For Poantrex:
Treatment of idiopathic and postvaricocelectomy oligozoospermia with oral tamoxifen citrate
T.C. Kadioglu, I.T. Köksal, M. Tunç, I. Nane and S. Tellaloglu
1 Department of Urology, Faculty of Medicine, Istanbul University, Istanbul, Turkey
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Objective
To identify a subgroup of men who may benefit from tamoxifen citrate (a widely prescribed drug for male infertility) among those with normogonadotrophic and hypergonadotrophic oligozoospermia, either idiopathic or after varicocelectomy.
Patients and methods
The study included infertile men with oligozoospermia, 136 referred to our outpatient clinic and 84 infertile after varicocelectomy. All patients received tamoxifen citrate (10 mg twice daily); semen analysis and hormone tests were repeated at the end of 3 and 6 months of treatment, the values being compared with those before treatment.
Results
The levels of follicle-stimulating hormone, luteinizing hormone and testosterone increased in all groups receiving tamoxifen citrate. Normogonadotrophic patients had a significant increase in sperm count and concentration, while the slight increase detected in the hypergonadotrophic group was statistically insignificant.
Conclusion
In patients with normogonadotrophic oligozoospermia, tamoxifen citrate may be offered as a practical and economic alternative before using any assisted reproduction techniques. However, double-blind placebo-controlled trials are needed to confirm the findings of this preliminary study.
Keywords: Tamoxifen citrate, infertility, oligozoospermia, varicocelectomy
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Introduction
Patients and methods Results Discussion References
One of the widely prescribed drugs for male infertility is tamoxifen citrate, a pure anti-oestrogen that is a nonsteroidal derivative of triphenyl ethylene [1]. Tamoxifen inhibits hypothalamic oestrogen receptors [2]; thus GnRH secretion is stimulated and as a result, gonadotrophin levels increase to stimulate Leydig cells and seminiferous tubules [2–5]. Although the direct effects of tamoxifen on the testis are still debated, it probably blocks oestrogenic receptors of the Leydig cells and increases testosterone production by increasing the sensitivity to serum LH [1,4,5].
Assisted reproduction techniques are used widely in patients with idiopathic oligozoospermia, and in those who cannot attain normal sperm counts and attempt paternity after varicocelectomy. Alternative treatments should be considered before referring patients for such expensive and distressing treatment options, that have limited success and known complication rates. Many different medical treatment options have been tried in oligozoospermic infertile men, but controlled studies showed no significant benefit [6]. In the present study, we aimed to identify a subgroup of men with oligospermia who would benefit from treatment with tamoxifen citrate, among those normogonadotrophic and hypergonadotrophic either idiopathically or after varicocelectomy.
Patients and methods
Introduction Results Discussion References
The study included infertile men with oligospermia, comprising 136 (idiopathic) referred to our outpatient clinic and 84 infertile after varicocelectomy (mean age 29 years, range 21–37). All patients had a history of infertility of at least 2 years, with their spouses confirmed to have had a normal gynaecological evaluation. All patients had sperm counts below the WHO threshold (20×106/mL) on two semen analyses. All patients provided three blood samples at 20 min intervals which were pooled; the FSH, LH and testosterone levels were determined to identify normo- and hypergonadotrophism before initiating medication. All patients received 10 mg tamoxifen citrate twice daily and the semen analysis and hormone tests were repeated after 3 and 6 months. The early (3-month) assessment was conducted only to document changes in hormone levels, as tamoxifen citrate influences the early stages of spermatogenesis and was not expected to affect the early semen analysis values. Thus the 3-month results were not included in the statistical analyses. Pregnancies achieved during the treatment were not assessed because other supplementary nonmedical treatments, e.g. timed coitus, intrauterine insemination, in vitro fertilization and intracytoplasmic injection, were introduced.
The semen analyses and hormone results before treatment were compared with those after 6 months and analysed using the paired Student’s t-test. Values were expressed as the mean (sd), with P<0.05 considered to indicate statistical significance.
Results
Introduction Patients and methods Discussion References
The FSH, LH and testosterone levels increased in all groups receiving tamoxifen citrate; while FSH levels increased by »50%, LH and testosterone levels almost doubled in normogonadotrophic patients (Table 1). The hormone level increases were less prominent in hypergonadotrophic men. Semen analysis in all groups showed no change in any variable other than sperm concentration and count (Table 1). Normogonadotrophic men had a significant increase in sperm count and concentration, while the slight increase detected in hypergonadotrophic men was statistically insignificant.
Discussion
Introduction Patients and methods Results References
Tamoxifen citrate is preferred to clomiphene citrate as its oestrogenic activity is practically insignificant [7]. Clomiphene citrate is a combination of two isomers and exerts both anti-oestrogenic and oestrogenic effects simultaneously [7,8]. The oestrogenic effect increases plasma oestrogen levels in men with oligozoospermia and increased FSH levels. Thus testosterone and sex-hormone binding protein synthesis may decline, decreasing spermatogenesis [7,9]. Because tamoxifen lacks this intrinsic oestrogenic effect, it may be more appropriate to use in male infertility. Although tamoxifen is also a trans isomer, animal and human studies confirm its oestrogenic activity to be minimal or negligible [10–12].
Tamoxifen is believed to enhance spermatogenesis by increasing FSH and testosterone levels [7,13]; that it was ineffective in hypergonadotrophic men supports this contention [10,11]. Studies claiming tamoxifen to be ineffective for oligozoospermia used low doses, had few patients and did not evaluate hormonal levels before initiating drug therapy [3,7,14]. In the present study, tamoxifen therapy increased sperm count and concentration in normogonadotrophic men of both groups and the higher counts were sustained. As others have reported, tamoxifen does not change semen values (e.g. volume, pH, motility, morphology, viability) other than sperm count and density [2,4,7,14,15]. Therefore it is believed that tamoxifen is effective on the seminiferous tubules during the early stages of spermatogenesis [4,11,12]. The increase in LHRH level by tamoxifen causes endogenous LH and FSH to increase, which is more physiologically acceptable than their exogenous administration. Thus hypergonadotrophic men cannot benefit from this treatment as their testes are already sufficiently stimulated [10,11]. In the present study, testosterone and LH levels doubled, and FSH increased by »50% during medication, as reported elsewhere [5,11].
These results suggest that tamoxifen citrate may be useful in normogonadotrophic oligozoospermic men, as a practical and economic alternative before any assisted-reproduction techniques. If the total motile count in such men after sperm processing for intrauterine insemination is low (1–5 million), tamoxifen should also be considered for increasing the count and thus the potential for fertilization [16]. In infertile men with oligozoospermia (idiopathic or after varicocelectomy) the hormone levels should be assessed to identify those who are normogonadotrophic, and who may thus benefit from oral tamoxifen therapy, before attempting expensive and invasive assisted-reproduction techniques, which are better reserved as a last option. However, these results must be confirmed in double-blind placebo-controlled randomized trials.
References
Introduction Patients and methods Results Discussion
1
Noci I, Chello E, Saltarelli O et al.Tamoxifen and oligospermia. Arch Androl 1985; 15: 83–8
2
Comhaire F. Treatment of oligospermia with tamoxifen. Int J Fertil 1976; 21: 232–8
3
Comhaire F, Dhondt MInfluence of current modes of treatment in male infertility on the hypothalamo-pituitary testicular function. In Schellen T, ed. Releasing Factors and Gonadotropic Hormones in Male and Female Sterility. Ghent: European Press Medicon1975; 117
4
Kotoulas JG, Mitropoulas D, Carmadakis E et al.Tamoxifen treatment in male infertility. I. Effect on spermatozoa. Fertil Steril 1994; 6: 911–4
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Hampl R, Heresova J, Lachman M et al.Hormonal changes in tamoxifen treated men with idiopathic oligozoospermia. Exp Clin Endocrinol 1988; 92: 211–6
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Török L. Treatment of oligospermia with tamoxifen. Andrologia 1985; 17: 497–50
7
Buvat J, Ardaens K, Lemaire A et al.Increased sperm count in 25 cases of idiopathic normogonadotropic oligospermia following treatment with tamoxifen. Fertil Steril 1983; 39: 700–3
8
Czygan PJ, Schultz KDStudies of the anti-oestrogenic and oestrogenic like actions of clomiphen citrate in women. In Hubinont PO, Hendeles SM, Preumont P, eds, Hormones and Agonists. Basel: S Karger,1972; 450
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Wu FCW, Schultz IA, Baird DT. Raised plasma oestrogens in infertile men with elevated levels of FSH. Clin Endocrinol 1982; 16: 39
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Barts G, Scheiber K. Tamoxifen treatment in oligozoospermia. Eur Urol 1981; 7: 283–7
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Vermeulen A, Comhaire F. Hormonal effects an antiestrogen, tamoxifen in normal and oligospermic men. Fertil Steril 1978; 29: 320–7
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Harper MJK, Walpole AL. Contrasting endocrine activities of cis and trans isomers in a series of substituted triphenylethylenes. Nature 1966; 212: 87
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Willis KJ, London DR, Bevis MA et al.Hormonal effects of tamoxifen in oligospermia men. J Endocrinol 1977; 73: 171
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Schill WB, Landthaler M. Tamoxifen treatment in oligospermia. Andrologia 1980; 12: 546–8
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Dony JMJ, Smals AGH, Rolland R et al.Effect of lower versus higher doses of tamoxifen on pituitary-gonadal function and sperm indices in oligozoospermic men. Andrologia 1985; 17: 369–78
16
Oehninger S, Acosta AA, Morshedi M et al. Corrective measures and pregnancy outcome in in vitro fertilization in patients with severe sperm morphology abnormalities. Fertil Steril 1988; 50: 283
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