The
n e w e ng l a n d j o u r na l
of
m e dic i n e
c or r e sp ondence
Letrozole or Clomiphene for Infertility in the Polycystic Ovary Syndrome To the Editor: In the article by Legro et al. (July 10 issue),1 further clarification is needed regarding the eligibility criteria of male partners of patients with the polycystic ovary syndrome. In a separate article by the authors2 (cited as reference 8 in their article), eligibility included a sperm concentration of 14 million per milliliter in at least one ejaculate within the past year, with at least some motile sperm, yet the present article in the Journal states that the criterion was documented motility according to World Health Organization (WHO) cutoff points. The WHO criteria, which are outlined by Cooper et al.3 (cited as reference 11 in the article), list the lower limit of progressive motility as 28% (2.5th percentile) in a population of men who are presumed to be fertile. Given the potential effect of different levels of sperm motility on the likelihood of conception, the methods used to control for this factor need to be presented in further detail. Richard Bronson, M.D. Stony Brook University Medical Center Stony Brook, NY [email protected] No potential conflict of interest relevant to this letter was reported. 1. Legro RS, Brzyski RG, Diamond MP, et al. Letrozole versus
clomiphene for infertility in the polycystic ovary syndrome. N Engl J Med 2014;371:119-29. 2. Legro RS, Kunselman AR, Brzyski RG, et al. The Pregnancy in Polycystic Ovary Syndrome II (PPCOS II) trial: rationale and design of a double-blind randomized trial of clomiphene citrate
this week’s letters 1462 Letrozole or Clomiphene for Infertility in the Polycystic Ovary Syndrome 1464 Additional Events in the RE-LY Trial
1462
and letrozole for the treatment of infertility in women with polycystic ovary syndrome. Contemp Clin Trials 2012;33:470-81. 3. Cooper TG, Noonan E, von Eckardstein S, et al. World Health Organization reference values for human semen characteristics. Hum Reprod Update 2010;16:231-45. DOI: 10.1056/NEJMc1409550
To the Editor: Legro et al. report that treatment with letrozole was superior to treatment with clomiphene in terms of higher live-birth and ovulation rates among infertile women with the polycystic ovary syndrome. We wonder whether serum prolactin levels were evaluated at baseline and throughout the study. The polycystic ovary syndrome and hyperprolactinemia are both common causes of infertility in women. Up to 64% of women with mild hyperprolactinemia fulfill the modified Rotterdam diagnostic criteria for the polycystic ovary syndrome.1 Therefore, we believe that it is mandatory to measure serum prolactin levels when assessing the cause of infertility, even if the patient has the polycystic ovary syndrome. Furthermore, it is important to elucidate the cause of hyperprolactinemia and to assess the need for treatment with dopamine agonists.2 In addition, there is some evidence that letrozole regulates the expression of pituitary prolactin and luteinizing hormone and affects serum prolactin levels.3 Serum prolactin positively correlates with insulin resistance, which has an important role in the pathogenesis of the polycystic ovary syndrome. Hence, the superiority of letrozole over clomiphene in the current study might be explained by the effect of letrozole on serum prolactin levels. Ivan Kruljac, M.D. Dražan Butorac, M.D. Milan Vrkljan, M.D., Ph.D. University of Zagreb Zagreb, Croatia [email protected]
n engl j med 371;15 nejm.org october 9, 2014
The New England Journal of Medicine Downloaded from nejm.org on August 10, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
correspondence No potential conflict of interest relevant to this letter was reported.
14
1. Bahceci M, Tuzcu A, Bahceci S, Tuzcu S. Is hyperprolactine
The Authors Reply: Bronson points out the disparity between our published descriptions of the entry criteria regarding semen analysis. In our protocol, available with the full text of the article at NEJM.org, and in the original published protocol summary,1 the correct criteria are a sperm concentration of 14 million per milliliter in at least one ejaculate within the past year, with at least some motile sperm. We apologize for this miscommunication. However, we disagree that sperm motility is an important predictive factor for pregnancy outcome. We addressed this issue in a previous study of semen qualities in fertile and infertile men (performed under a standardized semen-analysis protocol), in which we found that none of the individual semen qualities (concentration, motility, or morphologic variables) alone or in combination was a powerful discriminator of fertility.2 There is a well-documented large within-person variation in sperm properties in both fertile and infertile men over time. One study showed that sperm motility can vary by up to a factor of 4 in an individual man over time.3 In our study, couples had regular intercourse without inseminations, so it is unlikely that the semen properties that were observed in the baseline sample were highly correlated with those present during intercourse. We have completed the analysis of a large, multicenter study involving couples with unexplained infertility in which the female patients underwent a single intrauterine insemination per cycle after ovulation triggering.4 In that study, we prospectively evaluated all key semen properties in each sample, and we believe that these data are more suited to answering Bron son’s inquiry about the contribution of sperm motility to conception. Kruljac et al. inquire about the role of mild prolactin excess in the outcomes of our study. As noted in our article, prolactin excess was an ex-
10 8 6 4 2 0
Al l O vu la tio N n o O vu Co la nt tio ra n ce N pt o iv Co e nt Us ra e ce pt Cl iv e in Us ica e N lly ot P re Cl gn in ica an t lly Pr eg na nt Li ve Bi rth N o Li ve Bi rth
DOI: 10.1056/NEJMc1409550
Letrozole
12
Prolactin Value (ng/ml)
mia associated with insulin resistance in non-obese patients with polycystic ovary syndrome? J Endocrinol Invest 2003;26:655-9. 2. Filho RB, Domingues L, Naves L, Ferraz E, Alves A, Casulari LA. Polycystic ovary syndrome and hyperprolactinemia are distinct entities. Gynecol Endocrinol 2007;23:267-72. 3. Pepe GJ, Lynch TJ, Davies WA, Albrecht ED. Regulation of baboon fetal pituitary prolactin expression by estrogen. Biol Reprod 2009;80:1189-95.
Clomiphene
Figure 1. Screening Serum Prolactin Levels, According to Treatment Group and Outcome. The data shown are means, and the I bars indicate standard errors.
clusion criterion in the study. We did not follow prolactin levels during the study, so we cannot specifically address the question of the effect of letrozole on prolactin levels. However, we found that the mean prolactin levels at screening (as determined in the local study-site laboratories) were well within normal limits, with no difference between the treatment groups, regardless of the pregnancy outcomes, including ovulation, pregnancy, and live birth (Fig. 1) (P>0.35 for all comparisons). Richard S. Legro, M.D. Penn State College of Medicine Hershey, PA [email protected]
Heping Zhang, Ph.D. Yale University School of Public Health New Haven, CT
for the Eunice Kennedy Shriver NICHD Reproductive Medicine Network Since publication of their article, the authors report no further potential conflict of interest. 1. Legro RS, Kunselman AR, Brzyski RG, et al. The Pregnancy
in Polycystic Ovary Syndrome II (PPCOS II) trial: rationale and design of a double-blind randomized trial of clomiphene citrate and letrozole for the treatment of infertility in women with polycystic ovary syndrome. Contemp Clin Trials 2012;33:470-81. 2. Guzick DS, Overstreet JW, Factor-Litvak P, et al. Sperm morphology, motility, and concentration in fertile and infertile men. N Engl J Med 2001;345:1388-93.
n engl j med 371;15 nejm.org october 9, 2014
The New England Journal of Medicine Downloaded from nejm.org on August 10, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
1463
The
n e w e ng l a n d j o u r na l
3. Keel BA. Within- and between-subject variation in semen
parameters in infertile men and normal semen donors. Fertil Steril 2006;85:128-34. 4. Diamond MP. Outcomes of the NICHD’s comparative effectiveness Assessment of Multiple Intrauterine Gestations from
of
m e dic i n e
Ovarian Stimulation (AMIGOS) Trial: the NICHD Cooperative Reproductive Medicine Network. Fertil Steril 2014;102:Suppl:e39. abstract. DOI: 10.1056/NEJMc1409550
Additional Events in the RE-LY Trial To the Editor: Boehringer Ingelheim recently conducted a targeted review of the 1387 deaths that occurred during the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial,1 which evaluated the effects of two doses of dabigatran, as compared with warfarin, on rates of stroke or systemic embolism and major bleeding. Also included in this review were the deaths of 6 patients who did not undergo randomization and 10 deaths that occurred after the end of the study. This review was conducted to determine whether a concurrent event may have occurred with respect to each death, even though such an event was not originally reported. In addition, all fatal bleeding episodes, hemorrhagic strokes, and hospitalizations for trauma were similarly
reviewed. In total, more than 1500 cases were reevaluated. The review of these cases, which was performed by 27 medically trained reviewers and additional staff members at Boehringer Ingelheim, resulted in the identification of 34 deaths in which the reviewers thought that another event might have occurred in association with the death but had not been separately reported. In addition, 7 possible cases were identified by plaintiffs’ attorneys in a lawsuit related to dabigatran. These cases were then reviewed by the two former cochairs of the RE-LY adjudication committee. After review and discussion, they concluded that there were 20 cases in which another unreported event had occurred in addition
Table 1. Comparison of Results before and after a Review of Deaths in the RE-LY Trial. Variable
Dabigatran, 110 mg Dabigatran, 150 mg (N = 6015) (N = 6076)
no. of rate/100 patients person-yr
Warfarin (N = 6022)
no. of patients
rate/100 person-yr
no. of patients
rate/100 person-yr
Dabigatran, 110 mg, vs. Warfarin
Dabigatran, 150 mg, vs. Warfarin
Relative Risk (95% CI)
P Value
Relative Risk (95% CI)
P Value
Results before review Stroke or systemic embolism
183
1.54
134
1.11
202
1.71
0.90 (0.74–1.10)
0.29
0.65 (0.52–0.81)
n e w e ng l a n d j o u r na l
of
m e dic i n e
c or r e sp ondence
Letrozole or Clomiphene for Infertility in the Polycystic Ovary Syndrome To the Editor: In the article by Legro et al. (July 10 issue),1 further clarification is needed regarding the eligibility criteria of male partners of patients with the polycystic ovary syndrome. In a separate article by the authors2 (cited as reference 8 in their article), eligibility included a sperm concentration of 14 million per milliliter in at least one ejaculate within the past year, with at least some motile sperm, yet the present article in the Journal states that the criterion was documented motility according to World Health Organization (WHO) cutoff points. The WHO criteria, which are outlined by Cooper et al.3 (cited as reference 11 in the article), list the lower limit of progressive motility as 28% (2.5th percentile) in a population of men who are presumed to be fertile. Given the potential effect of different levels of sperm motility on the likelihood of conception, the methods used to control for this factor need to be presented in further detail. Richard Bronson, M.D. Stony Brook University Medical Center Stony Brook, NY [email protected] No potential conflict of interest relevant to this letter was reported. 1. Legro RS, Brzyski RG, Diamond MP, et al. Letrozole versus
clomiphene for infertility in the polycystic ovary syndrome. N Engl J Med 2014;371:119-29. 2. Legro RS, Kunselman AR, Brzyski RG, et al. The Pregnancy in Polycystic Ovary Syndrome II (PPCOS II) trial: rationale and design of a double-blind randomized trial of clomiphene citrate
this week’s letters 1462 Letrozole or Clomiphene for Infertility in the Polycystic Ovary Syndrome 1464 Additional Events in the RE-LY Trial
1462
and letrozole for the treatment of infertility in women with polycystic ovary syndrome. Contemp Clin Trials 2012;33:470-81. 3. Cooper TG, Noonan E, von Eckardstein S, et al. World Health Organization reference values for human semen characteristics. Hum Reprod Update 2010;16:231-45. DOI: 10.1056/NEJMc1409550
To the Editor: Legro et al. report that treatment with letrozole was superior to treatment with clomiphene in terms of higher live-birth and ovulation rates among infertile women with the polycystic ovary syndrome. We wonder whether serum prolactin levels were evaluated at baseline and throughout the study. The polycystic ovary syndrome and hyperprolactinemia are both common causes of infertility in women. Up to 64% of women with mild hyperprolactinemia fulfill the modified Rotterdam diagnostic criteria for the polycystic ovary syndrome.1 Therefore, we believe that it is mandatory to measure serum prolactin levels when assessing the cause of infertility, even if the patient has the polycystic ovary syndrome. Furthermore, it is important to elucidate the cause of hyperprolactinemia and to assess the need for treatment with dopamine agonists.2 In addition, there is some evidence that letrozole regulates the expression of pituitary prolactin and luteinizing hormone and affects serum prolactin levels.3 Serum prolactin positively correlates with insulin resistance, which has an important role in the pathogenesis of the polycystic ovary syndrome. Hence, the superiority of letrozole over clomiphene in the current study might be explained by the effect of letrozole on serum prolactin levels. Ivan Kruljac, M.D. Dražan Butorac, M.D. Milan Vrkljan, M.D., Ph.D. University of Zagreb Zagreb, Croatia [email protected]
n engl j med 371;15 nejm.org october 9, 2014
The New England Journal of Medicine Downloaded from nejm.org on August 10, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
correspondence No potential conflict of interest relevant to this letter was reported.
14
1. Bahceci M, Tuzcu A, Bahceci S, Tuzcu S. Is hyperprolactine
The Authors Reply: Bronson points out the disparity between our published descriptions of the entry criteria regarding semen analysis. In our protocol, available with the full text of the article at NEJM.org, and in the original published protocol summary,1 the correct criteria are a sperm concentration of 14 million per milliliter in at least one ejaculate within the past year, with at least some motile sperm. We apologize for this miscommunication. However, we disagree that sperm motility is an important predictive factor for pregnancy outcome. We addressed this issue in a previous study of semen qualities in fertile and infertile men (performed under a standardized semen-analysis protocol), in which we found that none of the individual semen qualities (concentration, motility, or morphologic variables) alone or in combination was a powerful discriminator of fertility.2 There is a well-documented large within-person variation in sperm properties in both fertile and infertile men over time. One study showed that sperm motility can vary by up to a factor of 4 in an individual man over time.3 In our study, couples had regular intercourse without inseminations, so it is unlikely that the semen properties that were observed in the baseline sample were highly correlated with those present during intercourse. We have completed the analysis of a large, multicenter study involving couples with unexplained infertility in which the female patients underwent a single intrauterine insemination per cycle after ovulation triggering.4 In that study, we prospectively evaluated all key semen properties in each sample, and we believe that these data are more suited to answering Bron son’s inquiry about the contribution of sperm motility to conception. Kruljac et al. inquire about the role of mild prolactin excess in the outcomes of our study. As noted in our article, prolactin excess was an ex-
10 8 6 4 2 0
Al l O vu la tio N n o O vu Co la nt tio ra n ce N pt o iv Co e nt Us ra e ce pt Cl iv e in Us ica e N lly ot P re Cl gn in ica an t lly Pr eg na nt Li ve Bi rth N o Li ve Bi rth
DOI: 10.1056/NEJMc1409550
Letrozole
12
Prolactin Value (ng/ml)
mia associated with insulin resistance in non-obese patients with polycystic ovary syndrome? J Endocrinol Invest 2003;26:655-9. 2. Filho RB, Domingues L, Naves L, Ferraz E, Alves A, Casulari LA. Polycystic ovary syndrome and hyperprolactinemia are distinct entities. Gynecol Endocrinol 2007;23:267-72. 3. Pepe GJ, Lynch TJ, Davies WA, Albrecht ED. Regulation of baboon fetal pituitary prolactin expression by estrogen. Biol Reprod 2009;80:1189-95.
Clomiphene
Figure 1. Screening Serum Prolactin Levels, According to Treatment Group and Outcome. The data shown are means, and the I bars indicate standard errors.
clusion criterion in the study. We did not follow prolactin levels during the study, so we cannot specifically address the question of the effect of letrozole on prolactin levels. However, we found that the mean prolactin levels at screening (as determined in the local study-site laboratories) were well within normal limits, with no difference between the treatment groups, regardless of the pregnancy outcomes, including ovulation, pregnancy, and live birth (Fig. 1) (P>0.35 for all comparisons). Richard S. Legro, M.D. Penn State College of Medicine Hershey, PA [email protected]
Heping Zhang, Ph.D. Yale University School of Public Health New Haven, CT
for the Eunice Kennedy Shriver NICHD Reproductive Medicine Network Since publication of their article, the authors report no further potential conflict of interest. 1. Legro RS, Kunselman AR, Brzyski RG, et al. The Pregnancy
in Polycystic Ovary Syndrome II (PPCOS II) trial: rationale and design of a double-blind randomized trial of clomiphene citrate and letrozole for the treatment of infertility in women with polycystic ovary syndrome. Contemp Clin Trials 2012;33:470-81. 2. Guzick DS, Overstreet JW, Factor-Litvak P, et al. Sperm morphology, motility, and concentration in fertile and infertile men. N Engl J Med 2001;345:1388-93.
n engl j med 371;15 nejm.org october 9, 2014
The New England Journal of Medicine Downloaded from nejm.org on August 10, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
1463
The
n e w e ng l a n d j o u r na l
3. Keel BA. Within- and between-subject variation in semen
parameters in infertile men and normal semen donors. Fertil Steril 2006;85:128-34. 4. Diamond MP. Outcomes of the NICHD’s comparative effectiveness Assessment of Multiple Intrauterine Gestations from
of
m e dic i n e
Ovarian Stimulation (AMIGOS) Trial: the NICHD Cooperative Reproductive Medicine Network. Fertil Steril 2014;102:Suppl:e39. abstract. DOI: 10.1056/NEJMc1409550
Additional Events in the RE-LY Trial To the Editor: Boehringer Ingelheim recently conducted a targeted review of the 1387 deaths that occurred during the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial,1 which evaluated the effects of two doses of dabigatran, as compared with warfarin, on rates of stroke or systemic embolism and major bleeding. Also included in this review were the deaths of 6 patients who did not undergo randomization and 10 deaths that occurred after the end of the study. This review was conducted to determine whether a concurrent event may have occurred with respect to each death, even though such an event was not originally reported. In addition, all fatal bleeding episodes, hemorrhagic strokes, and hospitalizations for trauma were similarly
reviewed. In total, more than 1500 cases were reevaluated. The review of these cases, which was performed by 27 medically trained reviewers and additional staff members at Boehringer Ingelheim, resulted in the identification of 34 deaths in which the reviewers thought that another event might have occurred in association with the death but had not been separately reported. In addition, 7 possible cases were identified by plaintiffs’ attorneys in a lawsuit related to dabigatran. These cases were then reviewed by the two former cochairs of the RE-LY adjudication committee. After review and discussion, they concluded that there were 20 cases in which another unreported event had occurred in addition
Table 1. Comparison of Results before and after a Review of Deaths in the RE-LY Trial. Variable
Dabigatran, 110 mg Dabigatran, 150 mg (N = 6015) (N = 6076)
no. of rate/100 patients person-yr
Warfarin (N = 6022)
no. of patients
rate/100 person-yr
no. of patients
rate/100 person-yr
Dabigatran, 110 mg, vs. Warfarin
Dabigatran, 150 mg, vs. Warfarin
Relative Risk (95% CI)
P Value
Relative Risk (95% CI)
P Value
Results before review Stroke or systemic embolism
183
1.54
134
1.11
202
1.71
0.90 (0.74–1.10)
0.29
0.65 (0.52–0.81)
