Addition of recombinant follicle-stimulating hormone to human chorionic gonadotropin treatment in adolescents and young adults with hypogonadotropic hypogonadism promotes normal testicular growth and may promote early spermatogenesis Margaret Zacharin, M.B.B.S.,a Matthew A. Sabin, Ph.D.,a Veena V. Nair, M.D.,b and Preeti Dagabdhao, M.D.b a
Murdoch Childrens Research Institute, Royal Children's Hospital and University of Melbourne, Parkville, Victoria, Australia; and b Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
Objective: To assess the effect on spermatogenesis of adding recombinant follicle-stimulating hormone (FSH) to human chorionic gonadotropin (hCG) treatment protocols for adolescent/young adult males with hypogonadotropic hypogonadism (HH). Design: Observational descriptive study. Setting: Outpatient clinics. Patient(s): Nineteen males with hypogonadotropic hypogonadism, aged 14.5 to 31.0 years. Intervention(s): Treatment with either hCG treatment alone (n ¼ 9; group 1) or in combination with recombinant FSH (n ¼ 10; group 2), over 6 to 9 months. Main Outcome Measure(s): Combined testicular volume (CTV) and testosterone, inhibin B, semen/urine analysis at 6 to 9 months. Result(s): There were no differences between the two groups in baseline variables or changes in CTV with treatment. Despite this, evidence of spermatogenesis was present in all group 2 patients by 9 months (range 0.2 to 15 106/mL) compared with three of nine patients in group 1 (range 0 to <1 106/mL). Whole group and subgroup analyses did not demonstrate any statistically signiﬁcant correlations between age at onset of treatment and either CTV or sperm count. Conclusion(s): The addition of recombinant FSH to hCG treatment protocols in adolescent/ Use your smartphone young adult HH males results in normal testicular growth and may hasten induction of spermatoto scan this QR code genesis. (Fertil SterilÒ 2012;98:836–42. Ó2012 by American Society for Reproductive Medicine.) and connect to the Key Words: Fertility, FSH, hypogonadotropic hypogonadism, puberty, spermatogenesis Discuss: You can discuss this article with its authors and with other ASRM members at http:// fertstertforum.com/zacharinmr-rfsh-hcg-treatment-adolescents-hypogonadotrophic-hypgo nadism-spermatogenesis/
Received March 1, 2012; revised and accepted June 12, 20122012; published online July 3, 2012. M.Z. has received travel support from Merck Sorono. M.A.S. has nothing to disclose. V.V.N. has nothing to disclose. P.D. has nothing to disclose. Supported by the Victorian Government Operational Infrastructure Support Program (to M.Z., M.A.S.), and a National Health and Medical Research Council Health Professional Training Fellowship (APP1012201) (to M.A.S.). Reprint requests: Margaret Zacharin, M.B.B.S., Department of Endocrinology, Royal Children's Hospital, Parkville, Victoria 3052, Australia (E-mail: [email protected]
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xogenous androgen therapy in adolescence, with later fertility treatment using gonadotropin therapy in adulthood, is the mainstay of management for males with hypogonadotropic hypogonadism (HH) (1, 2). This traditional approach leads to a mixed response with prolonged VOL. 98 NO. 4 / OCTOBER 2012
Fertility and Sterility® periods of fertility treatment often being necessary in adult life, with consequent variable levels of fertility (3). Such uncertainty has an adverse effect on the psychological well-being of affected individuals (4), so alternative approaches to optimize long-term fertility in males with HH are sought. It is known that testosterone therapy alone is inadequate to induce fertility in adults, and that human chorionic gonadotropin (hCG) is required for this process (5). Exogenous hCG administration alone has been reported to be successful in initiating, maintaining, and even reinitiating spermatogenesis in gonadotropin-deﬁcient men (6, 7), although the addition of recombinant follicle-stimulating hormone (FSH) to treatment schedules has been shown to further increase seminal antim€ ullerian hormone AMH levels, which then positively correlate with sperm densities and testicular volumes (8). Although FSH may not be fundamentally required for fertility induction, given the evidence that men who have inactivating mutations of the FSH receptor may still be fertile (despite small testes and reduced levels of spermatogenesis) (9), it has been shown that combination treatment with recombinant FSH and hCG leads to improved outcomes in HH males (10, 11). Questions remain however as to the optimal timing of treatment with recombinant FSH. Intracytoplasmic sperm injection (ICSI) has been shown to be required to achieve fertility after failed gonadotropin treatment in men treated for the ﬁrst time at ages 25 to 28 (12), and there is evidence that childhood FSH exposure may facilitate later spermatogenesis (13). Murine investigations in this area have limited applicability because spermatogenesis and fertility appear to be inducible and sustainable with testosterone alone in complete congenital gonadotropin deﬁciency (14–16) as well as in mice with either inactivating mutations of the FSH beta subunit gene (17) or the FSH receptor (18). There is thus a clear need for more clinical data from adolescents and young adults treated with hCG with or without recombinant FSH. The majority of clinical reports to date are either of disparate cohorts of gonadotropin-deﬁcient men (some of whom developed late gonadotropin deﬁciency after development of intracranial pathology subsequent to normal puberty) (3), or of small cases series of adolescent boys with HH who received pubertal induction with gonadotropins at various times (8, 13, 19, 20). Therefore, we further investigated the effect on spermatogenesis of adding recombinant FSH (recombinant FSH) to hCG treatment protocols for adolescent and young adult males with HH who were either testosterone naïve or who had been exposed only to brief courses of testosterone.
MATERIALS AND METHODS Patients Nineteen adolescent and young adult males with HH (age range: 14.5 to 31.0 years; median 18.9 years) were treated for pubertal induction with hCG (Pregnyl; Merck Sharp & Dohme) with or without recombinant FSH (Gonal-F, Merck Serono S.A.) in Australia and India. Underlying diagnoses were idiopathic HH (n ¼ 11), congenital hypopituitarism VOL. 98 NO. 4 / OCTOBER 2012
(n ¼ 6), and postcraniopharyngioma treatment (including cranial radiation) before puberty (n ¼ 2). One had a history of cryptorchidism that required surgery. There were no cases of varicocele. The clinical details for all patients are provided in Table 1. Diagnostic criteria for HH for all groups included gonadotropin levels below the level of assay sensitivity (>0.5 IU/L), the presence of associated anosmia (formally tested), or lack of any signs of pubertal onset by age 18 or later. For those with panhypopituitarism, failure to enter puberty by age 14.5 years in association with other pituitary deﬁcits was used. All patients in Australia and India were examined before and during treatment by one author (M.Z.), but the data were examined retrospectively for the Australians as they were not part of a speciﬁc study group (as we will discuss). All of the Indian cohort was allocated to hCG alone due to limitation of available funds and their wish to try an alternative that might possibly improve their fertility outlook. All patients were entirely prepubertal at time of their initial diagnosis with combined testicular volumes (CTV) of 2 to 8 mL. All those who received short courses of testosterone had used 250 mg testosterone enanthate or succinate as an intramuscular injection every 2 to 4 weeks, according to compliance.
Ethics and Consent Young males in the Australian cohort were treated individually between 2004 and 2009 and were not part of a targeted study. Human chorionic gonadotropin is licensed for treatment of HH in adolescent males in Australia, and recombinant FSH is licensed for induction of fertility in males over the age of 16 with this disorder. Written informed consent for the use of hCG and recombinant FSH was obtained from all patients aged R18 years, and from parents for those %18 years who were unable to personally provide full informed consent. Speciﬁc ethics approval was also obtained from the Royal Children's Hospital, Melbourne, for publication of deidentiﬁed data for these patients, most of whom had previously attended that hospital in childhood. Those from India were subsequently recruited as part of a formal research study, with ethics approval granted by the Sanjay Gandhi Postgraduate Institute of Medical Sciences (Lucknow, India) for full participation in the study, including semen analyses.
Data Grouping Data were divided into two treatment groups for analysis. The doses of hCG and FSH, where used, were identical between groups. Group 1 (hCG alone) consisted of nine entirely prepubertal males (age range: 14.5 to 31.0 years; median: 18.1 years) who received hCG alone, initially at a dose of 500 IU twice weekly, with increases to 1,000 IU at 6 months and, as puberty progressed, to 1,500 IU two times per week. Six were completely naïve to previous testosterone treatment. In the remainder, hCG was commenced 3 months after the last testosterone injection. 837
Clinical, biochemical, and semen analysis parameters for nine adolescent males with hypogonadotropic hypogonadism (HH) treated with human chorionic gonadotropin (hCG) alone, and nine treated with hCG and recombinant follicle-stimulating hormone (rFSH).
Patient study no.
Treatment type (group)
Decimal age at treatment (y)
Testicular maldescent D/– associated features
Previous testosterone therapy (duration in mo)
Combined testicular volumes (CTVs) at 0 and 9 mo (mL)
Inhibin B concentration at 6–9 mo (pg/mL)
Testosterone concentration at 9 mo (nmol/L)
Sperm concentration at 6 mo (3106/mL)
Sperm concentration at 9 (and 12 where available) mo (3106/mL)
6 and 20 4 and 11
Urine ¼ 0 Urine ¼ 0
4 and 30 2 and 14
4 and 7
No Inguinal hernia No
No Yes (6)
2 and 3 4 and 6
8 and NA
No No No
Yes (6) No No
NA 3 and 30 4 and 11
NA 42 31
NA 30.6 33.0
NA 0 2.8
3 and 16
Congenital hypopituitarism Anosmia, Kallmann, HH
4 and 16
hCG/rFSH (2) hCG/rFSH (2)
HH Anosmia, Kallmann, HH
Yes (12) Yes (24)
4 and 18 4 and 20
hCG/rFSH (2) hCG/rFSH (2)
Yes (12) Yes (24)
2 and 8 4 and 20
0.2 1.7 (5)
Anosmia, Kallmann, HH Congenital hypopituitarism HH
2 and 20
4 and 50
hCG (1) hCG (1)
hCG (1) hCG (1)
hCG (1) hCG (1)
hCG (1) hCG/rFSH (2) hCG/rFSH (2)
31.0 16.0 17.9
9 10 11
Craniopharyngioma Congenital hypopituitarism HH Congenital hypopituitarism Congenital hypopituitarism Anosmia, Kallmann, HH Anosmia, Kallmann, HH Congenital hypopituitarism HH Craniopharyngioma HH
VOL. 98 NO. 4 / OCTOBER 2012
Note: NA ¼ not available. a Indicates an Indian patient. Zacharin. Recombinant FSH in hypogonadotropic hypogonadism. Fertil Steril 2012.
<0.01 1.2 9.5 5 15 (31) 0.7 6
Percentage motility and abnormal morphology (reported only for counts >2 3 106/mL)
Motility 12.3% Abnormal 87% Motility 20% Abnormal 92% Motility 15% Abnormal >99% Motility 23% Abnormal 86%
Motility 20% Abnormal 98%
ORIGINAL ARTICLE: ANDROLOGY
Fertility and Sterility® Group 2 (combination hCG þ recombinant FSH) consisted of 10 patients (age range: 16 to 25 years; median: 20.9 years), who were given 500–1,500 IU of hCG twice weekly, with incremental increases every 6 months as puberty progressed, with addition of 150–300 IU of recombinant FSH three times per week, from the fourth month of the higher hCG dose. Five were prepubertal at commencement of treatment, and ﬁve had previously received exogenous testosterone for a maximum time of 1 to 2 years for pubertal induction. In the latter group, hCG was commenced 3 months after the last testosterone injection.
ceiving prior testosterone treatment as well as those achieving evidence of spermatogenesis with each treatment. Whole group and subgroup analyses investigated potential associations between decimal age at treatment and either CTV, change in CTV, or sperm count at 9 months. These were performed with Pearson's correlation coefﬁcients when data were normally distributed or Spearman's correlation coefﬁcients when Kolmogorov-Smirnov testing returned a statistically signiﬁcant result. The statistical package IBM SPSS version 19 (SPSS, Inc.) was used for statistical analyses. P< .05 was considered statistically signiﬁcant.
Semen Analysis and Storage Semen storage was offered, accepted, and undertaken for all patients who had evidence of spermatogenesis, with semen storage in accordance with Victoria, Australia legislation, collected at the andrology units of the Royal Women's Hospital or the Monash Medical Centre, Melbourne. Treatment with FSH and hCG was continued until sufﬁcient semen for storage was collected. Brieﬂy, each sample was initially incubated for 15 minutes to allow liquefaction, and a manual count was performed. Where the count was >2 million/mL, dilution was then performed with ﬂuorescence before an automated count using an Integrated Visual Optical System (IVOS) Sperm Analyser (Hamilton Thorne). The sample was then slowly cooled over 30 minutes to 80 C using an in-house developed cryopreservant and was stored in liquid nitrogen.
Outcome Measures The clinical parameters of height, weight, and combined testicular volume (CTV) were measured at three monthly intervals to 9 months of treatment by a single observer (M.Z.) using a Prader orchidometer, alongside testicular ultrasound when approved by the patients. The biochemical parameters of testosterone and inhibin B were measured in the majority at 0, 3, 6, and 9 months. Semen analysis was performed at 6 and 9 months on the same days as serum sampling. When the patient refused semen analysis, collection of an early morning urine sample was used to provide surrogate evidence of spermatogenesis (21).
Assays Testosterone quantiﬁcation was by radioimmunoassay (RIA) in both India (DiaSorin) and Australia (Beckman Coulter): intra-assay coefﬁcient of variation (CV) 5.2% and interassay CV 7%, and intra-assay CV 10% and interassay CV 11.7%, respectively. Inhibin B concentrations in samples from India and Australia were determined using a commercially available enzyme-linked immunosorbent assay (ELISA; Beckman Coulter): intra-assay CV 2.7%, and interassay CV 4.6%.
Statistical Analyses Unpaired Student's t-tests were used to compare normally distributed data (age at treatment, and inhibin B and testosterone concentrations), and Mann-Whitney U tests were used to compare non-Gaussian data (CTV). Fisher's exact test was used to analyze proportional differences in those reVOL. 98 NO. 4 / OCTOBER 2012
RESULTS All boys who had not achieved their ﬁnal height grew normally throughout the period of study, and all achieved a ﬁnal height appropriate for their midparental expectation (height and weight data not shown). Normal virilization (Tanner stage progressing from stage 1 to 4; data not shown) and increases in combined testicular volumes (CTV) occurred over a time period consistent with normal pubertal development, with similar increases in CTV occurring between groups 1 and 2 (Table 1). Treatment was well tolerated by all, with no reports of behavioral, social, or emotional upheaval. There were no differences between groups 1 and 2 for age at treatment (P¼ .5) or for the proportion who received prior testosterone treatment (P¼ .65). Group 1 males had a median CTV at baseline of 4 mL (range: 2–8 mL), which changed to 11 mL (range: 3–30 mL) at 9 months. Semen analysis showed no evidence of spermatogenesis at 6 months in six boys, while there was minimal evidence of spermatogenesis in three of the nine boys by 9 months (sperm count <1 106/mL in all) (see Table 1). Group 2 males had a median CTV at baseline of 4 mL (range: 2–8 mL), which changed to 19 mL (range: 8–50 mL) at 9 months, with no statistically signiﬁcant differences between groups 1 and 2 at either time point (P¼ .24 and P¼ .11, respectively). There were also no statistically signiﬁcant differences between inhibin B (P¼ .33) and testosterone concentrations (P¼ .10) between the two groups. In group 2, however, the semen analysis at 6 months showed evidence of spermatogenesis in 8 of 10 boys, with the analysis at 9 months showing evidence of spermatogenesis in all. Comparison with the semen analysis of group 1 patients showed a statistically signiﬁcant difference in the number achieving demonstrable evidence of spermatogenesis at 9 months (Fisher's exact test, P¼ .003). Motile sperm could be visualized in all samples where the sperm count was >0 106/mL; the percentage motility along with percentage abnormal sperm is reported in Table 1 for counts >2 106/mL. In the analysis of the whole group, no correlation was seen between decimal age at treatment and CTV at 9 months (r ¼ 0.12; P¼ .64) or between decimal age at treatment and change in CTV between 0 and 9 months (r ¼ 0.1; P¼ .69). Subgroup analyses for these analyses were r ¼ 0.34 (P¼ .46) and r ¼ 0.3 (P¼ .52) for group 1, and r ¼ 0.4 (P¼ .26) and 0.4 (P¼ .25) for group 2, respectively. There was also no statistically signiﬁcant correlation between 839
ORIGINAL ARTICLE: ANDROLOGY decimal age at treatment and sperm count at 9 months in either the whole group (r¼0.24; P¼ .32), group 1 (r ¼ 0.41; P¼ .27), or group 2 (r¼0.36; P¼ .31). In the whole group, CTV at 9 months was statistically signiﬁcantly associated with sperm count at 9 months (r¼0.49; P¼ .047), as was change in CTV and sperm count at 9 months (r¼0.50; P¼ .042), but the sperm counts were too low in group 1 to allow this analysis, and statistically signiﬁcant correlations were not seen in the analysis of only group 2 participants (CTV and sperm count P¼ .63; change in CTV and sperm count P¼ .64). Of the group 2 participants, three patients also have further data available after 12 months of combined treatment, and these are also reported in Table 1. Fertility was achieved on two occasions for patient 18, with delivery of two full-term infants, the second of whom has panhypopituitarism.
DISCUSSION This study provides additional clinical data to the limited evidence that combined treatment with recombinant FSH/hCG in adolescence or early adult life in males with HH leads to statistically signiﬁcant levels of spermatogenesis after only 9 months of combined treatment. Despite similar circulating concentrations of testosterone and inhibin B, alongside comparable changes in CTV, evidence of spermatogenesis at 9 months was evident in all patients treated with combination recombinant FSH/hCG in comparison with just one-third of patients treated with hCG alone. The treatment response with 100% successful evidence of spermatogenesis is statistically signiﬁcantly higher than reported for similarly treated older men who had prior long-term use of testosterone (22, 23). Of the hCG-alone group, the mean sperm concentration was <1 106 in all three cases, compared with the combined hCG/recombinant FSH group where counts were much higher. No differences were evident in the sperm counts between those with congenital/acquired hypopituitarism and HH, suggesting that other pituitary hormone deﬁcits in the former did not adversely impinge on outcome. Despite a history of micropenis and/or cryptorchidism in patients 13 and 19, indicating severity of HH, both achieved spermatogenesis with early use of gonadotropins, similar to other reports (8, 19), which perhaps indicates that early stimulation of testicular growth may be advantageous. Accurate ﬁgures for prevalence of cryptorchidism in HH are not available, other than reports of it being ‘‘common,’’ although for our cohort this was not the case. The number of patients with later childhood onset of HH after tumor-induced hypopituitarism in this cohort is too small to provide evidence as to whether the normal infant gonadotropin surge may improve later spermatogenesis as has been suggested (13, 24). This was not the case for our patients who had childhood onset hypopituitarism. The presence of motile sperm in one-third of patients treated with hCG alone, alongside the increases in testicular size and rising inhibin B concentrations (as an indicator of onset of spermatogenesis), has been shown previously in several studies at similar levels of spermatogenesis to our 840
hCG-alone cohort. However, ICSI has been shown to often be required to achieve fertility in these men (12). Previous ﬁndings where hCG alone was used in a cohort of men with a mean age of 30.1 years showed 61% failed to achieve spermatogenesis until addition of FSH (after which 47% of those men achieved success) (22). Reported differences in response might be due to ethnic differences, but four of the nine boys treated with hCG alone were in the Australian cohort, and no such differences in spermatogenesis have previously been reported. Sperm production has been reported in 7 of 14 within a similar cohort (19), and in another study (8) where 11 patients had sperm counts of 5–10 106/mL by 12 months of combined treatment (with no sperm seen with hCG treatment alone). In a mixed cohort (23), the youngest of whom was 26 years (mean age: 36 years), the median time to sperm production was 7.1 months and to conception 28 months. However, none of that cohort were completely prepubertal at start of gonadotropin therapy. Additional data for three of our group 2 patients indicate that ongoing treatment resulted in a rapid increase in sperm concentration. Most of the cohort did not continue with gonadotropin after onset of spermatogenesis and semen storage, as fertility was not desired at the time. Several of our cohort were older than 21 years at the time of initial hCG/FSH treatment, but these men were either testosterone naïve or had only received testosterone for minimal periods in the past. As they achieved statistically signiﬁcant evidence of spermatogenesis over 9 months, this ﬁnding is in keeping with the previous suggestion that the long-term use of testosterone may have an adverse effect on fertility potential by maintaining testes in an immature state (13, 23). Although further studies will be required to conﬁrm or refute this, it is likely that gonadotropin exposure at the time of normal puberty, or during later adolescence or early adulthood, is more physiologic and may reduce the duration required for later fertility induction in these individuals (as shown for reinduction times to adequate sperm production in other studies) (3). It is also of interest to note that our younger patients treated with combination hCG/recombinant FSH demonstrated increased testicular growth to a median CTV of 19 mL by 9 months. Previous studies have clearly demonstrated that testicular size is an important predictor of fertility outcome (23) and, in a previous long-term 30-year retrospective series, only 36% of men with small testes achieved fertility with hCG (or human menopausal gonadotropin) treatment, compared with 71% who had larger volume testes (25). The rate of change of testicular size varies during puberty. A series that enrolled 142 Swiss males, reported in 1983, found wide variability with no discernible trend for duration of change in testicular size, with 2 to 25 mL occurring between 2.0 and 3.5 years from the start of puberty (26). Although one of our cohort had a more rapid increase in testicular size, the others were within the population range. The age of spermarche is ill-deﬁned in the literature and depends mainly on a single report that used spermaturia as a surrogate measure (27) where it was demonstrated that VOL. 98 NO. 4 / OCTOBER 2012
Fertility and Sterility® sperm were evident at a median age of 13.4 years and testicular volume of 11.5 mL before the maximal growth spurt. Given that a growth spurt occurs toward the end of a normal puberty in boys, around 18 to 24 months from its onset, we believe that the onset of spermatogenesis in our cohort closely mimics the distribution that was described. Furthermore, as idiopathic HH is rarely diagnosed unless there is a family history or late puberty, the time from onset of virilizing change, rather than age, must be used. There are no articles in the literature looking at semen analysis in normal boys to deﬁne this, and it would be very difﬁcult to get ethics permission to do such a study today. Inhibin B levels did not correlate well with sperm production in some young men. It is likely that inhibin B is a highly sensitive indicator of active treatment. Should the patient omit one or more hCG/FSH injections, the inhibin B level may fall rapidly, whereas sperm will still be present. Compliance with medication for adolescents is a chronic problem, and the discrepancy between inhibin B levels and sperm counts could be explained by this and/or other factors. Finally, note should be taken of the sperm morphology ﬁndings of our patients, which suggested a high proportion (>90%) of abnormal sperm in several men, mainly with absent acrosomes and heads. This observation in our treated adolescents/young men may be due to the early sampling, and with further treatment more normal morphologic features may be seen. This remains to be determined.
CONCLUSION Evidence from this descriptive clinical study conﬁrms and extends previous data, suggesting that combined hCG and recombinant FSH treatment in adolescent and young adult males with HH results in normal linear growth and testis growth, and may hasten spermatogenesis over a time-span similar to that of normal puberty. Use of hCG alone can also induce spermatogenesis but appears to be less efﬁcient. Further studies are now required to address whether early introduction of gonadotropins is responsible for this effect or whether standard protocols of prolonged exogenous testosterone treatment may have an adverse effect on future spermatogenic potential. We suggest that early induction of spermatogenesis may reduce the time required for appearance of sperm and for future conception, and may reduce the need for prolonged cycles of gonadotropin treatment in adult life.
16. 17. 18.
Acknowledgment: The authors thank Professor David Handelsman for expert advice and guidance in the analysis and presentation of data described in this manuscript.
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