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Corifollitropin Alfa Combined With Human Chorionic Gonadotropin in Adolescent Boys With Hypogonadotropic Hypogonadism (2022)
R. Ravi Shankar, Suneri Shah, Hee-Koung Joeng, Geraldine Mendizabal, Julia R. DiBello, Yanfen Guan, Barbara J. Stegmann, Eberhard Nieschlag, Hermann M. Behre, Ronald S. Swerdloff, Michelle C. Fox, and Keith D. Kaufman
Abstract
Context: Adolescent males with hypogonadotropic hypogonadism (HH) have traditionally been treated with exogenous testosterone (T) or human chorionic gonadotropin (hCG) to produce virilization; however, those modalities do not result in the growth of the testes and may promote premature maturation and terminal differentiation of Sertoli cells prior to their proliferation, which may impact future fertility. Another option is to use gonadotropins in those individuals to induce testicular growth, proliferation, and maturation of Sertoli cells, and production of endogenous T with consequent virilization.
Objective: We examined the efficacy and safety of corifollitropin alfa (CFA) combined with hCG for the induction of testicular growth and pubertal development in adolescent boys with HH.
Methods: This was a 64-week, multicenter, open-label, single-group study of CFA in adolescent boys, aged 14 to younger than 18 years, with HH. Seventeen participants initiated a 12-week priming period with CFA (100 μg if weight ≤ 60 kg, or 150 μg if weight > 60 kg) given subcutaneously once every 2 weeks, after which they entered a 52-week combined treatment period with CFA, once every 2 weeks, and subcutaneous hCG, twice-weekly (hCG dose adjusted between 500 IU and 5000 IU to keep total T and estradiol levels within protocol-specified ranges). The primary efficacy endpoint was change from baseline in testicular volume (TV), measured as the sum of volumes of the left and right testes by ultrasound.
Results: After 64 weeks of therapy with CFA/CFA combined with hCG, the geometric mean fold increase from baseline in TV was 9.43 (95% CI, 7.44-11.97) (arithmetic mean of change from baseline at week 64, 13.0 mL). Hormonal, Tanner stage, and growth velocity changes were consistent with the initiation and progression of puberty. Treatment was generally well tolerated. No participant developed anti-CFA antibodies.
Conclusion: Treatment of adolescent boys with HH with CFA alone for 12 weeks followed by CFA combined with hCG for 52 weeks induced testicular growth accompanied by pubertal progression, increased T, and a pubertal growth spurt (EudraCT: 2015-001878-18).
Male hypogonadotropic hypogonadism (HH) is characterized by impaired secretion of the pituitary gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH), resulting in insufficient testicular function including deficiencies in testosterone (T) production and spermatogenesis (1). HH can be the result of a primary defect in gonadotropin secretion by the pituitary gonadotrophs, or it can result from defects in gonadotropin-releasing hormone (GnRH) secretion by the hypothalamus. The clinical manifestations of HH depend on the stage of development at which the deficiency occurred (prepubertal or postpubertal). When the condition occurs before puberty (prepubertal), puberty is delayed or absent. The condition can be congenital or acquired and can occur in isolation, in association with anosmia/hyposmia, or it can occur as part of multiple pituitary hormone deficiency syndromes (2, 3). HH in young boys is associated with significant psychosocial impact and physical consequences leading to depression, anxiety, sexual dysfunction, and a lower quality of life (QoL), all of which may improve considerably with treatment (4). The standard treatment for HH in males is androgen (T) therapy in adolescence and human chorionic gonadotropin (hCG) with or without FSH when fertility is desired.
An important goal in the treatment of adolescent boys with HH is to increase serum T levels, leading to a pubertal growth spurt and the development of male secondary sexual characteristics (5-7). This can be achieved either through the administration of exogenous T or by using hCG to stimulate LH receptors on Leydig cells of the testes, thereby inducing the production of endogenous T. Another important goal in the treatment of adolescent boys with HH is to stimulate spermatogenesis, at an appropriate time, to support future fertility. Treatment with hCG alone can induce spermatogenesis, especially in patients with testicular volume (TV) greater than 4 mL at baseline (8), but may require prolonged treatment (9, 10). In contrast, a shorter duration of treatment with gonadotropins (both FSH and hCG) to induce puberty during adolescence has been reported to result in spermatogenesis (11). While the sequence of gonadotropins used in these treatment regimens to induce puberty has varied, when FSH is initiated before stimulation of the LH receptor, increases in TV, serum inhibin B levels into the adult range, and Sertoli cell and spermatogonia numbers in the testes, as well as a reduction in Sertoli cell to germ cell ratio (by biopsy) have been reported (3) when compared to a group in which both FSH and LH receptors were stimulated simultaneously from the start of therapy. Historically, adolescent boys with HH were not treated with FSH, as support for fertility was not the main goal of treatment at this age (5-7). Instead, these patients were administered exogenous T in a sufficient quantity to induce the development of male secondary sexual characteristics, and from then on, to maintain normal male T levels. However, T therapy alone does not induce testicular changes necessary to support fertility. It is possible that adolescent boys who are not exposed to FSH during the critical pubertal window required for Sertoli cell proliferation may miss this crucial period in testicular development; however, data on the responses to fertility induction in men with HH treated with T during adolescence are scant. Meta-analyses or reviews of the literature suggest mixed results, and it is possible that this results from a combination of patients with prepubertal as well as postpubertal onsets of HH (12, 13). One study that assessed this reported mixed responses to fertility-inducing therapies in men who were treated with T in adolescence (14). Treatment with hCG alone to induce endogenous production of T has the potential of inducing terminal differentiation of Sertoli cells before they have had the opportunity to undergo proliferation and maturation (3).
Treatment protocols using gonadotropins to induce puberty in adolescent boys with HH have involved pretreatment with hCG, followed by combined treatment with hCG and FSH or pulsatile GnRH (11, 15); or simultaneous initiation of hCG and FSH or use of pulsatile GnRH (16); or pretreatment with FSH followed by combined treatment with hCG and FSH or pulsatile GnRH (2, 17). Stimulation of endogenous T production with hCG is preferred over administration of exogenous T to induce virilization because hCG induces higher levels of intratesticular T, which promotes spermatogenesis and can stimulate additional testicular growth if the testes are still at a suboptimal volume (6). Inhibin B has been shown to be a useful surrogate for monitoring spermatogenic activity in boys when the semen analysis is not feasible (18).
Owing to its short half-life, recombinant FSH (recFSH) needs to be injected multiple times per week to maintain therapeutically effective levels; a treatment for HH that requires fewer injections may be more acceptable to adolescent boys and may result in fewer medication errors and improved adherence. Corifollitropin alfa (CFA; Elonva) is a recombinant gonadotropin consisting of the α-subunit of human FSH and a hybrid subunit composed of the sequence of the β-subunit of human FSH and the C-terminal peptide part of the β-subunit of hCG. CFA acts at the same gonadal FSH receptor as recFSH, but it has an approximately 2-fold longer elimination half-life and an almost 4-fold increase in time to peak serum levels (Tmax) compared with recFSH. A single injection of CFA replaces 7 days of daily recFSH injections when used to induce the development of ovarian follicles in women undergoing controlled ovarian stimulation during assisted reproductive technologies (19). For the treatment of males with HH, a single injection of CFA every 2 weeks is intended to replace FSH injections administered 2 to 3 times per week. A previous study in men with HH demonstrated that CFA administered once every 2 weeks in combination with hCG for 52 weeks increased TV significantly and induced spermatogenesis in 77% of patients who had remained azoospermic after a 12-week treatment with hCG alone (20). The present study examined the efficacy and safety of 64 weeks of therapy with CFA administered once every 2 weeks (alone for 12 weeks and then combined with hCG for weeks 12-64) in adolescent boys aged 14 to younger than 18 years with HH. The sequence of gonadotropin therapy used in this study, with CFA alone (priming period) followed by combined treatment with CFA and hCG, was chosen to approximate normal pubertal changes as well as to optimize increases in Sertoli cell number (and TV) before their maturation due to exposure to T.
Results
*Demographics and Baseline Characteristics
*Corifollitropin Alfa Serum Concentration
*Testicular Development
*Anthropometric Measures and Growth Velocity
*Tanner Staging
*Hormonal and Sex Hormone–binding Globulin Responses
*Safety
In conclusion, treatment with CFA (alone for 12 weeks and then combined with hCG for weeks 12-64) was generally well tolerated and demonstrated benefit for the induction of testicular growth and normal pubertal development in adolescent boys with HH. These results suggest that CFA can replace recFSH as an option involving fewer injections in the treatment of adolescent boys with HH in whom support of spermatogenesis is an important component of the desired outcome. Furthermore, fewer injections with CFA are needed compared with a treatment regimen that uses recFSH, and this may decrease the treatment burden and improve adherence, a benefit considered particularly attractive for an adolescent male population.
R. Ravi Shankar, Suneri Shah, Hee-Koung Joeng, Geraldine Mendizabal, Julia R. DiBello, Yanfen Guan, Barbara J. Stegmann, Eberhard Nieschlag, Hermann M. Behre, Ronald S. Swerdloff, Michelle C. Fox, and Keith D. Kaufman
Abstract
Context: Adolescent males with hypogonadotropic hypogonadism (HH) have traditionally been treated with exogenous testosterone (T) or human chorionic gonadotropin (hCG) to produce virilization; however, those modalities do not result in the growth of the testes and may promote premature maturation and terminal differentiation of Sertoli cells prior to their proliferation, which may impact future fertility. Another option is to use gonadotropins in those individuals to induce testicular growth, proliferation, and maturation of Sertoli cells, and production of endogenous T with consequent virilization.
Objective: We examined the efficacy and safety of corifollitropin alfa (CFA) combined with hCG for the induction of testicular growth and pubertal development in adolescent boys with HH.
Methods: This was a 64-week, multicenter, open-label, single-group study of CFA in adolescent boys, aged 14 to younger than 18 years, with HH. Seventeen participants initiated a 12-week priming period with CFA (100 μg if weight ≤ 60 kg, or 150 μg if weight > 60 kg) given subcutaneously once every 2 weeks, after which they entered a 52-week combined treatment period with CFA, once every 2 weeks, and subcutaneous hCG, twice-weekly (hCG dose adjusted between 500 IU and 5000 IU to keep total T and estradiol levels within protocol-specified ranges). The primary efficacy endpoint was change from baseline in testicular volume (TV), measured as the sum of volumes of the left and right testes by ultrasound.
Results: After 64 weeks of therapy with CFA/CFA combined with hCG, the geometric mean fold increase from baseline in TV was 9.43 (95% CI, 7.44-11.97) (arithmetic mean of change from baseline at week 64, 13.0 mL). Hormonal, Tanner stage, and growth velocity changes were consistent with the initiation and progression of puberty. Treatment was generally well tolerated. No participant developed anti-CFA antibodies.
Conclusion: Treatment of adolescent boys with HH with CFA alone for 12 weeks followed by CFA combined with hCG for 52 weeks induced testicular growth accompanied by pubertal progression, increased T, and a pubertal growth spurt (EudraCT: 2015-001878-18).
Male hypogonadotropic hypogonadism (HH) is characterized by impaired secretion of the pituitary gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH), resulting in insufficient testicular function including deficiencies in testosterone (T) production and spermatogenesis (1). HH can be the result of a primary defect in gonadotropin secretion by the pituitary gonadotrophs, or it can result from defects in gonadotropin-releasing hormone (GnRH) secretion by the hypothalamus. The clinical manifestations of HH depend on the stage of development at which the deficiency occurred (prepubertal or postpubertal). When the condition occurs before puberty (prepubertal), puberty is delayed or absent. The condition can be congenital or acquired and can occur in isolation, in association with anosmia/hyposmia, or it can occur as part of multiple pituitary hormone deficiency syndromes (2, 3). HH in young boys is associated with significant psychosocial impact and physical consequences leading to depression, anxiety, sexual dysfunction, and a lower quality of life (QoL), all of which may improve considerably with treatment (4). The standard treatment for HH in males is androgen (T) therapy in adolescence and human chorionic gonadotropin (hCG) with or without FSH when fertility is desired.
An important goal in the treatment of adolescent boys with HH is to increase serum T levels, leading to a pubertal growth spurt and the development of male secondary sexual characteristics (5-7). This can be achieved either through the administration of exogenous T or by using hCG to stimulate LH receptors on Leydig cells of the testes, thereby inducing the production of endogenous T. Another important goal in the treatment of adolescent boys with HH is to stimulate spermatogenesis, at an appropriate time, to support future fertility. Treatment with hCG alone can induce spermatogenesis, especially in patients with testicular volume (TV) greater than 4 mL at baseline (8), but may require prolonged treatment (9, 10). In contrast, a shorter duration of treatment with gonadotropins (both FSH and hCG) to induce puberty during adolescence has been reported to result in spermatogenesis (11). While the sequence of gonadotropins used in these treatment regimens to induce puberty has varied, when FSH is initiated before stimulation of the LH receptor, increases in TV, serum inhibin B levels into the adult range, and Sertoli cell and spermatogonia numbers in the testes, as well as a reduction in Sertoli cell to germ cell ratio (by biopsy) have been reported (3) when compared to a group in which both FSH and LH receptors were stimulated simultaneously from the start of therapy. Historically, adolescent boys with HH were not treated with FSH, as support for fertility was not the main goal of treatment at this age (5-7). Instead, these patients were administered exogenous T in a sufficient quantity to induce the development of male secondary sexual characteristics, and from then on, to maintain normal male T levels. However, T therapy alone does not induce testicular changes necessary to support fertility. It is possible that adolescent boys who are not exposed to FSH during the critical pubertal window required for Sertoli cell proliferation may miss this crucial period in testicular development; however, data on the responses to fertility induction in men with HH treated with T during adolescence are scant. Meta-analyses or reviews of the literature suggest mixed results, and it is possible that this results from a combination of patients with prepubertal as well as postpubertal onsets of HH (12, 13). One study that assessed this reported mixed responses to fertility-inducing therapies in men who were treated with T in adolescence (14). Treatment with hCG alone to induce endogenous production of T has the potential of inducing terminal differentiation of Sertoli cells before they have had the opportunity to undergo proliferation and maturation (3).
Treatment protocols using gonadotropins to induce puberty in adolescent boys with HH have involved pretreatment with hCG, followed by combined treatment with hCG and FSH or pulsatile GnRH (11, 15); or simultaneous initiation of hCG and FSH or use of pulsatile GnRH (16); or pretreatment with FSH followed by combined treatment with hCG and FSH or pulsatile GnRH (2, 17). Stimulation of endogenous T production with hCG is preferred over administration of exogenous T to induce virilization because hCG induces higher levels of intratesticular T, which promotes spermatogenesis and can stimulate additional testicular growth if the testes are still at a suboptimal volume (6). Inhibin B has been shown to be a useful surrogate for monitoring spermatogenic activity in boys when the semen analysis is not feasible (18).
Owing to its short half-life, recombinant FSH (recFSH) needs to be injected multiple times per week to maintain therapeutically effective levels; a treatment for HH that requires fewer injections may be more acceptable to adolescent boys and may result in fewer medication errors and improved adherence. Corifollitropin alfa (CFA; Elonva) is a recombinant gonadotropin consisting of the α-subunit of human FSH and a hybrid subunit composed of the sequence of the β-subunit of human FSH and the C-terminal peptide part of the β-subunit of hCG. CFA acts at the same gonadal FSH receptor as recFSH, but it has an approximately 2-fold longer elimination half-life and an almost 4-fold increase in time to peak serum levels (Tmax) compared with recFSH. A single injection of CFA replaces 7 days of daily recFSH injections when used to induce the development of ovarian follicles in women undergoing controlled ovarian stimulation during assisted reproductive technologies (19). For the treatment of males with HH, a single injection of CFA every 2 weeks is intended to replace FSH injections administered 2 to 3 times per week. A previous study in men with HH demonstrated that CFA administered once every 2 weeks in combination with hCG for 52 weeks increased TV significantly and induced spermatogenesis in 77% of patients who had remained azoospermic after a 12-week treatment with hCG alone (20). The present study examined the efficacy and safety of 64 weeks of therapy with CFA administered once every 2 weeks (alone for 12 weeks and then combined with hCG for weeks 12-64) in adolescent boys aged 14 to younger than 18 years with HH. The sequence of gonadotropin therapy used in this study, with CFA alone (priming period) followed by combined treatment with CFA and hCG, was chosen to approximate normal pubertal changes as well as to optimize increases in Sertoli cell number (and TV) before their maturation due to exposure to T.
Results
*Demographics and Baseline Characteristics
*Corifollitropin Alfa Serum Concentration
*Testicular Development
*Anthropometric Measures and Growth Velocity
*Tanner Staging
*Hormonal and Sex Hormone–binding Globulin Responses
*Safety
In conclusion, treatment with CFA (alone for 12 weeks and then combined with hCG for weeks 12-64) was generally well tolerated and demonstrated benefit for the induction of testicular growth and normal pubertal development in adolescent boys with HH. These results suggest that CFA can replace recFSH as an option involving fewer injections in the treatment of adolescent boys with HH in whom support of spermatogenesis is an important component of the desired outcome. Furthermore, fewer injections with CFA are needed compared with a treatment regimen that uses recFSH, and this may decrease the treatment burden and improve adherence, a benefit considered particularly attractive for an adolescent male population.
