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The beneficial effects of toremifene administration on the hypothalamic-pituitary-testicular axis and sperm parameters in men with idiopathic oligozoospermia

      Objective

      To evaluate whether toremifene, a selective estrogen receptor modulator (SERM), has a beneficiary effect on all three main sperm parameters.

      Design

      Prospective interventional clinical study.

      Setting

      University hospital.

      Patient(s)

      One-hundred subfertile men with idiopathic oligozospermia.

      Intervention(s)

      Toremifene (60 mg daily) was administered to all men for 3 months. At baseline and at the end of each month, serum concentrations of follicle-stimulating hormone (FSH), testosterone, inhibin B, and sex hormone–binding globulin (SHBG) were measured. At baseline and at the end, semen analysis was performed and sperm concentration, spermatozoal motility and normal sperm forms were determined.

      Main Outcome Measure(s)

      Gonadotropin, testosterone, inhibin-B levels, total sperm count, sperm morphology and motility.

      Result(s)

      Toremifene administration resulted in a significant increase in FSH, testosterone, SHBG, and inhibin B levels, as well as in sperm concentration, percentage motility and normal sperm forms. Twenty-two men's partners achieved pregnancy within 2 months of the end of treatment. At the end of the third month, serum FSH levels were significantly higher in the men whose partners did not achieve pregnancy, and total sperm count and normal sperm forms were significantly lower compared with the group of men whose partners achieved pregnancy.

      Conclusion(s)

      Toremifene administration for a period of 3 months in men with idiopathic oligozoospermia is associated with significant improvements of sperm count, motility, and morphology, mediated by increased gonadotropin secretion and possibly a direct beneficial effect of toremifene on the testes. The above findings are also indicative of a better testicular exocrine (improved sperm parameters) response to treatment in men whose partners achieved pregnancy compared with those who did not. Further randomized, placebo-controlled trials should be conducted to determine whether this particular selective estrogen receptor modulator can be useful as an initial approach in men with oligozoospermia.

      Key Words

      A selective estrogen receptor modulator (SERM) is a compound that can act as an estrogen agonist or antagonist, depending on the specific target tissue (
      • Plouffe Jr., L.
      • Siddhanti S.
      The effect of selective estrogen receptor modulators on parameters of the hypothalamic-pituitary-gonadal axis.
      ). At present, four SERMs are approved for clinical use: clomiphene, raloxifene, tamoxifen, and toremifene. Three of these compounds belong to the triphenylethylene family: clomifene, tamoxifen, and toremifene. Raloxifene belongs to the benzothiophene family (
      • Plouffe Jr., L.
      Selective estrogen receptor modulators (SERMs) in clinical practice.
      ).
      Most of the unique pharmacology of SERMs can be explained by three interactive mechanisms. The first is differential estrogen-receptor expression in a given target tissue. The second consists of the differential estrogen-receptor conformation on ligand binding. The third is the differential expression and binding to the estrogen receptor of coregulator proteins (
      • Riggs B.L.
      • Hartmann L.C.
      Selective estrogen receptor modulators. Mechanisms of action and application to clinical practice.
      ).
      In women, at least three SERMs have been shown to increase circulating levels of gonadotropin. The exact mechanism for this effect is based on the estrogen antagonistic properties of SERMs at the hypothalamic and pituitary level (
      • Adashi E.Y.
      Ovulation induction: clomiphene citrate.
      ). In addition, SERMs have been shown to increase sex hormone–binding globulin (SHBG) levels, which can be attributed to the estrogen agonist activity of SERMs in the liver (
      • Plouffe Jr., L.
      Selective estrogen receptor modulators (SERMs) in clinical practice.
      ,
      • Riggs B.L.
      • Hartmann L.C.
      Selective estrogen receptor modulators. Mechanisms of action and application to clinical practice.
      ).
      There have been relatively few studies of SERMs in males. Clomiphene citrate and tamoxifen have been proposed for the management of male factor infertility (
      • Plouffe Jr., L.
      • Siddhanti S.
      The effect of selective estrogen receptor modulators on parameters of the hypothalamic-pituitary-gonadal axis.
      ). Tamoxifen citrate was introduced 30 years ago as an empiric treatment for idiopathic oligozoospermia because of its stimulatory action on gonadotropin secretion and its postulated direct effects on Leydig cell function and 5α-dihydrotestosterone production in seminiferous tubules and epididymis (
      • Comhaire F.
      Treatment of oligozoospermia with tamoxifen.
      ). The main effect of tamoxifen on spermatogenesis is stimulatory, resulting in a twofold increase in spermatozoa concentration. Such an increase in spermatozoa concentration may be important because a change of this magnitude at the low range of spermatozoa concentrations found in oligozoospermic men has been associated with disproportionately higher fecundity. However, this particular SERM has not been shown to induce any marked changes in motility and morphology (
      • Buvat J.
      • Ardaens K.
      • Lemaire A.
      • Gauthier A.
      • Gasnault J.P.
      • Buvat-Herbaut M.
      Increased sperm count in 25 cases of idiopathic normozoospermic oligospermia following treatment with tamoxifen.
      ,
      • Kotoulas I.G.
      • Cardamakis E.
      • Michopoulos J.
      • Mitropoulos D.
      • Dounis A.
      Tamoxifen treatment in male infertility. I. Effect on spermatozoa.
      ).
      The effect of treatment with tamoxifen citrate on cumulative achievement of pregnancy over a long period of time is similar to that of assisted reproductive techniques (ART) (
      • Comhaire F.
      • Milingos S.
      • Liapi A.
      • Gordts S.
      • Campo R.
      • Depypere H.
      • et al.
      The effective cumulative pregnancy rate of different modes of treatment of male infertility.
      ,
      • Comhaire F.
      • Zalata A.
      • Mahmoud A.
      Critical evaluation of the effectiveness of different modes of treatment of male infertility.
      ). On the basis of these results (
      • Buvat J.
      • Ardaens K.
      • Lemaire A.
      • Gauthier A.
      • Gasnault J.P.
      • Buvat-Herbaut M.
      Increased sperm count in 25 cases of idiopathic normozoospermic oligospermia following treatment with tamoxifen.
      ,
      • Adamopoulos D.A.
      • Nicopoulou S.
      • Kapolla N.
      • Karamertzanis M.
      • Andreou E.
      The combination of testosterone undecanoate with tamoxifen citrate enhances the effect of each agent given independently on seminal parameters in men with idiopathic oligozoospermia.
      ,
      • Adamopoulos D.
      • Pappa A.
      • Billa E.
      • Nicopoulou S.
      • Koukkou E.
      • Michopoulos J.
      Effectiveness of combined tamoxifen citrate and testosterone undecanoate treatment in men with idiopathic oligozoospermia.
      ), tamoxifen citrate was proposed by a World Health Organization working committee as the first line of treatment for idiopathic oligozoospermia (
      • Rowe P.
      • Comhaire F.
      • Hargreave T.
      • Mahmoud A.
      WHO manual for the standardized investigation, diagnosis and management of the infertile male.
      ).
      Because tamoxifen increases spermatozoa concentration but has no marked effect on spermatozoa motility and morphology, this study was designed to evaluate whether another SERM, toremifene, has a beneficiary effect on all three main semen parameters. To the best of our knowledge, no previous data have been reported concerning the effect of this specific SERM on the hypothalamic-pituitary-testicular axis and semen parameters in men with idiopathic abnormalities in one or more of the three main semen parameters.

      Materials and methods

       Patients

      One hundred subfertile men with idiopathic oligozoospermia, mean (± SEM) age 20 to 47 years (33.53 ± 0.5 years), were consecutively recruited from the fertility center of our department. All of the men were characterized as subfertile because they had been unsuccessful in achieving pregnancy with their partners for 12 months, although their partners did not show any of the known causes of female subfertility.
      Idiopathic oligozoospermia was defined as quantitative and/or qualitative aberrations of sperm variables according to World Health Organization criteria (
      • Rowe P.
      • Comhaire F.
      • Hargreave T.
      • Mahmoud A.
      WHO manual for the standardized investigation, diagnosis and management of the infertile male.
      ). Men with known or demonstrable causes of oligozoospermia (varicocele, infections, autoimmunity, stress, chromosomal abnormalities, environmental factors, or epididymitis) were excluded.
      Careful clinical examination showed that all of the men had complete development of the secondary sex characteristics, with a mean (± SEM) right testicular volume of 18.45 ± 0.39 cm3 and mean (± SEM) left testicular volume 17.80 ± 0.41 cm3 (mean testicular volume 18.14 ± 0.39 cm3). Total testicular volume was assessed by comparison with a standard value on orchidometry. None of the men had received any medication during the 6-month period preceding the study.

       Study Protocol

      All of the men received toremifene as monotherapy at a dose of 60 mg daily for a period of 3 months. At baseline, and at the end of the first, second, and third month of treatment, blood samples were collected at 9 am after an overnight fast.
      All samples were centrifuged immediately, and serum was stored at −70°C until assayed for FSH, testosterone, inhibin B, and SHBG. Sperm was examined at baseline and at the end of the third month of treatment. All participants were properly informed about the purpose of the study and gave informed written consent. The study was approved by the ethics committee of the hospital.

       Hormonal Measurements

      We measured FSH (IU/L) using the FSH IRMA kits from Biosource Technologies (Vacaville, CA). Total testosterone (ng/dL) was measured by enzyme-linked immunosorbent assay (ELISA; testosterone enzyme immunoassay test kit, LI7603; Linear Chemicals). The serum levels of SHBG (nmol/L) were measured by ELISA (SHBG ELISA, MX 520 11; IBL, Hamburg, Germany). Inhibin B levels were measured using ELISA kits from Oxford Bio Innovation DSL Ltd (Upper Heyford, Bicester, Oxfordshire, United Kingdom).

       Semen Analysis

      Semen was collected by masturbation into sterilized glass containers after a 3- to 6-day abstinence. After evaluation of liquefaction and measurement of viscosity and volume, motility was measured, at room temperature (22° to 25°C), 1 hour after ejaculation, as previously described elsewhere (
      • Rowe P.
      • Comhaire F.
      • Hargreave T.
      • Mahmoud A.
      WHO manual for the standardized investigation, diagnosis and management of the infertile male.
      ,
      • Kalahanis J.
      • Rousso D.
      • Kourtis A.
      • Mavromatidis G.
      • Makedos G.
      • Panidis D.
      Round-headed spermatozoa in semen specimens from fertile and subfertile men.
      ,
      • Rousso D.
      • Kourtis A.
      • Mavromatidis G.
      • Gkoutzioulis F.
      • Makedos G.
      • Panidis D.
      Pyriform head: a frequent but little-studied morphological abnormality of sperm.
      ,
      • Panidis D.
      • Rousso D.
      • Matalliotakis I.
      • Kourtis A.
      • Mavromatidis G.
      • Mamopoulos M.
      • Koumantakis E.
      Do characteristic spermatozoal morphological abnormalities exist in patients who have undergone unilateral orchiectomy and preventive radiotherapy?.
      ).
      Sperm morphology was evaluated from Papanicolaou-stained smears, and the classification of abnormal sperm forms was made according to the guidelines of the WHO (
      • Rowe P.
      • Comhaire F.
      • Hargreave T.
      • Mahmoud A.
      WHO manual for the standardized investigation, diagnosis and management of the infertile male.
      ). One hundred spermatozoa were studied from each semen specimen, and the same individual (D.P.) evaluated all smears. The percentage of motile spermatozoa was measured by the subjective method at room temperature (22° to 25°C), and sperm concentration was determined in an undiluted semen specimen with the use of Makler's Counting Chamber (
      • Makler A.
      The improved ten-micrometer chamber for rapid sperm count and motility evaluation.
      ,
      • Panidis D.
      • Matalliotakis I.
      • Skiadopoulos S.
      • Rousso D.
      • Koumantakis E.
      • Mamopoulos M.
      The sperm deformity and multiple anomalies indices: are they reliable in the identification of fertile and infertile semen?.
      ).

       Statistical Analysis

      Statistical analysis was performed with SPSS statistical software, v. 13.0 (SPSS Inc, Chicago, IL). Two-tailed statistical significance was set at 5%. Categorical parameters (smoking status) were compared with Fischer's exact test. The normality of distribution was assessed with the Kolmogorov-Smirnov test (K-S) test. Values that did not fit the normal distribution were log-transformed.
      Mean was compared at baseline with Student's t-test and during treatment with general linear model–based two-way repeated measures of analysis of variance (ANOVA); time (treatment) was set as the within-groups factor and achievement of pregnancy as the between-subjects factor. Within-groups post hoc analysis was performed after Bonferroni adjustment for multiple comparisons. Between groups post hoc analysis was based on model parameter estimates.
      For those parameters where statistically significant or borderline differences or interactions between the men whose partners achieved pregnancy and those who failed were observed, binary logistic regression analysis was also performed to assess prognostic value.

      Results

      The basal epidemiologic and anthropometric features of the men studied are presented in Table 1. Twenty-two men had partners who achieved pregnancy within 2 months from the end of treatment (22%; 95% CI, 15.0–31.1%). The hormonal features before and during treatment with toremifene of the men whose partners eventually achieved pregnancy (group 1) and those whose partners did not (group 2) are summarized in Table 2, and their semen parameters are presented in Table 3. Men whose partners achieved pregnancy did not differ significantly in epidemiologic and somatotopic features from the other group (see Table 1).
      Table 1Epidemiologic and anthropometric features of the men in couples who eventually achieved pregnancy (group 1) and those who did not (group 2).
      Group 1 (n = 22)Group 2 (n = 78)P
      Age (years)32.86 ± 1.1433.72 ± 0.57.487
      Age of spouse (years)30.23 ± 0.9829.77 ± 0.58.707
      Right testicle volume (mL)18.86 ± 0.7918.33 ± 0.46.584
      Left testicle volume (mL)18.91 ± 0.8317.49 ± 0.47.157
      Mean testicle volume (mL)18.89 ± 0.7317.94 ± 0.45.316
      Body mass index (kg/m2)28.23 ± 0.8326.85 ± 0.41.125
      Smoking status (smokers)10/2237/78.532
      Note: Baseline is mean ± SEM. Statistical significance determined by Student's t-test after log-transformation, Fischer's exact test for smoking status.
      Farmakiotis. Toremifene in male infertility. Fertil Steril 2007.
      Table 2Basic hormonal features before and during treatment with toremifene of the men in couples who eventually achieved pregnancy (group 1) and those who did not (group 2).
      FSH (mIU/mL)T (mmol/L)SHBG (nmol/L)FAIINH (pg/mL)
      Group 1 (n = 22)
       Baseline4.99 ± 0.545.10 ± 0.3321.82 ± 1.4796.55 ± 13.28148.54 ± 15.62
       1 m8.05 ± 0.787.18 ± 0.4526.46 ± 2.20116.81 ± 18.05158.98 ± 16.46
       2 m8.36 ± 0.917.28 ± 0.7225.25 ± 1.42109.00 ± 12.05163.57 ± 17.15
       3 m9.20 ± 0.916.91 ± 0.5424.89 ± 1.62109.47 ± 9.79160.02 ± 20.61
      Group 2 (n = 78)
       Baseline6.78 ± 0.614.85 ± 0.8617.65 ± 0.6596.55 ± 13.27146.28 ± 8.64
       1 m9.51 ± 0.776.87 ± 0.2323.16 ± 0.96116.81 ± 18.05152.41 ± 8.86
       2 m10.22 ± 0.746.91 ± 0.2621.73 ± 0.84109.00 ± 12.05156.33 ± 9.48
       3 m10.73 ± 0.747.19 ± 0.2423.60 ± 0.77109.47 ± 9.79155.65 ± 8.21
      Group
      F3.432.0863.5190.210.078
      P.067.7700.0640.648.781
      Time
      F87.48032.81412.7933.9823.385
      P<.001<.001<0.0010.013.025
      Group × Time
      F.518.8481.6570.474.143
      P.670.4680.1900.665.909
      Note: Mean ± SEM. Statistical significance by two-way repeated measures analysis of variance after log-transformation. FAI, free androgen index; FSH, follicle-stimulating hormone; INH, inhibin B; T, testosterone; SHBG, sex hormone–binding globulin.
      Farmakiotis. Toremifene in male infertility. Fertil Steril 2007.
      Table 3Semen parameters before and during treatment with toremifene of the men in couples who eventually achieved pregnancy (group 1) and those who did not (group 2).
      Sperm concentration (× 106/mL)Total sperm count (× 106)Spermatozoal motility (%)Normal sperm forms (%)
      Group 1 (n = 22)
       Baseline29.48 ± 4.04109.62 ± 16.2139.97 ± 3.4323.86 ± 3.32
       3 m45.57 ± 4.13171,58 ± 22.8849.76 ± 1.9137.23 ± 3.02
      Group 2 (n = 78)
       Baseline26.86 ± 1.7991.71 ± 7.1935.94 ± 1.6221.67 ± 1.29
       3 m38.19 ± 2.46121.71 ± 8.8945.02 ± 1.6229.92 ± 1.57
      Group
      F1.3494.2232.2092.726
      P.248.043.140.102
      Time
      F70.28730.41732.61262.905
      P<.001<.001<.001<.001
      Group ×Time
      F2.1233.674.0463.510
      P.148.058.831.064
      Note: Mean ± SEM. Statistical significance by two-way repeated measures analysis of variance after log-transformation.
      Farmakiotis. Toremifene in male infertility. Fertil Steril 2007.

       Effect of Treatment

      During treatment with toremifene, a significant increase in circulating levels of FSH (Fig. 1), testosterone, and inhibin B levels was observed (P<.001 for FSH, and T, P<.05 for inhibin-B; Table 2). SHBG levels (P<.001) and free androgen index (FAI) values (P<.05) (Fig. 2) levels was observed. The number of spermatozoa per mL, as well as per ejaculation, and the percentage of spermatozoa with normal motility and morphology were also significantly increased at 3 months (P<.001; Table 3).
      Figure thumbnail gr1
      Figure 1Follicle-stimulating hormone levels (mean ± SEM) of the men whose partners eventually achieved pregnancy and those whose partners did not, before and during treatment with toremifene. P<.05 versus previous value, †P <.05 between the men whose partners became pregnant and those whose partners did not.
      Farmakiotis. Toremifene in male infertility. Fertil Steril 2007.
      Figure thumbnail gr2
      Figure 2Inhibin B (INH) levels (mean ± SEM) of the men whose partners eventually achieved pregnancy and those whose partners did not, before and during treatment with toremifene.
      Farmakiotis. Toremifene in male infertility. Fertil Steril 2007.
      The increase in FSH levels was basically observed during the first (P<.001) and second (P<.05) months of treatment, whereas the change during the last month was not significant. Testosterone (T) and SHBG levels (P<.001), as well as FAI values (P<.05), were significantly increased only during the first month (P<.001), while the increase in SHBG levels was significant during both the first and second month (P<.001); no significant change in T levels, SHBG concentration, or FAI was observed during the second and third month of treatment.

       Differences between Men Whose Partners Achieved Pregnancy and Those Whose Partners Did Not

      Overall, FSH levels were borderline higher in those men whose partners did not achieve pregnancy compared with those whose partners did (P=.067; see Table 2, Fig. 1). The difference between the two groups was statistically significant at the end of treatment (P<.05; see Fig. 1). Likewise, the total number of spermatozoa per ejaculation was, overall, statistically significantly higher in men whose partners achieved pregnancy (P<.05; see Table 2, Fig. 3). This difference was, again, statistically significant at 3 months (P<.05) but not at baseline (see Fig. 3).
      Figure thumbnail gr3
      Figure 3Total number of spermatozoa (SZ) per ejaculation (mean ± SEM) of the men whose partners eventually achieved pregnancy and those whose partners did not, before and after 3-month-treatment with toremifene. P <.05 versus previous value. †P <.05 between the men whose partners became pregnant and those whose partners did not.
      Farmakiotis. Toremifene in male infertility. Fertil Steril 2007.
      A borderline interaction between time and treatment outcome (pregnancy or no pregnancy) was observed with respect to the total number of spermatozoa per ejaculation (P=.058; see Table 2, Fig. 3) and the percentage of spermatozoa with normal morphology (P=.064; see Table 2). Men whose partners achieved pregnancy had a statistically significantly higher percentage of spermatozoa with normal morphology at the end of treatment (P<.05).
      In univariate logistic regression analysis, FSH levels (B = −1.894 ± 0.959), sperm count per ejaculation (B = 0.006 ± 0.003), and the percentage of spermatozoa with normal morphology (B = 0.04 ± 0.02) after treatment had a statistically significant prognostic value for the achievement of pregnancy (P<.05). In multivariate logistic regression, FSH levels at 3 months were the most statistically significant independent parameter of the three (B = −1.73 ± 1.02, P=.089).

      Discussion

      Tamoxifen citrate, a selective estrogen receptor modulator (SERM), has been proposed as an empiric treatment for idiopathic oligozoospermia because of its stimulatory action on gonadotropin secretion and its postulated direct effects on Leydig cell function and 5α-dihydrotestosterone production in seminiferous tubules and epididymis (
      • Comhaire F.
      Treatment of oligozoospermia with tamoxifen.
      ,
      • Buvat J.
      • Ardaens K.
      • Lemaire A.
      • Gauthier A.
      • Gasnault J.P.
      • Buvat-Herbaut M.
      Increased sperm count in 25 cases of idiopathic normozoospermic oligospermia following treatment with tamoxifen.
      ,
      • Adamopoulos D.A.
      • Nicopoulou S.
      • Kapolla N.
      • Karamertzanis M.
      • Andreou E.
      The combination of testosterone undecanoate with tamoxifen citrate enhances the effect of each agent given independently on seminal parameters in men with idiopathic oligozoospermia.
      ,
      • Adamopoulos D.
      • Pappa A.
      • Billa E.
      • Nicopoulou S.
      • Koukkou E.
      • Michopoulos J.
      Effectiveness of combined tamoxifen citrate and testosterone undecanoate treatment in men with idiopathic oligozoospermia.
      ,
      • Rowe P.
      • Comhaire F.
      • Hargreave T.
      • Mahmoud A.
      WHO manual for the standardized investigation, diagnosis and management of the infertile male.
      ). Based on the above evidence, the present study was designed to investigate whether toremifene, another compound from the same category (
      • Kalahanis J.
      • Rousso D.
      • Kourtis A.
      • Mavromatidis G.
      • Makedos G.
      • Panidis D.
      Round-headed spermatozoa in semen specimens from fertile and subfertile men.
      ), has a beneficiary effect on the main semen parameters as well.
      In the present study, a statistically significant increase in serum FSH was observed after administration of toremifene at a dose of 60 mg daily. This increase was more marked at the end of the first month of treatment; FSH levels were also statistically significantly increased after one additional month of treatment, reaching a plateau after the end of the second month with no statistically significant increase during the last month of toremifene administration (see Table 2, Fig. 1). This increase should be attributed to the well-known anti-estrogenic properties of SERMs in general (
      • Riggs B.L.
      • Hartmann L.C.
      Selective estrogen receptor modulators. Mechanisms of action and application to clinical practice.
      ) and toremifene in specific (
      • Kangas L.
      Review of the pharmacological properties of toremifene.
      ,
      • Labrie F.
      • Labrie C.
      • Belanger A.
      • Simard J.
      • Gauthier S.
      • Luu-The V.
      • et al.
      EM-652 (SCH 57068), a third generation SERM acting as pure antiestrogen in the mammary gland and endometrium.
      ). The stimulatory effect of SERMs on hypophyseal gonadotropin secretion has been proposed as a possible mechanism for its beneficial effect on semen quality (
      • Comhaire F.
      Treatment of oligozoospermia with tamoxifen.
      ).
      Toremifene administration also induced a statistically significant increase in total testosterone levels, which was again significant only during the first month of treatment, reaching a plateau afterward (see Table 2). The increased gonadotropin secretion could be the reason for this observed increase in total testosterone levels (
      • Plouffe Jr., L.
      • Siddhanti S.
      The effect of selective estrogen receptor modulators on parameters of the hypothalamic-pituitary-gonadal axis.
      ,
      • Riggs B.L.
      • Hartmann L.C.
      Selective estrogen receptor modulators. Mechanisms of action and application to clinical practice.
      ). However, it should be noted that SERMs have also been reported to have direct stimulating effects on Leydig cell function (
      • Zalaka A.
      • Hafez T.
      • Verdonck L.
      • Vermoulen L.
      • Comhaire F.
      Androgens in seminal plasma: markers of the surface epithelium on the male genital tract.
      ) and 5α-dihydrotestosterone production in seminiferous tubules and epididymis (
      • Comhaire F.
      Treatment of oligozoospermia with tamoxifen.
      ,
      • Smals A.G.H.
      • Pieters G.F.M.
      • Drayer J.I.M.
      Tamoxifen suppresses gonadotropin-induced 16-alpha-hydroxy-progesterone accumulation in normal men.
      ).
      Despite the increase in testosterone levels, which would be expected to suppress SHBG production by the liver (
      • de Ronde W.
      • van der Schouw Y.T.
      • Muller M.
      • Grobbee D.E.
      • Gooren L.J.
      • Pols H.A.
      • de Jong F.H.
      Associations of sex-hormone-binding globulin (SHBG) with non-SHBG-bound levels of testosterone and estradiol in independently living men.
      ), the levels of this globulin were statistically significantly increased during the first and the second months of toremifene administration (see Table 2). These results are indicative of the estrogenic activity of toremifene at the liver, which is consistent with previous reports on SERM properties (
      • Duschek E.J.
      • Gooren L.J.
      • Netelenbos C.
      Effects of raloxifene on gonadotrophins, sex hormones, bone turnover and lipids in healthy elderly men.
      ).
      An interesting finding of this study, which, to the best of our knowledge, has not been previously reported, was the statistically significant increase in circulating inhibin B after toremifene administration (see Table 2, Fig. 2). Inhibin production by the testes is stimulated by FSH; moreover, inhibin secretion has been proposed as a reliable index of Sertoli cell function. Therefore, the increase of inhibin levels observed in the present study could be attributed to both increased FSH secretion (see Table 2, Fig. 1) and the potential beneficiary effect of SERMs on testicular function (
      • Comhaire F.
      Treatment of oligozoospermia with tamoxifen.
      ,
      • Zalaka A.
      • Hafez T.
      • Verdonck L.
      • Vermoulen L.
      • Comhaire F.
      Androgens in seminal plasma: markers of the surface epithelium on the male genital tract.
      ,
      • Smals A.G.H.
      • Pieters G.F.M.
      • Drayer J.I.M.
      Tamoxifen suppresses gonadotropin-induced 16-alpha-hydroxy-progesterone accumulation in normal men.
      ).
      Toremifene administration for a period of 3 months resulted in a statistically significant improvement of all three main semen parameters, namely, sperm count (see Table 3, Fig. 3), motility, and morphology (see Table 3). It should be noted that, although tamoxifen has also been shown to induce a statistically significant increase in spermatozoa count, this particular SERM has not been shown to induce any marked changes in motility and morphology (
      • Buvat J.
      • Ardaens K.
      • Lemaire A.
      • Gauthier A.
      • Gasnault J.P.
      • Buvat-Herbaut M.
      Increased sperm count in 25 cases of idiopathic normozoospermic oligospermia following treatment with tamoxifen.
      ,
      • Kotoulas I.G.
      • Cardamakis E.
      • Michopoulos J.
      • Mitropoulos D.
      • Dounis A.
      Tamoxifen treatment in male infertility. I. Effect on spermatozoa.
      ).
      The partners of 22 men achieved pregnancy within 2 months from the end of treatment. At baseline, these men presented with lower serum FSH levels compared with those whose partners did not achieve pregnancy but not statistically significantly so. Although treatment with toremifene induced a statistically significant increase in FSH levels in both groups, FSH levels were statistically significantly lower (P<.05) in men whose partners achieved pregnancy at the end of the third month of treatment (see Fig. 1). We postulate that lower FSH levels in the men whose partners achieved pregnancy are due to a more functional negative feedback from the testes, thus reflecting better testicular response to treatment. This trend was also apparent in the higher levels of inhibin observed in the group of men whose partners eventually became pregnancy, although a level of statistical significance was not reached.
      At baseline, no statistically significant differences in the three main semen parameters of sperm count, motility, and morphology were observed between men whose partners achieved pregnancy and those whose partners did not, although there was a trend for increased values in the former group. Notably, total sperm count as well as spermatozoa morphology was improved with toremifene administration; this change was more marked in the group of men whose partners achieved pregnancy (see Table 3, Fig. 3). Moreover, total sperm count and spermatozoa morphology at the end of treatment had statistically significant prognostic value for the achievement of pregnancy within the subsequent 2 months. This finding is again consistent with better testicular functional response in the subgroup of men whose partners achieved pregnancy.
      Conclusively, the present study shows that toremifene administration for a period of 3 months in men with idiopathic oligozoospermia results in statistically significant improvements in all three main semen parameters of sperm count, motility, and morphology, mediated by increased gonadotropin secretion and possibly a direct beneficial effect of toremifene on the testes. It is possible, therefore, that this particular SERM could be useful as an initial approach in the treatment of subfertile men with idiopathic oligozoospermia. Nevertheless, the precise standards of treatment need to be further investigated by randomized, placebo-controlled trials.

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