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The effect of selective estrogen receptor modulator administration on the hypothalamic-pituitary-testicular axis in men with idiopathic oligozoospermia

      This study evaluates, compares, and contrasts the effects of three selective estrogen receptor modulators (SERMs), namely, tamoxifen, toremifene, and raloxifene, on the hypothalamic-pituitary-testicular axis in 284 consecutive subfertile men with idiopathic oligozoospermia using three therapeutic protocols: [1] tamoxifen, 20 mg, once daily (n = 94); [2] toremifene, 60 mg, once daily (n = 99); and [3] raloxifene, 60 mg, once daily (n = 91). The antiestrogenic effects of SERMs at the hypothalamic level result in a statistically significant increase of gonadotropin levels, which is more marked for tamoxifen and toremifene compared with raloxifene.
      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. Most of the unique pharmacology of SERMs can be explained by three interactive mechanisms: [1] differential estrogen-receptor expression in a given target tissue, [2] differential estrogen-receptor conformation on ligand binding, and [3] differential binding to the estrogen receptor of coregulator proteins (
      • 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.
      ).
      In women, SERMs have been shown to increase gonadotropin circulating levels, which are based on the estrogen antagonistic properties of SERMs at the hypothalamic and pituitary level (
      • Adashi E.Y.
      Ovulation induction: clomiphene citrate.
      ). In addition, it has been shown that the estrogen agonist activity of SERMs in the liver causes a significant increase of sex hormone–binding globulin (SHBG) levels (
      • 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. 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.
      ). As a result, the administration of tamoxifen led to a twofold increase in spermatozoa concentration. 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.
      World Health Organisation manual for the standardized investigation, diagnosis and management of the infertile male.
      ).
      In a recent study, we have shown that the administration of toremifene, at a dose of 60 mg, once daily, for a period of 3 months in men with idiopathic oligozoospermia is also associated with significant improvements in sperm count and in motility and morphology as well, mediated by increased gonadotropin secretion and possibly a direct beneficial effect of toremifene on the testes. Notably, these findings were indicative of a better testicular exocrine response to treatment in men whose partners achieved pregnancy (22%) compared with those partners who did not (
      • Farmakiotis D.
      • Farmakis C.
      • Rousso D.
      • Kourtis A.
      • Katsikis I.
      • Panidis D.
      The beneficial effects of toremifenee administration on the hypothalamic-pituitary-testicular axis and sperm parameters in men with idiopathic oligozoospermia.
      ).
      The present study was designed to evaluate, compare, and contrast the effects of three selective estrogen receptor modulators (SERMs), namely, tamoxifen, toremifene, and raloxifene, on the hypothalamic-pituitary-testicular axis in subfertile men with idiopathic oligozoospermia. To the best of our knowledge, no previous study has compared the effects of the three most commonly used SERMs on the hypothalamic-pituitary-testicular axis in men with idiopathic oligozoospermia.
      We recruited 284 consecutive subfertile men with idiopathic oligozoospermia, aged 20 to 51 years (mean ± standard deviation [SD] 33.88 ± 4.90 years) from the fertility center of our department for a period comprising the last 3 years. All men were characterized as subfertile because their partners had been unsuccessful in achieving pregnancy for a period of more than 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.
      World Health Organisation 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) as well as azoospermic men and men with higher than normal follicle-stimulating hormone (FSH) levels were excluded. All men were examined by the same physician (an endocrinologist).
      Careful clinical examination showed that all men had complete development of the secondary sex characteristics, with a mean testicular volume (±SD) of 17.45 ± 3.80 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.
      The first 94 men received tamoxifen as monotherapy at a dose of 20 mg daily for a period of 3 months. Consecutively, 99 men received toremifene at a dose of 60 mg daily for the same period, and 91 men received raloxifene at a dose of 60 mg daily for 3 months. At baseline and at the end of the first, second, and third months 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 (within 6 months) for FSH, luteinizing hormone (LH), and testosterone. At baseline and at the end of the third month, we performed semen analysis, and the sperm concentration, spermatozoal motility, and normal sperm forms were determined (Table 1).
      Table 1Basic hormonal features and semen parameters.
      FSH (mIU/mL)LH (mIU/mL)T (ng/dL)Sperm concentration (× 106 / mL)Normal sperm forms (%)
      Tamoxifen (n = 94)
       BL5.72 ± 2.714.54 ± 1.78496.59 ± 175.1832.08 ± 19.3918.91 ± 9.72
       1 month8.23 ± 4.307.65 ± 3.37740.27 ± 227.98
       2 months8.36 ± 4.607.73 ± 4.08835.06 ± 230.96
       3 months8.42 ± 4.957.84 ± 4.59763.34 ± 219.4541.94 ± 27.7331.64 ± 12.20
      Toremifene (n = 99)
       BL5.64 ± 3.384.05 ± 1.96498.96 ± 154.6625.84 ± 17.5623.09 ± 12.47
       1 month8.15 ± 4.596.62 ± 2.99696.13 ± 202.21
       2 months9.07 ± 4.865.14 ± 2.28709.79 ± 266.23
       3 months9.53 ± 4.946.54 ± 2.73743.92 ± 238.6037.82 ± 22.3931.73 ± 13.53
      Raloxifene (n = 91)
       BL6.39 ± 3.364.18 ± 1.67583.55 ± 162.4927.01 ± 24.1714.72 ± 11.31
       1 month7.05 ± 4.534.63 ± 2.00630.98 ± 195.23
       2 months5.91 ± 4.264.54 ± 2.16619.92 ± 172.21
       3 months6.87 ± 4.294.75 ± 2.12604.35 ± 178.1832.64 ± 28.9721.86 ± 15.41
      Time
      F163.05122.43190.5221.90693.71
      P value.000.000.000.000.000
      Group × Time
      F57.4220.0538.831.1562.793
      P value.000.000.000.000.000
      Notes: Mean ± standard deviation. Statistical significance by two-way repeated measures AN(C)OVA after log-transformation) of the three groups, before and during treatment; .000: <.001. BL, baseline; FSH, follicle-stimulating hormone; T, testosterone.
      All participants were properly informed about the purpose of the study and gave written informed consent. The study was approved by the ethics committee of the hospital.
      We measured FSH and LH using the immunoradiometric assay (IRMA) kits from Biosource Technologies (Fleurus, Belgium). Total testosterone was measured by enzyme-linked immunosorbent assay (ELISA; testosterone enzyme immunoassay test kit, LI7603; Linear Chemicals, Barcelona, Spain).
      Statistical analysis was performed with SPSS statistical software, v. 15.0 (SPSS Inc., Chicago, IL). Two-tailed statistical significance was set at 5%. The normality of distribution was assessed with the Kolmogorov-Smirnov test. Values that did not fit the normal distribution were log-transformed. Means were compared at baseline with Student's t-test and during treatment with general linear model (GLM)-based two-way repeated measures analysis of (co)variance (AN[C]OVA); time (treatment) was set as the within-groups factor and treatment group (tamoxifen vs. toremifene vs. raloxifene) as the between-subjects factor.
      The FSH levels (before and during the 3-month treatment period) in men of the three groups are presented in Table 1. The FSH levels were increased in the men of all three groups (F = 163.05, P<.001), with the greater increase to be observed at the end of the first month of treatment (P<.001). A statistically significant interaction was observed (F = 57.42, P<.001) overall and for each time interval separately. The increase in FSH levels was greater in men from the tamoxifen and toremifene groups compared with men from the raloxifene group, resulting in statistically significantly higher FSH levels in men from the first two groups compared with those in the raloxifene group at the end of the first, the second, and the third months of treatment (P<.05). Moreover, a statistically significant increase of FSH levels was observed in men from the toremifene group at the end of the second and the third months of treatment (P<.001); in men from the raloxifene group, FSH levels were decreased at the end of the second and increased at the end of the third month of treatment (P<.001).
      The LH levels (before and during the 3-month treatment period) in men from all three groups are presented in Table 1. The LH levels were increased in the men from all three groups (F = 122.43, P<.001), with the greater increase observed at the end of the first month of treatment (P<.001). A statistically significant interaction was observed (F = 20.05, P<.001) overall and for each time interval separately. The LH increase in men from the tamoxifen and toremifene groups compared with men from the raloxifene group was greater at the first month, resulting in higher LH levels in the tamoxifen and toremifene groups compared with the raloxifene group at the end of the first, second, and third months of treatment (P<.05). No statistically significant increase of LH levels was observed in men from the tamoxifen or raloxifene groups at the end of the first month of treatment; however, a statistically significant decrease of LH levels was observed in men from the toremifene group at the end of the second month, and an increase of LH levels was noticed at the end of the third month of treatment (P<.001). The LH levels were higher in men from the tamoxifen group compared with those of men in the toremifene group at the end of the first, second, and third months of treatment (P<.001).
      Testosterone levels (before and during the 3-month treatment period) in men from the three groups are presented in Table 1. Testosterone levels were increased in men from all three groups (F = 190.52, P<.001). A statistically significant interaction was observed (F = 38.83, P<.001) overall and for each time interval separately. In the tamoxifen group, testosterone levels were increased during the first and the second month but were decreased during the third month of treatment, although they remained higher than baseline levels (P<.001). In the toremifene group, testosterone levels were also increased at the end of the first month (P<.001) but with no further changes, resulting in statistically significant lower levels at the end of the second and the third months compared with those of the tamoxifen group (P<.05). In contrast, in the raloxifene group, a less marked increase of testosterone levels was observed at the end of the first month (P<.05) and a gradual decrease to baseline levels thereafter, resulting in lower levels compared with those in the other two groups at the end of the first, second, and third months of treatment (P<.01).
      Three selective estrogen receptor modulators (SERMs), namely, tamoxifen, toremifene, and raloxifene, were compared in terms of their effect on the hypothalamic-pituitary-testicular function of men with idiopathic oligozoospermia. The study design was based on substantial evidence concerning the beneficial effects of tamoxifen (
      • 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.
      ,
      • Rowe P.
      • Comhaire F.
      • Hargreave T.
      • Mahmoud A.
      World Health Organisation manual for the standardized investigation, diagnosis and management of the infertile male.
      ) and toremifene (
      • Farmakiotis D.
      • Farmakis C.
      • Rousso D.
      • Kourtis A.
      • Katsikis I.
      • Panidis D.
      The beneficial effects of toremifenee administration on the hypothalamic-pituitary-testicular axis and sperm parameters in men with idiopathic oligozoospermia.
      ), separately, in this particular population of subfertile men. To the best of our knowledge, no comparative study has been published so far.
      Serum FSH and LH (see Table 1) levels were increased after administration of tamoxifen at a dose of 20 mg daily and toremifene at a dose of 60 mg daily. This increase was basically observed during the first month of treatment. This finding indicates that these specific SERMs have a stimulatory effect on hypophyseal gonadotropin secretion due to their well-known antiestrogenic properties (
      • Riggs B.L.
      • Hartmann L.C.
      Selective estrogen receptor modulators. Mechanisms of action and application to clinical practice.
      ,
      • 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.
      ).
      In the raloxifene group, the gonadotropin increase was significantly less marked. It seems that the antiestrogenic action of tamoxifen and toremifene on hypophyseal gonadotropin secretion is more potent than that of raloxifene. It has to be noted that a statistically significant increase in gonadotropin levels had been observed with the double dose of raloxifene (120 mg daily) in a previous study in elderly men (60 to 70 years old) (
      • Duschek E.J.
      • Neele S.J.
      • Thomassen M.C.
      • Rosing J.
      • Netelenbos C.
      Effect of raloxifene on activated protein C (APC) resistance in postmenopausal women and homocysteine levels in elderly men: two randomized placebo-controlled studies.
      ). Therefore, it seems quite likely that the potency of SERM action depends on both the dosage and the endogenous gonadotropin levels.
      Tamoxifen and toremifene administration induced a statistically significant increase in total testosterone levels as well. The increased gonadotropin secretion could be the reason for this observed increase in 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.
      ). It should be noted though that tamoxifen has 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.
      ). Moreover, in a recent report (
      • Farmakiotis D.
      • Farmakis C.
      • Rousso D.
      • Kourtis A.
      • Katsikis I.
      • Panidis D.
      The beneficial effects of toremifenee administration on the hypothalamic-pituitary-testicular axis and sperm parameters in men with idiopathic oligozoospermia.
      ), toremifene administration led to a statistically significant increase in both testosterone production and sperm quality. This improvement in testicular function is apparently mediated by both increased gonadotropin secretion and a direct beneficial effect on the testes. In the raloxifene group, a less marked increase in testosterone levels was observed at the end of the first month as well as a gradual decrease to levels that did not differ from baseline. This difference could be attributed to the milder stimulatory effect of raloxifene on hypophyseal gonadotropin secretion.
      Our study has shown that the antiestrogenic effects of SERMs at the hypothalamic level result in a significant increase of gonadotropin levels, which is more marked for tamoxifen and toremifene compared with raloxifene. The increase in SHBG levels should be attributed to the estrogenic properties of tamoxifen and toremifene at the liver; in contrast, raloxifene seems to exert an antiestrogenic effect. The greater increase in testosterone levels after administration of tamoxifen and toremifene compared with raloxifene should be attributed to the greater stimulation of gonadotropin secretion, although a direct effect on the testis cannot be excluded.

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