone in serum and within the testis as well as preserve fertility (39, 44, 45). Although none of these have been approved by the US Food and Drug Administration (FDA) for the treatment of patients with hypogonadism or infertility, they are commonly used off-label by male fertility specialists. However, a paradoxical decline in the quality of semen and complications related to estrogen level change can be rare unintended effects of these medications (39).
*Selective estrogen receptor modulators
*Gonadotropins
*Aromatase inhibitors
Investigational therapies to increase endogenous testosterone
*Selective androgen receptor modulators
*Leydig stem cell transplantation
Conclusion
There has been a dramatic surge in the use of testosterone replacement therapy (TRT) over the past 2 decades (39, 76, 77). With numerous formulations continually being developed, patients and clinicians have many options to choose from with various factors to consider such as efficacy, cost-effectiveness, convenience, safety, and dosing flexibility (78). From 2000 to 2014, an average of 2.6 new transdermal TRT drugs was approved each year (76). Rao et al. (2017) performed a retrospective cross-sectional analysis assessing trends in TRT use from 2003 to 2013 and found a fourfold increase in TRT use in men ages 18-45, compared with a threefold increase in use in men ages 56-64 (39). However, despite the rise in exogenous TRT, there are concerns about long-term consequences of continued use such as gynecomastia, erythrocytosis, sleep apnea, and the potential risks of heart attack, which cannot be ignored. Therefore, large prospective multiethnic cohort studies are necessary for better clarifying both risk and hazard ratios of TRT (79).
Alternative treatments, including synthetic gonadotropins, selective estrogen receptor modulators (SERMs), and aromatase inhibitors, are being used off-label to raise serum and intratesticular testosterone levels while preserving fertility (39, 80). However, these may have unintended side effects, including a decline in semen quality and consequences for bone mineral density and libido due to changes in estrogen levels (80). Thus, there is a need to develop different approaches to restoring testosterone levels in patients that can both reduce negative side effects and preserve the HPG axis and fertility. The future of TRT in men desiring to preserve fertility is moving towards the stimulation of endogenous testosterone production by manipulating LSCs. Novel therapeutic approaches of transplanting LSCs in the various animal model testis have shown great promise in this endeavor (73, 74). Arora et al. (2019) was the first study of its kind to show successful ALC differentiation, increased testosterone production, and preservation of the HPG axis with subcutaneous autograft of LSCs in hypogonadal mice (75). Further in vivo studies are needed to assess the efficacy, safety, and clinical applicability of LSC transplant in practice.
