242
Correspondence
Obesity and estrogen To the Editors: To conserve or not to conserve the ovary in perimenopausal women? After an article like the recent one by Drs. Ranney and Abu-Ghazaleh entitled “The future function and fortune of ovarian tissue which is retained in vivo during hysterectomy” (AM. J. OBSTET. GYNECOL., 128: 626, 1977), the old controversy is stirred up. Once the pros and cons are put on the scale, it is usually easy to decide on a patient-to-patient basis, and most of the time this decision can be made only during operation, A well-prepared patient understands this. The difficulty arises when the pros and cons are evened out. If such a situation occurs, I look at the patient; if she is obese I remove the ovaries, and if she is slim I preserve them. My well-respected senior ex-partner called to my attention a long time ago that obese patients tolerate menopause better than slim ones. Now, a decade later, it has become recognized that peripheral conversion of androgens to estrogens is a significant source of estrogen in the postmenopausal woman. This conversion was recently demonstrated by Nimrod and Ryan’ in an in vitro study. My associate and I* reviewed the charts of 100 postmenopausal women who were not ingesting estrogen and had been admitted to our hospital because of fracture of the femoral neck. In comparing their weights with those of 100 comparable patients, it was found that the hip fracture group’s average weight was lower than that of the nonfracture group. It seems that the obese patients are better protected against hip fracture not only by their padding per se but also by the endogenous estrogen which is produced by their padding. If fat cells are truly capable of converting androgens to estrogen, it may be that, in view of the recent controversy about estrogen treatment of the climacteric, this observation can be used as a justification for the selective prescribing of estrogen to the slim rather than to the obese patient. Janos Balog, M.D. 2480 Mission Street, No. 215 San Francisco, California 94110 REFERENCES
1. Nimrod, A., and Ryan, K. J.: Aromatization of androgens by human abdominal and breast fat tissue, J. Clin. Endocrinol. Metab. 40: 367, 1975. 2. Balog, J., and Langhauser, C.: Unpublished data.
What Is the new advance in clinicel laboratory testing for pregnancy? To the Editors: In their article entitled “A capillary tube pregnancy test,” Lau, Linkins, and King (THIS JOURNAL 127: 394, 1977) have introduced a modification of latex agglutination which the authors state has a sensitivity of 0.5 U.
January 15, 1978 Am. J. Obstet. Gynecol.
of human chorionic gonadotropin (hCG) per milliliter. The authors have, however, not demonstrated any dose-response with known hCG to indicate the sensitivity. Furthermore, their methods for evaluation have numerous pitfalls. Over 90 per cent of the abortions tabulated are over 6 weeks of pregnancy so that they are of little practical use in demonstrating the value of a sensitive test. The four false negatives in 1,413 abortions are low, but again there were relatively, few pregnancies before 6 weeks, so that a distorted picture of the test’s accuracy at 99+ is presented. As the specimens are taken closer to ovulation, the false negatives in determination at the present time will rise, so that at 4 days all will be in this negative category.Eighteen cases were positive with the capillary tube test at 3, 4 and 5 weeks after menstruation. From our standard normal pregnancy curve with radioreceptorassay (RRA) the earliest positive at 3 weeks was most likely a delayed luteinizing hormone (LH) peak. At 0.5 U. per milliliter of hCG the earliest detection of pregnancy would be on day 26 of the cycle so that the 4 to 5 week specimen with a capillary tube method may rarely provide a positive test. At 3 weeks past the menses with hCG levels of under 0.6 I.U. per milliliter in the presence of early pregnancy, the endometrium may not show any signs of pregnancy, demonstrating only secretory or proliferative endometrium. The authors have not listed the patients who initially had a negative capillary tube test and returned 1 week or 2 later and found the test to be positive. There is a discussion of one case of missed abortion in which all agglutination tests were negative. Our experience with RRA has demonstrated that many of these early missed abortions are low positive assays, which are missed with less sensitive testing. Four ectopic pregnancies are detected, but with the sensitivity of this capillary test only 60 per cent will be detected. In this article there is no reference to or discussion about RRA’ or radioimmunoassay (RIA)’ to the beta subunit for pregnancy determination, which provides the earliest diagnosis of pregnancy-which this capillary agglutination tube test does not perform. At the first day of the first missed menses, the RRA or RIA is virtually 100 per cent accurate. The RIA for hCG using the antiserum to the beta subunit is equally sensitive to the RRA but requires from 24 to 72 hours of incubation. The quantitative RRA will pick up all ectopic pregnancies3 and many missed abortions4 which are clinically unrecognizable. The RRA provides the laboratory backup to prevent menstrual extraction or abortion without pregnancy.j The RRA is now clinically available (Biocept-G, which is set to measure pregnancy above 0.2 I.U. of hCG per milliliter). The test may be performed in less than an hour in any laboratory which is processing RIA’s. The test is highly sensitive and biospecific for the hCG molecule. At low levels there is some affinity to LH. However, LH has one-third the binding affinity of
Correspondence
hCG, which reduces the cross-reactivity, and further during pregnancy the secretion of LH is suppressed. The control nonpregnant sample containing basal levels of LH allows the measurement of hCG with virtually no interference with LH. This has been documented clinically in more than 5,000 women. It is of interest that RRA estimates higher values than RIA’s. In our impression the RRA is measuring only the full molecule whereas the immunologic tests measure variable immunoreactive material. Robert Landesman, M.D. Thr New York Hospital Ntw York, New York 1002 1 REFERENCES
Landesman, R., and Saxena, B. B.: Results of the first 1000 radioreceptorassays for the determination of human chorionic gonadotropin: A new, rapid and reliable pregnancy test, Fertil. Steril. 27: 357, 1976. Vaitukaitis, J. L., Braunstein, G. D., and Ross, G. T.: A radioimmunoassay which specifically measures human chorionic gonadotropin in the presence of human luteinizing hormone, AM. J. OBSTET. GYNECOL. 113: 751, 1972. Saxena, B. B., and Landesman, R.: The use of radioreceptorassay of choronic gonadotropin for the diagnosis of early abortion, Fertil. Steril. 46: 1105, 1975. Landesman, R., and Saxena, B. B.: Radioreceptorassay of human chorionic gonadotropin as an aid in miniabortion, Fertil. Steril. 25: 1022, 1974.
Reply to Dr. Landesman To the Editors: We welcome the above letter as an opportunity to present data which was deleted for the sake of conciseness in the original article. What’s new? The capillary tube pregnancy test was originally designed for population studies in developing countries, but it is also useful in developed countries because of its simplicity. Its main advantages are that it requires no refrigeration, which makes it suitable for remote areas, an,d that its compact size permits easy storage and transportation (500 tests easily fit into a shirt pocket). By contrast, the RRA requires refrigeration, a gamma counter, and a rather civilized laboratory facility. The reagents were titrated to give a test with a sensitivity of 0.5 I.U. per milliliter and this sensitivity was confirmed by dose-response experiments using different standards of hCG-the II International Standard and the U.S.P. hCG standard. The method of evaluation was a comparison of all test results against clinical and pathologic results. In Fig. 3 of our article, the abscissa should have been labeled “duration from the LMP (last menstrual period).” Of cases which had a positive half-unit test and which later were confirmed clinically and pathologically, four were 3 weeks from the LMP, three were 4 weeks from the LMP, and 11 were 5 weeks from the LMP. In another study using a half-unit test, 11 cases
243
had positive tests prior to the missed period and 21 cases had positive tests at or around the missed period. The conversion of negative to positive tests results in patients with timed coitus or artificial insemination will be reported later in detail. We have experienced no difficulty with missed abortions or ectopic pregnancies. In the case of the missed abortion described, the capillary test was performed relatively late (14 weeks from the LMP), which was approximately 4 weeks following fetal death, and the pathologic study showed ghost villi. suggesting a termination of hCG production, and correlated with the negative results found in all tests. Positive half-unit tests have been found with missed abortions which later gave negative test results. The disappearance of hCG following termination of pregnancy will be reported later in greater detail. Of the five ectopic pregnancies, all had positive half-unit capillary tests. Four presented with positive test results following termination procedures and were associated with histopathology reports of “decidua only-no villi”. Thus, 100 per cent of ectopic pregnancies, as far as we know, were detected by a sensitivity of 0.5 I.U. per milliliter in the capillary tests. We are unaware of how Dr. Landesman derives a presumed figure of 60 per cent. Granted, there is a place for RRA’s and RIA’s, but at sites having sources of electricity for refrigeration and a gamma counter. These procedures could not be simply performed in base camps at remote areas. Even in developed countries, the degree of sophistication entailed in a RRA or RIA requires heavy equipment and reagents used in stages. By contrast, the simple capillary test is a self-contained microtube which requires only dipping into urine and tilting to develop an end point. Each type of test has its place. The data on any test have more meaning if the test is compared with the clinical or histopathologic “truth” rather than with another test. This is because an interfering or peculiar substance in a urine may produce the same incorrect result in both tests. Throughout our series, we have compared the capillary test and other tests with clinical or histopathological results. This has not always been done for the RRA or the RIA. H. Lorrin La74 M.D., M.P.H. Department of Gynecology and Obstetric\ The John Hopkins University 601 North Broadway Baltimore, Maqland 21205
incompetent cervbl
OS
To the Editors: A young woman who had only recently experienced her second midtrimester spontaneous abortion was referred to me for psychiatric treatment of depression. There were indications of difficulty before these gynecologic problems, but undoubtedlv her inability to
Correspondence
Obesity and estrogen To the Editors: To conserve or not to conserve the ovary in perimenopausal women? After an article like the recent one by Drs. Ranney and Abu-Ghazaleh entitled “The future function and fortune of ovarian tissue which is retained in vivo during hysterectomy” (AM. J. OBSTET. GYNECOL., 128: 626, 1977), the old controversy is stirred up. Once the pros and cons are put on the scale, it is usually easy to decide on a patient-to-patient basis, and most of the time this decision can be made only during operation, A well-prepared patient understands this. The difficulty arises when the pros and cons are evened out. If such a situation occurs, I look at the patient; if she is obese I remove the ovaries, and if she is slim I preserve them. My well-respected senior ex-partner called to my attention a long time ago that obese patients tolerate menopause better than slim ones. Now, a decade later, it has become recognized that peripheral conversion of androgens to estrogens is a significant source of estrogen in the postmenopausal woman. This conversion was recently demonstrated by Nimrod and Ryan’ in an in vitro study. My associate and I* reviewed the charts of 100 postmenopausal women who were not ingesting estrogen and had been admitted to our hospital because of fracture of the femoral neck. In comparing their weights with those of 100 comparable patients, it was found that the hip fracture group’s average weight was lower than that of the nonfracture group. It seems that the obese patients are better protected against hip fracture not only by their padding per se but also by the endogenous estrogen which is produced by their padding. If fat cells are truly capable of converting androgens to estrogen, it may be that, in view of the recent controversy about estrogen treatment of the climacteric, this observation can be used as a justification for the selective prescribing of estrogen to the slim rather than to the obese patient. Janos Balog, M.D. 2480 Mission Street, No. 215 San Francisco, California 94110 REFERENCES
1. Nimrod, A., and Ryan, K. J.: Aromatization of androgens by human abdominal and breast fat tissue, J. Clin. Endocrinol. Metab. 40: 367, 1975. 2. Balog, J., and Langhauser, C.: Unpublished data.
What Is the new advance in clinicel laboratory testing for pregnancy? To the Editors: In their article entitled “A capillary tube pregnancy test,” Lau, Linkins, and King (THIS JOURNAL 127: 394, 1977) have introduced a modification of latex agglutination which the authors state has a sensitivity of 0.5 U.
January 15, 1978 Am. J. Obstet. Gynecol.
of human chorionic gonadotropin (hCG) per milliliter. The authors have, however, not demonstrated any dose-response with known hCG to indicate the sensitivity. Furthermore, their methods for evaluation have numerous pitfalls. Over 90 per cent of the abortions tabulated are over 6 weeks of pregnancy so that they are of little practical use in demonstrating the value of a sensitive test. The four false negatives in 1,413 abortions are low, but again there were relatively, few pregnancies before 6 weeks, so that a distorted picture of the test’s accuracy at 99+ is presented. As the specimens are taken closer to ovulation, the false negatives in determination at the present time will rise, so that at 4 days all will be in this negative category.Eighteen cases were positive with the capillary tube test at 3, 4 and 5 weeks after menstruation. From our standard normal pregnancy curve with radioreceptorassay (RRA) the earliest positive at 3 weeks was most likely a delayed luteinizing hormone (LH) peak. At 0.5 U. per milliliter of hCG the earliest detection of pregnancy would be on day 26 of the cycle so that the 4 to 5 week specimen with a capillary tube method may rarely provide a positive test. At 3 weeks past the menses with hCG levels of under 0.6 I.U. per milliliter in the presence of early pregnancy, the endometrium may not show any signs of pregnancy, demonstrating only secretory or proliferative endometrium. The authors have not listed the patients who initially had a negative capillary tube test and returned 1 week or 2 later and found the test to be positive. There is a discussion of one case of missed abortion in which all agglutination tests were negative. Our experience with RRA has demonstrated that many of these early missed abortions are low positive assays, which are missed with less sensitive testing. Four ectopic pregnancies are detected, but with the sensitivity of this capillary test only 60 per cent will be detected. In this article there is no reference to or discussion about RRA’ or radioimmunoassay (RIA)’ to the beta subunit for pregnancy determination, which provides the earliest diagnosis of pregnancy-which this capillary agglutination tube test does not perform. At the first day of the first missed menses, the RRA or RIA is virtually 100 per cent accurate. The RIA for hCG using the antiserum to the beta subunit is equally sensitive to the RRA but requires from 24 to 72 hours of incubation. The quantitative RRA will pick up all ectopic pregnancies3 and many missed abortions4 which are clinically unrecognizable. The RRA provides the laboratory backup to prevent menstrual extraction or abortion without pregnancy.j The RRA is now clinically available (Biocept-G, which is set to measure pregnancy above 0.2 I.U. of hCG per milliliter). The test may be performed in less than an hour in any laboratory which is processing RIA’s. The test is highly sensitive and biospecific for the hCG molecule. At low levels there is some affinity to LH. However, LH has one-third the binding affinity of
Correspondence
hCG, which reduces the cross-reactivity, and further during pregnancy the secretion of LH is suppressed. The control nonpregnant sample containing basal levels of LH allows the measurement of hCG with virtually no interference with LH. This has been documented clinically in more than 5,000 women. It is of interest that RRA estimates higher values than RIA’s. In our impression the RRA is measuring only the full molecule whereas the immunologic tests measure variable immunoreactive material. Robert Landesman, M.D. Thr New York Hospital Ntw York, New York 1002 1 REFERENCES
Landesman, R., and Saxena, B. B.: Results of the first 1000 radioreceptorassays for the determination of human chorionic gonadotropin: A new, rapid and reliable pregnancy test, Fertil. Steril. 27: 357, 1976. Vaitukaitis, J. L., Braunstein, G. D., and Ross, G. T.: A radioimmunoassay which specifically measures human chorionic gonadotropin in the presence of human luteinizing hormone, AM. J. OBSTET. GYNECOL. 113: 751, 1972. Saxena, B. B., and Landesman, R.: The use of radioreceptorassay of choronic gonadotropin for the diagnosis of early abortion, Fertil. Steril. 46: 1105, 1975. Landesman, R., and Saxena, B. B.: Radioreceptorassay of human chorionic gonadotropin as an aid in miniabortion, Fertil. Steril. 25: 1022, 1974.
Reply to Dr. Landesman To the Editors: We welcome the above letter as an opportunity to present data which was deleted for the sake of conciseness in the original article. What’s new? The capillary tube pregnancy test was originally designed for population studies in developing countries, but it is also useful in developed countries because of its simplicity. Its main advantages are that it requires no refrigeration, which makes it suitable for remote areas, an,d that its compact size permits easy storage and transportation (500 tests easily fit into a shirt pocket). By contrast, the RRA requires refrigeration, a gamma counter, and a rather civilized laboratory facility. The reagents were titrated to give a test with a sensitivity of 0.5 I.U. per milliliter and this sensitivity was confirmed by dose-response experiments using different standards of hCG-the II International Standard and the U.S.P. hCG standard. The method of evaluation was a comparison of all test results against clinical and pathologic results. In Fig. 3 of our article, the abscissa should have been labeled “duration from the LMP (last menstrual period).” Of cases which had a positive half-unit test and which later were confirmed clinically and pathologically, four were 3 weeks from the LMP, three were 4 weeks from the LMP, and 11 were 5 weeks from the LMP. In another study using a half-unit test, 11 cases
243
had positive tests prior to the missed period and 21 cases had positive tests at or around the missed period. The conversion of negative to positive tests results in patients with timed coitus or artificial insemination will be reported later in detail. We have experienced no difficulty with missed abortions or ectopic pregnancies. In the case of the missed abortion described, the capillary test was performed relatively late (14 weeks from the LMP), which was approximately 4 weeks following fetal death, and the pathologic study showed ghost villi. suggesting a termination of hCG production, and correlated with the negative results found in all tests. Positive half-unit tests have been found with missed abortions which later gave negative test results. The disappearance of hCG following termination of pregnancy will be reported later in greater detail. Of the five ectopic pregnancies, all had positive half-unit capillary tests. Four presented with positive test results following termination procedures and were associated with histopathology reports of “decidua only-no villi”. Thus, 100 per cent of ectopic pregnancies, as far as we know, were detected by a sensitivity of 0.5 I.U. per milliliter in the capillary tests. We are unaware of how Dr. Landesman derives a presumed figure of 60 per cent. Granted, there is a place for RRA’s and RIA’s, but at sites having sources of electricity for refrigeration and a gamma counter. These procedures could not be simply performed in base camps at remote areas. Even in developed countries, the degree of sophistication entailed in a RRA or RIA requires heavy equipment and reagents used in stages. By contrast, the simple capillary test is a self-contained microtube which requires only dipping into urine and tilting to develop an end point. Each type of test has its place. The data on any test have more meaning if the test is compared with the clinical or histopathologic “truth” rather than with another test. This is because an interfering or peculiar substance in a urine may produce the same incorrect result in both tests. Throughout our series, we have compared the capillary test and other tests with clinical or histopathological results. This has not always been done for the RRA or the RIA. H. Lorrin La74 M.D., M.P.H. Department of Gynecology and Obstetric\ The John Hopkins University 601 North Broadway Baltimore, Maqland 21205
incompetent cervbl
OS
To the Editors: A young woman who had only recently experienced her second midtrimester spontaneous abortion was referred to me for psychiatric treatment of depression. There were indications of difficulty before these gynecologic problems, but undoubtedlv her inability to
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