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Measures of Association—Smoking and Fecundity
FERTILITY AND STERILITY Copyright
©
In Vitro Fertilization at the Time of Diagnostic Laparoscopy-Utility?
To the Editor: Drs. Gindoff et al. (1) conclude that IVF at diagnostic laparoscopy has utility as a diagnostic test for fertilization. No evidence is given by the authors to support this conclusion. As a diagnostic test for fertilization, the literature contains only studies that conclude that one IVF has no value. In one study, 81.1 % of37 couples with unexplained infertility who failed to fertilize in vitro achieved fertilization in a second cycle (2). In another study, 81.2% of 44 male factor patients with no fertilization in vitro achieved fertilization in a next cycle, with a pregnancy rate expected only for couples with normal semen parameters. Of those male factor patients who failed to achieve fertilization in two IVF cycles, 66% achieved fertilization in a third cycle, a rate superior to that recorded by several micromanipulation programs (3). In a third study, 97.7% of 44 mechanically infertile couples with no fertilization in a first cycle achieved fertilization in a second or third cycle, with over half of those couples conceiving with IVF (4). Drs. Gindoff et al. also conclude that IVF at diagnostic laparoscopy has utility as a therapy. Again, no evidence is given, nor did I find any studies in the literature to indicate that IVF has any advantage over less costly, less invasive therapies, or even no therapy, for patients with normal hysterosalpingograms. The authors do supply evidence that IVF at diagnostic laparoscopy assists pregnancy at a rate comparable to transvaginal ultrasound (US) IVF. However, this evidence is diminished, if not invalidated, by the failure of the authors to control an important variable. Several studies have shown that a patient's chance to conceive with IVF is inversely related to her number of prior IVF failures. Patients undergoing a diagnostic laparoscopy might be expected to have had fewer failed therapies than transvaginal US IVF patients. By not controlling for prior IVF failures, the authors may have biased their results toward their conclusion. Having had IVF as a first therapy at diagnostic laparoscopy with poor fertilization and having conceived 2 months later with no treatment, I write out of concern for the welfare of other patients. In their endorsement of IVF at diagnostic laparoscopy, the 1350
Vol. 63, No.6, June 1995
1995 American Society for Reproductive Medicine
Letters-to-the-editor Letters-to-the-editor
Printed on acid-free paper in U. S. A.
only costs to the patient noted by the authors are financial. These are considerable, but overlooked are the physical burden and risks to fertility and health associated with ovarian stimulation and aspiration. Also not debited are the emotional costs. Patients have rated IVF as the most stressful of all fertility therapies. The month-long IVF protocol has been rated by patients to be as stressful as any other major life event, such as a divorce or the death of a loved one (5). Based on Dr. DeCherney's preface, I had hoped that Drs. Gindoff et al. would provide empirical support for the utility of IVF at diagnostic laparoscopy. Empirical evidence would seem to be a prerequisite to justify its risks and costs.
Janice Byer, M.L.S. Librarian, RESOLVE Washington Metropolitan Area Chapter Clifton, Virginia September 2, 1994 REFERENCES 1. Gindoff PR, Hall JL, Stillman RS. Utility of in vitro fertilization at diagnostic laparoscopy. Preface by DeCherney AH. Fertil Steril1994;62:237-41. 2. Lipitz S, Rabinovici J, Ben-Shlomo I, Bider D, Ben-Rafael Z, Mashiach S, et al. Complete failure offertilization in couples with unexplained infertility: implications for subsequent in vitro fertilization cycles. Fertil Steril 1993;59:348-52. 3. Ben-Shlomo I, Bider D, Dor J, Levran D, Mashiach S, BenRafael Z. Failure to fertilize in vitro in couples with male factor infertility: what next? Fertil SteriI1992;58:187-9. 4. Lipitz S, Rabinovici J, Goldenberg M, Bider D, Dor J, Mashiach S. Complete failure of fertilization in couples with mechanical infertility: implications for subsequent in vitro fertilization cycles. Fertil Steril 1994;61:863-5. 5. Covington SN. Preparing the patient for in vitro fertilization: psychological considerations. Clin Consult Obstet Gynecol 1994;6:131-7.
The authors elected not to respond. Paul G. McDonough, M.D., Editor, Letters Measures of Association-Smoking and Fecundity
To the Editor: We read with interest the article by Hughes et al. (1). The authors conclude that "among couples undergoing IVF neither female nor male smoking Fertility and Sterility
has a measurable deleterious effect on conception rate." We have several concerns about the study design, study population, and final interpretations that merit comment. The study design included patients who underwent lVF between March 1990 and April 1992. According to the authors, no patients declined involvement in the study. However, the mean age (:::':::SD) for never smokers was 34.3 : :': : 2.88 years, that for exsmokers was 34.3 : :': : 4.19 years, and that of active smokers was 33.5 : :': : 3.31 years. The oldest patient enrolled in that study was therefore 38.5 years, and most patients evaluated were less than 37 years of age. The reader is very interested to know why was the older population excluded or if the authors' lVF program excludes women over 39 years old? The authors also did not report any data on ovarian reserve. Were day 3 FSH and E2 done, was a clomiphene citrate (CC) challenge test performed to evaluate those women with diminished ovarian reserve? We recently published in this journal (2) a manuscript evaluating the effect of smoking on ovarian reserve. Based on animal data (3), smoking or its constituents accelerate the loss of ovarian function based on decreased hormonogenesis and gametogenesis. Our human data also suggest that smoking accelerates the development of this normal process that occurs with aging. However, this diminished ovarian reserve does not become clinically detectable until after age 35 years, and as we mentioned in our manuscript, "studies evaluating younger women will likely find no differences in stimulation quality and pregnancy rates because these women will not have had time to develop a clinically significant diminution in their ovarian reserve." We likewise analyzed our data on smokers younger than 35 years old and also found results similar to Hughes et al. (Sharara Fl, Scott RT, unpublished observations). We agree with the authors that age is a more significant prognosticator than smoking. However, the effect of smoking is to accelerate the diminution of ovarian reserve specifically in older women. Smokers should have their ovarian reserve checked (preferably by a CC challenge test) before assisted reproductive technology. As we have previously shown, smokers with adequate ovarian reserve have similar pregnancy rates (and miscarriage rates) as agematched nonsmokers (2). We hope the authors would incorporate this testing into their screening protocol and we await the results of their research with interest.
Fady 1. Sharara, M.D. Division of Reproductive Endocrinology and Immunology Vol. 63, No.6, June 1995
Department of Obstetrics and Gynecology (M / C 808) University of Illinois College of Medicine Chicago, Illinois Richard T. Scott, Jr., M.D. Division of Reproductive Endocrinology and Immunology Department of Obstetrics and Gynecology U.S. Public Health Service Bethesda, Maryland October 25, 1994 REFERENCES 1. Hughes EG, Yeo J, Claman P, YoungLai EV, Sagle MA, Daya S, et al. Cigarette smoking and the outcomes of in vitro fertilization: measurement of effect size and levels of action. Fertil Steril1994;62:807-14. 2. Sharara FI, Beatse SN, Leonardi MR, Navot D, Scott RT. Cigarette smoking accelerates the development of diminished ovarian reserve as evidenced by the clomiphene citrate challenge test. Fertil Steril1994;62:257-62. 3. Mattison DR, Plowchalk DR, Meadows MJ, Miller MM, Malek A, London S. The effect of smoking on oogenesis, fertilization, and implantation. Semin Reprod Endocrinol 1989; 7:291-304.
Reply of the Author: We are grateful to Drs. Sharara and Scott for their comments and will respond to them in the order presented. First, our IVF program female age limit was 38 years. We and others have previously demonstrated the importance of female age as a prognostic factor (1) and in providing publicly funded services, have been especially conscious of its influence on outcome. Second, we did include data relating to ovarian reserve, choosing to measure circulating immunoactive inhibin. We have previously demonstrated reduced inhibin production in women over the age of 35 years undergoing ovarian stimulation before lVF (2). Given the established links between cigarette smoking and gonadal aging (3), we felt that inhibin might be a useful marker in the assessment of one of the many levels of reproductive function at which toxins from cigarette smoke may act. The third comment that smokers "should have their ovarian reserve checked (preferably by a clomiphene citrate [CC] challenge test) before ART" is interesting. Presumably the goal here would be to reassure smokers with "normal" CC response that their prognosis is similar to nonsmokers. Given that the CC challenge test is at best an indirect test of oocyte quality and the data suggesting that cigarette Letters-to-the-editor Letters-to-the-editor
1351
smoking acts at various functional levels (3), we find the use of the CC challenge test difficult to support in this context. Furthermore, the statement that "smokers with adequate ovarian reserve have similar pregnancy rates (and miscarriage rates) as age matched non-smokers" is highly questionable, since it is founded on the results of only 29 cycles among smokers compared with 73 among nonsmokers (4). Clearly the power inherent in this sample size to support such a statement is lacking. To demonstrate a 20% difference in pregnancy rate (the clinically significant difference chosen by Sharara et al.) approximately 900 women would be required in each study arm (ex, two-tailed = 0.05, f3 = 0.20). Even if a ratio of three nonsmokers to one smoker was chosen, an evaluation of 600 smokers would be required. Because of limited power in our own study (155 cycles among smokers and 347 among nonsmokers), we included a meta-analysis of all published data (5). This suggested a significant reduction in fecundity rate among smokers, with a common odds ratio of 0.54 (95% CI 0.39 to 0.56). Although the range in validity of included studies makes their combination questionable, we remain concerned that these data probably reflect a significant reduction in IVF conception rate among smokers, even before considering their increased risk of spontaneous abortion. We therefore continue to monitor this question and counsel our patients that smoking should be stopped before treatment. Thank you again for the opportunity to respond.
Edward G. Hughes, M.B., Ch.B., F.R.C.S.C. McMaster [lniversity Chedoke-McMaster IVF Program January 23, 1995 REFERENCES 1. Hughes EG. The prognostic value of clinical factors in the
2.
3.
4.
5.
assessment of reproductive success. In: VanBlerkom J, editor. Developmental Failure in Early Human Development. Oxford University Press, 1994:29-65. Hughes EG, Robertson DM, Handelsman DJ, Hayward S, Healy DL, DeKretser DM. Inhibin and estradiol responses to ovarian hyperstimulation: effects of age and predictive value for in vitro fertilization outcome. J Clin Endocrinol Metab 1990; 70:358-64. Mattison DR, Thomford PJ. The effect of smoking on reproductive ability and reproductive lifespan. In: Rosenberg MJ, editor. Littleton, MA: PSG Publishing, Inc., 1987:47-54. Sharara FI, Beatse SN, Leonardi MR, Navot D, Scott RTJ. Cigarette smoking accelerates the development of diminished ovarian reserve as evidenced by the clomiphene citrate challenge test. Fertil Steril1994;62:257-62. Hughes EG, Yeo J, Claman P, YoungLai EV, Sagle MA, Daya S, et al. Cigarette smoking and the outcomes of in vitro fertilization: measurement of effect size and levels of action. Fertil SteriI1994;62:807-14.
1352
Letters-to-the-editor Letters-to-the-editor
Integrins! The Long Awaited Norm for Luteal Phase Evaluation-or Simply Another "Alloyed Gold Standard"?
To the Editor: I read with great interest the article by Castelbaum et al. (1) dealing with timing of endometrial biopsy for accurate diagnosis of luteal phase deficiency. Using light microscopy criteria of Noyes et al. (2), they found that midluteal biopsy detected a greater number of out-of-phase endometria than a late luteal biopsy. Moreover, they showed that the majority of midluteal out-of-phase biopsies demonstrated normal endometrial maturation at the time of the later biopsy, concluding that this phenomenon could represent a cryptic form of luteal deficiency. Women with premature ovarian failure under E and P therapy in an oocyte donation program are thought to represent a unique in vivo model that allows examination of endometrial development and receptivity. In the earlier reports of oocyte donation therapy, it was established that these women exhibit a midluteal glandular endometrial lag in the vast majority of cases and that this lag usually is caught up at the late luteal phase (3). These observations also were corroborated by other studies (4). However, this fact, did not prevent these oocyte donation programs to achieve implantation and maintain pregnancy, implying that midluteal lag did not adversely affect endometrial receptivity. It is our belief that a midluteal endometrial glandular lag does not assure a precise diagnosis ofluteal phase deficiency. It seems that the accuracy of morphological criteria to diagnose luteal phase deficiency is in question. Our efforts should be directed toward a different "gold standard" for a definitive diagnosis of this situation. The novel usage of endometrial integrins, including by this group (5), as a biochemical marker to assess uterine receptivity seems to be promising and should be encouraged.
Johnny S. Younis, M.D. Reproductive Endocrinology Clinic Department of Obstetrics and Gynecology Poriya Hospital Tiberias 15208, Israel October 26, 1994 REFERENCES 1. Castelbaum AJ, Wheeler J, Coutifaris CB, Mastroianni L Jr,
Lessey BA. Timing of the endometrial biopsy may be critical for the accurate diagnosis of luteal phase deficiency. Fertil Steri11994;61:443-7.
Fertility and Sterility
©
In Vitro Fertilization at the Time of Diagnostic Laparoscopy-Utility?
To the Editor: Drs. Gindoff et al. (1) conclude that IVF at diagnostic laparoscopy has utility as a diagnostic test for fertilization. No evidence is given by the authors to support this conclusion. As a diagnostic test for fertilization, the literature contains only studies that conclude that one IVF has no value. In one study, 81.1 % of37 couples with unexplained infertility who failed to fertilize in vitro achieved fertilization in a second cycle (2). In another study, 81.2% of 44 male factor patients with no fertilization in vitro achieved fertilization in a next cycle, with a pregnancy rate expected only for couples with normal semen parameters. Of those male factor patients who failed to achieve fertilization in two IVF cycles, 66% achieved fertilization in a third cycle, a rate superior to that recorded by several micromanipulation programs (3). In a third study, 97.7% of 44 mechanically infertile couples with no fertilization in a first cycle achieved fertilization in a second or third cycle, with over half of those couples conceiving with IVF (4). Drs. Gindoff et al. also conclude that IVF at diagnostic laparoscopy has utility as a therapy. Again, no evidence is given, nor did I find any studies in the literature to indicate that IVF has any advantage over less costly, less invasive therapies, or even no therapy, for patients with normal hysterosalpingograms. The authors do supply evidence that IVF at diagnostic laparoscopy assists pregnancy at a rate comparable to transvaginal ultrasound (US) IVF. However, this evidence is diminished, if not invalidated, by the failure of the authors to control an important variable. Several studies have shown that a patient's chance to conceive with IVF is inversely related to her number of prior IVF failures. Patients undergoing a diagnostic laparoscopy might be expected to have had fewer failed therapies than transvaginal US IVF patients. By not controlling for prior IVF failures, the authors may have biased their results toward their conclusion. Having had IVF as a first therapy at diagnostic laparoscopy with poor fertilization and having conceived 2 months later with no treatment, I write out of concern for the welfare of other patients. In their endorsement of IVF at diagnostic laparoscopy, the 1350
Vol. 63, No.6, June 1995
1995 American Society for Reproductive Medicine
Letters-to-the-editor Letters-to-the-editor
Printed on acid-free paper in U. S. A.
only costs to the patient noted by the authors are financial. These are considerable, but overlooked are the physical burden and risks to fertility and health associated with ovarian stimulation and aspiration. Also not debited are the emotional costs. Patients have rated IVF as the most stressful of all fertility therapies. The month-long IVF protocol has been rated by patients to be as stressful as any other major life event, such as a divorce or the death of a loved one (5). Based on Dr. DeCherney's preface, I had hoped that Drs. Gindoff et al. would provide empirical support for the utility of IVF at diagnostic laparoscopy. Empirical evidence would seem to be a prerequisite to justify its risks and costs.
Janice Byer, M.L.S. Librarian, RESOLVE Washington Metropolitan Area Chapter Clifton, Virginia September 2, 1994 REFERENCES 1. Gindoff PR, Hall JL, Stillman RS. Utility of in vitro fertilization at diagnostic laparoscopy. Preface by DeCherney AH. Fertil Steril1994;62:237-41. 2. Lipitz S, Rabinovici J, Ben-Shlomo I, Bider D, Ben-Rafael Z, Mashiach S, et al. Complete failure offertilization in couples with unexplained infertility: implications for subsequent in vitro fertilization cycles. Fertil Steril 1993;59:348-52. 3. Ben-Shlomo I, Bider D, Dor J, Levran D, Mashiach S, BenRafael Z. Failure to fertilize in vitro in couples with male factor infertility: what next? Fertil SteriI1992;58:187-9. 4. Lipitz S, Rabinovici J, Goldenberg M, Bider D, Dor J, Mashiach S. Complete failure of fertilization in couples with mechanical infertility: implications for subsequent in vitro fertilization cycles. Fertil Steril 1994;61:863-5. 5. Covington SN. Preparing the patient for in vitro fertilization: psychological considerations. Clin Consult Obstet Gynecol 1994;6:131-7.
The authors elected not to respond. Paul G. McDonough, M.D., Editor, Letters Measures of Association-Smoking and Fecundity
To the Editor: We read with interest the article by Hughes et al. (1). The authors conclude that "among couples undergoing IVF neither female nor male smoking Fertility and Sterility
has a measurable deleterious effect on conception rate." We have several concerns about the study design, study population, and final interpretations that merit comment. The study design included patients who underwent lVF between March 1990 and April 1992. According to the authors, no patients declined involvement in the study. However, the mean age (:::':::SD) for never smokers was 34.3 : :': : 2.88 years, that for exsmokers was 34.3 : :': : 4.19 years, and that of active smokers was 33.5 : :': : 3.31 years. The oldest patient enrolled in that study was therefore 38.5 years, and most patients evaluated were less than 37 years of age. The reader is very interested to know why was the older population excluded or if the authors' lVF program excludes women over 39 years old? The authors also did not report any data on ovarian reserve. Were day 3 FSH and E2 done, was a clomiphene citrate (CC) challenge test performed to evaluate those women with diminished ovarian reserve? We recently published in this journal (2) a manuscript evaluating the effect of smoking on ovarian reserve. Based on animal data (3), smoking or its constituents accelerate the loss of ovarian function based on decreased hormonogenesis and gametogenesis. Our human data also suggest that smoking accelerates the development of this normal process that occurs with aging. However, this diminished ovarian reserve does not become clinically detectable until after age 35 years, and as we mentioned in our manuscript, "studies evaluating younger women will likely find no differences in stimulation quality and pregnancy rates because these women will not have had time to develop a clinically significant diminution in their ovarian reserve." We likewise analyzed our data on smokers younger than 35 years old and also found results similar to Hughes et al. (Sharara Fl, Scott RT, unpublished observations). We agree with the authors that age is a more significant prognosticator than smoking. However, the effect of smoking is to accelerate the diminution of ovarian reserve specifically in older women. Smokers should have their ovarian reserve checked (preferably by a CC challenge test) before assisted reproductive technology. As we have previously shown, smokers with adequate ovarian reserve have similar pregnancy rates (and miscarriage rates) as agematched nonsmokers (2). We hope the authors would incorporate this testing into their screening protocol and we await the results of their research with interest.
Fady 1. Sharara, M.D. Division of Reproductive Endocrinology and Immunology Vol. 63, No.6, June 1995
Department of Obstetrics and Gynecology (M / C 808) University of Illinois College of Medicine Chicago, Illinois Richard T. Scott, Jr., M.D. Division of Reproductive Endocrinology and Immunology Department of Obstetrics and Gynecology U.S. Public Health Service Bethesda, Maryland October 25, 1994 REFERENCES 1. Hughes EG, Yeo J, Claman P, YoungLai EV, Sagle MA, Daya S, et al. Cigarette smoking and the outcomes of in vitro fertilization: measurement of effect size and levels of action. Fertil Steril1994;62:807-14. 2. Sharara FI, Beatse SN, Leonardi MR, Navot D, Scott RT. Cigarette smoking accelerates the development of diminished ovarian reserve as evidenced by the clomiphene citrate challenge test. Fertil Steril1994;62:257-62. 3. Mattison DR, Plowchalk DR, Meadows MJ, Miller MM, Malek A, London S. The effect of smoking on oogenesis, fertilization, and implantation. Semin Reprod Endocrinol 1989; 7:291-304.
Reply of the Author: We are grateful to Drs. Sharara and Scott for their comments and will respond to them in the order presented. First, our IVF program female age limit was 38 years. We and others have previously demonstrated the importance of female age as a prognostic factor (1) and in providing publicly funded services, have been especially conscious of its influence on outcome. Second, we did include data relating to ovarian reserve, choosing to measure circulating immunoactive inhibin. We have previously demonstrated reduced inhibin production in women over the age of 35 years undergoing ovarian stimulation before lVF (2). Given the established links between cigarette smoking and gonadal aging (3), we felt that inhibin might be a useful marker in the assessment of one of the many levels of reproductive function at which toxins from cigarette smoke may act. The third comment that smokers "should have their ovarian reserve checked (preferably by a clomiphene citrate [CC] challenge test) before ART" is interesting. Presumably the goal here would be to reassure smokers with "normal" CC response that their prognosis is similar to nonsmokers. Given that the CC challenge test is at best an indirect test of oocyte quality and the data suggesting that cigarette Letters-to-the-editor Letters-to-the-editor
1351
smoking acts at various functional levels (3), we find the use of the CC challenge test difficult to support in this context. Furthermore, the statement that "smokers with adequate ovarian reserve have similar pregnancy rates (and miscarriage rates) as age matched non-smokers" is highly questionable, since it is founded on the results of only 29 cycles among smokers compared with 73 among nonsmokers (4). Clearly the power inherent in this sample size to support such a statement is lacking. To demonstrate a 20% difference in pregnancy rate (the clinically significant difference chosen by Sharara et al.) approximately 900 women would be required in each study arm (ex, two-tailed = 0.05, f3 = 0.20). Even if a ratio of three nonsmokers to one smoker was chosen, an evaluation of 600 smokers would be required. Because of limited power in our own study (155 cycles among smokers and 347 among nonsmokers), we included a meta-analysis of all published data (5). This suggested a significant reduction in fecundity rate among smokers, with a common odds ratio of 0.54 (95% CI 0.39 to 0.56). Although the range in validity of included studies makes their combination questionable, we remain concerned that these data probably reflect a significant reduction in IVF conception rate among smokers, even before considering their increased risk of spontaneous abortion. We therefore continue to monitor this question and counsel our patients that smoking should be stopped before treatment. Thank you again for the opportunity to respond.
Edward G. Hughes, M.B., Ch.B., F.R.C.S.C. McMaster [lniversity Chedoke-McMaster IVF Program January 23, 1995 REFERENCES 1. Hughes EG. The prognostic value of clinical factors in the
2.
3.
4.
5.
assessment of reproductive success. In: VanBlerkom J, editor. Developmental Failure in Early Human Development. Oxford University Press, 1994:29-65. Hughes EG, Robertson DM, Handelsman DJ, Hayward S, Healy DL, DeKretser DM. Inhibin and estradiol responses to ovarian hyperstimulation: effects of age and predictive value for in vitro fertilization outcome. J Clin Endocrinol Metab 1990; 70:358-64. Mattison DR, Thomford PJ. The effect of smoking on reproductive ability and reproductive lifespan. In: Rosenberg MJ, editor. Littleton, MA: PSG Publishing, Inc., 1987:47-54. Sharara FI, Beatse SN, Leonardi MR, Navot D, Scott RTJ. Cigarette smoking accelerates the development of diminished ovarian reserve as evidenced by the clomiphene citrate challenge test. Fertil Steril1994;62:257-62. Hughes EG, Yeo J, Claman P, YoungLai EV, Sagle MA, Daya S, et al. Cigarette smoking and the outcomes of in vitro fertilization: measurement of effect size and levels of action. Fertil SteriI1994;62:807-14.
1352
Letters-to-the-editor Letters-to-the-editor
Integrins! The Long Awaited Norm for Luteal Phase Evaluation-or Simply Another "Alloyed Gold Standard"?
To the Editor: I read with great interest the article by Castelbaum et al. (1) dealing with timing of endometrial biopsy for accurate diagnosis of luteal phase deficiency. Using light microscopy criteria of Noyes et al. (2), they found that midluteal biopsy detected a greater number of out-of-phase endometria than a late luteal biopsy. Moreover, they showed that the majority of midluteal out-of-phase biopsies demonstrated normal endometrial maturation at the time of the later biopsy, concluding that this phenomenon could represent a cryptic form of luteal deficiency. Women with premature ovarian failure under E and P therapy in an oocyte donation program are thought to represent a unique in vivo model that allows examination of endometrial development and receptivity. In the earlier reports of oocyte donation therapy, it was established that these women exhibit a midluteal glandular endometrial lag in the vast majority of cases and that this lag usually is caught up at the late luteal phase (3). These observations also were corroborated by other studies (4). However, this fact, did not prevent these oocyte donation programs to achieve implantation and maintain pregnancy, implying that midluteal lag did not adversely affect endometrial receptivity. It is our belief that a midluteal endometrial glandular lag does not assure a precise diagnosis ofluteal phase deficiency. It seems that the accuracy of morphological criteria to diagnose luteal phase deficiency is in question. Our efforts should be directed toward a different "gold standard" for a definitive diagnosis of this situation. The novel usage of endometrial integrins, including by this group (5), as a biochemical marker to assess uterine receptivity seems to be promising and should be encouraged.
Johnny S. Younis, M.D. Reproductive Endocrinology Clinic Department of Obstetrics and Gynecology Poriya Hospital Tiberias 15208, Israel October 26, 1994 REFERENCES 1. Castelbaum AJ, Wheeler J, Coutifaris CB, Mastroianni L Jr,
Lessey BA. Timing of the endometrial biopsy may be critical for the accurate diagnosis of luteal phase deficiency. Fertil Steri11994;61:443-7.
Fertility and Sterility