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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-2768
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The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 5 1774-1783
Copyright © 2008 by The Endocrine Society

Determinants of the Rate and Extent of Spermatogenic Suppression during Hormonal Male Contraception: An Integrated Analysis

Peter Y. Liu, Ronald S. Swerdloff, Bradley D. Anawalt, Richard A. Anderson, William J. Bremner, Joerg Elliesen, Yi-Qun Gu, Wendy M. Kersemaekers, Robert. I. McLachlan, M. Cristina Meriggiola, Eberhard Nieschlag, Regine Sitruk-Ware, Kirsten Vogelsong, Xing-Hai Wang, Frederick C. W. Wu, Michael Zitzmann, David J. Handelsman and Christina Wang

Department of Andrology (P.Y.L., D.J.H.), ANZAC Research Institute and Concord Hospital, Concord 2139, Australia; Division of Endocrinology (R.S.S.), Department of Medicine, LABiomed and Harbor-UCLA Medical Center, Torrance, California 90509; Department of Medicine (B.D.A.), Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle, Washington 98195; Division of Reproductive and Developmental Sciences (R.A.A.), The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom; Department of Medicine (W.J.B.), University of Washington, Seattle, Washington 98195; Bayer Schering Pharma AG (J.E.), 93 HRB 283 Berlin, Germany; Department of Endocrinology (Y.-Q.G.), National Research Institute for Family Planning, Beijing 100081, China; Translational Medicine Department (W.M.K.), N.V. Organon, a part of Schering-Plough Corporation, Oss NL-5340 BH, The Netherlands; Prince Henry's Institute and Monash Medical Centre (R.I.M.), Monash University, Clayton 3168, Australia; Departments of Obstetrics and Gynecology (M.C.M.), S. Orsola-Malpighi Hospital and University of Bologna, 40138 Bologna, Italy; Institute of Reproductive Medicine (E.N., M.Z.), University Hospital, D-48149 Münster, Germany; Center for Biomedical Research (R.S.-W.), Population Council, and Rockefeller University, New York, New York 10021; The United Nations Development Programme/United Nations Fund for Population Activities/World Health Organization/World Bank Special Programme of Research (K.V.), Development and Research Training in Human Reproduction, Department of Reproductive Health and Research, World Health Organization, 1211 Geneva 27, Switzerland; Jiangsu Family Planning Research Institute (X.-H.W.), Jiangsu 210029, China; Department of Endocrinology (F.C.W.W.), Manchester Royal Infirmary, University of Manchester, Manchester M13 9WL, United Kingdom; and General Clinical Research Center (C.W.), LABiomed and Harbor-UCLA Medical Center, Torrance, California 90509

Address all correspondence and requests for reprints to: Peter Y. Liu, M.B.B.S., Ph.D., Department of Andrology, ANZAC Research Institute, University of Sydney and Concord Hospital, Concord, New South Wales 2139, Australia. E-mail: pliu{at}mail.usyd.edu.au; or Christina Wang, M.D., General Clinical Research Center, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, 1000 West Carson Street, Torrance, California 90509. E-mail: wang{at}labiomed.org.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Male hormonal contraceptive methods require effective suppression of sperm output.

Objective: The objective of the study was to define the covariables that influence the rate and extent of suppression of spermatogenesis to a level shown in previous World Health Organization-sponsored studies to be sufficient for contraceptive purposes (≤1 million/ml).

Design: This was an integrated analysis of all published male hormonal contraceptive studies of at least 3 months' treatment duration.

Setting: Deidentified individual subject data were provided by investigators of 30 studies published between 1990 and 2006.

Participants: A total of 1756 healthy men (by physical, blood, and semen exam) aged 18–51 yr of predominantly Caucasian (two thirds) or Asian (one third) descent were studied. This represents about 85% of all the published data.

Intervention(s): Men were treated with different preparations of testosterone, with or without various progestins.

Main Outcome Measure: Semen analysis was the main measure.

Results: Progestin coadministration increased both the rate and extent of suppression. Caucasian men suppressed sperm output faster initially but ultimately to a less complete extent than did non-Caucasians. Younger age and lower initial blood testosterone or sperm concentration were also associated with faster suppression, but the independent effect sizes for age and baseline testicular function were relatively small.

Conclusion: Male hormonal contraceptives can be practically applied to a wide range of men but require coadministration of an androgen with a second agent (i.e. progestin) for earlier and more complete suppression of sperm output. Whereas considerable progress has been made toward defining clinically effective combinations, further optimization of androgen-progestin treatment regimens is still required.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
Hormonal methods that exploit negative feedback suppression of pituitary gonadotropin secretion, analogous to ovulation inhibition by combined estrogen-progestin contraceptives, are effective and reversible (1, 2, 3, 4, 5, 6, 7). Androgen or androgen-progestin treatment combinations can inhibit spermatogenesis to azoospermia (no sperm in ejaculate) or near-azoospermia (≤1 million/ml semen), with some regimens being more effective than others (8, 9, 10, 11, 12, 13, 14, 15, 16). This degree of suppression of sperm output provides effective contraception with efficacy rates of 97–100% (1, 2, 3, 4). Recovery of sperm output to levels consistent with normal male fertility can also be expected in all men (5), and short-term safety parameters have been identified (17).

Understanding the factors responsible for suppression of sperm output to levels that provide reliable contraception is essential for designing optimal regimens for male hormonal contraceptives. In particular, understanding which factors predict rapid suppression of sperm output is especially important for a practical method that couples may wish to switch to without delay. Conversely, identifying which men are likely to suppress sperm output more slowly is equally important to allow antecedent counseling.

Physiological studies in humans and other primates suggest biphasic effects are plausible because gonadotropin withdrawal impairs different stages of spermatogenesis both early (spermatogonial proliferation) and late (spermiation) in the spermatogenic cycle (18). Different early, compared with late, rates of suppression of sperm output could thereby result. Previous work has implicated Asian (compared with Caucasian) ethnicity (19), lower baseline FSH concentration and greater gonadotropin suppression (4, 20), progestin coadministration (21, 22), and lower testosterone dose (22, 23) in more complete eventual suppression of sperm output. However, available studies were limited by relatively small sample sizes, which precluded adequately powered multivariate analyses. An integrated analysis, combining data from all available sources, would allow assessment of the relative and independent importance of putative predictors.

We therefore conducted an integrated analysis of individual participant data to examine factors that may influence the extent and the rate of spermatogenic suppression, to define predictors. Such an analysis was feasible because of the inherent consistency of study design and the standardized methods used to assess the primary endpoint (semen analysis) arising from a long history of collaboration and information sharing among investigators active in the field, with regular meetings sponsored for three decades by the World Health Organization (WHO) and more recently by international summit meetings. These groups have, in addition, developed comprehensive international advisory recommendations related to the development of hormonal regimens of male fertility regulation (6, 24, 25). We also recently analyzed the rate of recovery of spermatogenesis after hormonal methods are ceased (see Subjects and Methods) (5). In the current analysis, we examined both the rate and extent of spermatogenic suppression stratifying on a time-dependent variable to distinguish early from later influences using data largely derived previously (5).


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Data collection, subjects, and interventions

Studies in which men were administered an androgen or androgen-progestin regimen for at least 3 months were initially identified by PubMed search using key terms "androgen" or "testosterone" with "contraception." An exposure period of at least 3 months was chosen because the spermatogenic cycle requires about 70 d to complete (26, 27). Additional studies were located by scrutinizing reference lists and surveying members of the international hormonal male contraception summit group, which includes representatives of virtually all active clinical research groups studying male hormonal methods. All identified studies recruited healthy, eugonadal men on the basis of unremarkable reproductive history; physical examination (including testicular examination); blood hormonal, biochemical, and hematological parameters; and semen analysis (requiring two semen analysis with sperm concentration of at least 20 million/ml). Semen was consistently assessed by contemporaneous WHO-recommended methods (28) before and at least monthly (every 2–4 wk) during treatment in all studies. Baseline sperm concentration was defined as the mean sperm concentration from at least two individual semen analyses.

Thirty-four studies were identified at the time of data collection in 2005 (1, 2, 3, 4, 23, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57); however, four studies were excluded from the analysis because the necessary data were not available from study investigators (54, 55, 56, 57). Since the time of data collection, two additional studies have been published (58, 59) (Tables 1Go and 2Go). Data from these two recent studies were not included in the current analysis. Deidentified individual subject data were supplied by investigators of 20 single- and 10 multicenter studies spanning five continents (North and South America, Europe, Asia, and Australia) through a standardized worksheet that was approved by the Harbor-UCLA Medical Center Institutional Review Board (Table 1Go). Hence, about 85% of all individual subject data from all 36 published studies identified in 2007 were available for analysis, and the 30 included studies were similar to the six studies not included (Table 2Go). In all clinical studies, prior written informed consent was obtained from each subject after approval from the relevant human subjects research ethics committee. Men were aged 18–51 yr, were treated for 16–78 wk with im testosterone (T), T undecanoate (TU), T decanoate (TD), T enanthate (TE); oral T capsule (TU); transdermal T patch; biodegradable T pellets; or 7-{alpha} methyl-19-nor-testosterone (MENT) acetate implants with or without oral cyproterone acetate (CPA), oral or implants of levonorgestrel (LNG), oral or injections of norethisterone (NET), oral desogestrel (DSG), implants of etonogestrel (ENG), or injections of depot medroxyprogesterone acetate (DMPA). As shown, studies were either efficacy studies (in which pregnancies/contraceptive failures was the end point) or suppression studies (in which the end point was sperm output). For efficacy studies, treatment ceased if suppression of sperm concentration to azoospermia, 1 million/ml or less or 3 million/ml or less did not occur by 6 months (1, 2, 3, 4), and data were then censored statistically. For suppression studies, some of these were exploratory to determine best dose, delivery systems, or androgen-progestin combinations and hence were not optimized to ensure uniform suppression of spermatogenesis.


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  		TABLE 1. Included studies

 

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  		TABLE 2. Excluded studies

 
Information was collected for the present analysis from 1756 men (from a potential group of 2023 recruited into all 30 studies) who were exposed to a hormonal regimen for fertility control for at least 3 months. Not all data were obtained from all recruited men. As previously mentioned, this report includes data from a subgroup of men in which recovery of spermatogenesis after cessation of hormonal exposure was additionally documented (5). The primary end point (focal point) for the present study was time to suppress sperm output to a concentration of 1 million/ml or less. This degree of suppression is sufficient for reliable contraception (6). Subjects were censored when they dropped out of the study. These times were extracted by one investigator (P.Y.L.) from complete databases containing all individual semen data supplied by investigators from Sydney, Australia; Münster, Germany; Los Angeles, CA; Seattle, WA; and WHO. These data comprise about half of all sperm threshold data. Extracted data were provided by the investigators for the remaining studies.

Baseline subject and treatment data that might influence suppression times a priori were also collected (Tables 3Go and 4Go). All covariate data collected and used for this analysis are listed in these tables.


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  		TABLE 3. Participant characteristics at baseline

 

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  		TABLE 4. Univariate analysis of predictors of suppression of spermatogenesis to 1 million/ml

 
Calculations

We calculated the effective daily T dose according to known pharmacokinetics of testosterone preparations (60, 61, 62, 63). Calculation of daily effective dose is based on the following assumptions and mean values recognizing that there is considerable individual variation in pharmacokinetics. This was 5% of the administered dose for oral TU, 5 mg per patch for transdermal T and 1.3 mg per 200 mg T pellet. For im testosterone esters, the exact amount of T injected was calculated (using the known molecular weight of testosterone discounting the ester side chain) from which the total T dose administered over the entire nominal treatment period based on the injection frequency could be determined. From this the effective daily T dose was calculated.

Analysis

We examined the rate of suppression by means of an integrated reanalysis of individual subject data (64), not a metaanalysis of pooled summary study data. Hence, the unit of analysis was the individual subject, not the 30 identified studies. Univariate analyses of continuous (Cox) and categorical (Kaplan-Meier) variables were initially performed and analogously to a recently applied analytical strategy (5). A parsimonious model was identified by stepwise selection and confirmed by best subset selection of all possible covariate combinations. The best subset selection method chooses a sequence of models with increasing number of predictors, each of which is most predictive among competitors with the same number of predictors. We examined suppression of sperm concentration from baseline to 1 million/ml or less. Finally, we examined whether early or late effects on sperm suppression might differ by creating a time-dependent covariate to dichotomize and on which to stratify the extended Cox analysis (64).

As a separate analytical strategy, we also examined the extent of suppression of sperm output by dichotomizing men into those who did or did not ever suppress to a sperm concentration of 1 million/ml and assessed how they differed in baseline parameters (by two-sample Student t test or Fisher test for continuous and categorical variables, respectively). Significant variables were then analyzed simultaneously by stepwise multivariate logistic regression to identify independent predictive covariables.

All tests were two sided, with P < 0.05 considered significant. Data are shown as median (range) or mean ± SEM. These analyses were executed with SAS proc phreg, lifetest, and logistic (version 9.1; SAS Institute, Inc., Cary, NC). Proportional hazards assumptions were confirmed by graphical examination of Schoenberg residuals and supremum and related tests (64).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Rate of suppression

Tables 3Go and 4Go show baseline characteristics of the 1756 men identified from 30 studies and the univariate (unadjusted) utility of these characteristics as predictors of spermatogenic suppression. For categorical variables, these inferences are similar to those obtained with Kaplan-Meier log-rank tests: androgen, ethnicity, and progestin use (each P < 0.001).

A Kaplan-Meier (unadjusted) curve showing the proportion of men who suppressed their sperm concentrations to 1 million/ml or less was constructed (Fig. 1Go). This indicated that sperm concentration first falls to 1 million/ml or less after a median time of 2.73 (2.70–2.76 95% confidence interval) months.


Figure 1
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  		FIG. 1. Kaplan-Meier observed suppression plots showing the proportion of men who suppressed their sperm concentration to 1 million/ml. The number of men (n) remaining at 0, 2, 4, and 6 months are shown below. CI, Confidence interval.

 
Figure 2Go shows the multivariately adjusted hazard ratios and 95% confidence intervals of the final multivariate models selected after stepwise Cox regression from the potential set of all univariate variables (shown in Tables 3Go and 4Go). Hazard ratios exceeding 1.0 indicate faster, whereas those less than 1.0 signify slower, rates of suppression. Considerable overlap of 95% confidence intervals for hazards ratios indicate the comparability among the different T preparations (P < 0.009 vs. MENT for each), except for oral and transdermal T which, as a group, is associated with slower suppression. Faster rates of suppression were observed in Caucasian men or with concurrent progestin administration. Slower suppression occurred with older age, higher baseline blood testosterone, or higher baseline sperm concentration (each significant P < 0.001); however, these adjusted effect sizes were relatively small (hazard ratio > 0.98, for each) in comparison with the expected range of each of these parameters.


Figure 2
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  		FIG. 2. Final multivariate variables selected after stepwise Cox regression. Hazard ratios and 95% confidence intervals, with multivariate adjustment to exclude effects of other variables, are shown. Hazard ratios exceeding 1 indicate faster, whereas those less than 1 signify slower, rates of suppression for each unit increase in the corresponding variable. *, Hazard ratios that significantly differ from unity (vertical line). Note magnified hazard ratio scale for age, baseline sperm concentration, and baseline T.

 
Next, we repeated the same analysis but allowed for the rate of suppression of sperm output to differ early or late in time. Early epoch of time was defined as earlier than 3 months, based on the Kaplan-Meier analysis, which showed that the median time to suppression was 2–3 months, and on the 2.5-month duration of the spermatogenic cycle. Similar results were obtained if the early epoch of time is defined as earlier than 2 months. These data (not shown) all indicate that predictors, except for ethnicity, are invariant across time. The hazard ratio for ethnicity, in contrast, was significantly greater than 1 [hazard ratio 1.8430 (1.5330–2.2170), P < 0.0001] during the early time period but was significantly less than 1 [hazard ratio 0.5280 (0.4100–0.6810), P < 0.0001] during the late time period. This means that the rate of suppression of sperm output in Caucasian men is faster, compared with Asian men, during the first 2–3 months of exposure but slower, compared with Asian men thereafter.

Extent of suppression

Table 5Go shows the univariate analyses examining differences between men who suppressed their sperm concentration to 1 million/ml (n = 1513) from those who did not (n = 243). Table 6Go shows which of these variables are independently important by stepwise multivariate logistic regression. These analyses confirm the extended Cox analysis showing that the most important predictors of incomplete suppression based on effect size are Caucasian (vs. Asian) ethnicity and the use of androgen alone (vs. androgen with progestin) regimens. In addition, increasing obesity and exposure to a higher effective dose of testosterone increases the odds of nonsuppression, but these effects were numerically less important.


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  		TABLE 5. Univariate analysis of men who suppress spermatogenesis, compared with those who do not

 

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  		TABLE 6. Odds ratio of nonsuppression of spermatogenesis by multivariate logistic regression

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In this analysis, the most comprehensive of its kind, only six factors were independently identified as predicting the rate of suppression of sperm output, and only two factors (concurrent progestin use and ethnicity) are likely to be clinically important because of large effect size. The detection of these small effects (with hazard ratios of no less than 0.98 and therefore close to a no effect hazard ratio of 1) underscores the statistical power of the current data set and the methods of analysis. Furthermore, the highly significant inferences unveiled (often P < 10–3) highlights that these relationships were not due to multiple comparisons. These findings also suggest that it is unlikely that conventional clinical or laboratory variables could be used to identify men a priori who are more or less likely to suppress sperm output to levels consistent with reliable male contraception.

We conclusively show by both an extended Cox regression approach (to allow for time varying covariants) and multivariate logistic regression that progestin coadministration enhances both the rate and extent of spermatogenic suppression. For these reasons, a practical male hormonal method will require an androgen and progestin combination. An important caveat to this finding is that all progestins were considered equivalent for the purposes of this analysis to obtain an average progestin effect. In reality, progestins are likely to differ in their effects on the rate of suppression, but our data set had insufficient power for such a refined analysis because only about one third of the men received progestins, and only a few of the possible androgen-progestin combinations were applied. Progestins are known to differ according to rodent antiovulatory potency, ability to support pregnancy, and binding and activation of progesterone (and other steroid) receptors in various cell systems (65). How these differences translate to suppression of sperm output will ultimately require direct comparison through future experimentation among leading androgen and progestin combination candidate regimens to resolve this question.

The various T preparations examined exerted remarkably similar effects on spermatogenic suppression; increasing effective testosterone dose was a minor but significant predictor of nonsuppression, independent of concurrent progestin use. Although highly statistically significant, the actual dosage differences are relatively small. Nevertheless, this finding has been observed previously by others (23, 66). Increasing androgen administration should theoretically increase intratesticular T, provided the maximal limit to T-dependent feedback inhibition of gonadotropin secretion is reached. Such minor increases in intratesticular testosterone are sufficient to promote spermatogenesis in rodents or primates (67, 68, 69), although direct human evidence is lacking. We speculate that this mechanism may also partly explain why progestin coadministration, which allows lower androgen doses to be administered, is also associated with more complete spermatogenic suppression.

An unusual finding of the present analysis is that ethnicity exerts a time-differential effect on the rate of suppression of sperm output. Such an effect has been observed once before (20). More information concerning the impact of androgen-progestin regimens on sperm output in other non-Asian and non-Caucasian ethnicities (particularly Africans and Hispanics) is needed. An optimized androgen-progestin combination might also overwhelm any ethnic differences in suppression of sperm output, but this question cannot be answered by the current data set.

Increasing age, increasing baseline T, and increasing baseline sperm concentration each decreases the rate of suppression, but effect sizes were small in relation to the expected range for each of these parameters and very close to a no-effect hazard ratio of unity. This assertion is especially true for age, wherein an interval of only two to three decades was included in the current data set. However, clinically important differences in suppression rates may occur when comparing extreme combinations of age, sperm concentration, and blood testosterone. Nevertheless, in general, these factors are less important than ethnicity and concurrent progestin administration.

Increasing body mass index (BMI) was also associated with nonsuppression, and this effect may be clinically important with marked obesity. Morbid obesity is associated with increased metabolic clearance of androgens in women, which is presumed to be due to reduced SHBG (70) because SHBG directly alters metabolic clearance of steroids in primates (71). Reduced SHBG is also observed in obese men, and therefore, testosterone clearance is also likely to be increased. However, extrapolation to weight extremes is inadvisable because the vast majority of men included in this analysis were not markedly overweight (high body mass index was an exclusion criterion in most studies). Whether male hormonal methods are just as effective in completely suppressing sperm output in frankly obese men requires evaluation.

An important caveat in interpreting the present data are the comprehensive scope of this integrated analysis, which included exploratory studies in which the dose and/or methods of delivery of the androgen or progestin were suboptimal for spermatogenic suppression. For this reason, although 50% of men were observed to suppress their sperm output to 1 million/ml or less by 2–3 months, this is most likely an underestimate of the proportion of men who can achieve this degree of suppression of sperm output by this time. Indeed, modern androgen and androgen-progestin combinations report suppressibility in 80–95%, not 50%, of men within 2–3 months (3, 4), and these data compare favorably with the disappearance of sperm after vasectomy (72). Therefore, the inclusion of exploratory studies limits interpretation of absolute suppressibility and attempting to summarize these mostly nonefficacy studies for this purpose is flawed (73). However, we reasoned that a complete data set would enhance detection of more subtle predictors of the relative rate of suppression of sperm output, as was our goal here. Furthermore, our analysis suggests that reliable and timely contraception is a reasonable expectation for a wide range of couples of differing ethnicity, age, and other characteristics. Future research to improve timely suppression of sperm output may require initial coadministration of GnRH antagonists (31), optimization of progestin type and dose, or use of new synthetic androgen receptor modulators.

We conclude that androgen-progestin administration can suppress sperm output in a timely fashion to concentrations that are compatible with reliable contraception in most, but not all, men. The rate of suppression is comparable with that achieved after vasectomy. All available T preparations are broadly equivalent, although excessive T exposure may result in less complete spermatogenic suppression, presumably in the context of already maximal feedback suppression of gonadotropin output. Progestin coadministration is essential for timely and reliable suppression of spermatogenesis. Predicting which men will fail to adequately suppress sperm output is unlikely to be possible with conventional clinical or laboratory data. Whether pharmacogenetic factors may be helpful to determine responsiveness to hormonal contraceptive agents remains speculative.


   Acknowledgments
 
This manuscript is dedicated to Geoff Waites (1928–2005), a distinguished andrologist and a champion of male contraception. We thank the study participants, personnel, and investigators of the original clinical trials that formed the data for this report and Associate Professor Val Gebski, Ph.D., for invaluable statistical advice regarding extended Cox modeling. This focused report necessarily omits many primary references because of editorial constraints.


   Footnotes
 
Author Contributions and Declaration Statement: P.Y.L., R.S.S., D.J.H., and C.W. are the writing group and were responsible for study design, data analysis, and initial interpretation and preparation of the manuscript. All authors participated in data acquisition and interpretation, administrative and material support, manuscript revision, and approval of the final version of the manuscript. P.Y.L. had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis and was supported by Career Development Award 511929 from the National Health and Medical Research Council of Australia. There were no funding sources with an interest in this analysis. J.E. is an employee of Bayer-Schering, and W.M.K. is an employee of N.V. Organon, a part of Schering-Plough Corporation; however, neither of these pharmaceutical companies supported this study analysis. All other authors (P.Y.L., R.S.S., B.D.A., R.A.A., W.J.B., Y.-Q.G., R.I.M., M.C.M., E.N., R.S.-W., K.V., X.-H.W, M.Z., D.J.H., C.W.) have no conflicts of interest with entities directly related to the material being published; however, R.S.S. and F.C.W.W. both declare that they have consulted for Bayer-Schering and N.V. Organon, a part of Schering-Plough Corporation, and W.J.B. holds a patent (without licensing or royalties) for oral testosterone administration.

First Published Online February 26, 2008

Abbreviations: BMI, Body mass index; CPA, cyproterone acetate; DMPA, depot medroxyprogesterone acetate; DSG, desogestrel; ENG, etonogestrel; LNG, levonorgestrel; MENT, 7-{alpha} methyl-19-nor-testosterone; NET, norethisterone; T, testosterone; TD, T decanoate; TE, T enanthate; TU, T undecanoate.

Received December 17, 2007.

Accepted February 20, 2008.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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