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Prince Henry’s Institute of Medical Research (R.I.M., D.M.R., E.P.), Monash Medical Center, Clayton, Victoria 3168, Australia; School of Physiotherapy, University of Melbourne (A.U.), Melbourne, Victoria 3168, Australia; University of Washington (A.M.M., B.D.A., W.J.B.), Seattle, Washington 98195; and Department of Obstetrics and Gynecology and Core Laboratory, S. Orsola Hospital, University of Bologna (C.M.), Bologna, Italy I-40138
Address all correspondence and requests for reprints to: Robert I. McLachlan, M.D., Ph.D., Prince Henry’s Institute of Medical Research, P.O. Box 5152, Clayton 3168, Australia. E-mail: rob.mclachlan{at}med.monash.edu.au.
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Abstract |
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0.12 IU/liter; serum LH, 0.05 IU/liter) than oligospermic men (sperm concentrations, 0.1–5 million/ml; serum FSH, 0.23–0.5 IU/liter; serum LH, 0.05–0.56 IU/liter), but the relationship was weak, indicating the possible existence of other determinants. Multivariate logistic regression was used to identify the influence of candidate predictors of spermatogenic effects of the T plus progestin regimens. In the LNG and DSG studies, the marked suppression of serum LH to less than 5% of baseline values (<0.15 IU/liter) was a consistent and highly significant predictor of sperm concentration (reduced to 2–7% that seen at higher LH levels) and the likelihood of its suppression below 1 million/ml (a proposed threshold for contraceptive efficacy). Serum FSH was not a significant independent predictor. The use of DSG and CPA (but not LNG) was a significant independent predictor of sperm suppression, and regimens that contained 200 mg TE weekly caused less spermatogenic suppression than 100 mg TE weekly. These findings suggest that T-progestin contraceptive regimens suppress sperm concentration by gonadotropin-dependent and -independent mechanisms. The suppression of serum LH is a major predictor of the suppression of sperm concentration suppression in the LNG and DSG treatment studies. On the other hand, the greater spermatogenic suppression in regimens containing DSG or CPA suggests that these progestins have additional actions to suppress spermatogenesis via a gonadotropin-independent mechanism(s) |
Introduction |
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To ensure contraceptive efficacy, the attainment of azoospermia continues to be the goal of hormonal contraceptive regimens. Only about 70% of Caucasian men are rendered azoospermic, and 95% achieve sperm concentrations of 3 million/ml or less by T treatment alone (1, 2). Combined T plus progestin regimens appear more effective in achieving either azoospermia or the sperm concentration threshold of less than 1 million/ml, which is likely to provide satisfactory contraceptive efficacy (2). In about 5% of men, sperm concentrations fail to suppress to below 1 million/ml in response to T-based contraceptive treatments for reasons that are unclear.
The key role for FSH in spermatogonial development has been established in all species. In monkeys, we (16, 17) and others (18) have found that FSH levels correlate with spermatogonial development and that the failure to adequately suppress FSH is a potential reason for contraceptive failure. The importance of adequate FSH suppression in man has also been emphasized (19). Given the critical role of testicular T in spermatogenesis, the complete suppression of LH is also essential for effective and uniform spermatogenic suppression. Incomplete suppression of gonadotropins by suboptimal doses of T alone (20) or in combination with progestin (12) results in less complete and uniform spermatogenic suppression.
The hypothesis that the failure to fully suppress serum gonadotropins (i.e. to levels below 5% of baseline) leads to inadequate spermatogenic suppression in a contraceptive study context has been explored to some degree, although no correlations have been found. Handelsman et al. (21) found no relationship between the nadir serum gonadotropin levels and the occurrence of azoo- and oligospermia in men participating in WHO trials, although there were differences in baseline serum FSH levels. Similarly, Wallace et al. (22) could not attribute an azoo- vs. oligospermic response to T alone to differences in the extent of gonadotropin suppression. Recently, two studies have reported that gonadotropin levels are higher in men failing to become azoospermic in response to treatment (23, 24). Certainly, no clear threshold level below which either FSH or LH must be suppressed has been identified.
In exploring the potential relationship between gonadotropin levels and spermatogenesis, there are two key unresolved issues. First, the lower limits for biological effects of FSH and intratesticular T are not known. In GnRH-immunized rats, even when intratesticular T levels were markedly reduced (1–3% baseline), further inhibition of spermatogenesis was seen when an androgen receptor antagonist was coadministered (25), implying that low levels of androgens (due to LH-dependent or -independent secretion) still have a biological effect in the presence of undetectable serum immunoreactive LH. Similarly for FSH, the persistence of FSH levels below 5% of the baseline might have a significant effect on Sertoli cell function, although this is a harder issue to establish with in vivo models. The minimal threshold for intratesticular FSH and T levels might differ both between individual men and between ethnic groups. Such a hypothesis is exceedingly difficult to pursue in clinical studies.
The gonadotropin assay methods applied in previous clinical contraceptive studies have lacked sensitivity to confidently define gonadotropin levels below approximately 5% of baseline levels. Such assays have reported FSH and LH sensitivities of 0.02–0.05 IU/liter for both assays, respectively, but the extrapolation of the standard curves below the lower point on the standard curve and the lack of detailed assay performance data below this point have clouded the interpretation of these data. In essence, the term undetectable has been ill defined, and the kit manufacturers have not stated these sensitivity values.
To examine the relationship between sperm concentration and serum gonadotropin levels, serum samples were obtained from a series of studies in which T was combined with three different progestins. We used new, highly sensitive gonadotropin assays to test the hypothesis that profound suppression of gonadotropins (<5% of baseline) results in uniform suppression of sperm concentration to below 0.1 million/ml and the corollary that less complete spermatogenic suppression is due to incomplete suppression of circulating gonadotropins.
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Materials and Methods |
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The clinical studies investigated in this report are detailed in Table 1
and involved the administration of T enanthate (TE; 100 and 200 mg weekly) and daily oral doses of either cyproterone acetate (CPA; 5–100 mg) (11, 13, 23) for 3–4 months, levonogesterel (LNG; 150–500 µg) (3, 14), and desogesterel (DSG; 150–300 µg) (15) for 5–6 months. All studies were performed with the approval of the relevant institutional review boards, and all subjects gave their informed consent. Sera from these study centers were sent frozen in a dry liquid nitrogen shipper to Melbourne for LH and FSH assays. Other serum hormone data and sperm concentrations pertaining to these studies are detailed in the relevant publications. As these studies included several sperm concentrations at the end of treatment, and men quite often showed azoospermia in one sample and the occasional sperm only seen in the centrifuged ejaculate in another, for the purpose of analyses these men were grouped as below 0.1 million/ml. For all statistical calculations in this study, a previously reported azoospermic value was entered as 0.05 million/ml. The use of such a value recognizes the intrinsic difficulty of differentiating true azoospermia from exceedingly low sperm concentrations when evaluating the sample using WHO methods.
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Serum FSH and LH were determined by our sensitive immunofluorometric assays as previously detailed (26). These procedures are adaptations of commercial FSH and LH (Delfia, Wallac, Turku, Finland) immunofluorometric assays resulting in increased sensitivities (LH, 0.005 IU/liter; FSH, 0.008 IU/liter in this study) in application to serum. Assay sensitivity was improved by optimizing incubation times and the inclusion of gonadotropin-free serum obtained by exhaustive immunoabsorption to reduce assay matrix effects in the assay observed with high concentrations of serum. The reproducibility of the assays as assessed from the coefficient of variation of the repeated measurement (n = 12–13) of two serum pools with low and high gonadotropin levels was: for FSH, 15.6% (0.178 ± 0.028 IU/liter) and 9% (4.07 ± 0.37 IU/liter), respectively; and for LH, 11.5% (0.145 ± 0.017 IU/liter) and 8.1% (3.42 ± 0.28 IU/liter), respectively. Undetectable values were assigned the limits of assay detection for statistical and graphical analyses. When serum samples are stored under these conditions, no significant change in gonadotropin immunoreactivity has been observed (our unpublished observation).
Statistics
A number of approaches were employed to analyze these data. Firstly, data were divided into three groups according to the degree of sperm suppression, azoospermia/extreme oligospermia (<0.1 million/ml), moderate-severe oligospermia (0.1-<5 million/ml), or mild oligospermia (>5 million/ml), and were compared using Student’s t test. Secondly, given the interdependence of the variables to be assessed (T dosage, progestin usage, and gonadotropin levels), sperm concentration data were analyzed in two ways. 1) Sperm concentrations were divided above or below a nominated threshold of 1 or 3 million/ml. These threshold values were chosen because they have been proposed as upper limits for acceptable contraceptive efficacy (27). This outcome was then analyzed using logistic regression, with associations between predictors and the outcome expressed as odds ratios for achieving this threshold. 2) Regression analysis was performed, which allowed for interpretations of the results as fold increases (or decreases) in sperm concentration when comparing subsets of predictors. In such analyses the comparison is made with reference to a selected group, which is presented as unity. The regression analysis was performed with the sperm concentration outcome on a transformed, but continuous, scale. The transformation used was the natural logarithm (loge). This transformation resulted in residuals of the right form (approximately normal and constant variance).
For the purpose of analysis, all predictors were divided as follows. 1) To assess the dose-dependent effects of T, we compared men receiving 100 vs. 200 mg weekly. 2) As different progestins were used, and their bioequivalence for spermatogenic suppression could not be assessed, we compared groups of men treated with T plus no progestin vs. men treated with T plus LNG, DSG, or CPA (regardless of progestin dosage). 3) For analysis of gonadotropin suppression, men were grouped according to whether their gonadotropin levels suppressed above or below 5% of the mean baseline value of the whole group (for serum LH, 0.15 IU/liter; FSH, 0.11 IU/liter). This 5% baseline value, although arbitrary, was chosen to provide a basis for comparing the effects of low vs. high residual concentrations of serum gonadotropins.
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Results |
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5% of baseline) in men with sperm concentrations below 0.1 million/ml (Table 2). Higher serum gonadotropin values were observed during treatment in moderate-severe oligospermic (sperm concentration, 0.1–5 million/ml) and mildly oligospermic men (>5 million/ml), although these increases were not always significant. Serum gonadotropin levels were detectable in the majority of azoospermic men. For example, after 5 months of T plus progestin treatment (LNG and DSG studies), serum LH was detectable in 63% (38 of 61) and serum FSH was detectable in 85% (49 of 58) of men with azoospermia. After 4 months of T plus CPA treatment, serum LH was detectable in 24% (5 of 21) and serum FSH was detectable in 91% (19 of 21) of men with azoospermia.
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). A regression of serum FSH and LH across a wide range of normal-suppressed values showed an excellent correlation up until about 5% of control values (0.1 IU/liter; r = 0.84; P < 0.001; Fig. 2). However, at lower markedly suppressed levels, FSH did not continue to fall, whereas LH values declined toward the limit of assay detection.
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LNG and DSG studies
In both studies LH was a major predictor of sperm concentration after both 5 and 6 months of treatment. In DSG and LNG groups, LH values below 5% of the baseline (<0.15 IU/liter) were associated with sperm concentrations 2–7% of those seen in men in whom serum LH levels remained greater than 0.15 IU/liter. FSH showed a significant association in the univariate analysis, but not in the multivariate analysis (Table 3).
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The outcome of a sperm concentration below 1 million/ml showed similar trends (Table 4). Serum LH at levels less than 5% of the control values showed significant odds ratios of 14- to 56-fold for suppression to severe oligospermia, but lower ratios (1- to 10-fold), some of which were significant, were seen with FSH. Odds ratios for LNG usage (i.e. 0.5–2) were not significant, but the corresponding ratios for DSG were (i.e. 8–14).
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A dose of 100 mg TE weekly suppressed spermatogenesis significantly (8- to 12-fold) more than 200 mg TE weekly. The addition of CPA significantly reduced sperm concentration (4- to 18-fold) more at either 3 or 4 months of treatment. Neither serum LH nor FSH was a significant predictors of sperm concentration (Table 3
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Similar trends were observed when sperm concentrations were dichotomized as being above or below a nominated threshold (<1 million/ml), with significant changes attributed to TE dose and CPA usage, but not to serum LH or FSH levels (Table 4).
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Discussion |
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To identify potential predictors of the degree of spermatogenic suppression, logistic regression and odds ratio analyses were used to identify independent (multivariate analysis) or dependent (univariate analysis) factors. We have identified three independent predictors of the degree of sperm suppression and the likelihood of achieving a sperm concentration below 1 million/ml, the threshold below which contraceptive efficacy seems likely (2, 28, 29). These factors were 1) the dosage of T, 2) the suppression of serum LH below 5% of control levels, and 3) the use of progestin at any dose. On the other hand, the suppression of serum FSH below 5% of the control values (or below assay detection; data not shown) was not independently predictive of sperm suppression. This is not to say that substantial suppression of FSH is not important, but when gonadotropin levels are within the low range, it is LH (and, by implication, intratesticular T) that is the main determinant of more complete spermatogenic suppression.
We acknowledge that the number of subjects in the three studies is limited and that their time courses were variable. As a result, larger confirmatory studies would be desirable. However, these studies are unusual because incremental doses of T and/or the various progestins were available, enabling us to undertake a useful logistic regression analysis.
In both the LNG and DSG studies, LH was a strong and independent predictor of sperm concentration, whereas FSH has a dependent role, presumably through its close correlation with LH at higher LH/FSH serum levels. When serum LH levels were below 0.15 IU/liter (5% of the control), sperm concentrations were only 2–7% of those seen when serum LH levels were above this threshold. Through our use of highly sensitive gonadotropin assays, we have determined that there is a dissociation between the degree of suppression of serum FSH and LH levels below 0.1 IU/liter. Continued secretion of low levels of FSH probably occurs via GnRH-independent mechanisms, as the absence of serum LH (at least to <0.4% baseline) suggests the abolition of GnRH stimulation. There is evidence that there is GnRH-independent expression of FSH ß-subunit. For example, in rats, T exhibits such a stimulatory effect on pituitary FSH release (30). It is possible that a similar, if less marked, process is seen in men.
Previous studies in man have raised the possibility that exogenously administered androgens might act directly on the seminiferous epithelium to support spermatogenesis in a gonadotropin-depleted environment and that this effect ought be considered in the design of effective contraceptives (31, 32, 33). In this study we observed that 100 mg TE weekly suppressed spermatogenesis significantly (8- to 12-fold) more than 200 mg TE weekly. In recently reporting a subset of these CPA subjects (23), we also speculated that the use of this higher dose of T might induce or maintain low grade spermatogenesis in normal men. Our multivariate analysis corroborates this hypothesis. This effect might be due to a direct stimulatory action of T on the seminiferous epithelium as seen in rodents (34). Such an effect is difficult to directly demonstrate in man, although high dose T does support spermatogenesis in other primate models, such as the hypophysectomized monkey (35).
The pharmacokinetic profile of TE is clearly suboptimal in providing wide excursions in serum T and often excessive peak levels. As a result, this formulation is not favored for ongoing contraceptive studies, but nonetheless, our TE data provide valuable insight in direct T effects on spermatogenesis in man. The recent use of more physiological T regimens in male contraception (such as using longer acting im T formulations or implants) has been largely motivated by the need to reduce side-effects, but our analysis suggests that lower dose T regimens might be essential for uniform spermatogenic suppression.
The interaction between the administered T acting directly on the testis and serum gonadotropin levels has long been considered. For example, the addition of GnRH agonists to T was not found useful, perhaps due to the initial flare of gonadotropin secretion and the return of FSH levels over the longer term (36). On the other hand, GnRH antagonists appear promising in maintaining gonadotropin suppression, but did not augment spermatogenic suppression when combined with 200 mg TE weekly, leading to speculation that this high dose of T might have acted locally (33). Such work points to the avoidance of excessive T exposure and the maximal and sustained suppression of gonadotropins.
In addition to suppression of gonadotropins, progestins may suppress sperm concentration by nongonadotropic mechanisms. Differences were observed among the three progestins as independent predictors of sperm concentration. CPA and DSG showed marked gonadotropin-independent inhibitory effects, whereas LNG showed a smaller and largely insignificant effect. The relatively low power of the study might account for these differences. There are several explanations based on published observations that might account for these progestin effects. Progestins inhibit 5
-reductase activity (37) and thereby reduce the intratesticular level of dihydrotestosterone that might maintain spermatogenesis when LH levels are suppressed (10). We recently published androgen levels in the human testis during T plus progestin contraception and found that, despite a 98% decline in T levels, 5-reduced androgen levels were little changed (38). The effect of 5-reductase inhibition on spermatogenesis in the contraceptive setting (low LH and markedly lowered intratesticular T) has not been well addressed in previous small pilot studies using finasteride, which has little activity against the type 1 isoenzyme prevalent in the testis (28, 39). Up-regulation of the type 1 5-reductase enzyme is seen in the rat when LH levels are very low (40), and this phenomenon might also occur in men. Inhibition of this enzyme pathway might therefore be relevant to sperm suppression. Second, progestins inhibit 17-hydroxysteroid dehydrogenase (41, 42), a key step in androgen biosynthesis, and thereby reduce androgen action on the epithelium. This hypothesis has not been tested in men undergoing hormonal contraceptive treatments. Finally, it is possible that progestin have direct testicular effects, because progesterone receptors have been reported in the Leydig cells (43).
Progestins and their metabolites have different possible mechanisms of action on the gonadal axis. For example, DSG exhibits higher 5-reductase inhibitory activity than LNG (37). Our findings with CPA are interesting because there is a dramatic gonadotropin-independent inhibitory effect of CPA on sperm concentration. As previously proposed, CPA might act as an antiandrogen in the testis (13). Based on our analysis, the term progestin, which is classically defined based on endometrial effects, ought not be used to imply a uniform class effect on spermatogenesis. Of course other processes may contribute to the nonuniformity of suppression by hormonal contraception, such as heterogeneity of the CAG length of the androgen receptor as has been suggested (44, 45).
In conclusion, we suggest that T-progestin contraceptive regimens suppress sperm concentration by gonadotropin-dependent and -independent mechanisms. The suppression of serum LH, but not FSH, is a major predictor of sperm concentration suppression in the LNG and DSG treatment studies. In addition, 100 mg T weekly results in greater suppression of spermatogenesis than 200 mg T weekly. Our findings emphasize that the complete suppression of LH and intratesticular T levels is crucial for a uniformly effective male hormonal contraceptive. Finally, our data suggest that some progestins (e.g. DSG and CPA) suppress spermatogenesis by a gonadotropin-independent mechanism(s). We suggest that alternative strategies could be devised to increase the efficacy of male androgen-based contraceptives by exploiting the apparent differences in progestins in gonadotropin-dependent and -independent inhibition of spermatogenesis.
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Footnotes |
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Abbreviations: CPA, Cyproterone acetate; DSG, desogesterel; LNG, levonogesterel; T, testosterone; TE, testosterone enanthate.
Received April 8, 2003.
Accepted October 15, 2003.
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References |
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reductase inhibitor, for male hormonal contraception. Contraception 62:73–78[CrossRef][Medline]
-reductase by oral contraceptive progestins in vitro. Gynecol Endocrinol 14:223–230[Medline]
-reductase type 1 and 2 isoforms by testosterone and FSH. J Endocrinol 176:393–403[Abstract]
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