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Azoospermia after treatment with clomiphene citrate in patients with oligospermia
CASE REPORT Azoospermia after treatment with clomiphene citrate in patients with oligospermia Fabio Firmbach Pasqualotto, M.D., Ph.D., Gabriela Poglia Fonseca, M.D., and Eleonora Bedin Pasqualotto, M.D., Ph.D. Centro de Ci^encias Biologicas e da Saude, Universidade de Caxias do Sul, and CONCEPTION – Center for Human Reproduction, Caxias do Sul, RS, Brazil
Objective: To describe three cases of azoospermia in patients with oligospermia after clomiphene citrate (CC) intake. Design: Case report. Setting(s): Academic medical center. Patient(s): Three patients with oligospermia. Intervention(s): Three oligospermic men used CC, resulting in azoospermia. Main Outcome Measure(s): Semen analysis after CC use and after discontinuation of CC. Result(s): Three patients were sent to our clinic for investigation of their azoospermia after use of CC. They had severe oligozoospermia (sperm concentrations of 3.4, 2.8, and 4.1 106/mL, respectively) before treatment with CC. These patients were re-evaluated with two new semen analyses, showing azoospermia. After 3 months without use of the drug, the mean sperm concentration was 2.5 1.1 106/mL. Conclusion(s): The benefits of empiric treatment with CC must be balanced with the possible undesirable effects, such as azoospermia. (Fertil Steril 2008;90:2014.e11–e12. 2008 by American Society for Reproductive Medicine.) Key Words: Clomiphene, azoospermia, male, infertility, semen
Intracytoplasmic sperm injection has become a major breakthrough in the treatment of male infertility. However, although it results in excellent pregnancy rates, many couples prefer to establish pregnancy naturally. Over the years, clomiphene citrate (CC) has been extensively used in the treatment of idiopathic male infertility. It is one of a variety of empiric, nonspecific treatments that have been used to improve semen characteristics and fertility. Although a meta-analysis of randomized, placebo-controlled trials evaluating the use of antiestrogens in the empiric treatment of male infertility did not show better results than with placebo, many colleagues still prescribe CC for these couples (1). Here we describe three cases of azoospermia caused by CC treatment in idiopathic oligospermia. CASE REPORT Three patients were sent to our clinic for investigation of their azoospermia after use of CC. They had severe oligozoosperReceived September 30, 2007; revised March 12, 2008; accepted March 13, 2008. F.F.P. has nothing to disclose. G.P.F. has nothing to disclose. E.B.P. has nothing to disclose. ^ncias Reprints requests: Fabio Firmbach Pasqualotto, M.D., Centro de Cie gicas e da Sau de, Universidade de Caxias do Sul, Pinheiro Biolo ~o Pelegrino, Caxias do Sul, RS, CEP Machado, 2569, sl 23/24, Bairro Sa 5020172, Brazil (FAX: 55-54-215-169; E-mail: Fabio@conception-rs. com.br).
mia (sperm concentrations of 3.4, 2.8, and 4.1 106/mL, respectively) before treatment with CC. Data regarding testicular volume before treatment were not available. The FSH levels were considered normal in all patients (10.2 IU/mL, 9.5 IU/mL, and 11.5 IU/mL; reference value, <12 IU/mL). The mean (SD) age was 38.8 3.6 years. The mean duration of infertility was 2.1 0.9 years. The mean use of CC was 4.5 1.5 months of treatment. In all cases, we requested that patients stop using the drug and return for re-evaluation within 3 months (semen analysis and hormonal profile). In all three patients, sperm was present on follow-up semen analysis (mean concentration, 2.5 1.1 106/mL). The mean follow-up FSH level was 13.2 2.9 IU/mL. DISCUSSION Clomiphene citrate is a nonsteroidal antiestrogen that binds to hypothalamic estrogen receptors and weakens the negative feedback mechanism of LHRH secretion by estrogens. This leads to increased secretion of FSH and LH. The increased LH stimulates production of T by Leydig cells, whereas FSH and T stimulate Sertoli cells and germinal cells (1). On the basis of four trials that evaluated the effect of this drug in unexplained infertility, CC has a small and nonsignificant effect, producing 1 additional pregnancy in 76 CC cycles compared with untreated control cycles (2). A
2014.e11 Fertility and Sterility Vol. 90, No. 5, November 2008 Copyright ª2008 American Society for Reproductive Medicine, Published by Elsevier Inc.
0015-0282/08/$34.00 doi:10.1016/j.fertnstert.2008.03.036
randomized, double-blind, multicenter study from the World Health Organization evaluated 109 couples with idiopathic male infertility and failed to show any improvement in pregnancy rates after 6 months of treatment with CC (3). The potential side effects of this drug include headaches, nausea, visual disturbances, dizziness, abdominal discomfort, mouth ulcers, and cataract formation (3). This study shows that there is a real possibility for a decrease in semen quality, even azoospermia, after the use of CC in patients with severe idiopathic oligospermia. Therefore, the benefits of empiric treatment with CC must be
Fertility and Sterility
balanced with the possible undesirable effects, such as azoospermia. REFERENCES 1. Itoh N, Tsukamoto T, Nanbu A, Tachiki H, Nitta T, Akagashi K, et al. Changes in the endocrinological milieu after clomiphene citrate treatment for oligozoospermia: the clinical significance of the estradiol/testosterone ratio as a prognostic value. J Androl 1994;15:449–55. 2. The Practice Committee of the American Society for Reproductive Medicine. Effectiveness and treatment for unexplained infertility. Fertil Steril 2004;82:161–3. 3. World Health Organization. A double-blind trial of clomiphene citrate for the treatment of idiopathic male infertility. Int J Androl 1992;15:299–307.
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Objective: To describe three cases of azoospermia in patients with oligospermia after clomiphene citrate (CC) intake. Design: Case report. Setting(s): Academic medical center. Patient(s): Three patients with oligospermia. Intervention(s): Three oligospermic men used CC, resulting in azoospermia. Main Outcome Measure(s): Semen analysis after CC use and after discontinuation of CC. Result(s): Three patients were sent to our clinic for investigation of their azoospermia after use of CC. They had severe oligozoospermia (sperm concentrations of 3.4, 2.8, and 4.1 106/mL, respectively) before treatment with CC. These patients were re-evaluated with two new semen analyses, showing azoospermia. After 3 months without use of the drug, the mean sperm concentration was 2.5 1.1 106/mL. Conclusion(s): The benefits of empiric treatment with CC must be balanced with the possible undesirable effects, such as azoospermia. (Fertil Steril 2008;90:2014.e11–e12. 2008 by American Society for Reproductive Medicine.) Key Words: Clomiphene, azoospermia, male, infertility, semen
Intracytoplasmic sperm injection has become a major breakthrough in the treatment of male infertility. However, although it results in excellent pregnancy rates, many couples prefer to establish pregnancy naturally. Over the years, clomiphene citrate (CC) has been extensively used in the treatment of idiopathic male infertility. It is one of a variety of empiric, nonspecific treatments that have been used to improve semen characteristics and fertility. Although a meta-analysis of randomized, placebo-controlled trials evaluating the use of antiestrogens in the empiric treatment of male infertility did not show better results than with placebo, many colleagues still prescribe CC for these couples (1). Here we describe three cases of azoospermia caused by CC treatment in idiopathic oligospermia. CASE REPORT Three patients were sent to our clinic for investigation of their azoospermia after use of CC. They had severe oligozoosperReceived September 30, 2007; revised March 12, 2008; accepted March 13, 2008. F.F.P. has nothing to disclose. G.P.F. has nothing to disclose. E.B.P. has nothing to disclose. ^ncias Reprints requests: Fabio Firmbach Pasqualotto, M.D., Centro de Cie gicas e da Sau de, Universidade de Caxias do Sul, Pinheiro Biolo ~o Pelegrino, Caxias do Sul, RS, CEP Machado, 2569, sl 23/24, Bairro Sa 5020172, Brazil (FAX: 55-54-215-169; E-mail: Fabio@conception-rs. com.br).
mia (sperm concentrations of 3.4, 2.8, and 4.1 106/mL, respectively) before treatment with CC. Data regarding testicular volume before treatment were not available. The FSH levels were considered normal in all patients (10.2 IU/mL, 9.5 IU/mL, and 11.5 IU/mL; reference value, <12 IU/mL). The mean (SD) age was 38.8 3.6 years. The mean duration of infertility was 2.1 0.9 years. The mean use of CC was 4.5 1.5 months of treatment. In all cases, we requested that patients stop using the drug and return for re-evaluation within 3 months (semen analysis and hormonal profile). In all three patients, sperm was present on follow-up semen analysis (mean concentration, 2.5 1.1 106/mL). The mean follow-up FSH level was 13.2 2.9 IU/mL. DISCUSSION Clomiphene citrate is a nonsteroidal antiestrogen that binds to hypothalamic estrogen receptors and weakens the negative feedback mechanism of LHRH secretion by estrogens. This leads to increased secretion of FSH and LH. The increased LH stimulates production of T by Leydig cells, whereas FSH and T stimulate Sertoli cells and germinal cells (1). On the basis of four trials that evaluated the effect of this drug in unexplained infertility, CC has a small and nonsignificant effect, producing 1 additional pregnancy in 76 CC cycles compared with untreated control cycles (2). A
2014.e11 Fertility and Sterility Vol. 90, No. 5, November 2008 Copyright ª2008 American Society for Reproductive Medicine, Published by Elsevier Inc.
0015-0282/08/$34.00 doi:10.1016/j.fertnstert.2008.03.036
randomized, double-blind, multicenter study from the World Health Organization evaluated 109 couples with idiopathic male infertility and failed to show any improvement in pregnancy rates after 6 months of treatment with CC (3). The potential side effects of this drug include headaches, nausea, visual disturbances, dizziness, abdominal discomfort, mouth ulcers, and cataract formation (3). This study shows that there is a real possibility for a decrease in semen quality, even azoospermia, after the use of CC in patients with severe idiopathic oligospermia. Therefore, the benefits of empiric treatment with CC must be
Fertility and Sterility
balanced with the possible undesirable effects, such as azoospermia. REFERENCES 1. Itoh N, Tsukamoto T, Nanbu A, Tachiki H, Nitta T, Akagashi K, et al. Changes in the endocrinological milieu after clomiphene citrate treatment for oligozoospermia: the clinical significance of the estradiol/testosterone ratio as a prognostic value. J Androl 1994;15:449–55. 2. The Practice Committee of the American Society for Reproductive Medicine. Effectiveness and treatment for unexplained infertility. Fertil Steril 2004;82:161–3. 3. World Health Organization. A double-blind trial of clomiphene citrate for the treatment of idiopathic male infertility. Int J Androl 1992;15:299–307.
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