madman
Super Moderator
Considerations when treating male pubertal delay pharmacologically (2022)
Rodolfo A. Rey
ABSTRACT
Introduction: Delayed puberty, usually affects psychosocial well-being. Patients and their parents show concern about genital development and stature. The condition is transient in most patients; nonetheless, the opportunity should not be missed to diagnose an underlying illness.
Areas covered: The etiologies of pubertal delay in males and their specific pharmacological therapies are discussed in this review.
Expert opinion: High-quality evidence addressing the best pharmacological therapy approach for each etiology of delayed puberty in males is scarce, and most of the current practice is based on small case series or unpublished experiences. Male teenagers seeking attention for the pubertal delay most probably benefit from medical treatment to avoid psychosocial distress. While watchful waiting is appropriate in 12- to 14-year-old boys when the constitutional delay of growth and puberty (CGDP) is suspected, hormone replacement should not be delayed beyond the age of 14 years. When hypogonadism is diagnosed, hormone replacement should be proposed by the age of 12 years. Testosterone replacement has been used for decades and is fairly standardized. Aromatase inhibitors have arisen as an interesting alternative. Gonadotrophin therapy seems more physiological in patients with central hypogonadism, but its efficacy and timing still need to be established.
1. Introduction
Puberty is the most spectacularly changing period of postnatal development, characterized by the development of secondary sexual characteristics and the attainment of adult height and physiological features, including fertility [1–3]. Childhood shows a relatively constant height velocity, mainly regulated by the growth hormone (GH)–insulin-like growth factors (IGFs) axis. The reproductive axis shows a dissociated quiescence, characterized in males by reduced activity of the gonadotrophin-releasing hormone (GnRH)–luteinizing hormone (LH)– Leydig cell axis responsible for androgen secretion and a relatively more active follicle-stimulating hormone (FSH)– Sertoli cell axis responsible for anti-Müllerian hormone (AMH) and inhibin B production (Figure 1).
Pubertal onset is characterized by the reactivation of the GnRH-secreting neurons [4]. Consequently, FSH and LH levels increase progressively. FSH impacts the hitherto immature testicular Sertoli cells by inducing cell proliferation that results in an initial increase in testicular volume. LH promotes Leydig cell androgen secretion, thus increasing intratesticular testosterone concentration, which induces the maturation of Sertoli cells that cease to proliferate. Mature Sertoli cells dramatically decrease their AMH production, increase inhibin B secretion, and become capable of supporting adult spermatogenesis; the latter process is responsible for the notorious enlargement of the testes [5,6]. Concomitantly, Leydig cell testosterone secretion continues to increase, resulting in an elevation in circulating levels that drive the development of secondary sexual characteristics and the pubertal growth spurt and bone mass accrual, either directly or after androgen conversion to estrogens by the enzyme aromatase [7,8].
From a clinical standpoint, the first sign of male puberty is testicular enlargement attaining a volume of 4 ml as measured by comparison to Prader’s orchidometer, or 2.7 ml when measured by ultrasonography [9]. The clinical changes occurring during puberty, described in detail by Marshall and Tanner in 1970 [10], continue to be the milestones used in everyday practice for assessing pubertal disorders. Genital stage 1 (G1) reflects prepubertal features; stage G2 indicates the clinical onset of puberty, with 4-ml testes as its landmark; serum testosterone levels become detectable usually during stage G3 [11]; peak growth velocity occurs during stage G4, and stage G5 is the adult stage. Pubertal onset occurs in 95% of boys between the ages of 9.5 and 13.5 years [10,12–14]; therefore, consensus exists on defining pubertal delay in males when the testicular volume has not attained 4 ml by the age of 14 years, i.e. 2 to 2.5 standard deviations beyond the mean for the population [1,10,15,16]. Once triggered, puberty progresses at approximately one Tanner stage per year [2,10,12–14]; failure to achieve completion of pubertal development, i.e. testicular volume <15 ml and genital stage <G5, within 5 years prompts the diagnosis of arrested puberty.
The prevalence of pubertal delay in males has not been exhaustively studied. Based on the above-mentioned definition of delayed puberty, which is statistical, approximately 2.5% of male adolescents should experience delayed puberty. Nevertheless, the actual prevalence is likely higher because transient forms may remain undiagnosed [17]. Late pubertal onset usually affects psychosocial well-being in male teenagers. Patients and their parents are often concerned about stature and genital development. Even though the condition is benign and transient in approximately 2/3 of the cases, it represents an important opportunity to diagnose an underlying illness [16].
Another issue that needs to be considered in the physiology of pubertal growth is that sex steroids exert an important influence on pituitary growth hormone (GH) secretion and its action in target organs. Indeed, estrogens – and testosterone through its aromatization – upregulate central GH secretion resulting in higher serum levels of insulin-like growth factor 1 (IGF1), mainly produced by the liver, and the main responsible for linear growth in postnatal life [18]. Interestingly, dihydrotestosterone (DHT), a more potent androgen that is not aromatisable, is unable to induce GH secretion [19,20]. Additionally, testosterone elicits a peripheral action by amplifying GH-mediated IGF1 secretion [20].
2. Etiologies of pubertal delay in males
Strictly, underlying the concept of delayed puberty in males is the assumption that puberty will begin spontaneously before the age of 18 years [15–17]. It comes out clear that the diagnosis of pubertal delay is retrospective. In fact, when a boy seeks medical attention owing to the lack of pubertal signs, it is most frequently impossible on his first visit to predict whether puberty will occur spontaneously, and it often remains difficult even after performing the usual diagnostic tests [17,21,22]. Therefore, the term ‘absence of pubertal signs’ would be more adequate than ‘pubertal delay.’ However, since ‘pubertal delay’ and ‘delayed puberty’ are widely used in the literature to refer to the absence of pubertal signs, these expressions will be employed in this review for the sake of simplicity.
2.1. Constitutional delay of growth and puberty (CGDP)
2.2. Primary hypogonadism
2.3. Central hypogonadism
2.3.1. Functional central hypogonadism
2.3.2. Organic central hypogonadism
3. Pharmacological therapy options
The aims of treatment in teenagers with delayed puberty are the development of the genitalia and of secondary sexual characteristics, the adequate attainment of the growth spurt and peak bone mass – resulting in normal linear growth, body composition, muscle mass and bone density – [32], as well as the promotion of psychosexual development, thus preventing low self-esteem and body image concerns resulting in social withdrawal and sexual inactivity in later life [33]
3.1. No diagnosis established: to treat or not to treat?
3.2. CDGP
3.2.1. Androgenic drugs
3.2.1.1. Testosterone
3.2.1.2. Oxandrolone
3.2.2. Aromatase inhibitors
3.3. Central hypogonadism
3.3.1. Testosterone
3.3.2. Gonadotrophins
3.3.3. GnRH
3.3.4. Selective estrogen receptor modulators
3.4. Primary hypogonadism
4. Conclusion
Testosterone replacement therapy has been used for decades to induce secondary sexual characteristics and a pubertal growth spurt in male teenagers with delayed puberty for short periods in patients with CDGP and as a permanent treatment in those with primary or central hypogonadism. The longstanding experience indicates that low-dose starting treatments with progressive scaling to attain serum testosterone levels in the adult range within 2–3 years are safe and efficacious. Aromatase inhibitors have arisen as an alternative to induce pubertal androgenization while preserving the growth cartilage at the epiphyseal plate, thus especially interesting when short stature is a concern. Finally, pulsatile GnRH treatment using special pumps and gonadotrophin replacement therapies, starting with FSH and subsequently adding hCG or LH, is needed to induce spermatogenesis in patients with central hypogonadism. These treatments have only been used under research protocols. Whether these complex regimens should be used to induce pubertal changes, or only later in adulthood when fertility is sought, is still a matter of debate.
5. Expert opinion
Unfortunately, there is little high-quality evidence published addressing the best approach in the pharmacological therapy of delayed puberty in males. Most of the current practice is based on unpublished experience or limited case series. Notwithstanding, a wide consensus exists that male teenagers seeking medical attention for pubertal delay would most probably need pharmacologic therapy to avoid psychosocial distress, and that hormone replacement should not be delayed beyond the age of 14 years in order to harness the height potential and maximize the peak bone mass. While watchful waiting is appropriate between the ages of 12 and 14 years when no definitive etiological diagnosis could be reached – thus probably indicating that CGDP is the reason for the absence of pubertal signs – hormone replacement should be readily proposed by the age of 12 years in boys with a clearly established diagnosis of primary or central hypogonadism. The search for a general illness should not be overlooked in order to rule out functional central hypogonadism not needing hormonal replacement.
Pharmacological therapy may also be offered for a short term (3–6 months) to boys with a likely diagnosis of CDGP between 12 and 14 years of age when a clear lack of psychosocial adjustment is noticed. Nevertheless, the endocrinologist should be careful when indicating testosterone therapy in these cases. The psychosocial benefit needs to be better substantiated. Most of the conclusions are drawn from observational studies describing impaired self-esteem, and more prevalent psychopathology and risky behavior in teenagers with pubertal delay. Although time-series studies have shown some beneficial effects after testosterone therapy, quality of life scores remained significantly lower than in boys with normal pubertal timing in many aspects, e.g. emotional role difficulty and satisfaction with general health and social function [33]. The body changes produced by the low testosterone doses used in these cases may result insufficient as compared to those expected by the adolescent, and professional psychological support is certainly warranted.
Whether low-dose testosterone therapy ‘induces’ puberty remains elusive. It certainly induces physical changes in the genitals, skeleton, and muscles. However, there is not sufficient evidence to prove that it triggers the reactivation of the hypothalamic-gonadotroph axis. The existing time-series (or ‘before and after) studies show that after 6 months of testosterone treatment, there is an increased prevalence of higher gonadotropin levels and testicular enlargement as compared to before treatment. This could be due to the intervention, but also to the elapsed time. To test the hypothesis adequately, the study design would certainly be too complex and the sample size too big to justify the initiative.
No doubt exists that testosterone therapy is the only possibility in boys with delayed puberty due to primary hypogonadism and that treatment should be started with no delay when chronological age is 11.5–12 years and bone age is >11 years. If pubertal signs develop spontaneously, but the tempo of progression is too slow or puberty is arrested, testosterone therapy also seems warranted even though no clinical studies have specifically addressed this issue. The question is how long the attending physician should wait until starting testosterone replacement. Once again, there are no studies that could provide evidence, and the decision is mainly based on the knowledge of physiology: if a genital stage or serum testosterone concentrations persist with no significant change for more than 1 year, hormone replacement should be considered. This is the art of medicine and requires clinical judgment.
A hitherto unsolved question is whether gonadotrophin or GnRH treatment should be preferred over testosterone therapy for the induction of pubertal changes in teenagers with central hypogonadism. A physiology-based approach would support the use of GnRH or gonadotrophins, with FSH preceding LH or hCG, in order to obtain more efficient spermatogenesis. However, the practical answer should be given by controlled clinical trials with a sufficient sample size in the adequate population, i.e. teenagers aged 12–14 years (the available studies generally include older teenagers and young adults). One arm should receive GnRH/gonadotrophins for some time (androgenization and induction of spermatogenesis) before switching to testosterone (maintenance of androgenic and anabolic effects), while the other arm should be treated with testosterone all the time (no spermatogenesis, only androgenic and anabolic effects); then both groups should receive GnRH or gonadotrophins to (re) induce spermatogenesis and the primary fertility outcome should be compared in both groups. Many further questions arise. For how long should GnRH or gonadotrophin treatment be maintained both in the induction and the (re) induction phases? Which is the most adequate primary outcome: sperm count, pregnancy rate, time to pregnancy, or other? Once again, the necessary studies may prove too complex/long. A more pragmatic approach, based on the observation that previous testosterone therapy does not hamper the induction of spermatogenesis by gonadotrophin treatment during adolescence [45], would be to start with testosterone therapy and maintain it until the patient seeks fertility. Nonetheless, when gonadotrophin treatment is considered, attention should be driven to the negative predictors of response to treatment: a worse prognosis in terms of final testicular volume and sperm count is observed in patients with a history of bilateral cryptorchidism, low initial testicular volume or a genetic etiology associated with severe GnRH deficiency since fetal life [35,45,86,99].
Rodolfo A. Rey
ABSTRACT
Introduction: Delayed puberty, usually affects psychosocial well-being. Patients and their parents show concern about genital development and stature. The condition is transient in most patients; nonetheless, the opportunity should not be missed to diagnose an underlying illness.
Areas covered: The etiologies of pubertal delay in males and their specific pharmacological therapies are discussed in this review.
Expert opinion: High-quality evidence addressing the best pharmacological therapy approach for each etiology of delayed puberty in males is scarce, and most of the current practice is based on small case series or unpublished experiences. Male teenagers seeking attention for the pubertal delay most probably benefit from medical treatment to avoid psychosocial distress. While watchful waiting is appropriate in 12- to 14-year-old boys when the constitutional delay of growth and puberty (CGDP) is suspected, hormone replacement should not be delayed beyond the age of 14 years. When hypogonadism is diagnosed, hormone replacement should be proposed by the age of 12 years. Testosterone replacement has been used for decades and is fairly standardized. Aromatase inhibitors have arisen as an interesting alternative. Gonadotrophin therapy seems more physiological in patients with central hypogonadism, but its efficacy and timing still need to be established.
1. Introduction
Puberty is the most spectacularly changing period of postnatal development, characterized by the development of secondary sexual characteristics and the attainment of adult height and physiological features, including fertility [1–3]. Childhood shows a relatively constant height velocity, mainly regulated by the growth hormone (GH)–insulin-like growth factors (IGFs) axis. The reproductive axis shows a dissociated quiescence, characterized in males by reduced activity of the gonadotrophin-releasing hormone (GnRH)–luteinizing hormone (LH)– Leydig cell axis responsible for androgen secretion and a relatively more active follicle-stimulating hormone (FSH)– Sertoli cell axis responsible for anti-Müllerian hormone (AMH) and inhibin B production (Figure 1).
Pubertal onset is characterized by the reactivation of the GnRH-secreting neurons [4]. Consequently, FSH and LH levels increase progressively. FSH impacts the hitherto immature testicular Sertoli cells by inducing cell proliferation that results in an initial increase in testicular volume. LH promotes Leydig cell androgen secretion, thus increasing intratesticular testosterone concentration, which induces the maturation of Sertoli cells that cease to proliferate. Mature Sertoli cells dramatically decrease their AMH production, increase inhibin B secretion, and become capable of supporting adult spermatogenesis; the latter process is responsible for the notorious enlargement of the testes [5,6]. Concomitantly, Leydig cell testosterone secretion continues to increase, resulting in an elevation in circulating levels that drive the development of secondary sexual characteristics and the pubertal growth spurt and bone mass accrual, either directly or after androgen conversion to estrogens by the enzyme aromatase [7,8].
From a clinical standpoint, the first sign of male puberty is testicular enlargement attaining a volume of 4 ml as measured by comparison to Prader’s orchidometer, or 2.7 ml when measured by ultrasonography [9]. The clinical changes occurring during puberty, described in detail by Marshall and Tanner in 1970 [10], continue to be the milestones used in everyday practice for assessing pubertal disorders. Genital stage 1 (G1) reflects prepubertal features; stage G2 indicates the clinical onset of puberty, with 4-ml testes as its landmark; serum testosterone levels become detectable usually during stage G3 [11]; peak growth velocity occurs during stage G4, and stage G5 is the adult stage. Pubertal onset occurs in 95% of boys between the ages of 9.5 and 13.5 years [10,12–14]; therefore, consensus exists on defining pubertal delay in males when the testicular volume has not attained 4 ml by the age of 14 years, i.e. 2 to 2.5 standard deviations beyond the mean for the population [1,10,15,16]. Once triggered, puberty progresses at approximately one Tanner stage per year [2,10,12–14]; failure to achieve completion of pubertal development, i.e. testicular volume <15 ml and genital stage <G5, within 5 years prompts the diagnosis of arrested puberty.
The prevalence of pubertal delay in males has not been exhaustively studied. Based on the above-mentioned definition of delayed puberty, which is statistical, approximately 2.5% of male adolescents should experience delayed puberty. Nevertheless, the actual prevalence is likely higher because transient forms may remain undiagnosed [17]. Late pubertal onset usually affects psychosocial well-being in male teenagers. Patients and their parents are often concerned about stature and genital development. Even though the condition is benign and transient in approximately 2/3 of the cases, it represents an important opportunity to diagnose an underlying illness [16].
Another issue that needs to be considered in the physiology of pubertal growth is that sex steroids exert an important influence on pituitary growth hormone (GH) secretion and its action in target organs. Indeed, estrogens – and testosterone through its aromatization – upregulate central GH secretion resulting in higher serum levels of insulin-like growth factor 1 (IGF1), mainly produced by the liver, and the main responsible for linear growth in postnatal life [18]. Interestingly, dihydrotestosterone (DHT), a more potent androgen that is not aromatisable, is unable to induce GH secretion [19,20]. Additionally, testosterone elicits a peripheral action by amplifying GH-mediated IGF1 secretion [20].
2. Etiologies of pubertal delay in males
Strictly, underlying the concept of delayed puberty in males is the assumption that puberty will begin spontaneously before the age of 18 years [15–17]. It comes out clear that the diagnosis of pubertal delay is retrospective. In fact, when a boy seeks medical attention owing to the lack of pubertal signs, it is most frequently impossible on his first visit to predict whether puberty will occur spontaneously, and it often remains difficult even after performing the usual diagnostic tests [17,21,22]. Therefore, the term ‘absence of pubertal signs’ would be more adequate than ‘pubertal delay.’ However, since ‘pubertal delay’ and ‘delayed puberty’ are widely used in the literature to refer to the absence of pubertal signs, these expressions will be employed in this review for the sake of simplicity.
2.1. Constitutional delay of growth and puberty (CGDP)
2.2. Primary hypogonadism
2.3. Central hypogonadism
2.3.1. Functional central hypogonadism
2.3.2. Organic central hypogonadism
3. Pharmacological therapy options
The aims of treatment in teenagers with delayed puberty are the development of the genitalia and of secondary sexual characteristics, the adequate attainment of the growth spurt and peak bone mass – resulting in normal linear growth, body composition, muscle mass and bone density – [32], as well as the promotion of psychosexual development, thus preventing low self-esteem and body image concerns resulting in social withdrawal and sexual inactivity in later life [33]
3.1. No diagnosis established: to treat or not to treat?
3.2. CDGP
3.2.1. Androgenic drugs
3.2.1.1. Testosterone
3.2.1.2. Oxandrolone
3.2.2. Aromatase inhibitors
3.3. Central hypogonadism
3.3.1. Testosterone
3.3.2. Gonadotrophins
3.3.3. GnRH
3.3.4. Selective estrogen receptor modulators
3.4. Primary hypogonadism
4. Conclusion
Testosterone replacement therapy has been used for decades to induce secondary sexual characteristics and a pubertal growth spurt in male teenagers with delayed puberty for short periods in patients with CDGP and as a permanent treatment in those with primary or central hypogonadism. The longstanding experience indicates that low-dose starting treatments with progressive scaling to attain serum testosterone levels in the adult range within 2–3 years are safe and efficacious. Aromatase inhibitors have arisen as an alternative to induce pubertal androgenization while preserving the growth cartilage at the epiphyseal plate, thus especially interesting when short stature is a concern. Finally, pulsatile GnRH treatment using special pumps and gonadotrophin replacement therapies, starting with FSH and subsequently adding hCG or LH, is needed to induce spermatogenesis in patients with central hypogonadism. These treatments have only been used under research protocols. Whether these complex regimens should be used to induce pubertal changes, or only later in adulthood when fertility is sought, is still a matter of debate.
5. Expert opinion
Unfortunately, there is little high-quality evidence published addressing the best approach in the pharmacological therapy of delayed puberty in males. Most of the current practice is based on unpublished experience or limited case series. Notwithstanding, a wide consensus exists that male teenagers seeking medical attention for pubertal delay would most probably need pharmacologic therapy to avoid psychosocial distress, and that hormone replacement should not be delayed beyond the age of 14 years in order to harness the height potential and maximize the peak bone mass. While watchful waiting is appropriate between the ages of 12 and 14 years when no definitive etiological diagnosis could be reached – thus probably indicating that CGDP is the reason for the absence of pubertal signs – hormone replacement should be readily proposed by the age of 12 years in boys with a clearly established diagnosis of primary or central hypogonadism. The search for a general illness should not be overlooked in order to rule out functional central hypogonadism not needing hormonal replacement.
Pharmacological therapy may also be offered for a short term (3–6 months) to boys with a likely diagnosis of CDGP between 12 and 14 years of age when a clear lack of psychosocial adjustment is noticed. Nevertheless, the endocrinologist should be careful when indicating testosterone therapy in these cases. The psychosocial benefit needs to be better substantiated. Most of the conclusions are drawn from observational studies describing impaired self-esteem, and more prevalent psychopathology and risky behavior in teenagers with pubertal delay. Although time-series studies have shown some beneficial effects after testosterone therapy, quality of life scores remained significantly lower than in boys with normal pubertal timing in many aspects, e.g. emotional role difficulty and satisfaction with general health and social function [33]. The body changes produced by the low testosterone doses used in these cases may result insufficient as compared to those expected by the adolescent, and professional psychological support is certainly warranted.
Whether low-dose testosterone therapy ‘induces’ puberty remains elusive. It certainly induces physical changes in the genitals, skeleton, and muscles. However, there is not sufficient evidence to prove that it triggers the reactivation of the hypothalamic-gonadotroph axis. The existing time-series (or ‘before and after) studies show that after 6 months of testosterone treatment, there is an increased prevalence of higher gonadotropin levels and testicular enlargement as compared to before treatment. This could be due to the intervention, but also to the elapsed time. To test the hypothesis adequately, the study design would certainly be too complex and the sample size too big to justify the initiative.
No doubt exists that testosterone therapy is the only possibility in boys with delayed puberty due to primary hypogonadism and that treatment should be started with no delay when chronological age is 11.5–12 years and bone age is >11 years. If pubertal signs develop spontaneously, but the tempo of progression is too slow or puberty is arrested, testosterone therapy also seems warranted even though no clinical studies have specifically addressed this issue. The question is how long the attending physician should wait until starting testosterone replacement. Once again, there are no studies that could provide evidence, and the decision is mainly based on the knowledge of physiology: if a genital stage or serum testosterone concentrations persist with no significant change for more than 1 year, hormone replacement should be considered. This is the art of medicine and requires clinical judgment.
A hitherto unsolved question is whether gonadotrophin or GnRH treatment should be preferred over testosterone therapy for the induction of pubertal changes in teenagers with central hypogonadism. A physiology-based approach would support the use of GnRH or gonadotrophins, with FSH preceding LH or hCG, in order to obtain more efficient spermatogenesis. However, the practical answer should be given by controlled clinical trials with a sufficient sample size in the adequate population, i.e. teenagers aged 12–14 years (the available studies generally include older teenagers and young adults). One arm should receive GnRH/gonadotrophins for some time (androgenization and induction of spermatogenesis) before switching to testosterone (maintenance of androgenic and anabolic effects), while the other arm should be treated with testosterone all the time (no spermatogenesis, only androgenic and anabolic effects); then both groups should receive GnRH or gonadotrophins to (re) induce spermatogenesis and the primary fertility outcome should be compared in both groups. Many further questions arise. For how long should GnRH or gonadotrophin treatment be maintained both in the induction and the (re) induction phases? Which is the most adequate primary outcome: sperm count, pregnancy rate, time to pregnancy, or other? Once again, the necessary studies may prove too complex/long. A more pragmatic approach, based on the observation that previous testosterone therapy does not hamper the induction of spermatogenesis by gonadotrophin treatment during adolescence [45], would be to start with testosterone therapy and maintain it until the patient seeks fertility. Nonetheless, when gonadotrophin treatment is considered, attention should be driven to the negative predictors of response to treatment: a worse prognosis in terms of final testicular volume and sperm count is observed in patients with a history of bilateral cryptorchidism, low initial testicular volume or a genetic etiology associated with severe GnRH deficiency since fetal life [35,45,86,99].
