madman
Super Moderator
Subcutaneous self-administration of highly purified follicle-stimulating hormone and human chorionic gonadotrophin for the treatment of male hypogonadotropic hypogonadism (1997)
ABSTRACT
The efficacy and safety of highly purified follicle-stimulating hormone (FSH) associated with human chorionic gonadotrophin (HCG) were studied in 60 men with hypogonadotropic hypogonadism. Of these men, 16 suffered from Kallmann's syndrome, 19 from idiopathic hypogonadotropic hypogonadism, and 25 from hypopituitarism. Basal testosterone concentrations were found to be far below the normal range. At baseline, 26 patients were able to ejaculate and all of them showed azoospermia, while the remaining patients were aspermic. All patients self-administered s.c. injections of FSH (150 IU x three/week) and HCG (2500 IU x two/week) for at least 6 months and underwent periodic assessments of testicular function. Testosterone concentrations increased rapidly during treatment and all but one patient reached normal values. Testicular volume showed a sustained increase reaching almost 3-fold its baseline value. At the end of treatment, 48 patients (80.0%) had achieved a positive sperm count. The maximum sperm concentration during treatment was 24.5 +/- 8.1 x 10(6)/ml (mean +/- SEM). The median time to induce spermatogenesis was 5 months. Eleven patients reported adverse events, generally not related to treatment. Three patients experienced gynecomastia. No local reactions at the injection site were observed. In conclusion, s.c. self-administration of highly purified FSH + HCG was well tolerated and effective in stimulating spermatogenesis and steroidogenesis in these patients.
Introduction
Male hypogonadotropic hypogonadism (HH) has been successfully treated for several decades by the administration of gonadotropins (Finkel et al., 1985; Ley and Leonard, 1985; Okuyama et al., 1986), which allows the restoration of testicular steroidogenesis and spermatogenesis. Human chorionic gonadotrophin (HCG) is normally used as the source of luteinizing hormone (LH) activity to stimulate testosterone secretion by Leydig cells, whereas human menopausal gonadotrophin (HMG) has been generally used as the follicle-stimulating hormone (FSH) source to stimulate proliferation and maturation of germinal cells.
Since spermatogenesis is a time-consuming process, any attempt aimed at its restoration must rely on a long-term treatment; normally, thrice-weekly intramuscular (i.m.) HMG injections have been administered for several months. The i.m. administration involves various inconveniences, such as local pain or needs to visit a health center for injections, which are particularly relevant in the case of chronic treatment, thus decreasing compliance and often leading to the interruption of treatment before spermatogenesis has been achieved (Saal
et al., 1991). Thus, the availability of a treatment that could be given s.c. is especially advantageous since it would be less painful and could be done by the patient himself, with a better cost-benefit ratio. On the other hand, s.c. the route has been shown to produce more sustained and less fluctuating FSH concentrations as compared to those obtained by the i.m. route (Handelsman et al., 1995).
Recently, a new FSH preparation, highly purified FSH (FSH HP), has been made commercially available by Serono. Like HMG, FSH-HP is a gonadotropin obtained from the urine of menopausal women but it is purified by specific anti-FSH monoclonal antibodies, giving a purer product that can be self-administered s.c. by the patient (Le Cotonnec et al., 1993; Howles et al., 1994).
The purpose of this study was to assess the efficacy and safety of combined treatment with highly purified FSH and HCG, both administered s.c., to stimulate testicular spermatogenesis and steroidogenesis in males suffering from HH with azoospermia or aspermia.
Treatment schedule
Before starting combined gonadotrophin treatment, written informed consent was obtained from each patient, and compliance with eligibility criteria was verified; this included a positive testosterone response to HCG administration (2500 IU, twice a week) over weeks. Then, all eligible patients self-administered s.c. injections of FSH-HP (150 IU, three times a week) and HCG (2500 IU, twice a week). The HCG dose was reduced in three patients due to abnormal testosterone responses or gynecomastia. Combined treatment needed to be carried out for at least 6 months; at the end of this period, if no adequate spermatogenic response had been obtained, treatment was to be extended for at least 3 additional months.
Testosterone plasma concentrations
At the beginning of the study, all patients had testosterone concentrations far below the normal range (0.4 ± 0.1 ng/ml, mean ± SEM). As shown in Figure 1, testosterone plasma concentrations increased considerably in response to the HCG test and continued increasing during combined treatment with HCG and FSH-HP reaching a value of 8.8 ± 0.9 ng/ml (mean 6 SEM) after 6 months of treatment (P,0.001). All patients achieved testosterone concentrations within the normal range (>3 ng/ml), with the exception of one patient with a minimal testicular volume (0.4 ml), whose testicular biopsy after 9 months of treatment revealed interstitial fibrosis and absence of Leydig’s cells in both testes.
Testicular volume
Figure 2 shows the evolution of testicular volume, which experienced a sustained and significant increase with the treatment from 4.3 ± 0.5 ml at baseline to 11.1 ± 1.0 after 6 months (<0.001). All but one patient experienced an increase during treatment and 14 achieved a normal testicular volume for a healthy adult (>16 ml). The testicular volume at 6 months of treatment was significantly correlated with that shown at baseline (r = 0.5; P <0.01).
Spermatogenic response
At the beginning of the study, only 26 patients (43.3%) were able to ejaculate and all of them showed azoospermia, while the rest of the patients were aspermic. After 6 months of treatment, 28 patients (46.7%) had achieved a sperm concentration >1 x 10 6/ml and all of them finished the study at this point except four patients who were willing to continue therapy. The remaining 32 patients who had not achieved an adequate response was asked to extend treatment for at least 3 additional months. Three of these patients refused to continue therapy for personal reasons and another one was withdrawn from the study because of an adverse event, so 28 out of 32 patients with no adequate response continued treatment beyond 6 months.
The remaining 32 patients who had not achieved an adequate response was asked to extend treatment for at least 3 additional months. Three of these patients refused to continue therapy for personal reasons and another one was withdrawn from the study because of an adverse event, so 28 out of 32 patients with no adequate response continued treatment beyond 6 months.
Table II shows the proportion of patients who achieved a spermatogenic response during the study period. At the end of treatment, an adequate response was observed in 39 (65%) patients while another nine patients showed a positive sperm count with a sperm concentration <1 X 10 6/ml. Thus, the overall response rate was 48/60 (80.0%) (95% CI: 67.3– 88.8%). Testicular specimens were obtained in those non-responders who accepted biopsies; their examination generally revealed testicular fibrosis and/or spermatogenesis arrested at early stages.
A survival analysis of the time required to induce spermatogenesis is shown in Figure 3. The median time to achieve a positive sperm count was 5 months (95% CI: 3.31–6.69 months).
The evolution of sperm concentration throughout the study period is shown in Figure 4. All patients who were able to ejaculate basally (n = 26) showed azoospermia. Sperm concentration increased progressively over the treatment period achieving an average maximum value of 24.5 ± 8.1 X10 6/ml (mean ± SEM), significantly higher (P <0.001) than the pre-treatment value. In all, 14 patients reached a sperm concentration within the normal range (>20 X 10 6/ml, according to WHO criteria). Total sperm count showed a similar pattern, increasing from a 0 value at baseline up to a maximum of 59.8 ± 19.7 X 10 6 spermatozoa per ejaculate (mean ± SEM) during treatment (P <0.001).
Sperm motility, morphology, and viability could not be assessed at baseline since all the patients capable of ejaculating presented with azoospermia. After 3 months of treatment, motility was observed in 44.1 ± 4.0% (mean ± SEM) of spermatozoa, with normal morphology in 56.4 ± 8.5% and viability in 64.3 ± 4.9% of spermatozoa. These values did not show significant changes in subsequent assessments throughout the treatment period.
Ejaculate volume
Prior to the beginning of treatment, the ejaculate volume in those patients who produced sperm samples was 1.2 ± 0.2 ml (mean ± SEM). Ejaculate volume was promptly and significantly (P <0.001) increased by gonadotrophin treatment so that a normal volume was achieved, on average, at 3 months (2.4 ± 0.2 ml, mean ± SEM) and was maintained over the treatment period.
Out of 34 patients who were not able to ejaculate at the beginning, 30 started to do so during treatment and reached normal volumes.
Discussion
To the best of our knowledge, the present study represents the largest therapeutic trial in men with HH ever reported in the literature.
In conclusion, combined treatment with FSH-HP + HCG is effective and safe to stimulate spermatogenesis, steroidogenesis, and testicular growth in patients suffering from HH.
ABSTRACT
The efficacy and safety of highly purified follicle-stimulating hormone (FSH) associated with human chorionic gonadotrophin (HCG) were studied in 60 men with hypogonadotropic hypogonadism. Of these men, 16 suffered from Kallmann's syndrome, 19 from idiopathic hypogonadotropic hypogonadism, and 25 from hypopituitarism. Basal testosterone concentrations were found to be far below the normal range. At baseline, 26 patients were able to ejaculate and all of them showed azoospermia, while the remaining patients were aspermic. All patients self-administered s.c. injections of FSH (150 IU x three/week) and HCG (2500 IU x two/week) for at least 6 months and underwent periodic assessments of testicular function. Testosterone concentrations increased rapidly during treatment and all but one patient reached normal values. Testicular volume showed a sustained increase reaching almost 3-fold its baseline value. At the end of treatment, 48 patients (80.0%) had achieved a positive sperm count. The maximum sperm concentration during treatment was 24.5 +/- 8.1 x 10(6)/ml (mean +/- SEM). The median time to induce spermatogenesis was 5 months. Eleven patients reported adverse events, generally not related to treatment. Three patients experienced gynecomastia. No local reactions at the injection site were observed. In conclusion, s.c. self-administration of highly purified FSH + HCG was well tolerated and effective in stimulating spermatogenesis and steroidogenesis in these patients.
Introduction
Male hypogonadotropic hypogonadism (HH) has been successfully treated for several decades by the administration of gonadotropins (Finkel et al., 1985; Ley and Leonard, 1985; Okuyama et al., 1986), which allows the restoration of testicular steroidogenesis and spermatogenesis. Human chorionic gonadotrophin (HCG) is normally used as the source of luteinizing hormone (LH) activity to stimulate testosterone secretion by Leydig cells, whereas human menopausal gonadotrophin (HMG) has been generally used as the follicle-stimulating hormone (FSH) source to stimulate proliferation and maturation of germinal cells.
Since spermatogenesis is a time-consuming process, any attempt aimed at its restoration must rely on a long-term treatment; normally, thrice-weekly intramuscular (i.m.) HMG injections have been administered for several months. The i.m. administration involves various inconveniences, such as local pain or needs to visit a health center for injections, which are particularly relevant in the case of chronic treatment, thus decreasing compliance and often leading to the interruption of treatment before spermatogenesis has been achieved (Saal
et al., 1991). Thus, the availability of a treatment that could be given s.c. is especially advantageous since it would be less painful and could be done by the patient himself, with a better cost-benefit ratio. On the other hand, s.c. the route has been shown to produce more sustained and less fluctuating FSH concentrations as compared to those obtained by the i.m. route (Handelsman et al., 1995).
Recently, a new FSH preparation, highly purified FSH (FSH HP), has been made commercially available by Serono. Like HMG, FSH-HP is a gonadotropin obtained from the urine of menopausal women but it is purified by specific anti-FSH monoclonal antibodies, giving a purer product that can be self-administered s.c. by the patient (Le Cotonnec et al., 1993; Howles et al., 1994).
The purpose of this study was to assess the efficacy and safety of combined treatment with highly purified FSH and HCG, both administered s.c., to stimulate testicular spermatogenesis and steroidogenesis in males suffering from HH with azoospermia or aspermia.
Treatment schedule
Before starting combined gonadotrophin treatment, written informed consent was obtained from each patient, and compliance with eligibility criteria was verified; this included a positive testosterone response to HCG administration (2500 IU, twice a week) over weeks. Then, all eligible patients self-administered s.c. injections of FSH-HP (150 IU, three times a week) and HCG (2500 IU, twice a week). The HCG dose was reduced in three patients due to abnormal testosterone responses or gynecomastia. Combined treatment needed to be carried out for at least 6 months; at the end of this period, if no adequate spermatogenic response had been obtained, treatment was to be extended for at least 3 additional months.
Testosterone plasma concentrations
At the beginning of the study, all patients had testosterone concentrations far below the normal range (0.4 ± 0.1 ng/ml, mean ± SEM). As shown in Figure 1, testosterone plasma concentrations increased considerably in response to the HCG test and continued increasing during combined treatment with HCG and FSH-HP reaching a value of 8.8 ± 0.9 ng/ml (mean 6 SEM) after 6 months of treatment (P,0.001). All patients achieved testosterone concentrations within the normal range (>3 ng/ml), with the exception of one patient with a minimal testicular volume (0.4 ml), whose testicular biopsy after 9 months of treatment revealed interstitial fibrosis and absence of Leydig’s cells in both testes.
Testicular volume
Figure 2 shows the evolution of testicular volume, which experienced a sustained and significant increase with the treatment from 4.3 ± 0.5 ml at baseline to 11.1 ± 1.0 after 6 months (<0.001). All but one patient experienced an increase during treatment and 14 achieved a normal testicular volume for a healthy adult (>16 ml). The testicular volume at 6 months of treatment was significantly correlated with that shown at baseline (r = 0.5; P <0.01).
Spermatogenic response
At the beginning of the study, only 26 patients (43.3%) were able to ejaculate and all of them showed azoospermia, while the rest of the patients were aspermic. After 6 months of treatment, 28 patients (46.7%) had achieved a sperm concentration >1 x 10 6/ml and all of them finished the study at this point except four patients who were willing to continue therapy. The remaining 32 patients who had not achieved an adequate response was asked to extend treatment for at least 3 additional months. Three of these patients refused to continue therapy for personal reasons and another one was withdrawn from the study because of an adverse event, so 28 out of 32 patients with no adequate response continued treatment beyond 6 months.
The remaining 32 patients who had not achieved an adequate response was asked to extend treatment for at least 3 additional months. Three of these patients refused to continue therapy for personal reasons and another one was withdrawn from the study because of an adverse event, so 28 out of 32 patients with no adequate response continued treatment beyond 6 months.
Table II shows the proportion of patients who achieved a spermatogenic response during the study period. At the end of treatment, an adequate response was observed in 39 (65%) patients while another nine patients showed a positive sperm count with a sperm concentration <1 X 10 6/ml. Thus, the overall response rate was 48/60 (80.0%) (95% CI: 67.3– 88.8%). Testicular specimens were obtained in those non-responders who accepted biopsies; their examination generally revealed testicular fibrosis and/or spermatogenesis arrested at early stages.
A survival analysis of the time required to induce spermatogenesis is shown in Figure 3. The median time to achieve a positive sperm count was 5 months (95% CI: 3.31–6.69 months).
The evolution of sperm concentration throughout the study period is shown in Figure 4. All patients who were able to ejaculate basally (n = 26) showed azoospermia. Sperm concentration increased progressively over the treatment period achieving an average maximum value of 24.5 ± 8.1 X10 6/ml (mean ± SEM), significantly higher (P <0.001) than the pre-treatment value. In all, 14 patients reached a sperm concentration within the normal range (>20 X 10 6/ml, according to WHO criteria). Total sperm count showed a similar pattern, increasing from a 0 value at baseline up to a maximum of 59.8 ± 19.7 X 10 6 spermatozoa per ejaculate (mean ± SEM) during treatment (P <0.001).
Sperm motility, morphology, and viability could not be assessed at baseline since all the patients capable of ejaculating presented with azoospermia. After 3 months of treatment, motility was observed in 44.1 ± 4.0% (mean ± SEM) of spermatozoa, with normal morphology in 56.4 ± 8.5% and viability in 64.3 ± 4.9% of spermatozoa. These values did not show significant changes in subsequent assessments throughout the treatment period.
Ejaculate volume
Prior to the beginning of treatment, the ejaculate volume in those patients who produced sperm samples was 1.2 ± 0.2 ml (mean ± SEM). Ejaculate volume was promptly and significantly (P <0.001) increased by gonadotrophin treatment so that a normal volume was achieved, on average, at 3 months (2.4 ± 0.2 ml, mean ± SEM) and was maintained over the treatment period.
Out of 34 patients who were not able to ejaculate at the beginning, 30 started to do so during treatment and reached normal volumes.
Discussion
To the best of our knowledge, the present study represents the largest therapeutic trial in men with HH ever reported in the literature.
In conclusion, combined treatment with FSH-HP + HCG is effective and safe to stimulate spermatogenesis, steroidogenesis, and testicular growth in patients suffering from HH.
