Departments of Andrology, Concord Hospital & ANZAC Research Institute, University of Sydney, Sydney NSW 2139, Australia
1 To whom correspondence should be addressed. Email: djh{at}anzac.edu.au
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Abstract |
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Key words: androgen/contraception/progestin/sperm output/testosterone
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Introduction |
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In this study we use the uniquely large WHO dataset from the two male contraceptive efficacy studies to provide estimates of sperm suppression and recovery rates for testosterone-induced sperm suppression and recovery. Using these estimates, we evaluate the rates of suppression and recovery of men who participated in the first contraceptive efficacy study of a depot androgen/progestin combination in order to determine distinctive characteristics of the progestin used, medroxyprogesterone acetate, on suppression and recovery of sperm output.
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Materials and methods |
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Data analysis
Sperm concentrations were cube-root transformed to achieve near-gaussian distribution while also preserving appropriate handling of zeros (azoospermia) which are frequent in these data and crucial to the quantitative analyses (Handelsman, 2002). Log transformation (Berman et al., 1996
) was less suitable, as the arbitrary offset required for zeros would systematically influence regression estimates.
The start of treatment was defined as the date of first hormone administration. The end of treatment was defined as the date of the last treatment plus the time of one treatment administration (i.e. the date of the first missed hormone treatment). This was 1 week after the last weekly testosterone enanthate injection, 3 months after the last DMPA injection and 4 months after the last testosterone implant. In the combination study, where the end of two concurrent treatment cycles did not coincide, the later date was defined as the end of treatment. For analysis, because the exact date when samples were provided was known, each semen sample was pooled into the closest time-period (week, month) based on the number of days from start or end of treatment.
To estimate quantitatively the suppression and recovery rates, time was calculated from the start of treatment with the fall or rise of sperm output fitted by non-linear regression. Rate estimates were calculated according to two definitions of sperm output: one analysing the absolute sperm concentration and the other as the relative sperm concentration, defined as a proportion of the man's own geometric mean baseline (pre-treatment) sperm concentration.
Inspection of the data indicated that a non-linear regression was required, that the suppression was asymptotic and the recovery involved substantial delay followed by an increase to a plateau. Among families of non-linear curves (polynomial, peak, sigmoid, exponential, hyperbola, waveform, power, rational), the most suitable were exponential regression for suppression and a sigmoidal curve for recovery. Preliminary analysis balancing parsimony in model parameters against degrees of freedom (guided by the Akaike Information Criterion, AIC) aiming for the model to maximally reduce data entropy, we chose a three- rather than four- or five-parameter sigmoid and one-component rather than two- or more component exponential forms. These choices were confirmed by an analysis with TableCurve, which simultaneously evaluates 3665 in-built functional forms, including all non-linear curve families.
For suppression rate, the data were fitted by a two-parameter, single exponential non-linear regression that provided a rate coefficient which was back-transformed into an estimate of half-time for suppression. The recovery data were fitted by a three-parameter sigmoidal curve that provided estimates of a half-time to, and plateau of, recovery. Confidence intervals (CI) were estimated from the appropriate SE. Differences between categorical variables (study centres) were evaluated as main effects in log-linear regression for suppression rates and logistic regression for recovery rates using SPSS version 12 software. Non-linear regression was performed using Sigmaplot 8.0 software.
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Results |
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The rate of suppression (Figure 1) was well fitted by a two-parameter, single exponential decay curve:
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This provided an estimated time to reach half of maximal suppression of 5.5 weeks (95% confidence interval 5.25.9 weeks) for suppression. Estimated times to reach specific sperm output thresholds were 5.0 weeks (20 x 106/ml), 6.8 weeks (10 x 106/ml), 8.7 weeks (5 x 106/ml), 10.0 weeks (3 x 106/ml) and 13.0 weeks (1 x 106/ml).
There were significant differences between the 16 centres (F=16, P<0.001) in suppression rates. Although this appeared largely attributable to faster suppression by men in Chinese versus non-Chinese centres (F=83.8, P<0.001), there was also significant between-centre variability within Chinese (F=13, P<0.001) and non-Chinese (F=11.3, P<0.001) centres. From fitted regression curves to pooled data from centres by region, the six Chinese centres had shorter time to reach half suppression than the 10 non-Chinese centres but there were no systematic differences between the two Australian and the other eight Western centres in suppression rates (Table I). However, the differences between Chinese and non-Chinese centres in time to half suppression were small in magnitude (5.3 versus 5.6 weeks respectively).
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There were significant differences between the 16 centres (F=2.1, P=0.007) in recovery rates. This was attributable to slower recovery by men in Chinese versus non-Chinese centres (F=14.3, P<0.001) and there was no significant difference between centres among Chinese (F=1.8, P=0.103) or non-Chinese (F=1.1, P=0.389) centres. The time to reach half recovery plateau was longer in the six Chinese centres compared with the 10 non-Chinese centres but there were no significant difference between the two Australian and other Western centres (Table I).
Using the relative sperm outputs (sperm concentration for each individual as percentage of baseline sperm concentration), the recovery rate was well estimated by a three-parameter sigmoid with coefficients (SD=% baseline sperm concentration, T = time in weeks):
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The asymptotic plateau recovery was to 85% of pre-treatment baseline sperm concentration with an estimated time to reach half of the recovery plateau of 12.6 weeks (95% CI 7.118.1 weeks).
Australian study: suppression and recovery rates
The suppression rate (Figure 3) was significantly faster than in the WHO studies. The regression coefficients (SD = cube-root of sperm concentration, T = time in months) were:
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The recovery rate was significantly slower and less complete than for the WHO dataset and the goodness of fit was significantly inferior judged by coefficient of determination (R2). Using the absolute sperm outputs (Figure 3), the recovery rate was fitted to a three-parameter sigmoid with coefficients (SD = cube-root of sperm concentration, T = time in months):
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This provided an asymptotic plateau recovery in sperm output of 17 x 106/ml with an estimate of time to reach half of recovery plateau of 14.7 weeks (95% CI 129 weeks). As indicated by the time to reach half plateau recovery, the recovery rate in this study was slower than for men in the two Australian centres than for men in the eight other Western or the 10 non-Chinese centres (Table I).
Using the relative sperm outputs (sperm concentration for each individual as percentage of baseline sperm concentration, Figure 4), the recovery rate fitted a three-parameter sigmoid with coefficients (SD=% baseline sperm concentration, T = time in months):
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Discussion |
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Quantitative aspects of sperm suppression and recovery have so far mainly focused on extent of suppression of spermatogenesis, a widely accepted and convenient surrogate variable for selecting the most promising regimens for further evaluation (Anderson and Baird, 2002; Kamischke and Nieschlag, 2004
; Handelsman, 2005
). Beyond the extent of suppression of spermatogenesis, there has been little quantitative consideration of sperm suppression or recovery rates. This limitation, largely due to the small size of most studies, is overcome by the WHO database which provides a valuable resource to estimate rates of suppression and recovery of spermatogenesis. In this study both suppression and recovery rates differed between centres. This was largely because men in predominantly Chinese centres had faster suppression and slower recovery rates than men in non-Chinese centres. In recovery rates, the differences between centres appeared to be fully accounted for by the geographical factor whereas for suppression rates there remained significant variations between the six predominantly Chinese and between the 10 non-Chinese centres. This indicates that the geographical variations are likely to be multifactorial, consistent with the mixture of ethnic, genetic and environmental factors already identified. The present estimates from those androgen-alone studies suggest that onset of reliable contraception, using the criterion of sperm output of <1 x 106/ml, may take on average 3 months. Similarly, recovery to levels of normal fertility may take 913 weeks depending on the definition of normal (see below). As second generation hormonal regimens are now based on androgen/progestin combinations (Anderson and Baird, 2002
; Kamischke and Nieschlag, 2004
; Handelsman, 2005
), the WHO studies provide a convenient benchmark for speed of onset and offset of future combination regimens.
Estimates derived from the WHO studies are prima facie applicable to that study's regimen, weekly i.m. injections of 200 mg testosterone enanthate. Whether these estimates extend to other androgen-alone regimens, such as testosterone implants (Handelsman et al., 1992, 1996
), testosterone undecanoate (Zhang et al., 1999
; Kamischke et al., 2000
; Gu et al., 2002
) or a synthetic androgen such as the nandrolone analogue, MENT (7
-methyl-19-nortestosterone) (von Eckardstein et al., 2003
), cannot be considered certain a priori. To the extent that androgen-alone regimens work primarily by the common mechanism of gonadotrophin suppression, this is likely to be true. This would be highly advantageous as it is unlikely that any study in the near future will exceed the size of this WHO database, as weekly testosterone enanthate injections were only ever used as a convenient prototype androgen-alone regimen, although it is now considered obsolete for male contraceptive studies. It cannot be excluded, however, that the supraphysiological steady-state blood testosterone levels produced by regular weekly testosterone enanthate injections may produce systematic differences in spermatogenic suppression and recovery (Michel et al., 1985
; Meriggiola et al., 2002
). By contrast, superior depot testosterone preparations such as testosterone implants or testosterone undecanoate injections maintain more physiological blood testosterone levels. These could lead to differences in spermatogenic suppression, particularly if excessive blood testosterone concentrations counteract the rate or extent of depletion of intratesticular testosterone and thereby delay suppression of spermatogenesis (McLachlan et al., 2002
). This hypothesis regarding counter-productive effects of excessive androgen action is plausible because the threshold of testicular testosterone required to support spermatogenesis is remarkably low (Handelsman et al., 1999
; McLachlan et al., 2002
; Zhang et al., 2003
). Nevertheless, previous studies with testosterone implants indicate that, while a better depot may be dose-sparing for systemic androgenic effects, the rate and extent of spermatogenic suppression did not differ significantly from the WHO studies regimen of weekly i.m. injections of testosterone enanthate (Handelsman et al., 1992
). Although this suggests that the present estimates may be robust for all androgen-alone regimens, further studies of other androgen-alone regimens are needed to evaluate this proposition. To overcome the consistently small size of these studies, this would require a quantitative summary data analysis.
This study provides the first detailed quantitative information on the effects of a depot progestin, depot medroxyprogesterone acetate (DPMA), on the rate of suppression and recovery of human sperm output in the Australian study. While a limited meta-analysis had previously shown that DMPA demonstrated greater proportionate reduction in sperm output at 1 month after starting treatment (Turner et al., 2003), the present, more detailed, quantitative analysis shows that DMPA effects include not only strikingly faster suppression throughout the suppression phase, but also markedly slower and less complete recovery compared with the testosterone enanthate injections used in the WHO studies. The reasons for these differences are not immediately apparent but may include prolonged depot pharmacokinetics of DMPA with persistent blood MPA concentrations due to secondary fat depots (Ortiz et al., 1977
; Lan et al., 1984
; Kaunitz, 1994
; Mishell, 1996
) and/or direct progestin effects on the testis (Worgul et al., 1979
; McLachlan et al., 2004
), sperm (Blackmore, 1993
; Blackmore et al., 1996
; Luconi et al., 1998
) or Leydig cells (Pino and Valladares, 1988
; El-Hefnawy et al., 2000
; Williams et al., 2000
). Whether the same accelerated suppression and retarded recovery applies to other depot progestins is not known and will require further analysis.
The rate of suppression of sperm out depends on the stage of spermatogenic cycle most prominently affected (McLachlan et al., 2002) together with the time taken to clear residual pre-formed sperm from the male ductular system. Although sperm transit time through the human epididymis is estimated at <15 days based on the appearance of labelled sperm in the ejaculate following tracer administration (Rowley et al., 1970
) or quantitative estimates of distribution of homogenization-resistant nuclei counts in the testis and epididymis (Amann and Howards, 1980
; Johnson and Varner, 1988
), recent estimates of sperm clearance rate following vasectomy indicate that clearance to azoospermia may take 34 months (Barone et al., 2004
; Sokal et al., 2004
). The reason for these disparities is unclear but it is possible that surgical manipulation of the vas deferens may slow sperm transit time. Conversely, the similar times to azoospermia after hormonal regimens and vasectomy suggest that the hormonal regimens abolish active spermatogenesis quite rapidly despite ongoing sperm output in the ejaculate, which constitutes a lagging indicator of testicular sperm production. In any case, the time required to clear pre-formed sperm from the ductular system sets a minimum on the time to onset of reliable contraception for any hormonal male contraceptive as it does for vasectomy.
This analysis resolved some methodological issues. One was the definition of the end of treatment raised by the use of depot regimens. Unlike short-acting drugs where there is negligible difference between the time of last administered dose and cessation of drug action, these time-points differ significantly for depot drugs and become troublesome when two or more depot agents with distinctive kinetics are used. We defined the end of treatment as the date of the first missed hormone dose as the most realistic time-point from which to estimate cessation of the last depot dose effects. The use of one dosage interval beyond the last administered dose is justified where there is no drug accumulation, an assumption that may be violated if DMPA has secondary depot effects. A second methodological issue was the use of a power rather than the more conventional log transform. This was a superior approach for quantitative analyses of sperm output where zeros (azoospermia) are important because the log transform requires an arbitrary offset for the zeros which distorts regression estimates. Thirdly, the specific curve-fits we employed may not be optimal or universal. Despite performing very satisfactorily in this analysis, different models may be useful in future studies.
An unexpected and important feature of this analysis is that despite increased sperm output after cessation of treatment, return to the participants' own pre-treatment geometric mean baseline was not achieved consistently. The definition of recovery is crucial to such analyses but no singular definition is intuitively obvious. We therefore employed both the absolute and relative (to baseline) analyses and both gave concordant patterns. The major reason for the apparently incomplete recovery may be due to the lack of unambiguous criteria for recovery because this requires a definition of normal sperm output. It is well known that there is no satisfactory, evidence-based and widely accepted definition of population-based normal sperm output with or without regard to male fertility. Conventional semen parameters fail to allow clear distinction between men defined as fertile, infertile or the majority who, at any time, may have undefined fertility (MacLeod and Gold, 1951; Meistrich and Brown, 1983
; Guzick et al., 2001
). The WHO Semen Manual's arbitrary definition of a normal sperm concentration of 20 x 106/ml is based on oracular wisdom rather than empirical evidence and, in the absence of conclusive evidence, it is claimed that this level is too low (Bonde et al., 1998
; Zinaman et al., 2000
) or too high (Handelsman, 1997
; Lemcke et al., 1997
; Ombelet et al., 1997
; Chia et al., 1998
; Andersen et al., 2000
). The inability to obtain representative samples from the healthy male community (Handelsman, 2001
; Cohn et al., 2002
) probably precludes ever arriving at a satisfactory definition of normal by the standards of all other biochemical pathology tests. In our view, the most probable reason for the failure of sperm output to reach the participants' own pre-treatment baseline in the WHO studies is the combined effects of regression to the mean (Bland and Altman, 1994
) with unrealistically high WHO norms for sperm concentration. Sperm concentration has high within-subject variability (Schwartz et al., 1979
) and if the study entry criterion of 20 x 106/ml is higher than the true, but unknown, community norm, then some men enter the study with higher than their own mean sperm concentration. Subsequently, over time, they would resume a lower mean sperm output regardless of treatment. The alternative interpretation of these data is that hormonal regimens may have mild but irreversible effects in sperm output, an effect that, if true, could increase with prolonged or subsequent courses of treatment. While this latter interpretation seems unlikely, excluding this possibility will require analysis of larger numbers of previous and future studies of hormonal suppression of sperm output.
Male reproductive physiology dictates that some delay is inevitable in the onset and offset of contraception using a male hormonal regimen. Such delay is an accepted facet of vasectomy and is also congruent with likely niches for a male hormonal method. For example, post-partum contraception is a context where hormonal contraceptive treatment can be commenced during pregnancy leaving ample time to establish reliable contraception without risk of conception while assisting mothers to avoid hormonal contraception during lactation. Similarly, delaying vasectomy until the decision for permanent sterilization is well thought out and justified. This may reduce regret and requests for reversal (Holman et al., 2000), just as the use of a reversible hormonal contraceptive is considered a desirable prelude to a permanent decision for female sterilization. Some delay in onset of reliable contraceptive efficacy is also congruent with male hormonal contraception being primarily directed towards family planning/spacing for couples in stable relationships. By contrast, barrier methods such as the condom are far better suited to men having unplanned sex outside a stable relationship where dual protection against sexually transmitted infections has greater importance. In any case, accurate estimates of time of onset and offset and resumption of normal fertility as well as the criteria to define return to normality require more concerted attention in further studies.
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Acknowledgements |
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Notes |
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References |
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Submitted on December 7, 2004; resubmitted on February 1, 2005; accepted on February 9, 2005.
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