1 Department of Andrology and ANZAC Research Institute, Concord Hospital, and 2 NHMRC Clinical Trials Centre, University of Sydney, Sydney NSW 2139, Australia
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Abstract |
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Key words: gonadotrophin deficiency/gonadotrophin therapy/men/survival analysis
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Introduction |
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Few studies have reported the efficacy of gonadotrophin therapy in gonadotrophin-deficient infertile men. Most are small and none compare different forms of FSH. This is largely because the community prevalence of gonadotrophin deficiency is low and such men seek fertility on few occasions, so that even specialized centres accumulate small numbers. Even among the larger studies (Burger and Baker, 1984; Finkel et al., 1985
; Okuyama et al., 1986
; Burris et al., 1988
; Liu et al., 1988
; Mastrogiacomo et al., 1991
; Saal et al., 1991
; Schopohl et al., 1991
; Okada et al., 1992
; Vicari et al., 1992
; Kirk et al., 1994
; Kung et al., 1994
; Burgues and Calderon, 1997
; Anonymous, 1998a
; Büchter et al., 1998
), only three involved more than 20 men (Burgues and Calderon, 1997
; Anonymous, 1998a
; Büchter et al., 1998
) and multi-centre studies (Burgues and Calderon, 1997
; Anonymous, 1998a
) may not maintain consistency of management compared with a single centre. Few studies have estimated time to achievement of pregnancy (Kung et al., 1994
; Büchter et al., 1998
) and none have previously employed correlated analysis. Therefore, quantitative estimates of important and basic data such as the expected time to sperm output thresholds and conception are not available. Hence, retrospective studies utilizing survival analysis techniques in large population groups are desirable. We report the largest series of treatment courses in gonadotrophin-deficient men desiring fertility within a single centre to estimate time to spermatogenic thresholds and conception using correlated multivariate survival analysis modelling. Survival analysis includes all available data, including treatment failures, so is less biased (Peto et al., 1976
). The present study also provides the first comparison between the efficacy of rFSH and urinary (u)FSH for induction of spermatogenesis and male fertility.
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Materials and methods |
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Treatment commenced by substituting androgen replacement therapy (if used) with HCG (Pregnyl; Organon or Profasi; Serono) at one ampoule (1500 or 2000 IU respectively) administered twice weekly, usually by self-injection under the skin of the abdomen or upper thigh. Adequacy of HCG dosage was evaluated after the first month. If the trough plasma testosterone (measured immediately before the next injection) remained subnormal and/or if androgenic effects were not well maintained, the same dosage was increased to three times or, rarely, four times weekly. HCG treatment was maintained alone for 36 months and, if no sperm had appeared by at most 6 months of adequate HCG treatment, FSH was added. The initial dose of uFSH (Pergonal; Serono or Humegon; Organon) was 75 IU three times weekly and for rFSH (Gonal F; Serono or Puregon; Organon) 150 IU three times weekly. When using both gonadotrophins, they were mixed and administered in the same syringe. If testis growth and sperm output was inadequate, the FSH dosage was increased to 150 IU three times weekly and, rarely, to 150 IU daily. The typical dose required was 150 IU three times weekly.
During gonadotrophin treatment, men were reviewed at 3 monthly intervals. At each visit clinical features (androgenic effects, increases in testis size) were monitored and blood (plasma testosterone) and semen samples were obtained. Testis size was measured using a Prader orchidometer. Semen samples were collected by masturbation and analysed according to the standard World Health Organization methods described in the then current World Health Organization manual (World Health Organization, 1980, 1987
, 1992
). Treatment was continued until completion of the first trimester when pregnancy was confirmed or when the couple decided to terminate therapy. No pregnancies included in this analysis involved IVF or related procedures.
Data analysis
The present study reviewed all data for gonadotrophin-deficient infertile men treated with gonadotrophin therapy between 1982 and 1998 at this centre. Data from all treatment cycles were collected prospectively according to a standard data sheet. This report includes data from a previously published report (Liu et al., 1999). Testis volume was analysed as the mean of the left and right testis volumes.
Conception dates were estimated to the nearest week, if possible, usually extrapolated from the date of positive urinary pregnancy tests, otherwise the 15th day of the estimated month was designated. Semen analysis at the time of conception was taken as the semen sample analysed closest to, and usually 1 month before, conception.
Statistical analysis
Data are expressed as median (SE; range). For continuous variables, differences between groups were tested by parametric or non-parametric tests as appropriate. Categorical data were analysed by exact methods for contingency tables. Two-tailed P-values of < 0.05 were considered statistically significant. Analyses were performed using the Statview 5.0 (Calderola et al., 1998) and StatXact 4.0 (Anonymous, 1998b
) statistical software. Correlated survival analysis was performed using Accord 1.1 (Anonymous, 2000
).
Since the goal of therapy for all subjects was pregnancy, some subjects may have ceased treatment due to their knowledge that their sperm count was not increasing. It is thus important to examine whether these subjects give rise to so-called `informed censoring' which may violate the assumptions of statistical methods used to analyse time to event data (Cox regression, logrank tests etc.). Examination of whether the censoring mechanism was related to outcome (time to pregnancy) will provide some idea as to whether standard statistical methods are still appropriate. The relationship was examined by fitting a logistic regression assuming an extreme case where all subjects who did not obtain a sperm concentration of 5x106/ml were classified as having withdrawn from treatment due to informed censoring. Survival analysis was then used to model underlying fertility estimated as the time to various sperm output thresholds (0, 5 or 20x106 sperm/ml) and to pregnancy. KaplanMeier product-limit estimates of median times to the various sperm concentration thresholds and to conception were also calculated.
Potential categorical covariates (all considered a-priori predictors of spermatogenesis or conception) were evaluated by log-rank (MantelCox) test in a KaplanMeier model and continuous variables by Wald test in a Cox proportional hazards regression model. The categorical variables studied were the presence of adverse fertility factors (comprising cryptorchidism, female factors or poor compliance), multiple pituitary hormone deficiency (hypopituitarism versus isolated gonadotrophin deficiency), completion of puberty prior to diagnosis, treatment modality (HCG alone or with uFSH or rFSH) and prior androgen or gonadotrophin treatment. The continuous variables studied were testis volume, age and partner's age at the start of treatment. In addition, subgroup analyses were performed examining the effect of prior androgen or gonadotrophin therapy. These analyses were performed to examine the effect of prior gonadotrophin therapy, to allow comparison with the published literature which has generally treated multiple treatment courses in single individuals as independent. These were also used as an exploratory measure to determine potentially important predictors prior to performing correlated analyses. Log cumulative hazard and KaplanMeier plots of each variable were examined.
A model predicting sperm thresholds and conception using these variables was developed using forward stepwise variable selection with verification of the model by backward stepping in a correlated Cox proportional hazards model (Lee et al., 1992). The correlated Cox proportional hazards model allows analysis of time to event data using observations that are correlated, meaning that more than one observation per individual can be used. The P-value for inclusion and exclusion of the variables was 0.05. The model was checked manually at each step to examine for interactions, particularly for variables found to be significant from the exploratory KaplanMeier analysis. The unit of measure for continuous variables was years (for age) and millilitres (for testicular volume).
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Results |
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The median age of men was 36 years (range 2652) with no difference according to diagnosis, pubertal status, treatment, previous androgen treatment or adverse fertility factors. As expected, men receiving their second course (n = 16, median age 39 years) were marginally but significantly (P < 0.05) older than those treated for the first time (n = 26, median age 35 years). The female partners were younger than the men with a median age of 30 years (range 2041).
The median pre-treatment testis volume was 8 ml (range 120). Cryptorchid men had significantly lower testis volume (median 2, range 24 ml) compared with non-cryptorchid men (median 8, range 120 ml, P < 0.005). Prior androgen therapy (n = 29 courses) was associated with smaller testis volume (median 6 versus 12.5 ml in those who had not received prior androgen therapy, P = 0.03). Most men (except one) who did not receive prior androgen therapy also did not fully complete puberty, were often diagnosed as having `delayed puberty' and were subsequently found to have hypothalamic disease (IHH or KS). There was a non-significant trend towards increased testicular volume among those who completed puberty (median 6 versus 10.5 ml, P = 0.07) and, to a lesser extent, in those previously treated with gonadotrophin therapy (median 6 versus 8 ml, P = 0.38). There were no consistent differences according to diagnosis or treatment.
Treatment
The details of the courses of treatment are summarized in Table I. Each course for any man was separated by at least 6 months and was considered independently. Three of the 29 men were treated elsewhere for their first course of therapy and details of their first course were not available, and hence there were 26 first, 16 second and one third course of therapy included in this study. Since these same three men had their second course of therapy at our institute, complete details for two courses of treatment were available for 13 men, although 16 had previously received a course of gonadotrophin therapy. Seven men had not received androgens prior to their first course of gonadotrophin therapy. One man initially treated with HCG and uFSH for 2 years was switched to pulsatile GnRH for <4 weeks before conception was confirmed and hence was included in the analysis. No other patients received pulsatile GnRH. There was no association between treatment type, diagnosis and course number (P = 0.60, extended Fisher's exact test).
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In the subgroup of 13 men with two evaluable cycles of gonadotrophin treatment, there was a median time interval between cycles of 16.2 months (SE 3.2; range 7.943.5). In this subgroup, median testis volume remained larger at the start of the second course compared with that at the start of the first course of treatment (median 11 versus 6 ml; P < 0.01, Wilcoxon signed rank test).
Among the subgroup of 26 men who had never previously received gonadotrophin therapy, those who had received prior androgen therapy tended to be younger (median 34 versus 38 years) and to have smaller initial testicular volumes (median 6 versus 12 ml), but these differences were not significant.
Time to thresholds: sperm output and conception
The KaplanMeier survival analysis estimate of median time to appearance of sperm was 5.5 months (SE 1.1), to a sperm concentration of 5x106/ml was 12.4 months (SE 2.3) and to a sperm concentration of 20x106/ml was 29.1 months (SE 1.9) (Figure 1). Six men were not azoospermic at the start of therapy. All had sperm concentrations of <1x106/ml, most with only occasional sperm, except one man with a sperm concentration of 28x106/ml. This man had not been able to impregnate his wife for >3 years and was markedly androgen deficient.
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Univariate predictors of spermatogenesis and fertility
The KaplanMeier product limit estimates are summarized in Table II.
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There was no consistent or significant effect of cryptorchidism, different treatment regimens, hypopituitarism (versus isolated gonadotrophin deficiency), or completion of puberty prior to treatment.
Larger pre-treatment testis volume was a significant (P < 0.002) predictor of shorter time to all sperm thresholds. Pre-treatment testis volume did not significantly predict conception unless other adverse fertility factors were excluded (P = 0.048). Age of partner was not a predictor for any sperm threshold or conception.
Multivariate predictors of spermatogenesis and fertility and variable interaction
Using forward stepwise inclusion, testicular volume (P < 0.005) was selected in all models of sperm thresholds and pregnancy. Post-pubertal status was a signficant predictor of first sperm appearance, achieving a sperm concentration of 5x106/ml and pregnancy. No other variables consistently predicted sperm thresholds and pregnancy. However, larger testis volume, post-pubertal onset of hypogonadism, increasing age, no adverse fertility factors and the absence of multiple pituitary hormone deficiency predicted a better response. Prior androgen use and partner's age were not significant predictors for any model. The best models are shown in Table IV. Backward stepwise variable exclusion confirmed stability and log cumulative hazard and KaplanMeier plots (not shown) confirmed validity of these models. Logistic regression of time to pregnancy on sperm output failed to show a significant relationship, suggesting that informed censoring (if it was present) did not invalidate the results of the log-rank and Cox regression analyses.
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Discussion |
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Our data show that during gonadotrophin replacement therapy, testis volume is the single most important predictor of sperm output and a significant predictor of pregnancy. This is because testis volume is largely physically determined by the amount of spermatogenic tissue present and it is this tissue which controls spermatogenesis. The effect size (hazard ratio) was remarkably consistent for all spermatogenic endpoints, being 1.271.28 (see Table IV), and comparable for conception and not necessarily small since increases in testicular volume of >1 ml result in proportionally greater increases in absolute hazard. The pre-eminence of testis volume as an explanatory factor for sperm output thresholds is supported by the published literature, which is summarized graphically as a bivariate plot of initial testicular volume versus duration to induce spermatogenesis (Figure 3
). Given the heterogeneity of the data (varying measures of central tendency and differing sample sizes), it is not appropriate to perform regression analysis. Ten studies of gonadotrophin treatment for gonadotrophin-deficient men that reported baseline testis volume and estimates (mean or median) of time to appearance of sperm in at least seven men were found by a Medline review of the literature published since 1966, supplemented by hand searching (Ley and Leonard, 1984
; Liu et al., 1988
; Saal et al., 1991
; Schopohl et al., 1991
; Okada et al., 1992
; Jones and Darne, 1993
; Kliesch et al., 1994
; Kung et al., 1994
; Burgues and Calderon, 1997
; Anonymous, 1998a
; Büchter et al., 1998
). One (Kliesch et al., 1994
) was subsequently incorporated into a larger analysis (Büchter et al., 1998
) and was excluded from further analysis. All these studies used gonadotrophin dose regimens similar to those described in this study except for one study, which appeared to use much lower doses (Okada et al., 1992
).
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In the present study, first appearance of sperm occurred more rapidly (3.5 versus 7.1 months) among men with prior exposure to gonadotrophin therapy. Pregnancy also occurred more rapidly, especially when adverse fertility factors were taken into account. Furthermore, the effect of prior gonadotrophin therapy was sustained, with a 5 ml increase in median testis volume persisting even after cessation of gonadotrophin therapy for >16 months. Three other studies have examined the effect of prior gonadotrophin therapy, but have not been conclusive. One found that pregnancy occurred more rapidly in those previously treated with gonadotrophins, but four out of the 16 pregnancies reported in that study were achieved via assisted reproduction, and surprisingly, no significant effect on spermatogenesis was seen (Büchter et al., 1998) consistent with an earlier, but smaller analysis from the same group (Kliesch et al., 1994
). Another noted that men previously exposed to HCG for induction of puberty subsequently required a lower dose of HCG for normalization of testosterone levels and induction of testicular growth (Kung et al., 1994
). The third study reported a non-significant (P = 0.3) trend for improved response rate (Burgues and Calderon, 1997
). It may be that earlier gonadotrophin exposure, whether due to natural puberty or prior gonadotrophin treatment, may prime the testis and enhance spermatogenic response to subsequent gonadotrophin therapy.
Our study confirms that the beneficial effect of natural completion of puberty on spermatogenesis is not mediated by larger testis volume, since the effect was apparent even when testis volume was accounted for. Furthermore, these spermatogenic effects translated into beneficial effects on conception. This is consistent with an additional priming effect of gonadotrophins at puberty, confirming most (Finkel et al., 1985; Mastrogiacomo et al., 1991
; Burgues and Calderon, 1997
) but not all (Kung et al., 1994
) reports. Long-term gonadotrophin therapy has also been successfully used to induce spermatogenesis and androgenization in adolescent males (Barrio et al., 1999
; Bouvattier et al., 1999
), but this approach has been little used due to the limited availability, cost and inconvenience of gonadotrophins. Given the beneficial effects of prior gonadotrophin therapy as well as spontaneous completion of puberty, it is an intriguing but untested possibility that pubertal gonadotrophin treatment culminating in chronologically appropriate testis growth and spermatogenesis may facilitate later induction of spermatogenesis and/or fertility (Bouvattier et al., 1999
). This concept is further supported by the greater delay in inducing spermatogenesis reported when treatment of acquired gonadotrophin deficiency is delayed by >2 years (Tachiki et al., 1998
). It remains to be established whether gonadotrophin therapy administered to complete puberty can mimic the beneficial effect of naturally occurring puberty.
Prior androgen therapy has an apparently deleterious effect on attainment of sperm concentration of 20x106/ml in the exploratory KaplanMeier analysis, but not on lower sperm output thresholds or on pregnancy, and importantly, no effect was detected by correlated Cox analysis. Furthermore, this exploratory analysis was confounded because prior androgen therapy was associated with significantly lower testis volume. The replication of these results in gonadotrophin-naïve men suggests that this quantitative effect on the rapidity and extent of induction of spermatogenesis could be due to the prior use of androgens instead of gonadotrophins. It is likely that men with more severe gonadotrophin deficiency and lower pre-treatment testis volumes, may also be more overtly androgen deficient and hence more likely to have previously received androgen therapy. The prolonged times may therefore reflect selection bias rather than the prior use of androgens per se. Since a marked effect on time to conception was not shown and others have not found any relationship between the duration of androgen therapy and the time to detect sperm (Okada et al., 1992) nor any difference between prior androgen or prior gonadotrophin therapy (Kliesch et al., 1994
), androgen use per se is not likely to be detrimental.
Our data show that multiple pituitary hormone deficiency is deleterious to spermatogenesis. However, this effect appeared only to be important for the induction of spermatogenesis and, critically, did not appear important for conception. The presence of multiple pituitary hormone deficiency (hypopituitarism) has been variously reported as being advantageous (Okuyama et al., 1986) or detrimental (Ley and Leonard, 1984
) in small studies (
5 men). Larger studies have reported no significant effect on spermatogenesis (Kung et al., 1994
; Burgues and Calderon, 1997
) although a trend favouring those with hypopituitarism (Büchter et al., 1998
) has been noted. Since hypopituitarism tends to occur post-pubertally and is therefore also associated with larger testicular volume (Kliesch et al., 1994
), these other confounders must be adjusted for. Our data confirm this since the categories of completion of puberty and the presence of hypopituitarism were virtually identical, differing by only one man.
The presence of adverse fertility factors, including cryptorchidism, was a negative prognostic predictor of conception. Due to small numbers, the effect of cryptorchidism alone could not be studied, although there was a clear relationship with smaller testicular volume. In a study of 13 cryptorchid men, matched with 13 non-cryptorchid men with similar testicular volume (<4 ml), a statistically significant reduction in testicular growth and spermatogenesis was reported (Kirk et al., 1994) suggesting an additional detrimental effect not accounted for by testicular volume. This is consistent with our data. The remainder of the studies have examined fewer men, have not controlled for testicular volume and have variably reported significant (Ley and Leonard, 1984
; Finkel et al., 1985
), equivocal (Saal et al., 1991
; Büchter et al., 1998
) or no (Jones and Darne, 1993
) association.
Age, but not partner's age, was found to be a significant predictor of attainment of only high sperm concentration (20x106/ml) and pregnancy. Furthermore, the effect is small given that the unit of measurement is years, and the age range was 2652 years.
This study found no significant difference in spermatogenic or pregnancy outcomes when comparing rFSH with uFSH. Importantly, univariate estimates of median time to sperm output thresholds and conception differed by only 20%, nor were there any consistent differences in the multivariate analyses. Therefore, despite the limitations of these retrospective data, including differing initial FSH dosage (although maintenance dosage was identical) and small numbers in the rFSH group, any differences are considered likely to be small.
Our KaplanMeier estimate of 5.5 months of treatment to induce spermatogenesis is in close agreement with published estimates in men with similar testicular volumes. Figure 2 shows that spermatogenesis should occur after 315 months of gonadotrophin therapy. This is consistent with other studies of gonadotrophin therapy (de Sanctis et al., 1988
; Mastrogiacomo et al., 1991
; Tachiki et al., 1995
) or GnRH (Mortimer et al., 1974
; Aulitzky et al., 1988
).
Our KaplanMeier estimate that 20.5 months of treatment is required before pregnancy occurs is in agreement with the limited published data. A median treatment duration of 20 months (range 478) was found in a study of 12 successful pregnancies (Kung et al., 1994). Median treatment durations of 23 (range 754) (Burris et al., 1988
) and 43 (range 1964) months (Vicari et al., 1992
) have been reported in two other studies, each reporting successful pregnancies in seven couples and both employing long-term HCG treatment. Although the duration of therapy is longer in the latter study, it is not clear whether gonadotrophin therapy was discontinued at conception. Shorter mean treatment durations of 9 (range 121) and 8 (range 246) months have also been reported in a study where 26 (out of 36) courses of treatment resulted in pregnancy (Büchter et al., 1998
). However, this is likely to be an underestimate since it included three couples who achieved pregnancy through ICSI and two further pregnancies that occurred after 40 months of therapy were not included in the above estimates.
Conception occurred at a median sperm concentration of 5x106/ml which is in keeping with many reports of 38x 106/ml (Burger and Baker, 1984; Burris et al., 1988
; Vicari et al., 1992
; Kung et al., 1994
; Büchter et al., 1998
). The KaplanMeier survival plots indicate that, since conception occurs after
20 months and a sperm concentration of 5x106/ml after
12 months, pregnancy can be predicted on average 8 months after a sperm concentration of 5x106/ml is detected. Interestingly, our KaplanMeier survival plot (Figure 1
) also showed that the risk of pregnancy seemed to parallel the risk of achieving a sperm concentration of >5, rather than 0 or 20x106/ml. This is consistent with World Health Organization male contraception studies where this sperm output threshold appeared to demarcate subnormal from normal pregnancy rates (World Health Organization Task Force on Methods for the Regulation of Male Fertility, 1996
). This is at variance with a recent prospective study of planned pregnancies which claimed a higher threshold (40x106/ml); however, that study population may be subfertile in that it excluded the most fertile couples who had accidental pregnancies (Bonde et al., 1998
).
In summary, the present study in conjunction with the published literature suggests that when gonadotrophin-deficient men are treated with gonadotrophin therapy, sperm can be expected to appear within 6 months for a testis volume of 4 ml and over 9 months for smaller testis volumes. These durations may become more significant if the goal of gonadotrophin therapy is to induce enough sperm for ICSI. Furthermore, if pregnancy does not occur after 20 months, or 8 months after achieving a sperm concentration of 5x106/ml, assisted reproductive technologies may be considered time-effective. Cryostorage of sperm may be possible, but may not be of sufficient quality post-thaw to allow subsequent insemination without the risk of ovulation induction required for IVF. Larger testicular volume, prior gonadotrophin therapy, completion of puberty, the absence of adverse fertility factors and possibly the absence of multiple pituitary hormone deficiency predicted a favourable response. The efficacy of rFSH and uFSH appeared similar. Although our study was retrospective, no significant association between the type of treatment and diagnosis, course number, age or initial testicular volume was found, suggesting that there was no systemic bias in our study population. The recent commercial availability of rFSH, HCG and LH (Laml et al., 1999
) in clinical trials suggests that the previous limitations on gonadotrophin supply may be overcome, and that it is timely to re-evaluate the role of gonadotrophin therapy for induction of testis growth and spermatogenesis in adolescence, particularly in the light of recent advances in reproductive technologies.
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Acknowledgements |
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Notes |
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Submitted on May 10, 2001; resubmitted on September 21, 2001
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References |
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---|
Anonymous (1998b) StatXact-4. Cytel Software Corporation.
Anonymous (2000) Accord. Boffin Software, Sydney.
Aulitzky, W., Frick, J. and Galvan, G. (1988) Pulsatile luteinizing hormone-releasing hormone treatment of male hypogonadotropic hypogonadism. Fertil. Steril., 50, 480486.[ISI][Medline]
Barrio, R., de Luis, D., Alonso, M., Lamas, A. and Moreno, J.C. (1999) Induction of puberty with human chorionic gonadotropin and follicle-stimulating hormone in adolescent males with hypogonadotropic hypogonadism. Fertil. Steril., 71, 244248.[ISI][Medline]
Bonde, J.P., Ernst, E., Jensen, T.K., Hjollund, N.H., Kolstad, H., Henriksen, T.B., Scheike, T., Giwercman, A., Olsen, J. and Skakkebaek, N.E. (1998) Relation between semen quality and fertility: a population-based study of 430 first-pregnancy planners [see comments]. Lancet, 352, 11721177.[ISI][Medline]
Bouvattier, C., Tauber, M., Jouret, B., Chaussain, J.L. and Rochiccioli, P. (1999) Gonadotropin treatment of hypogonadotropic hypogonadal adolescents. J. Pediat. Endocrinol. Metab., 12 (Suppl. 1), 33944.[ISI][Medline]
Büchter, D., Behre, H.M., Kliesch, S. and Nieschlag, E. (1998) Pulsatile GnRH or human chorionic gonadotropin/human menopausal gonadotropin as effective treatment for men with hypogonadotropic hypogonadism: a review of 42 cases. Eur. J. Endocrinol., 139, 298303.[ISI][Medline]
Burger, H.G. and Baker, H.W.G. (1984) Therapeutic considerations and results of gonadotropin treatment in male hypogonadotropic hypogonadism. Ann. NY Acad. Sci., 438, 447453.[ISI][Medline]
Burgues, S. and Calderon, M.D. (1997) Subcutaneous self-administration of highly purified follicle stimulating hormone and human chorionic gonadotrophin for the treatment of male hypogonadotrophic hypogonadism. Spanish Collaborative Group on Male Hypogonadotropic Hypogonadism. Hum. Reprod., 12, 980986.[ISI][Medline]
Burris, A.S., Rodbard, H.W., Winters, S.J. and Sherins, R.J. (1988) Gonadotropin therapy in men with isolated hypogonadotropic hypogonadism: the response to human chorionic gonadotropin is predicted by initial testicular size. J. Clin. Endocrinol. Metab., 66, 11441151.[Abstract]
Calderola, J., Dilmaghani, A., Gagnon, J., Haycock, K.A., Roth, J., Soper, C. and Wasserman, E. (1998) Statview. SAS Institute Inc., Cary.
Cochius, J.I., Burns, R.J., Blumbergs, P.C., Mack, K. and Alderman, C.P. (1990) CreutzfeldtJakob disease in a recipient of human pituitary-derived gonadotrophin. Aust. NZ J. Med., 20, 592593.[ISI][Medline]
de Sanctis, V., Vullo, C., Katz, M., Wonke, B., Nannetti, C. and Bagni, B. (1988) Induction of spermatogenesis in thalassaemia. Fertil. Steril., 50, 969975.[ISI][Medline]
Finkel, D.M., Phillips, J.L. and Snyder, P.J. (1985) Stimulation of spermatogenesis by gonadotropins in men with hypogonadotropic hypogonadism. New Engl. J. Med., 313, 651655.[Abstract]
Gordon Baker, H.W. (2001) Male Infertility, Vol. 3, Endocrinology. Saunders, Philadelphia.
Healy, D.L. and Evans, J. (1993) CreutzfeldtJakob disease after pituitary gonadotrophins [editorial]. Br. Med. J., 307, 517518.[ISI][Medline]
Jones, T.H. and Darne, J.F. (1993) Self-administered subcutaneous human menopausal gonadotrophin for stimulation of testicular growth and the initiation of spermatogenesis in hypogonadotropic hypogonadism. Clin. Endocrinol., 38, 203208.[ISI][Medline]
Kamischke, A., Behre, H.M., Bergmann, M., Simoni, M., Schafer, T. and Nieschlag, E. (1998) Recombinant human follicle stimulating hormone for treatment of male idiopathic infertility: a randomized, double-blind, placebo-controlled, clinical trial. Hum. Reprod., 13, 596603.[Abstract]
Kirk, J.M.W., Savage, M.O., Grant, D.B., Bouloux, P.M.G. and Besser, G.M. (1994) Gonadal function and response to human chorionic and menopausal gonadotrophin therapy in male patients with idiopathic hypogonadotrophic hypogonadism. Clin. Endocrinol., 41, 5763.[ISI][Medline]
Kliesch, S., Behre, H.M. and Nieschlag, E. (1994) High efficacy of gonadotrophin or pusatile gonadotrophin-releasing hormone treatment in hypogonadotrophic hypogonadal men. Eur. J. Endocrinol., 131, 347354.[ISI][Medline]
Kung, A.W., Zhong, Y.Y., Lam, K.S. and Wang, C. (1994) Induction of spermatogenesis with gonadotrophins in Chinese men with hypogonadotrophic hypogonadism. Int. J. Androl., 17, 241247.[ISI][Medline]
Laml, T., Obruca, A., Fischl, F. and Huber, J.C. (1999) Recombinant luteinizing hormone in ovarian hyperstimulation after stimulation failure in normogonadotropic women. Gynecol. Endocrinol., 13, 98103.[ISI][Medline]
Lee, E.W., Wei, L.J. and Amato, D.A. (1992) Cox-type regression analysis for large numbers of small groups of correlated failure time observations. In Klein, J.P. and Goel, P.K. (eds), Survival Analysis: State of the Art. Kluwer, Dordrecth, pp. 237247.
Ley, S.B. and Leonard, J.M. (1984) Male hypogonadotropic hypogonadism: factors influencing response to human chorionic gonadotropin and human menopausal gonadotropin, including prior exogenous androgens. J. Clin. Endocrinol. Metab., 61, 746752.[Abstract]
Liu, L., Banks, S.M., Banres, K.M. and Sherins, R.J. (1988) Two year comparison of testicular responses to pulsatile gonadotropin-releasing hormone and exogenous gonadotropins from the inception of therapy in men with isolated hypogonadotropic hypogonadism. J. Clin. Endocrinol. Metab., 67, 11401145.[Abstract]
Liu, P.Y., Turner, L., Rushford, D., McDonald, J., Gordon Baker, H.W., Conway, A.J. and Handelsman, D.J. (1999) Efficacy and safety of recombinant human follicle stimulating hormone (Gonal-F) with urinary human chorionic gonadotrophin for induction of spermatogenesis and fertility in gonadotrophin-deficient men. Hum. Reprod., 14, 15401545.
Mastrogiacomo, I., Motta, R.G., Botteon, S., Bonanni, G. and Schiesaro, M. (1991) Achievement of spermatogenesis and genital tract maturation in hypogonadotropic hypogonadic subjects during long term treatment with gonadotropins or LHRH. Andrologia, 23, 285289.[ISI][Medline]
Mortimer, C.H., McNeilly, A.S., Fisher, R.A., Murray, M.A. and Besser, G.M. (1974) Gonadotrophin-releasing hormone therapy in hypogonadal males with hypothalamic or pituitary dysfunction. Br. Med. J., 4, 617621.[Medline]
Okada, Y., Kondo, T., Okamoto, S. and Ogawa, M. (1992) Induction of ovulation and spermatogenesis by hMG/hCG in hypogonadotropic GH-deficient patients. Endocrinol. Japon., 39, 3143.[Medline]
Okuyama, A., Nakamura, M., Namiki, M., Aono, T., Matsumoto, K., Utsunomiya, M., Yoshioka, T., Itoh, H., Itatani, H., Mizutani, S. and Sonoda, T. (1986) Testicular responsiveness to long-term administration of hCG and hMG in patients with hypogonadotrophic hypogonadism. Hormone Res., 23, 2130.[ISI][Medline]
Peto, R., Pike, M.C., Armitage, P., Breslow, N.E., Cox, D.R., Howard, S.V., Mantel, N., McPherson, K., Peto, J. and Smith, P.G. (1976) Design and analysis of randomised clinical trials requiring prolonged observation of each patient: I. Introduction and design. Br. J. Cancer, 34, 585612.[ISI][Medline]
Saal, W., Happ, J., Cordes, U., Baum, R.P. and Schmidt, M. (1991) Subcutaneous gonadotropin therapy in male patients with hypogonadotropic hypogonadism. Fertil. Steril., 56, 319324.[ISI][Medline]
Schaison, G., Young, J., Pholsena, M., Nahoul, K. and Couzinet, B. (1993) Failure of combined follicle-stimulating hormonetestosterone administration to initiate and/or maintain spermatogenesis in men with hypogonadotropic hypogonadism. J. Clin. Endocrinol. Metab. 77, 15451549.[Abstract]
Schopohl, J., Mehltretter, G., von Zumbusch, R., Eversmann, T. and von Werder, K. (1991) Comparison of gonadotropin-releasing hormone and gonadotropin therapy in male patients with idiopathic hypothalamic hypogonadism. Fertil. Steril., 56, 11431150.[ISI][Medline]
Tachiki, H., Kumamoto, Y., Itoh, N., Maruta, H. and Tsukamoto, T. (1995) [Testicular findings, endocrine features and therapeutic responses of men with idiopathic hypogonadotropic hypogonadism]. Nippon Naibunpi Gakkai ZasshiFolia Endocrinol. Japon., 71, 605622.
Tachiki, H., Ito, N., Maruta, H., Kumamoto, Y. and Tsukamoto, T. (1998) Testicular findings, endocrine features and therapeutic responses of men with acquired hypogonadotropic hypogonadism. Int. J. Urol., 5, 8085.[Medline]
Vicari, E., Mongioi, A., Calogero, A.E., Moncada, M.L., Sidoti, G., Polosa, P. and D'Agata, R. (1992) Therapy with human chorionic gonadotrophin alone induces spermatogenesis in men with isolated hypogonadotrophic hypogonadismlong-term follow-up. Int. J. Androl., 15, 320329.[ISI][Medline]
World Health Organization (1980) Laboratory Manual For The Examination of Human Semen and SpermCervical Mucus Interaction. Press Concern, Singapore.
World Health Organization (1987) WHO Laboratory Manual For The Examination of Human Semen and SpermCervical Mucus Interaction. Cambridge University Press, Cambridge.
World Health Organization (1992) WHO Laboratory Manual For The Examination of Human Semen and SpermCervical Mucus Interaction. Cambridge University Press, Cambridge.
World Health Organization Task Force on Methods for the Regulation of Male Fertility (1996) Contraceptive efficacy of testosterone-induced azoospermia and oligozoospermia in normal men. Fertil. Steril., 65, 821829.[ISI][Medline]
accepted on November 13, 2001.