madman
Super Moderator
Testosterone Use in Adolescent Males: Current Practice and Unmet Needs
Maria Vogiatzi, James P. Tursi, Jonathan S. Jaffe, Sue Hobson, and Alan D. Rogol
Abstract
Testosterone replacement therapy (TRT) is routinely prescribed in adolescent males with constitutional delay of growth and puberty (CDGP) or hypogonadism. With many new testosterone (T) formulations entering the market targeted for adults, we review current evidence and TRT options for adolescents and identify areas of unmet needs. We searched PubMed for articles (in English) on testosterone therapy, androgens, adolescence, and puberty in humans. The results indicate that short-term use of T enanthate (TE) or oral T undecanoate is safe and effective in inducing puberty and increasing growth in males with CDGP. Reassuring evidence is emerging on the use of transdermal T to induce and maintain puberty. The long-term safety and efficacy of TRT for puberty completion and maintenance have not been established. Current TRT regimens are based on consensus and expert opinion, but evidence-based guidelines are lacking. Limited guidance exists on when and how T should be administered and optimal strategies for monitoring therapy once it is initiated. Only TE and T pellets are US Food and Drug Administration approved for use in adolescent males in the United States. Despite the introduction of a wide variety of new T formulations, they are designed for adults, and their metered doses are difficult to titrate in adolescents. In conclusion, TRT in adolescent males is hindered by a lack of long-term safety and efficacy data and limited options approved for use in this population. Additional research is needed to identify the route, dose, duration, and optimal timing for TRT in adolescents requiring androgen therapy.
Testosterone (T) therapy is routinely prescribed in adolescent males with constitutional delay of growth and puberty (CDGP) or hypogonadism. T plays a critical role in male sexual development and function, beginning in utero and continuing through infancy, adolescence, and beyond [1]. In addition, T has numerous effects on various tissues and systems. These include the acceleration of linear growth during adolescence, a positive effect on bone mass and accretion [1-3], and changes in body composition associated with an increase in lean mass and a reduction and redistribution of fat mass [1, 4]. Recent evidence indicates that T and other androgens are involved in sexually dimorphic differences in certain brain regions, such as the amygdala [1, 5, 6], while their effects on neurocognition and behaviors are being actively investigated [7, 8].
T therapy in boys with CDGP is applied for a limited time, typically 3 to 6 months [1, 9]. The goals are to initiate sexual changes, increase growth, and ameliorate the negative psychosocial aspects associated with CDGP [1, 10-21]. Testosterone replacement in adolescents with primary or secondary hypogonadism is a long-term therapy. By using escalating T doses, such therapy induces progressive pubertal changes that mimic the physiologic course of puberty in healthy males [1, 22]. Despite the importance and routine administration of T to these populations, there has been marked variation in its use and little consensus on proper procedures [1, 22]. To add to the complexity, T therapy in boys and adolescent males is largely given “off label” [23]. T enanthate (TE) and T pellets are the only formulations approved by the US Food and Drug Administration (FDA) for the treatment of males with delayed puberty [23-25]. No preparation is FDA approved for long-term use in adolescents. Additional pediatric uses of exogenous T, which are not FDA approved, but have been suggested, including the treatment of microphallus in infants and the management of diminished or absent mini puberty, as well as its rapidly emerging use as cross-sex hormone therapy for transgender males [1, 26-30].
T replacement therapy (TRT) has recently expanded in adults because of its increased use among men with functional hypogonadism [31]. A number of new T preparations have entered the market, with improved pharmacokinetics, ease of administration, and likely increased adherence [22, 32]. However, all focus on adult males, and dose formulations are frequently not metered for pediatric use. The Endocrine Society and multiple other medical societies have developed practice guidelines for the care of adult patients, with little or no reference to adolescents [32-35]. This review summarizes the T options available to adolescent males and the evidence that supports current TRT practice in this population. We will use the results of this analysis to address the unmet needs and challenges related to TRT in adolescents and highlight areas for investigation likely to lead to improved care in these patients.
2. Quantitating the Need for Testosterone Therapy in Adolescence
3. Testosterone Formulations: Pediatric Applications and Regulatory Perspectives
4. Current Options for Testosterone Therapy in Adolescents and Evidence From Pediatric Studies
A. Injectable Testosterone Esters
B. Oral Testosterone Undecanoate
C. Transdermal Testosterone
D. Testosterone Pellets
E. More Recent Testosterone Formulations
5. Unmet Needs
6. The Current Practice of Testosterone Therapy in Adolescent Boys
A. Therapeutic Regimens and Their Challenges
B. Monitoring Therapy
7. Patient Satisfaction and Adherence to Therapy
8. Conclusions
Tens of thousands of adolescent males require TRT annually. In this review, we have identified 2 broad areas of unmet needs for these patients. The first involves the absence of data on the impact of TRT, as it is currently implemented, on various health parameters, including quality of life and adult health outcomes. Although androgens have a positive influence on the multiple physiologic processes that mature during puberty, from bone accrual and changes in body composition to cardiometabolic and mental health, the specific TRT regimen that will optimize these parameters and ameliorate the long-term comorbidities associated with hypogonadism for an individual is uncertain and requires assessment in controlled, prospective studies. The lack of TRT guidelines for adolescent males reflects the lack of appropriate data to guide recommendations. The specific needs of adolescent males with chronic illnesses and functional hypogonadism should also be addressed.
The second area of unmet needs involves the scarcity of T formulations that are suitable for use in adolescent males. Many new T formulations have entered the market recently, but all are designed for adults. As a result, their dosing is not very flexible and does not permit easy titration, which is essential for therapy in adolescents. According to World Health Organization guidelines, the ideal formulation should be safe, effective, affordable, convenient, and flexible in dosing, and it should possess a pharmacokinetic profile similar to that observed in pubertal physiology [130]. With TE being the main T option for adolescents, TRT practice in this patient population remains far from this ideal recommendation.
Maria Vogiatzi, James P. Tursi, Jonathan S. Jaffe, Sue Hobson, and Alan D. Rogol
Abstract
Testosterone replacement therapy (TRT) is routinely prescribed in adolescent males with constitutional delay of growth and puberty (CDGP) or hypogonadism. With many new testosterone (T) formulations entering the market targeted for adults, we review current evidence and TRT options for adolescents and identify areas of unmet needs. We searched PubMed for articles (in English) on testosterone therapy, androgens, adolescence, and puberty in humans. The results indicate that short-term use of T enanthate (TE) or oral T undecanoate is safe and effective in inducing puberty and increasing growth in males with CDGP. Reassuring evidence is emerging on the use of transdermal T to induce and maintain puberty. The long-term safety and efficacy of TRT for puberty completion and maintenance have not been established. Current TRT regimens are based on consensus and expert opinion, but evidence-based guidelines are lacking. Limited guidance exists on when and how T should be administered and optimal strategies for monitoring therapy once it is initiated. Only TE and T pellets are US Food and Drug Administration approved for use in adolescent males in the United States. Despite the introduction of a wide variety of new T formulations, they are designed for adults, and their metered doses are difficult to titrate in adolescents. In conclusion, TRT in adolescent males is hindered by a lack of long-term safety and efficacy data and limited options approved for use in this population. Additional research is needed to identify the route, dose, duration, and optimal timing for TRT in adolescents requiring androgen therapy.
Testosterone (T) therapy is routinely prescribed in adolescent males with constitutional delay of growth and puberty (CDGP) or hypogonadism. T plays a critical role in male sexual development and function, beginning in utero and continuing through infancy, adolescence, and beyond [1]. In addition, T has numerous effects on various tissues and systems. These include the acceleration of linear growth during adolescence, a positive effect on bone mass and accretion [1-3], and changes in body composition associated with an increase in lean mass and a reduction and redistribution of fat mass [1, 4]. Recent evidence indicates that T and other androgens are involved in sexually dimorphic differences in certain brain regions, such as the amygdala [1, 5, 6], while their effects on neurocognition and behaviors are being actively investigated [7, 8].
T therapy in boys with CDGP is applied for a limited time, typically 3 to 6 months [1, 9]. The goals are to initiate sexual changes, increase growth, and ameliorate the negative psychosocial aspects associated with CDGP [1, 10-21]. Testosterone replacement in adolescents with primary or secondary hypogonadism is a long-term therapy. By using escalating T doses, such therapy induces progressive pubertal changes that mimic the physiologic course of puberty in healthy males [1, 22]. Despite the importance and routine administration of T to these populations, there has been marked variation in its use and little consensus on proper procedures [1, 22]. To add to the complexity, T therapy in boys and adolescent males is largely given “off label” [23]. T enanthate (TE) and T pellets are the only formulations approved by the US Food and Drug Administration (FDA) for the treatment of males with delayed puberty [23-25]. No preparation is FDA approved for long-term use in adolescents. Additional pediatric uses of exogenous T, which are not FDA approved, but have been suggested, including the treatment of microphallus in infants and the management of diminished or absent mini puberty, as well as its rapidly emerging use as cross-sex hormone therapy for transgender males [1, 26-30].
T replacement therapy (TRT) has recently expanded in adults because of its increased use among men with functional hypogonadism [31]. A number of new T preparations have entered the market, with improved pharmacokinetics, ease of administration, and likely increased adherence [22, 32]. However, all focus on adult males, and dose formulations are frequently not metered for pediatric use. The Endocrine Society and multiple other medical societies have developed practice guidelines for the care of adult patients, with little or no reference to adolescents [32-35]. This review summarizes the T options available to adolescent males and the evidence that supports current TRT practice in this population. We will use the results of this analysis to address the unmet needs and challenges related to TRT in adolescents and highlight areas for investigation likely to lead to improved care in these patients.
2. Quantitating the Need for Testosterone Therapy in Adolescence
3. Testosterone Formulations: Pediatric Applications and Regulatory Perspectives
4. Current Options for Testosterone Therapy in Adolescents and Evidence From Pediatric Studies
A. Injectable Testosterone Esters
B. Oral Testosterone Undecanoate
C. Transdermal Testosterone
D. Testosterone Pellets
E. More Recent Testosterone Formulations
5. Unmet Needs
6. The Current Practice of Testosterone Therapy in Adolescent Boys
A. Therapeutic Regimens and Their Challenges
B. Monitoring Therapy
7. Patient Satisfaction and Adherence to Therapy
8. Conclusions
Tens of thousands of adolescent males require TRT annually. In this review, we have identified 2 broad areas of unmet needs for these patients. The first involves the absence of data on the impact of TRT, as it is currently implemented, on various health parameters, including quality of life and adult health outcomes. Although androgens have a positive influence on the multiple physiologic processes that mature during puberty, from bone accrual and changes in body composition to cardiometabolic and mental health, the specific TRT regimen that will optimize these parameters and ameliorate the long-term comorbidities associated with hypogonadism for an individual is uncertain and requires assessment in controlled, prospective studies. The lack of TRT guidelines for adolescent males reflects the lack of appropriate data to guide recommendations. The specific needs of adolescent males with chronic illnesses and functional hypogonadism should also be addressed.
The second area of unmet needs involves the scarcity of T formulations that are suitable for use in adolescent males. Many new T formulations have entered the market recently, but all are designed for adults. As a result, their dosing is not very flexible and does not permit easy titration, which is essential for therapy in adolescents. According to World Health Organization guidelines, the ideal formulation should be safe, effective, affordable, convenient, and flexible in dosing, and it should possess a pharmacokinetic profile similar to that observed in pubertal physiology [130]. With TE being the main T option for adolescents, TRT practice in this patient population remains far from this ideal recommendation.
