1

Systematic Review 49
urologypracticejournal.com
2 50
3 51
4 52
5
Male Factor Infertility and Clomiphene Citrate: A Meta-AnalysisdThe 53
6 Effect of Clomiphene Citrate on Oligospermia 54
7 55
8 56
9 Naima Bridges,* Vera Tromenko,* Sally Fields,* Douglas Carrell,* 57
10 Kenneth Aston* and James Hotalingy,z 58
11 59
12 From the Departments of Obstetrics and Gynecology, University of California-Davis (NB), Davis, California, Department of Urology, University 60
13 of Utah (VT, DC, KA, JH), Salt Lake City, Utah, and Department of Statistical Analysis, University of Illinois (SF), Chicago, Illinois 61
14 62
15 63
16 64
17 Abstract Abbreviations 65
18 and Acronyms 66
19 Introduction: Clomiphene citrate has long been administered with inconclusive outcomes. It has CC = clomiphene citrate 67
20 often been used as empirical treatment for male factor infertility, presumably by increasing the 68
sperm concentration. However, to our knowledge there has been no meta-analysis of the exact FSH = follicle stimulating
21 hormone 69
impact on semen parameters. We performed a systematic review and meta-analysis of the impact of
22 70
clomiphene citrate on sperm parameters in men with oligospermia. LH = luteinizing hormone
23 71
Methods: We systematically reviewed pertinent randomized, controlled, prospective trials using RCT = randomized,
24 72
the bibliographic databases MEDLINE (1966 to 2013), Embase (1980 to 2013) and the controlled trial
25 73
Cochrane Collaboration. References of selected articles were reviewed for additional relevant
26 74
citations. The net treatment effect of the observed change in sperm concentration was analyzed.
27 75
28 Results: Data pooled from 2 randomized, controlled trials and 1 prospective trial in men with 76
29 infertility and oligospermia included a total of 197 men with a mean age of 32.8 years (range 18 to 77
65). In the treatment arm 115 men were treated with a minimum dose of 25 mg clomiphene citrate
30 78
at least every other day for a minimum of 3 months. The placebo or no treatment arm included
31 82 men. Pooled meta-analysis data revealed a highly signicant increase of 7.7 million sperm per 79
32 ml after administering clomiphene citrate compared to placebo or no treatment. There was no 80
33 evidence of signicant heterogeneity across the groups. 81
34 82
Conclusions: Available data suggest that clomiphene citrate is associated with an increased sperm
35 count compared to placebo. 83
36 84
37 Key Words: testis; infertility, male; oligospermia; spermatozoa; clomiphene 85
38 86
39 87
40 88
41 Infertility can affect up to 17% of couples1 with male 89
Submitted for publication July 12, 2014.
42 *
No direct or indirect nancial incentive associated with publishing this
factor infertility, which impacts up to 58% of all couples 90
43 article. evaluated for infertility.2 Oligospermia accounts for 21% to 91
y
44 Correspondence: Department of Urology, Utah Center for Reproductive 51% of these males depending on the population.3e5 92
Medicine, 675 Arapeen Way, Suite 205, Salt Lake City, Utah 84108 (FAX:
45 801-585-2891; e-mail address: Jim.Hotaling@hsc.utah.edu). Hussein et al reported that correcting hypogonadism can 93
46 z
Financial interest and/or other relationship with Andro360 and Spermdx. double the sperm retrieval rate in azoospermic men who 94
47 95
48 2352-0779/15/24-1/0 http://dx.doi.org/10.1016/j.urpr.2014.10.007 96
UROLOGY PRACTICE Vol. 2, 1-7, July 2015
2015 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC. Published by Elsevier
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 2 Male Factor Infertility and Clomiphene Citrate

97 undergo sperm extraction.6 However, the exact impact of CC Randomized, placebo controlled trials and randomized, 148
98 on sperm concentrations is highly variable in the literature.7,8 prospective studies were included regardless of size. For 149
99 Clomiphene citrate is a FDA (Food and Drug Adminis- data extraction and meta-analysis we dened exposure as 150
100 tration) approved therapy for female infertility. It improves males 18 to 65 years old with oligospermia who received at 151
101 ovulatory function by blocking the feedback inhibition of least 25 mg CC every other day for a minimum of 3 months. 152
102 estradiol at the levels of the hypothalamus and the pituitary Only studies including sperm concentration statistics with 153
103 gland, increasing the release of gonadotropin-releasing the SD when comparing CC treatment to placebo or no 154
104 hormone and LH/FSH, respectively.9 While CC has not treatment were included in our meta-analysis. In all included 155
105 gained FDA approval for male infertility, it is among the studies clomiphene citrate was used as a single agent except 156
106 most commonly prescribed agents for managing male the series by Ghanem et al, in which CC was combined with 157
107 infertility and it is prescribed more than 90% of the time.10 vitamin E.22 Exclusion criteria included men who had fe- 158
108 Administration leads to increased LH, which increases male partners with documented female factor infertility, men 159
109 testicular synthesis of testosterone, thereby improving sperm with varicocele and men with azoospermia. 160
110 maturation and spermatogenesis. 161
111 Published studies dating to the 1960s were done to examine 162
112 the effects of CC on male infertility, often with variable and Data Extraction 163
113 inconclusive results.11 An improved sperm concentration For each study the extracted information included authors, 164
114 was reported in many studies8,12e15 but others showed no journal, publication year, study design and eligibility 165
115 improvement or had inconclusive results.2,7,9,16e20 Under- criteria, and the number of participants, cases and controls in 166
116 standing the exact impact of CC on the sperm prole of a each group. The outcome measures extracted were pre- 167
117 man would provide valuable information for clinicians to treatment and posttreatment sperm concentration in million 168
118 counsel patients and recommend the optimal CC dose, of sperm per ml with respective SDs. At baseline there was 169
119 particularly to facilitate articial insemination, which requires no difference in the sperm concentration between subjects in 170
120 a total motile count of 5 million sperm per ml.21 the placebo and treatment group in all 3 studies. 171
121 To consolidate information on this topic we performed a 172
122 systematic review and meta-analysis of all available literature 173
123 on oligospermia, male factor infertility and CC. We studied Meta-Analysis 174
124 the effects of CC vs placebo in men with infertility attribut- 175
125 able to idiopathic oligospermia. Although previous data are For continuous outcomes the net treatment effect was 176
126 abundant, they are inconclusive on the clinical signicance of analyzed using standard meta-analysis methods. Treatment 177
127 CC in men with oligospermia with extensive heterogeneity effect was dened as the mean outcome in treatment groups 178
128 among previous studies. Thus, a meta-analysis is needed. minus the mean outcome in control groups or the change in 179
129 the mean outcome with treatment. According to the proce- 180
130 dure recommended by Sutton et al23 we considered mean  181
Patients and Methods SD outcomes in the treatment and control groups in each
131 182
132 series. A test for heterogeneity between studies was done to 183
Relevant Study Identication and Eligibility
133 determine the choice of methods to calculate a pooled 184
134 We searched MEDLINE (1966 to 2013) and the Cochrane estimate of the treatment effect and the 95% CI. 185
135 Library Collaboration with the search terms clomiphene; 186
136 infertility, male; clomiphene or clomiphene citrate treat- 187
ment, hypogonadal; and androgen deciency. We also Results
137 188
138 searched Embase (1980 to 2013) using the same search We obtained and screened 237 abstracts. From these 189
139 terms with the parameters meta-analysis, RCT, systematic abstracts we further read and reviewed all 12 articles that 190
140 review, article (in press), conference abstract/paper/review, compared CC and semen outcomes in a prospective trial or 191
141 male and humans. No language limit was set. RCT. To analyze continuous outcomes for this meta- 192
142 analysis we dened effect size as the difference between 193
143 Inclusion and Exclusion Criteria
the mean sperm concentration in men treated with CC and 194
144 the mean sperm concentration in those who received pla- 195
145 Studies ultimately included in the meta-analysis had com- cebo or no treatment divided by the average SD. Only 196
146 plete data sets and evaluated the comparison between CC articles comparing placebo to a minimum dose of 25 mg CC 197
147 use in male factor infertility compared to a placebo group. at least every other day for a minimum of 3 months were 198

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 Male Factor Infertility and Clomiphene Citrate 3

199 included. Three articles were excluded secondarily due The independent sample t-test was used to compare the 250
200 to the lack of complete recorded data sets,8,14,24 1 was mean sperm concentration before and after treatment. The 251
201 excluded based on the reporting of SDs for change scores overall pooled treatment effect of CC on sperm concentra- 252
202 only18 and an additional 5 were excluded that compared CC tion was highly signicant (p <0.0001). The overall effect 253
203F1 to other treatments (g. 1).8,14,17,20,25,26 estimate was an increase of 7.7 million per ml (variance 254
204 The 3 remaining studies each recruited men from a 0.18). On overall analysis there was no evidence of signif- 255
205 different country, including Yugoslavia, Egypt and Hong icant SD heterogeneity in the primary outcome across the 256
206T1 Kong (see table).20,22,27 Two studies were published in 3 studies (p 0.86). For the outcome of sperm concentra- 257
207 Fertility and Sterility, 20,22
and 1 was published in The tion after treatment heterogeneity between studies was not 258
208 Journal of Urology.27 Mean age of participating men was signicant and xed effects methods were used (g. 2). F2259
209 32.8 years but 1 article did not comment on age. All series 260
210 were single center prospective or randomized studies with a 261
211 placebo or no treatment group serving as the control. No Discussion 262
212 study used power calculations but all 3 included SD and 263
Analysis of pooled data from the 3 placebo controlled
213 signicance data. Semen was collected and analyzed for 264
studies in this meta-analysis demonstrated a 7.7 million per
214 oligospermia or oligozoospermia and these men were 265
ml increase in the sperm concentration between the CC
215 recruited into the studies. In all 3 articles oligospermia was 266
treatment and control groups. This result is consistent with
216 dened as less than 20 million sperm per ml. Patterns of 267
ndings in a number of individual studies showing a sig-
217 recruitment and clinical settings varied. In 1 trial CC was 268
nicant difference in sperm concentration with the admin-
218 administered in combination with vitamin E (see table).22 269
istration of CC.8,12e15 The nding is consistent with the
219 270
recent meta-analysis by Chua et al, which demonstrated a
220 271
5.2 million per ml increase in the sperm concentration after
221 Meta-Analysis Main Results 272
treatment with the estrogen antagonist tamoxifen or
222 273
We analyzed 115 males treated with a minimum dose of Clomid.28 In that series estrogen antagonists were asso-
223 274
25 mg CC at least every other day for a minimum of ciated with a statistically signicant increased pregnancy
224 275
3 months and 82 monitored patients who served as controls. rate compared to controls (OR 2.4). In contrast to the study
225 276
226 277
227 278
228 279
229 280
230 281
231 282
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234 285
235 286
236 287
237 288
238 289
239 290
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242 293
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245 296
246 297
247 298
248 299
249 Figure 1. Meta-analysis abstract identication and selection. 300

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 4 Male Factor Infertility and Clomiphene Citrate

301 Table. uncommon. Visual disturbances (blurred or double vision 352

302 Data used for meta-analysis and sensitivity to light) are also occasionally observed but 353
303 Mean  SD Posttreatment have been generally reversible with the cessation of the 354
Sperm Concentration
304 References (treatment group) No. Pts (million/ml) medication. Transient azoospermia was reported in 3 men 355
305 Micic and Dotlic:27 on CC for idiopathic infertility but discontinuing the drug 356
306 Clomid 50 mg/day 56 16.00  2.14 restored sperm production in each case.30 357
307 Placebo 45 8.28  2.21 The sources of discrepancy in the literature on the effect 358
Ghanhem et al:22
308 Clomiphene 25 mg/day 30 18.00  15.00 of CC on sperm concentration can partly be attributable to 359
309 vitamin E variability in study design, which presents a challenge when 360
310 Placebo 30 12.00  8.60 making comparisons among studies. Only 5% of treatment 361
Wang et al:20
311 Clomid 25 or 50 mg/day 29 12.57  12.78 studies that were screened for the current meta-analysis were 362
312 Placebo 7 8.30  5.60 prospective trials and RCTs. In individual trials there were 363
313 observed differences in infertility duration,7 absent specic 364
314 by Chua et al, we focused on Clomid specically as a means inclusion criteria,7 loss to followup,7 varied therapy dosing 365
315 of improving sperm concentration, thereby targeting its and duration,16,31 and small sample size, making the series 366
316 applicability to subfertile patients attempting to improve under powered to adequately detect a difference.18,20,24 367
317 semen parameters before pursuing intrauterine insemination Additional confounding factors that complicate compari- 368
318 or in vitro fertilization. son among studies is administering CC together with other 369
319 The clinical relevance of this series lies in providing supplements22 and the variability in reported end point 370
320 practitioners with information that could be used to prog- outcomes, including the sperm concentration, the estrogen- 371
321 nosticate the quantitative impact of CC on sperm parameters to-testosterone ratio and the pregnancy rate. 372
322 in men with oligospermia by selecting patients who would A strength of our series is the inclusion of prospective 373
323 likely attain a sperm concentration that would make them cohort studies and randomized, controlled studies, thereby 374
324 eligible for articial insemination.21,29 Current criteria for allowing this meta-analysis to provide the highest level of 375
325 patients who are more likely to benet from CC treatment evidence available for CC use. However, this meta-analysis 376
326 are a diagnosis of idiopathic infertility, a sperm concentra- has limitations. Although 12 articles met the parameters of 377
327 tion of less than 20 million but greater than 10 million per ml, our initial search, a number did not include complete data 378
328 low FSH and LH, and normal or slightly below normal sets or SDs, which precluded inclusion in analysis. In 379
329 motility and morphology. There does not appear to be an particular the WHO 1992 Task Force on Infertility per- 380
330 additional benet to a dose of 50 mg daily compared to 25 mg formed a large, placebo controlled study that could not be 381
331 daily.11 included due to the absence of cited SDs, which precluded 382
332 Although studies of CC are relatively small, the data its eligibility for our statistical model.19 383
333 suggest that CC may have positive effects on sperm pro- When analyzing the available data, the study by Micic 384
334 duction, fertility, testosterone and estrogen levels, the and Dotlic biased the meta-analysis due to population and 385
335 testosterone-to-estrogen ratio, testicular volume and sexual effect sizes.27 The number of subjects in the other 2 studies 386
336 function. While CC is well tolerated by most patients, side was relatively low,20,22 potentially limiting the broader 387
337 effects such as gastric upset and gynecomastia are not applicability of these ndings, although the pooled outcome 388
338 389
339 390
340 391
341 392
342 393
343 394
344 395
345 396
346 397
347 398
348 399
349 400
350 401
351 Figure 2. Pooled treatment effect of CC on sperm concentration. 402

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 Male Factor Infertility and Clomiphene Citrate 5

403 was signicant. Heterogeneity was added to this meta- 2. Charny C: Clomiphene therapy in male infertility: a negative 454
404 analysis by the study by Ghanem et al.22 They reviewed report. Fertil Steril 1979; 32: 551. 455
405 the positive effects of Clomid plus vitamin E, a potential 3. Mehta R, Makwana S, Ranga G et al: Prevalences of oligozoo- 456
406 confounding variable, on sperm count and motility. Addi- spermia and azoospermia in male partners of infertile couples 457
407 tionally, the effect of clomiphene on testosterone levels from different parts of India. Asian J Androl 2006; 8: 89. 458
408 could not be assessed since only 1 series included these 4. Ahmed A, Bello A, Mbibu N et al: Epidemiological and aetio- 459
409 data. logical factors of male infertility in northern Nigeria. Niger J Clin 460
410 Perhaps most important is the controversial question of Pract 2010; 13: 205. 461
411 whether sperm concentration is a reliable marker of the 5. Thonneau P, Marchand S and Tallec A: Incidence and main 462
412 success of fertility therapy. Statistically signicant increases causes of infertility in a resident population (1 850 000) of three 463
French regions (1988e1989). Hum Reprod 1991; 6: 811.
413 in sperm concentration in patients who receive CC do not 464
414 always translate to an increased pregnancy rate.20,24,27 These 6. Hussein A, Ozgok Y, Ross L et al: Optimization of 465
415 ndings suggest that there may be factors other than those spermatogenesis-regulating hormones in patients with non- 466
obstructive azoospermia and its impact on sperm retrieval:
416 assessed during routine semen analysis that affect pregnancy 467
a multicentre study. BJU Int 2013; 111: E110.
417 and reinforce the need for outcomes that are not based only 468
418 on semen parameters. Future directions for similar meta- 7. Abel B, Carswell G and Elton R: Randomized trial of clomiphene 469
citrate treatment and vitamin C for male infertility. Br J Urol 1982;
419 analyses would be to analyze the effect of CC on testos- 54: 780.
470
420 terone, total motile count and pregnancy outcomes. 471
421 8. Check J and Rakoff A: Improved fertility in oligospermic males 472
treated with clomiphene citrate. Fertil Steril 1977; 28: 1226.
422 473
423 Conclusions 9. Emperaire J, Riviere J, Rufe A et al: Clomiphene test and 474
424 clomiphene therapy in idiopathic male infertility. Arch Androl 475
Although clomiphene is often administered in men with 1979; 2: 223.
425 476
oligospermia and male factor infertility, the available evi-
426 10. Ko E, Siddiqi K, Brannigan R et al: Empirical medical therapy for 477
dence is conicting. We performed a systematic review and idiopathic male infertility: a survey of the American Urological
427 478
meta-analysis of RCTs and prospective trials of the impact Association. J Urol 2012; 187: 973.
428 479
of CC on the sperm concentration. Our analysis of pooled
429 11. Willets A, Corbo J and Brown J: Clomiphene for the treatment of 480
data from the meta-analysis suggests that CC 25 mg at least male infertility. Reprod Sci 2013; 20: 739.
430 481
every other day for 3 months is associated with an increased
431 12. Paulson D: Cortisone acetate versus clomiphene citrate in per- 482
sperm concentration compared to placebo in men with male
432 germinal idiopathic oligospermia. J Urol 1979; 121: 432. 483
factor infertility. The conclusions of this meta-analysis
433 13. Newton R, Schinfeld J and Schiff I: Clomiphene treatment of 484
cannot be generalized with certainty to broader pop-
434 infertile men: failure of response with idiopathic oligospermia. 485
ulations due to the small number of studies included and the
435 Fertil Steril 1980; 34: 399. 486
absence of large, controlled trials. However, results to date
436 14. Ross L, Kandel G, Prinz L et al: Clomiphene treatment of the 487
are consistent with the proposed mechanism of action by
437 idiopathic hypofertile male: High-dose, alternate-day therapy. 488
which these improvements reect normalization of the Fertil Steril 1980; 33: 618.
438 489
hypothalamic-pituitary-gonadal axis. The magnitude of this
439 15. Homonnai Z, Yavetz H, Yogev L et al: Clomiphene citrate 490
effect could be quantied by reproductive specialists to
440 treatment in oligozoospermia: comparison between two regimens 491
counsel patients with male factor infertility. The lack of of low-dose treatment. Fertil Steril 1988; 50: 801.
441 492
consensus treatment recommendations for male infertility
442 16. Mroueh A, Lytton B and Kase N: Effect of clomiphene citrate on 493
reects the need for more research on this subject in large
443 oligospermia. Am J Obstet Gynecol 1967; 98: 1033. 494
RCTs with consistent inclusion criteria and clinically rele-
444 17. Rnnberg L: The effect of clomiphene citrate on different sperm 495
vant outcomes that include the pregnancy rate and change in
445 parameters and serum hormone levels in preselected infertile men: 496
semen parameters.
446 a controlled double-blind cross over study. Int J Androl 1980; 497
3: 479.
447 498
448 References
18. Sokol R, Steiner B, Bustillo M et al: A controlled comparison of 499
449 the efcacy of clomiphene citrate in male infertility. Fertil Steril 500
1988; 49: 865.
450 1. Boivin J, Bunting L, Collins JA et al: International estimates 501
451 of infertility prevalence and treatment-seeking: potential need 19. Srivannaboon S, Dhall G, De Krester D et al: A double-blind trial 502
452 and demand for infertility medical care. Hum Reprod 2007; of clomiphene citrate for the treatment of idiopathic male infer- 503
22: 1506. tility. Int J Androl 1992; 15: 299.
453 504

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505 20. Wang C, Chan C, Wong K et al: Comparison of the effectiveness 26. Patankar S, Kaore S, Sawane M et al: Effect of clomiphene citrate 556
506 of placebo, clomiphene citrate, mesterolone, pentoxifylline, and on sperm density in male partners of infertile couples. Indian J 557
testosterone rebound therapy for the treatment of idiopathic oli- Physiol Pharmacol 2007; 51: 195.
507 gospermia. Fertil Steril 1983; 40: 358.
558
508 27. Micic S and Dotlic R: Evaluation of sperm parameters in clinical 559
509 21. Merviel P, Heraud M, Grenier N et al: Predictive factors for trial with clomiphene citrate of oligospermic men. J Urol 1985; 560
pregnancy after intrauterine insemination (IUI): an analysis of 133: 221.
510 1038 cycles and a review of the literature. Fertil Steril 2008; 93: 79.
561
511 28. Chua ME, Escusa KG, Luna S et al: Revisiting oestrogen antago- 562
512 22. Ghanem H, Shaeer O and El-Segini A: Combination clomiphene nists (clomiphene or tamoxifen) as medical empiric therapy for 563
citrate and antioxidant therapy for idiopathic male infertility: idiopathic male infertility: a meta-analysis. Andrology 2013; 1: 749.
513 a randomized controlled trial. Fertil Steril 2010; 93: 2232. 564
514 29. Hussein A, Ozgok Y, Ross C et al: Clomiphene administration for 565
23. Sutton AJ, Song F, Gilbody SM et al: Modelling publication bias cases of non-obstructive azoospermia: a multicenter study.
515 566
in meta-analysis: a review. Stat Methods Med Res 2000; 9: 421. J Androl 2005; 26: 787.
516 567
517 24. World Health Organization Task Force on the Prevention and 30. Pasqualotto F, Fonseca G and Pasqualotto E: Azoospermia after 568
Management of Infertility: A double-blind trial of clomiphene treatment with clomiphene citrate in patients with oligospermia.
518 569
citrate for the treatment of idiopathic male infertility. Int J Androl Fertil Steril 2008; 90: 11.
519 1992; 15: 299. 570
520 31. Heller C, Rowley M and Heller G: Clomiphene citrate: a corre- 571
25. Matsumiya K, Kitamura M and Kishikawa H: A prospective lation of its effect on sperm concentration and morphology, total
521 comparative trial of a gonadotropin-releasing hormone analogue gonadotropins, ICSH, estrogen and testosterone excretion, and
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522 with clomiphene citrate for the treatment of oligoasthenozoo- testicular cytology in normal men. J Clin Endocrinol Metab 1969; 573
523 spermia. Int J Urol 1998; 5: 361. 29: 638. 574
524 575
525 576
526 Editorial Commentary 577
527 578
528 CC is not a panacea for male infertility. This selective is important to understand which patients would most benet 579
529 estrogen receptor modulator has been used off label to treat from CC and how to appropriately select these individuals 580
530 male infertility for the last 5 decades with mixed success.1 It for CC therapy. Because CC increases gonadotropins 581
531 was hypothesized that CC stimulates spermatogenesis by (FSH and LH) treatment with CC would be most benecial in 582
532 inhibiting the negative feedback of estrogen on the hypo- men with gonadotropin levels that are normal or below 583
533 thalamus and pituitary, resulting in increased gonadotropin normal. Theoretically increasing FSH and LH would in- 584
534 production.2 Unfortunately there are few controlled trials of crease intratesticular testosterone, which in turn would pu- 585
535 CC for male infertility and as such the current meta-analysis tatively lead to improved spermatogenesis. CC and the newer 586
536 of 3 studies does not enable us to reach a denite conclusion isomer of CC, enclomiphene citrate, have reliably increased 587
537 on drug efcacy. In the largest study to date performed in serum testosterone.4 Whether improved serum testosterone 588
538 1992 at WHO 190 men were randomized to 25 mg CC daily levels correlate with improved spermatogenesis remains 589
539 or to placebo (reference 19 in article). At 6 months there was controversial. CC would not be benecial in men with 590
540 no change in semen parameters in men treated with CC. More increased FSH as a result of severe testicular failure. These 591
541 importantly the pregnancy rate in their partners remained men typically have azoospermia or severe oligospermia 592
542 similar to that in the partners of men who received placebo. secondary to an inherent germ cell defect and further stim- 593
543 The limitations of the studies of CC and male infertility ulation of spermatogenesis through increased gonadotropins 594
544 published to date include small sample sizes, lack of control is unlikely to yield any additional benet. Until larger, well 595
545 groups, heterogeneous patient populations and poorly controlled, randomized studies are performed CC can be 596
546 dened outcomes. A Cochrane Review evaluating the role of used selectively in men with idiopathic infertility and low or 597
547 CC in the treatment of idiopathic male infertility was with- normal gonadotropin. However, a positive outcome remains 598
548 drawn due to numerous aws in the published literature.3 speculative. 599
549 Despite the lack of strong evidence on the role of CC in 600
550 male infertility more than 90% of polled AUA members Ranjith Ramasamy, Jason M. Scovell 601
551 stated that they would use CC to treat idiopathic male and Larry I. Lipshultz 602
552 infertility (reference 10 in article). CC treatment is not Department of Urology 603
553 without adverse effects, including fatigue, weight gain, uid Baylor College of Medicine 604
554 retention, gynecomastia and venous thrombosis. Therefore, it Houston, Texas 605
555 606

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607 References 3. Vandekerckhove P, Lilford R, Vail A et al: WITHDRAWN: 615

608 Clomiphene or tamoxifen for idiopathic oligo/asthenospermia. 616
609 1. Sorbie PJ and Perez-Marrero R: The use of clomiphene citrate in Cochrane Database Syst Rev 1996; CD000151. 617
610 male infertility. J Urol 1984; 131: 425. 618
611 4. Wiehle RD, Fontenot GK, Wike J et al: Enclomiphene citrate 619
612 2. Kumar R, Gautam G and Gupta NP: Drug therapy for idiopathic stimulates testosterone production while preventing oligospermia: a 620
613 male infertility: rationale versus evidence. J Urol 2006; 176: randomized phase II clinical trial comparing topical testosterone. 621
614 1307. Fertil Steril 2014; 102: 720. 622

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