madman
Super Moderator
Abstract
Delayed puberty (DP) defines retardation of onset/progression of sexual maturation beyond the expected age from either a lack/delay of the hypothalamic-pituitary-gonadal axis activation or a gonadal failure. DP usually gives rise to concern and uncertainty in patients and their families, potentially affecting their immediate psychosocial well-being and also creating longer-term psychosexual sequelae. The most frequent form of DP in younger teenagers is self-limiting and may not need any intervention. Conversely, DP from hypogonadism requires prompt and specific treatment that we summarize in this review. Hormone therapy primarily targets genital maturation, development of secondary sexual characteristics, and the achievement of target height in line with genetic potential, but other key standards of care include body composition and bone mass. Finally, pubertal induction should promote psychosexual development and mitigate both short and long-term impairments comprising low self-esteem, social withdrawal, depression, and psychosexual difficulties. Different therapeutic options for pubertal induction have been described for both males and females, but we lack the necessary larger randomized trials to define the best approaches for both sexes. We provide an in-depth and updated literature review regarding therapeutic options for inducing puberty in males and females, particularly focusing on recent therapeutic refinements that better encompass the heterogeneity of this population, and underlining key differences in therapeutic timing and goals. We also highlight persistent shortcomings in clinical practice, wherein strategies directed at “the child with delayed puberty of uncertain etiology” risk being misapplied to older adolescents likely to have permanent hypogonadism.
The conventional normal age ranges for the beginning of puberty are reported to be between 8 and 13 years of age in females, and 9 to 14 years in males, although secular changes are reported. The first clinical signs marking its onset are the enlargement of testis volume (TV) ≥ 4 mL or scrotum enlargement/pigmentation in males (designating progression from Tanner genital stage G1 to G2), and the appearance of breast buds in females (designating progression from Tanner stage B1 to B2) (1). Delayed puberty (DP) is defined as retardation of pubertal onset beyond the expected age (> 2-2.5 SDs above the mean of the reference population) (2); thus, no breast development by the age of 13 years in girls and no testicular enlargement by the age of 14 years in boys (1). The lack of Tanner stage progression after the beginning of puberty, evaluable on the basis of available nomograms (3, 4), together with a sudden drop in hormonal levels, has to be considered pathologic as well. The most common cause of DP in both sexes is a constitutional delay of growth and puberty (CDGP), a self-limited form of delayed puberty resulting from a transient GnRH deficiency often considered an extreme of the normal spectrum of pubertal timing. Pathological causes of DP (Table 1) must always be ruled out with an appropriate diagnostic workup (5-7), particularly in the presence of clinical suspicion.
Differentiating between CDGP and functional and congenital hypogonadotropic hypogonadism (CHH) during early adolescence is particularly challenging because of the many overlapping clinical, biochemical, and radiological features (5, 6, 8, 9), but the distinction is a necessary one as these conditions then diverge hugely in respect of their long-term outcomes. Permanent forms of hypogonadism causing DP requires specific treatment to induce or complete pubertal development, and reaching a correct and timely diagnosis thereof is crucial to promote patients’ somatic and sexual maturation and psychosocial well-being. It is also vital not to misdiagnose as CDGP those patients with retardation of growth and puberty resulting from parasellar lesion or systemic illness such as bowel disease or an eating disorder.
*We present here an in-depth review of the literature regarding therapeutic options available for pubertal induction in both males and females with hypogonadism, beginning with the more consolidated approaches and then proceeding to more novel advances in the field, considering the heterogeneity of this population and underlining differences in therapeutic timing and goals. We emphasize that CDGP should be a diagnosis of exclusion and not of default: notably, among older adolescents approaching the end of their teenage years, CDGP is no longer the majority and should not be seriously considered beyond 18 to 20 years of age. Based on Bayesian principles, the adverse consequences of not intervening pharmacologically.
Goals and Timing
Therapy should lead to the maturation of genitalia and of secondary sexual characteristics of patients with DP, whether young adolescents or older individuals who “slipped through the net,” and linear growth, body composition, muscle mass, and normal bone density should also be achieved (2, 10, 11)
Induction of Puberty in Males
Testosterone is the most frequently adopted pharmacological treatment in hypogonadal boys with DP because of its efficacy in inducing secondary sexual characteristics, growth spurt, bone maturation, and psychosexual development and its limited side effects and costs. However, testosterone alone cannot stimulate testicular growth or induce spermatogenesis, nor induce testicular descent in those with cryptorchidism (1, 2, 8, 29), whereas these goals can all be achieved in most CHH patients with combined gonadotropin treatment (2, 34-36), which may also give these patients significant psychological encouragement and enhance their self-confidence (2). Early induction of spermatogenesis may reduce the time required to reinduce it in adult life (29, 35, 37). CHH patients treated with gonadotropins achieve an androgen profile (both testosterone precursors and metabolites) that is closer to normal biochemistry than what is achievable with testosterone treatment (38), although the clinical relevance of this finding remains uncertain.
*Testosterone: types and routes of administration
*Testosterone: proposed therapeutic schemes
*Gonadotropins: types and routes of administration
*Gonadotropins: proposed therapeutic schemes and applications
*Patients’ follow-up and life-long replacement therapy
Induction of Puberty in Females
In females, adequate maturation of secondary sex characteristics is achieved with estrogen alone, whereas the main role of progesterone is to prevent endometrial hyperplasia. Indeed, clinical experience suggests that premature treatment with progestogen may be deleterious to both final breast and probably also final uterine maturation.
*Estrogens: types and routes of administration
*Progesterone: types and routes of administration
*Proposed therapeutic schemes
*Patients’ follow-up and life-long replacement therapy
Conclusions
Pubertal induction needs to be performed within a physiological timeframe to guarantee harmonious growth and sexual and psychological development. Hitherto, mainly studies with small case series or isolated experiences have been conducted for pubertal induction, often recruiting patients with different etiologies of hypogonadism or within broad age ranges at the start of treatment. It is hopeful to have carefully designed studies performed among specific and uniform populations to establish which treatment protocol is the most effective in each clinical condition, considering the heterogeneity of the populations to treat (180). Furthermore, as some treatments are still off-label, despite being already validated in clinical practice (such as gonadotropin treatment), multicenter randomized controlled trials would allow to officially extend the indication of these drugs to pubertal induction in young patients. These will need to be funded by national agencies, given that sex hormones are by and large low-cost drugs for which the costs of applying for a variation in product license are excessive compared with the additional earnings that would accrue to the relevant pharmaceutical company.
Hitherto, no standard of care exists for pubertal induction; however, some treatment strategies have consolidated in clinical practice. Useful tips for clinical practice in terms of both treatment strategies and clinical, laboratory, and instrumental assessments during follow-up are listed in Table 6.
Delayed puberty (DP) defines retardation of onset/progression of sexual maturation beyond the expected age from either a lack/delay of the hypothalamic-pituitary-gonadal axis activation or a gonadal failure. DP usually gives rise to concern and uncertainty in patients and their families, potentially affecting their immediate psychosocial well-being and also creating longer-term psychosexual sequelae. The most frequent form of DP in younger teenagers is self-limiting and may not need any intervention. Conversely, DP from hypogonadism requires prompt and specific treatment that we summarize in this review. Hormone therapy primarily targets genital maturation, development of secondary sexual characteristics, and the achievement of target height in line with genetic potential, but other key standards of care include body composition and bone mass. Finally, pubertal induction should promote psychosexual development and mitigate both short and long-term impairments comprising low self-esteem, social withdrawal, depression, and psychosexual difficulties. Different therapeutic options for pubertal induction have been described for both males and females, but we lack the necessary larger randomized trials to define the best approaches for both sexes. We provide an in-depth and updated literature review regarding therapeutic options for inducing puberty in males and females, particularly focusing on recent therapeutic refinements that better encompass the heterogeneity of this population, and underlining key differences in therapeutic timing and goals. We also highlight persistent shortcomings in clinical practice, wherein strategies directed at “the child with delayed puberty of uncertain etiology” risk being misapplied to older adolescents likely to have permanent hypogonadism.
The conventional normal age ranges for the beginning of puberty are reported to be between 8 and 13 years of age in females, and 9 to 14 years in males, although secular changes are reported. The first clinical signs marking its onset are the enlargement of testis volume (TV) ≥ 4 mL or scrotum enlargement/pigmentation in males (designating progression from Tanner genital stage G1 to G2), and the appearance of breast buds in females (designating progression from Tanner stage B1 to B2) (1). Delayed puberty (DP) is defined as retardation of pubertal onset beyond the expected age (> 2-2.5 SDs above the mean of the reference population) (2); thus, no breast development by the age of 13 years in girls and no testicular enlargement by the age of 14 years in boys (1). The lack of Tanner stage progression after the beginning of puberty, evaluable on the basis of available nomograms (3, 4), together with a sudden drop in hormonal levels, has to be considered pathologic as well. The most common cause of DP in both sexes is a constitutional delay of growth and puberty (CDGP), a self-limited form of delayed puberty resulting from a transient GnRH deficiency often considered an extreme of the normal spectrum of pubertal timing. Pathological causes of DP (Table 1) must always be ruled out with an appropriate diagnostic workup (5-7), particularly in the presence of clinical suspicion.
Differentiating between CDGP and functional and congenital hypogonadotropic hypogonadism (CHH) during early adolescence is particularly challenging because of the many overlapping clinical, biochemical, and radiological features (5, 6, 8, 9), but the distinction is a necessary one as these conditions then diverge hugely in respect of their long-term outcomes. Permanent forms of hypogonadism causing DP requires specific treatment to induce or complete pubertal development, and reaching a correct and timely diagnosis thereof is crucial to promote patients’ somatic and sexual maturation and psychosocial well-being. It is also vital not to misdiagnose as CDGP those patients with retardation of growth and puberty resulting from parasellar lesion or systemic illness such as bowel disease or an eating disorder.
*We present here an in-depth review of the literature regarding therapeutic options available for pubertal induction in both males and females with hypogonadism, beginning with the more consolidated approaches and then proceeding to more novel advances in the field, considering the heterogeneity of this population and underlining differences in therapeutic timing and goals. We emphasize that CDGP should be a diagnosis of exclusion and not of default: notably, among older adolescents approaching the end of their teenage years, CDGP is no longer the majority and should not be seriously considered beyond 18 to 20 years of age. Based on Bayesian principles, the adverse consequences of not intervening pharmacologically.
Goals and Timing
Therapy should lead to the maturation of genitalia and of secondary sexual characteristics of patients with DP, whether young adolescents or older individuals who “slipped through the net,” and linear growth, body composition, muscle mass, and normal bone density should also be achieved (2, 10, 11)
Induction of Puberty in Males
Testosterone is the most frequently adopted pharmacological treatment in hypogonadal boys with DP because of its efficacy in inducing secondary sexual characteristics, growth spurt, bone maturation, and psychosexual development and its limited side effects and costs. However, testosterone alone cannot stimulate testicular growth or induce spermatogenesis, nor induce testicular descent in those with cryptorchidism (1, 2, 8, 29), whereas these goals can all be achieved in most CHH patients with combined gonadotropin treatment (2, 34-36), which may also give these patients significant psychological encouragement and enhance their self-confidence (2). Early induction of spermatogenesis may reduce the time required to reinduce it in adult life (29, 35, 37). CHH patients treated with gonadotropins achieve an androgen profile (both testosterone precursors and metabolites) that is closer to normal biochemistry than what is achievable with testosterone treatment (38), although the clinical relevance of this finding remains uncertain.
*Testosterone: types and routes of administration
*Testosterone: proposed therapeutic schemes
*Gonadotropins: types and routes of administration
*Gonadotropins: proposed therapeutic schemes and applications
*Patients’ follow-up and life-long replacement therapy
Induction of Puberty in Females
In females, adequate maturation of secondary sex characteristics is achieved with estrogen alone, whereas the main role of progesterone is to prevent endometrial hyperplasia. Indeed, clinical experience suggests that premature treatment with progestogen may be deleterious to both final breast and probably also final uterine maturation.
*Estrogens: types and routes of administration
*Progesterone: types and routes of administration
*Proposed therapeutic schemes
*Patients’ follow-up and life-long replacement therapy
Conclusions
Pubertal induction needs to be performed within a physiological timeframe to guarantee harmonious growth and sexual and psychological development. Hitherto, mainly studies with small case series or isolated experiences have been conducted for pubertal induction, often recruiting patients with different etiologies of hypogonadism or within broad age ranges at the start of treatment. It is hopeful to have carefully designed studies performed among specific and uniform populations to establish which treatment protocol is the most effective in each clinical condition, considering the heterogeneity of the populations to treat (180). Furthermore, as some treatments are still off-label, despite being already validated in clinical practice (such as gonadotropin treatment), multicenter randomized controlled trials would allow to officially extend the indication of these drugs to pubertal induction in young patients. These will need to be funded by national agencies, given that sex hormones are by and large low-cost drugs for which the costs of applying for a variation in product license are excessive compared with the additional earnings that would accrue to the relevant pharmaceutical company.
Hitherto, no standard of care exists for pubertal induction; however, some treatment strategies have consolidated in clinical practice. Useful tips for clinical practice in terms of both treatment strategies and clinical, laboratory, and instrumental assessments during follow-up are listed in Table 6.
