madman
Super Moderator
Abstract
Background
Male hypogonadism may be associated with micropenis and cryptorchidism in newborns, absent or incomplete pubertal development when it occurs during childhood. During puberty, androgen replacement therapy plays a pivotal role in subjects with hypogonadism to induce sexual maturation, growth acceleration, anabolic effects on fat-free mass growth increasing muscle strength, directly and indirectly on the attainment of peak bone mass in young men. Moreover, in newborns with congenital hypogonadism, androgen therapy could be effective to increase genital size.
Summary
Testosterone replacement therapy (TRT) represents the cornerstone of the management of hypogonadism in boys. During puberty, replacement therapy needs to be modulated with gradual dosing increase to better mimic the physiologic pubertal development. Currently, intramuscular testosterone esters (in particular testosterone enanthate, TE) and subcutaneous testosterone pellets are the only formulations approved by the US Food and Drug Administration (FDA) for delayed puberty, while no preparation is approved for long-term use in the adolescent age. Several new testosterone (T) formulations (as transdermal, nasal, subcutaneous, and oral formulation) are recently developed to improve the pharmacokinetic profile and to ease the administration route increasing patient compliance in adult males with hypogonadism. All these formulations are not approved for pediatric age, although some of them are used as “off-label” regimens. This special issue is aimed to illustrate new T formulations and their potential role as replacement therapy in the pediatric population, as well as to highlight investigational areas to contribute to health care improvement in these patients.
Key Messages
Despite the lack of evidence-based guidelines regarding the choice of T formulation in the pediatric population, new formulations appear to have a potential role for TRT in adolescent age. They have been designed for adult age with a little flexibility of dosage, although a few formulations may be attractive for pubertal induction and penile enlargement thanks to their greater flexibility and easing of administration. On the other hand, long-acting and stable formulations could meet post-pubertal needs, increasing TRT compliance in a critical phase as the adolescent age. Further controlled, long-term safety and efficacy studies for all these new T formulations within the pediatric population are needed.
Introduction
Hypogonadism in males refers to a decrease in sperm and testosterone (T) production. It may be related to gonadal failure (primary hypogonadism) or hypothalamus-pituitary disease (secondary hypogonadism). Primary hypogonadism is characterized by low serum T and elevated FSH and LH levels (hypergonadotropic hypogonadism, HeH), while secondary hypogonadism presents both T and gonadotropin hormone deficiency (hypogonadotropic hypogonadism, HoH). Clinical features of hypogonadism may vary greatly, depending upon when this occurs. Congenital androgen defects during the first trimester of intrauterine time result in uncompleted virilization of male fetuses, while later decreased T production, during the third trimester in fetuses and the mini puberty in newborns, is associated with a small penis (so-called micropenis) and cryptorchidism. Lastly, when hypogonadism occurs during childhood or peri-pubertal time, it is associated with absent or incomplete pubertal development. Hypogonadism can also cause short- and long-term consequences such as secondary osteoporosis [1], increased risk for metabolic syndrome [2, 3], and depression with consequent impaired psychosexual health [4-6].
Both hypergonadotropic and hypogonadotropic forms of hypogonadism may be either due to congenital or acquired disease. The most frequent causes are summarized in Table 1. Androgen replacement therapy should be aimed to reproduce the physiological effect of T on many different tissues and systems. In newborns with the absence of mini-puberty, short-term therapy with androgens (both T and 5-dihydrotestosterone) could be effective to correct micropenis [7-11]. In infants with HoH, combined gonadotropin (FSH plus LH recombinant) or GnRH injective therapy seems to be able to restore the hormonal pathway of mini-puberty allowing the descent of retractile testis, as well as Sertoli and germ cell proliferation and initial maturation [12-15]. This suggests that early gonadotropin therapy may improve the fertility potential and the response to gonadotropin therapy during adolescence and adult life [15-17]. These therapies represent a valid alternative to androgens therapy, although they are more invasive, and their therapeutic use is beyond the scope of this review. During puberty, beyond inducing sexual maturation, androgens play an anabolic role on bone mass, both directly and through their conversion to estrogen by aromatase, contributing to the attainment of peak bone mass in young men [18, 19]. Sex steroids are able to induce growth acceleration, defined also pubertal “spurt”, thanks to their synergic effects on GH-IGF1 secretion, through estrogen conversion, and directly interacting with androgen receptors localized in the growth plate cartilage [20-22]. T has also anabolic effects on muscle mass and body composition [23-25]. Several studies have demonstrated the effects of testosterone replacement therapy (TRT) in hypogonadal men to increase fat-free mass, muscle strength and to reduce fat mass [2, 25-27]. Finally, young men with untreated hypogonadism have lower HDL cholesterol levels and increased cardiometabolic risk, compared to healthy controls [28].
*For all these reasons, T therapy represents the cornerstone of the management of hypogonadism in boys. Although testosterone enanthate (TE) and subcutaneous testosterone pellets are the only formulations approved by the US Food and Drug Administration (FDA) for adolescent males [29-31], a number of new formulations are currently used as “off-label” regimens. This report is aimed to illustrate new T formulations and their potential role as replacement therapy in newborn, child, and adolescent males with hypogonadism.
Main Text
The most common use of T therapy in childhood is related to pubertal induction in boys with constitutional delay in growth and puberty (CDGP), the most frequent and self-limited form of HoH. In boys with delayed puberty, short-term therapy with a low dose of T may be proposed as an alternative to expectant observation for psychological reasons. Furthermore, it could be useful to differentiate CDGP to permanent HoH, often indiscernible prior to the T therapy. In adolescents with persistent hypogonadism, TRT is a long-term therapy with the peculiarity of the need to be modulated with a gradual increase of the dose to mimic the physiologic pubertal maturation. Since the mid-20th century, several T formulations have been developed to improve their pharmacokinetics and to reduce potential adverse effects. The first available formulations, introduced between the 1940s and 1950s, included subcutaneous pellets and intramuscular injection of T esters (propionate, enanthate, and cypionate). Current TRT formulations and their pediatric dosing regimens are summarized in Table 2.
Pellets, available only in the USA, UK, and Australia, are implanted subcutaneously every 3 to 6 months, requiring a minor surgical procedure for the implantation. This formulation was well tolerated when used in adolescent males, even if few cases have been described [32, 33]. In addition, it was reported wide variability in circulating T levels, with excessively high serum T values for the early stage of puberty. No reports are available upon the use of pellets for pubertal induction. Despite the limited number of prospective studies involving adolescent males [34, 35], intramuscular TE is the most frequently used therapy for induction and progression of puberty in boys. Different regimens have been reported with a positive effect on pubertal maturation in boys with delayed puberty [36-39], while no data are available concerning titration schemes to adult T doses and long-term safety and efficacy. Some escalation schemes from pubertal induction to adulthood doses have been proposed [40-42]. During the neonatal period, short-term low-dose injective T esters therapy could also be used to increase penile size in hypogonadal boys [43, 44], although a standardized dosing regimen has not been established.
Intramuscular T therapy presents some pitfalls. Indeed, both enanthate and cypionate esters are unable to mimic the physiological testosterone levels due to their pharmacokinetic profiles. T rises to supraphysiological concentrations a few days after injection, with a gradual decrease to sub-physiological levels within the following 2 to 3 weeks [45]. Propionate ester is uncommonly used for hypogonadism treatment, due to its short-term formulation and wide T fluctuations. A possible inconvenience of T esters is related to intramuscular injections and relative discomfort, although no specific data upon its influence on compliance are available
Oral T undecanoate (TU) was developed in the 1980s to avoid the liver inactivation of earlier natural oral T formulation. It is absorbed into the lymphatic system, bypassing liver inactivation, even if oral bioavailability is unreliable depending upon the lipid content of meals [46, 47]. Some authors have reported oral TU use in the pediatric population [48-50], although the short half-life and the requirement of multiple daily doses make it difficult to use in long-term replacement therapy.
Transdermal T patches introduced in the 1990s were designed for adult doses and cannot be divided. For this reason, their use in males during childhood and adolescence is extremely limited [51, 52]. From the 2000s novel, testosterone formulations have become available with the introduction of topical gels, oral soft gel, nasal preparation, subcutaneous depot, and a long-acting intramuscular formulation. New T formulations, their relative advantages or disadvantages, and their possible use in the pediatric population are summarized in Table 3.
*Transdermal gel formulations
*New oral Testosterone undecanoate soft capsule
*Nasal Testosterone gel
*Subcutaneous formulation
*Long-acting intramuscular formulation
Conclusion
New T formulations are demonstrated to be safe, effective, and well-accepted as TRT in males with hypogonadism. Unfortunately, these formulations are approved only for adults due to the lack of randomized controlled trials in the pediatric population. However emerging data support safety, efficacy, and high compliance of transdermal formulation for TRT also in adolescent age [59, 60]. At present, pubertal induction is typically enabled with IM testosterone esters, given the major clinical experience with this preparation, and then switched to newer formulation with “off-label” regimens once adult dosing is reached. Many fewer data are available upon T use during mini puberty in newborns with micropenis and hypogonadism, with only a few schemes of therapy based on expert opinions [8].
Despite no evidence-based guidelines regarding pubertal induction dosing regimens or optimal T formulation, TRT should be individualized to the patient’s age and needs. It would be desirable to use a slow titration dosing regimen during pubertal induction, up to adult dosage when adult height is reached. In this direction, the flexibility of dosing and easing of administration of some formulations, as a few transdermal gels or subcutaneous TE, could make them attractive for pubertal induction in adolescent age. In this respect, it should be noted that the majority of new T formulations may be used in the pediatric population only from mid puberty onwards, due to their little flexibility of dosing. On the other hand, long-acting and stable formulations, as IM UT, could meet the post-pubertal needs of the adolescent population, increasing TRT compliance in a critical phase for acceptance of chronic diseases. Finally, nasal gel and oral soft capsule daily formulation may represent a good pain-less and non-invasive choice for after-pubertal long-term TRT of male hypogonadism also in children. Further controlled, long-term safety, and efficacy studies for all these new T formulations on the pediatric population are needed.
Background
Male hypogonadism may be associated with micropenis and cryptorchidism in newborns, absent or incomplete pubertal development when it occurs during childhood. During puberty, androgen replacement therapy plays a pivotal role in subjects with hypogonadism to induce sexual maturation, growth acceleration, anabolic effects on fat-free mass growth increasing muscle strength, directly and indirectly on the attainment of peak bone mass in young men. Moreover, in newborns with congenital hypogonadism, androgen therapy could be effective to increase genital size.
Summary
Testosterone replacement therapy (TRT) represents the cornerstone of the management of hypogonadism in boys. During puberty, replacement therapy needs to be modulated with gradual dosing increase to better mimic the physiologic pubertal development. Currently, intramuscular testosterone esters (in particular testosterone enanthate, TE) and subcutaneous testosterone pellets are the only formulations approved by the US Food and Drug Administration (FDA) for delayed puberty, while no preparation is approved for long-term use in the adolescent age. Several new testosterone (T) formulations (as transdermal, nasal, subcutaneous, and oral formulation) are recently developed to improve the pharmacokinetic profile and to ease the administration route increasing patient compliance in adult males with hypogonadism. All these formulations are not approved for pediatric age, although some of them are used as “off-label” regimens. This special issue is aimed to illustrate new T formulations and their potential role as replacement therapy in the pediatric population, as well as to highlight investigational areas to contribute to health care improvement in these patients.
Key Messages
Despite the lack of evidence-based guidelines regarding the choice of T formulation in the pediatric population, new formulations appear to have a potential role for TRT in adolescent age. They have been designed for adult age with a little flexibility of dosage, although a few formulations may be attractive for pubertal induction and penile enlargement thanks to their greater flexibility and easing of administration. On the other hand, long-acting and stable formulations could meet post-pubertal needs, increasing TRT compliance in a critical phase as the adolescent age. Further controlled, long-term safety and efficacy studies for all these new T formulations within the pediatric population are needed.
Introduction
Hypogonadism in males refers to a decrease in sperm and testosterone (T) production. It may be related to gonadal failure (primary hypogonadism) or hypothalamus-pituitary disease (secondary hypogonadism). Primary hypogonadism is characterized by low serum T and elevated FSH and LH levels (hypergonadotropic hypogonadism, HeH), while secondary hypogonadism presents both T and gonadotropin hormone deficiency (hypogonadotropic hypogonadism, HoH). Clinical features of hypogonadism may vary greatly, depending upon when this occurs. Congenital androgen defects during the first trimester of intrauterine time result in uncompleted virilization of male fetuses, while later decreased T production, during the third trimester in fetuses and the mini puberty in newborns, is associated with a small penis (so-called micropenis) and cryptorchidism. Lastly, when hypogonadism occurs during childhood or peri-pubertal time, it is associated with absent or incomplete pubertal development. Hypogonadism can also cause short- and long-term consequences such as secondary osteoporosis [1], increased risk for metabolic syndrome [2, 3], and depression with consequent impaired psychosexual health [4-6].
Both hypergonadotropic and hypogonadotropic forms of hypogonadism may be either due to congenital or acquired disease. The most frequent causes are summarized in Table 1. Androgen replacement therapy should be aimed to reproduce the physiological effect of T on many different tissues and systems. In newborns with the absence of mini-puberty, short-term therapy with androgens (both T and 5-dihydrotestosterone) could be effective to correct micropenis [7-11]. In infants with HoH, combined gonadotropin (FSH plus LH recombinant) or GnRH injective therapy seems to be able to restore the hormonal pathway of mini-puberty allowing the descent of retractile testis, as well as Sertoli and germ cell proliferation and initial maturation [12-15]. This suggests that early gonadotropin therapy may improve the fertility potential and the response to gonadotropin therapy during adolescence and adult life [15-17]. These therapies represent a valid alternative to androgens therapy, although they are more invasive, and their therapeutic use is beyond the scope of this review. During puberty, beyond inducing sexual maturation, androgens play an anabolic role on bone mass, both directly and through their conversion to estrogen by aromatase, contributing to the attainment of peak bone mass in young men [18, 19]. Sex steroids are able to induce growth acceleration, defined also pubertal “spurt”, thanks to their synergic effects on GH-IGF1 secretion, through estrogen conversion, and directly interacting with androgen receptors localized in the growth plate cartilage [20-22]. T has also anabolic effects on muscle mass and body composition [23-25]. Several studies have demonstrated the effects of testosterone replacement therapy (TRT) in hypogonadal men to increase fat-free mass, muscle strength and to reduce fat mass [2, 25-27]. Finally, young men with untreated hypogonadism have lower HDL cholesterol levels and increased cardiometabolic risk, compared to healthy controls [28].
*For all these reasons, T therapy represents the cornerstone of the management of hypogonadism in boys. Although testosterone enanthate (TE) and subcutaneous testosterone pellets are the only formulations approved by the US Food and Drug Administration (FDA) for adolescent males [29-31], a number of new formulations are currently used as “off-label” regimens. This report is aimed to illustrate new T formulations and their potential role as replacement therapy in newborn, child, and adolescent males with hypogonadism.
Main Text
The most common use of T therapy in childhood is related to pubertal induction in boys with constitutional delay in growth and puberty (CDGP), the most frequent and self-limited form of HoH. In boys with delayed puberty, short-term therapy with a low dose of T may be proposed as an alternative to expectant observation for psychological reasons. Furthermore, it could be useful to differentiate CDGP to permanent HoH, often indiscernible prior to the T therapy. In adolescents with persistent hypogonadism, TRT is a long-term therapy with the peculiarity of the need to be modulated with a gradual increase of the dose to mimic the physiologic pubertal maturation. Since the mid-20th century, several T formulations have been developed to improve their pharmacokinetics and to reduce potential adverse effects. The first available formulations, introduced between the 1940s and 1950s, included subcutaneous pellets and intramuscular injection of T esters (propionate, enanthate, and cypionate). Current TRT formulations and their pediatric dosing regimens are summarized in Table 2.
Pellets, available only in the USA, UK, and Australia, are implanted subcutaneously every 3 to 6 months, requiring a minor surgical procedure for the implantation. This formulation was well tolerated when used in adolescent males, even if few cases have been described [32, 33]. In addition, it was reported wide variability in circulating T levels, with excessively high serum T values for the early stage of puberty. No reports are available upon the use of pellets for pubertal induction. Despite the limited number of prospective studies involving adolescent males [34, 35], intramuscular TE is the most frequently used therapy for induction and progression of puberty in boys. Different regimens have been reported with a positive effect on pubertal maturation in boys with delayed puberty [36-39], while no data are available concerning titration schemes to adult T doses and long-term safety and efficacy. Some escalation schemes from pubertal induction to adulthood doses have been proposed [40-42]. During the neonatal period, short-term low-dose injective T esters therapy could also be used to increase penile size in hypogonadal boys [43, 44], although a standardized dosing regimen has not been established.
Intramuscular T therapy presents some pitfalls. Indeed, both enanthate and cypionate esters are unable to mimic the physiological testosterone levels due to their pharmacokinetic profiles. T rises to supraphysiological concentrations a few days after injection, with a gradual decrease to sub-physiological levels within the following 2 to 3 weeks [45]. Propionate ester is uncommonly used for hypogonadism treatment, due to its short-term formulation and wide T fluctuations. A possible inconvenience of T esters is related to intramuscular injections and relative discomfort, although no specific data upon its influence on compliance are available
Oral T undecanoate (TU) was developed in the 1980s to avoid the liver inactivation of earlier natural oral T formulation. It is absorbed into the lymphatic system, bypassing liver inactivation, even if oral bioavailability is unreliable depending upon the lipid content of meals [46, 47]. Some authors have reported oral TU use in the pediatric population [48-50], although the short half-life and the requirement of multiple daily doses make it difficult to use in long-term replacement therapy.
Transdermal T patches introduced in the 1990s were designed for adult doses and cannot be divided. For this reason, their use in males during childhood and adolescence is extremely limited [51, 52]. From the 2000s novel, testosterone formulations have become available with the introduction of topical gels, oral soft gel, nasal preparation, subcutaneous depot, and a long-acting intramuscular formulation. New T formulations, their relative advantages or disadvantages, and their possible use in the pediatric population are summarized in Table 3.
*Transdermal gel formulations
*New oral Testosterone undecanoate soft capsule
*Nasal Testosterone gel
*Subcutaneous formulation
*Long-acting intramuscular formulation
Conclusion
New T formulations are demonstrated to be safe, effective, and well-accepted as TRT in males with hypogonadism. Unfortunately, these formulations are approved only for adults due to the lack of randomized controlled trials in the pediatric population. However emerging data support safety, efficacy, and high compliance of transdermal formulation for TRT also in adolescent age [59, 60]. At present, pubertal induction is typically enabled with IM testosterone esters, given the major clinical experience with this preparation, and then switched to newer formulation with “off-label” regimens once adult dosing is reached. Many fewer data are available upon T use during mini puberty in newborns with micropenis and hypogonadism, with only a few schemes of therapy based on expert opinions [8].
Despite no evidence-based guidelines regarding pubertal induction dosing regimens or optimal T formulation, TRT should be individualized to the patient’s age and needs. It would be desirable to use a slow titration dosing regimen during pubertal induction, up to adult dosage when adult height is reached. In this direction, the flexibility of dosing and easing of administration of some formulations, as a few transdermal gels or subcutaneous TE, could make them attractive for pubertal induction in adolescent age. In this respect, it should be noted that the majority of new T formulations may be used in the pediatric population only from mid puberty onwards, due to their little flexibility of dosing. On the other hand, long-acting and stable formulations, as IM UT, could meet the post-pubertal needs of the adolescent population, increasing TRT compliance in a critical phase for acceptance of chronic diseases. Finally, nasal gel and oral soft capsule daily formulation may represent a good pain-less and non-invasive choice for after-pubertal long-term TRT of male hypogonadism also in children. Further controlled, long-term safety, and efficacy studies for all these new T formulations on the pediatric population are needed.
