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,
From the * Department of Environmental Health
Sciences, University of Michigan School of Public Health, Ann Arbor, Michigan;
the Department of Environmental Health,
Harvard School of Public Health, Boston, Massachusetts; and the
Vincent Memorial Obstetrics and Gynecology
Service, Andrology Laboratory and MGH Fertility Center, Massachusetts General
Hospital, Boston, Massachusetts.
| Correspondence to: John Meeker, Department of Environmental Health Sciences, University of Michigan School of Public Health, M6226 SPH II, 109 S. Observatory St, Ann Arbor, MI 48109 (e-mail: meekerj{at}umich.edu). |
| Received for publication August 22, 2006; accepted for publication November 20, 2006. |
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Abstract |
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Key words: Epidemiology, human, male, reproduction, sperm, thyroid
A study of 349 Danish men who had not previously attempted pregnancy found that serum inhibin B was positively correlated with sperm concentration, while FSH was negatively correlated with sperm concentration (Jensen et al, 1997). That study also reported that the predictive power (positive predictive value) of detecting sperm counts below 20 x 106/mL in men with inhibin B levels below 80 pg/mL and with FSH above 10 IU/L was 100% (the positive predictive value for individual hormones was 80.0% and 85.7% for inhibin B and FSH, respectively). Similarly, in a small Belgian study of 47 subfertile men, Mahmoud and coworkers (1998) have reported higher inhibin B and lower FSH levels in men with sperm concentrations greater than or equal to 20 x 106/mL. They also reported good ability to predict sperm concentrations greater than or less than 20 x 106/mL with the same cutoff levels for serum inhibin B (sensitivity = 0.42; positive predictive value = 100%) and FSH (sensitivity = 0.74; positive predictive value = 96.3%). In the US, a prospective clinical study of 145 normal couples of reproductive age with proven fertility found significant positive correlations between inhibin B and sperm concentration, motility and morphology, and significant negative correlations between FSH and sperm concentration and morphology (Uhler et al, 2003). They reported that 17 of the 22 men in the study with sperm concentrations of less than 20 x 106/mL had inhibin B levels of less than 80 pg/mL and FSH levels of more than 10 IU/L (sensitivity = 0.77).
Aside from the Danish study (Jensen et al, 1997), previous studies on the relationship between hormone levels and semen quality have been largely conducted on either fertile (Uhler et al, 2003) or infertile (Sina et al, 1975; Subhan et al, 1995; Mahmoud et al, 1998) men. In the present study, the relationship between hormones and semen quality was explored in a population that included men recruited from an infertility clinic as part of an ongoing study of factors involved in altered male reproductive health. The couples who attended the clinic did so because of male factors, female factors or a combination of both male and female factors, so this population included men with normal fertility, subfertility, and male factor infertility. In addition, the previous studies did not measure other hormones, such as LH, testosterone, and thyroid hormones, or they failed to detect associations between these other hormones and semen quality, possibly as a result of small sample sizes or crude statistical analyses. In the present study, we assessed a wider range of reproductive and thyroid hormones among a larger study population, and utilized several statistical modeling approaches to report the degree of observed associations between hormones and semen quality.
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Materials and Methods |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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Collection of Semen Samples
Semen was collected by masturbation into a sterile plastic specimen cup at
the hospital. Subjects were instructed to abstain from ejaculation for at
least 48 hours prior to producing the semen sample. The sample was liquefied
for at least 20 minutes, but no longer than 1 hour prior to performing a
routine semen analysis, which included measurements of volume, pH, sperm
concentration, sperm motility, progressive motility, and sperm morphology.
Laboratory Evaluation
Concentration and motility—
Semen samples were analyzed for sperm concentration and motion parameters
using a computer-aided semen analyzer (CASA, version 10 HTM-IVOS; Hamilton
Thorne Research, Beverly, Mass). Setting parameters and the definition of
measured sperm motion parameters for CASA were established by the
manufacturer. To measure both sperm concentration and motility, 5 µL of
semen from each sample was placed into a prewarmed (37°C) Makler counting
chamber (Sefi Medical Instruments, Haifa, Israel). A minimum of 200 sperm
cells from at least four different fields was analyzed from each specimen.
Motile sperm were defined according to the World Health Organization (WHO)
grade as `a' grade sperm (rapidly progressive with a velocity 
25 µm/s
at 37°C) and `b' grade sperm (slow/sluggish progressive with a velocity
5 µm/s but <25 µm/s) (WHO,
1999). Progressive motile sperm were defined as grade `a' sperm
(WHO, 1999).
Morphology— At least two slides were made for each fresh semen sample. The resulting thin smear was allowed to air dry for 1 hour before staining with the Diff-Quik staining kit (Dade Behring AG, Dudingen, Switzerland). Morphological assessment was performed with a Nikon microscope using an oil immersion 100x objective (Nikon Company, Tokyo, Japan). A minimum of 200 sperm cells was counted from the 2 slides for each specimen. Strict scoring criteria were used to classify men as having normal or subnormal morphology (Kruger et al, 1988).
Reproductive Hormones— One nonfasting blood sample was drawn between 0900 and 1600 hours on the same day that the semen sample was collected. Blood samples were centrifuged and the sera were stored at –80°C until analysis. Testosterone was measured directly using the Coat-A-Count RIA kit (Diagnostics Products, Los Angeles, CA), which has interassay and intra-assay coefficients of variation (CV) of 12% and 10%, respectively, with a sensitivity of 4 ng/dL (0.139 nmol/L). The free androgen index (FAI) was calculated as the molar ratio of total testosterone to sex hormone-binding globulin (SHBG). SHBG was measured using a fully automated system (Immulite; DPC Inc, Los Angeles, Calif), which uses a solid-phase two-site chemiluminescent enzyme immunometric assay and has an interassay CV of less than 8%. Inhibin B was measured using a commercially available, double-antibody, enzyme-linked immunosorbent assay (Oxford Bioinnovation, Oxford, United Kingdom) with interassay and intra-assay CVs of 20% and 8%, respectively, limit of detection (LOD) of 15.6 pg/mL, and a functional sensitivity (20% CV) of 50 pg/mL. The serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) concentrations were determined by microparticle enzyme immunoassay using an automated Abbott AxSYM system (Abbott Laboratories, Chicago, Ill). The Second International Reference Preparation (WHO 71/223) was used as the reference standard. The assay sensitivities for LH and FSH were 1.2 IU/L and 1.1 IU/L, respectively. The intra-assay CVs for LH and FSH were less than 5% and less than 3%, respectively, with interassay CVs for both hormones of less than 9%. The LH:testosterone ratio, which is a measure of Leydig cell function, was calculated by dividing LH (IU/L) by testosterone (nmol/L).
Thyroid Hormones and TSH— Free T4, total T3, and the TSH concentrations were determined in serum samples by microparticle enzyme immunoassay using the AxSYM system. The assay sensitivities for free T4 and total T3 were 0.01 ng/dL and 0.15 ng/mL, respectively. The interassay CVs for both hormones were less than 9%. For TSH, the ultrasensitive hTSH II assay (Abbott Diagnostics) was used with a functional sensitivity of 0.03 µIU/L, and interassay CVs of less than 8%.
Statistical Analysis
Data analysis was performed using SAS version 8.1 (SAS Institute Inc, Cary,
NC). Descriptive statistics on subject demographics were calculated, along
with the distributions of hormone levels and semen parameters. Hormone levels
and semen parameters were stratified by demographic categories to investigate
the potential for confounding. Spearman correlation coefficients were used to
determine correlations among hormones, among semen parameters, and between
semen parameters and hormone levels.
Statistical analyses were performed using semen parameters as both a continuous measure and dichotomized using WHO reference values for sperm concentration (<20 x 106/mL) and motility (<50% motile sperm) (WHO, 1999). The Tygerberg Strict Criteria for morphology were used to determine below-reference morphology (<4% normal morphology) (Kruger et al, 1988). Men with above-reference values for all three semen parameters were used as comparison subjects in multivariate logistic regression. Using logistic regression to explore the shape of the hormone-semen quality relationships, the hormone levels were categorized in tertiles, and then in quintiles. To compare the abilities of serum inhibin B and FSH to predict sperm concentrations below the WHO reference level in the present study with those reported in previous studies (Jensen et al, 1997; Mahmoud et al, 1998), the sensitivity,ü specificity, and positive predictive values were calculated using the same criteria (inhibin B < 80 pg/mL and FSH < 10 IU/L).
Multivariate linear regression was used to explore the continuous relationships between hormones and semen parameters. The concentrations of testosterone, inhibin B, free T4, and total T3 closely approximated normality and were used untransformed in statistical models, while the distributions of the FSH, LH, SHBG, FAI, and TSH concentrations were skewed right and transformed to the natural log (ln) for statistical analyses. Sperm concentration was also ln-transformed, while sperm motility and morphology were modeled untransformed. To improve interpretability, the regression coefficients were back-transformed and expressed as a change in the dependent variable (ie, semen parameters) for an interquartile range (IQR) increase in hormone levels.
Inclusion of covariates was based on statistical and biologic considerations (Hosmer and Lemeshow, 1989). Age and BMI were modeled as a continuous variable, smoking status was dichotomized by current smoker versus never smoked or former smoker, and race/ethnicity was categorized into four groups: White, African-American, Hispanic, and other. Previous exam for infertility (yes or no), prior ability to impregnate a partner (yes or no), and timing of blood sample by season (Winter vs Spring, Summer or Fall) and time of day (0900–1259 hours vs 1300–1600 hours) were considered for inclusion as dichotomous variables in the models.
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Results |
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In the preliminary bivariate analyses, there was a significant positive (linear) association between the ordinal abstinence categories and sperm concentration, and an inverse (linear) association between abstinence and sperm morphology. For the hormones, FSH was positively correlated with LH and inversely correlated with inhibin B. Age was associated with decreased FAI, free T4, and total T3, and BMI was associated with decreased inhibin B, testosterone, and SHBG. There was a positive association between BMI and FAI. There were positive associations between the ordinal abstinence time categories and LH and FSH, where men with abstinence times of more than 6 days had higher LH and FSH levels than men who abstained for 3 or fewer days. Current smokers had higher total T3 concentrations and lower TSH concentrations than former and non-smokers. Inhibin B and free T4 levels were lower in men who had blood samples collected in Winter than in men with samples collected in the Spring, Summer or Fall, while blood samples collected in the morning (between 0900 and 1259) showed higher inhibin B and testosterone levels than those collected in the afternoon.
Using multivariate logistic regression analysis, semen parameters (dichotomized based on WHO reference cutoff points) were regressed on hormone tertiles (Table 4). Compared with men in the lowest FSH tertile, men in the highest FSH tertile were nearly five-times more likely to have below-reference (<20 x 106/mL) sperm concentrations (odds ratio [OR] = 4.6; 95% confidence intervals [CI] 1.9 to 11.2). In addition, men in the highest FSH tertile were more than 2 times more likely to have below-reference (<4% normal) sperm morphology (OR = 2.3; 95% CI 1.2 to 4.4). The highest LH tertile was also associated with below-reference sperm concentration (OR = 3.9; 95% CI 1.7 to 9.2), as was the highest LH:testosterone ratio tertile. Conversely, men in the medium and highest inhibin B tertiles were more likely to have above-reference sperm concentrations (high inhibin B tertile OR = 0.2; 95% CI 0.1 to 0.5) and sperm morphology (high inhibin B tertile OR = 0.6; 95% CI 0.3 to 1.1) compared to the lowest tertile. These associations, some of which did not appear to be monotonic, were also observed when the hormone levels were further divided into quintiles (Figures 1 and 2). The increased odds for below-reference sperm concentration among only the highest FSH quintile and among only the lowest inhibin B quintile may support the notion of a threshold for below-normal sperm concentration in association with these hormones. However, the abilities of inhibin B and FSH to predict below-reference sperm concentration were limited. Of only 26 men with both inhibin B of less than 80 pg/mL and FSH greater than 10 IU/L, 18 (69%) had sperm concentrations less than or equal to 20 x 106/mL.
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The results from the multivariate linear regression analyses, which are similar to the crude linear regression results, are presented in Table 5. Consistent with the logistic regression results, FSH was inversely associated with sperm concentration and morphology. An IQR increase in FSH was associated with a 38% (95% CI 45% to 29%) decline in sperm concentration and a 0.89% decline in the percentage of sperm with normal morphology. For the median level of sperm with normal morphology (7%), this represents an approximate 13% (95% CI 20% to 5%) decline in sperm morphology for an IQR increase in FSH. LH was also inversely associated with sperm concentration and morphology. An IQR increase in LH was associated with a 31% (95% CI 41% to 20%) decline in sperm concentration and a 9% decline (95% CI 17% to <1%) in the median percentage of sperm with normal morphology (7%). Unlike the logistic regression results, IQR increases in both FSH and LH were associated with 4.5% declines in sperm motility. Associations between semen parameters and LH:testosterone ratios were similar to those of LH, although the inverse association between LH:testosterone and sperm motility appeared slightly stronger.
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Higher inhibin B and free T4 levels were associated with higher
sperm concentrations. IQR increases in inhibin B and free T4 were
associated with 29% (95% CI 15% to 39%)and 27% (95% CI 4% to 63%) increases in
sperm concentration, respectively. Finally, there was a suggestive positive
association between testosterone and sperm motility. Interestingly, when men
were stratified by motility reference level (50% motile sperm),
testosterone was associated with above-reference motility (P = .007)
but not with below-reference motility (P = .70).
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Discussion |
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FSH, which is a gonadotropin that is produced and secreted by the anterior pituitary, acts on Sertoli cells in the seminiferous tubules to initiate spermatogenesis. Sertoli cells secrete inhibin B, which is a protein hormone. Thus, as found in previous studies, an association between inhibin B and sperm concentration was to be expected, since the regulation of both factors is dependent upon Sertoli cell function. In addition, the inverse associations of FSH with inhibin B and with sperm concentration may be due to the feedback effects exerted by inhibin B on the anterior pituitary to inhibit FSH secretion (Anawalt et al, 1996; Vander et al, 1998). Information on the specific mechanisms underlying the other observations made in the present study is limited, although they may also be related to altered spermatogenesis. Our results suggest that FSH, LH, and inhibin B play roles in sperm development (morphology), whereby increased levels of FSH and LH, but decreased levels of inhibin B, reduce the proportions of normal sperm. Our results also suggest that FSH, LH, and testosterone impact sperm motion (motility). Testosterone facilitates spermatogenesis locally in the Sertoli cells as a paracrine agent, and also serves to provide feedback for GnRH and LH secretion, which suggests that the observed associations with semen parameters involving testosterone (increased sperm motility) and LH (decreased sperm concentration, motility, and morphology) in the present study are related to disruptions and compensatory mechanisms in the hypothalamo-pituitary-gonadal axis.
In the present study, multiple logistic regression revealed an association between free T4 and reduced odds of having sperm motility of less than 50%, while multiple linear regression showed a positive association between free T4 and sperm concentration. While infertility is a common clinical manifestation of thyroid hormone deficiency (Nussey and Whitehead, 2001), previous reports of subclinical changes in thyroid hormone levels and semen quality could not be located. Thus, more research is necessary to determine the potential roles of thyroid hormones in semen quality and male fertility.
Consistent with previous studies, we found evidence of a threshold for increased risk of having a sperm concentration of less than 20 x 106/mL among men in either the highest serum FSH quintile or the lowest serum inhibin B quintile (Figure 1). However, when using previously published hormone cutoff levels (>10 IU/L FSH and <80 pg/mL inhibin B), the ability in the present study to predict men with sperm concentrations of less than 20 x 106/mL was lower than that described in earlier reports (Jensen et al, 1997; Mahmoud et al, 1998; Uhler et al, 2003). In the present study, an FSH concentration greater than 10 IU/L was predictive a sperm concentration of less than 20 x 106/mL with a sensitivity of 0.55 (specificity = 0.79; positive predictive value = 28%). An inhibin B concentration of less than 80 pg/mL had a lower sensitivity (0.38) than FSH for predicting below-reference sperm concentration (specificity = 0.96; positive predictive value = 56%). For 26 of the 388 men with both FSH greater than 10 IU/L and inhibin B less than 80 pg/mL, only 18 had a sperm concentration of less than 20 x 106/mL (positive predictive value = 69%). Thus, although we found evidence of FSH and inhibin B thresholds for having below-reference sperm concentration, the present study does not fully support using hormone levels to predict semen quality in epidemiology studies based on these FSH and/or inhibin B cutoff values, as has been proposed previously (Jensen et al, 1997; Uhler et al, 2003). However, we are currently unable to comment on the ability of inhibin B to predict fecundability (Mabeck et al, 2005) or other markers of spermatogenesis (Pierik et al, 1998, 2003).
In the present study, we found associations between hormones and several covariates under consideration as potential confounders (age, BMI, smoking, abstinence time, season, time of day). Of these, several have been reported previously. For example, smoking has been associated with lower TSH levels in the general population (Schlienger et al, 2003). Consistent with our bivariate BMI analysis, a recent study of over 1500 Danish men has shown that increased BMI is associated with reduced levels of inhibin B, testosterone, and SHBG, and with increased FAI (Jensen et al, 2004). In the present study, we observed higher inhibin B and testosterone levels in samples collected in the morning than in those collected in the afternoon, which is consistent with published reports (Veldhuis et al, 1987; Carlsen et al, 1999). In contrast to our observation that inhibin B levels were lower among blood samples collected in Winter, a recent study has reported no seasonal variation in inhibin B levels among healthy men (Andersson et al, 2003). However, our analysis of seasonal inhibin B variation did not simultaneously take into account the time of day of sample collection. For semen quality parameters, our observations of a positive association between abstinence time and sperm concentration and negative association between abstinence time and sperm morphology are consistent with the findings presented in a previous report (Pellestor et al, 1994).
A potential limitation of the present study was the collection of only a single semen sample to assess semen parameters, and the collection of a single blood sample to measure serum hormone levels. However, our analyses were adjusted for several factors associated with interindividual and intraindividual variability in hormone levels and semen quality, and the collection of a single sample is not expected to greatly affect our results. For example, despite the diurnal and pulsatile fluctuations in serum hormone levels, a single blood sample can be used to provide a reliable measure of reproductive hormones over both short and long time periods in population studies (Vermeulen and Verdonck, 1992; Schrader et al, 1993; Andersson et al, 2003). In addition, a requirement for multiple blood samples may limit participation rates in epidemiologic studies (Schrader et al, 1993). Collection of only one semen sample is also not expected to affect our results. Uhler and coworkers (2003) collected multiple semen samples (between 2 and 4) from each subject at time intervals that coincided with their partners' menstrual cycles, but found that the subsequent semen samples did not add value compared to using only the first semen sample collected on the same day as the serum hormone measures.
In conclusion, we show that several hormones are associated with semen quality parameters among a cohort of men from an infertility clinic, which included both infertile men and fertile men who were partners in an infertile relationship. Several of the associations were consistent with previous reports, while others have not been reported elsewhere. Consistent with previous studies, our results showing strong associations between semen quality and FSH and inhibin B and evidence of a threshold support the use of FSH and/or inhibin B as surrogates for semen quality in reproductive epidemiologic studies that are prone to low participation rates for semen sample collection. However, following sensitivity calculations in our population, which included both fertile and infertile men, we found that these hormones have lower predictive abilities than previously reported in other populations. Further investigations of additional male populations are needed for a better understanding of the relationship between hormones and semen quality.
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Acknowledgments |
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