262
Letters
lular sodium over the course of their pregnancy." Given that the authors found elevated levels of endoxin in the hypertensive group, it would be interesting to learn the intracellular values of sodium in subjects with significantly elevated endoxin values. Robert C. Goodlin, MD City and County of Denver, Denver General Hospital, 77 Hancock St., Denver, CO 80204-4507
REFERENCES I. Tranquilli AL, Brandis S, Rabini RA, et al. Altered cation transport in gestational hypertension. 1. The significance of intracellular sodium. Clin Exp Hypertens 1988;B7: 11-22. 2. Weissberg PL, Weaver J, Woods KL, West HJ, Beevers DG. Pregnancy-induced hypertension: evidence for increased cell membrane permeability to sodium. Br Med J 1983; 287:707-11.
Reply To the Editors: Although increased circulating endoxin may be expected to inhibit sodium-potassium adenosine triphosphatase activity and thereby reduce intracellular sodium levels, our data do not support this. However, our findings are consistent with a previous report that chronic exposure to digoxin does not result in reduced sodium pump activity or increased intracellular sodium levels, although short-term treatment does result in these effects. 1 In addition, we found that both plasma endoxin and erythrocyte sodium-potassium adenosine triphosphatase activity exhibit significant increases during pregnancy! Further, there is a significant positive correlation between the two (r = 0.72) rather than the expected inverse relationship, suggesting that the sodium-potassium adenosine triphosphatase exhibits an adaptive response to the high endoxin levels. 2Thus, these data further support the finding that increased endoxin levels in patients with preeclampsia does not result in a chronic suppression of sodium-potassium adenosine triphosphatase activity and thereby an increase in intracellular sodium levels. James R. Sowers, MD, and Michael B. Zemel, PhD Wayne State University School of Medicine, Department of Medicine, Division of Endocrinology, UHC, 4201 St. Antoine, Detroit, M1 48201.
REFERENCES 1. Cumberbatch M, Zarcian K, Davidson C, Morgan DB, Swamini S. The early and late effects of digoxin treatment on the sodium content and Na+,K+-ATPase of erythrocytes. Br J PharmacoI1981;1l:565. 2. Sowers JR, Zemel MB, Walsh MF, et al. Effects of normal pregnancy on cellular cation metabolism and peripheral vascular resistance. AmJ Hyperten 1990;3:16-22.
Screening infertile women for subclinical hypothyroidism To the Editors: Wilansky and Greisman reported an association between menorrhagia and an abnormal thyroliberin (thyrotropin releasing hormone) stimulation test (Wilansky DL, Greisman B. Early hypothyroidism in patients with menorrhagia. AM J OBSTET GYNECOL 1989;160:673-7). Administration of L-thyroxine re-
July 1990 Am ] Obstet Gynecol
sulted in elimination of menorrhagia. Bohnet et al. 1 reported that subclinical hypothyroidism was found in 20 of 150 infertile women with anovulation or luteal insufficiency. Thus, it is common practice to screen infertile women with the use of thyroid function tests (thyroxine, thyrotropin, triiodothyronine resin uptake, and free thyroxine index). However, a cursory review of thyroid function test results of infertile women at our institution suggested a low prevalence of abnormal thyroid function test results from such screening. Therefore, we performed a survey to determine the prevalence of subclinical hypothyroidism in a population of infertile women and to ascertain whether routine screening of this population for subclinical hypothyroidism with thyroid function tests, especially thyrotropin measurement, is justified. We reviewed the records of 210 patients enrolled in our infertility clinic during a I-year period. None of these patients had clinical or laboratory findings consistent with the presence of overt thyroid disease, thyroid enlargement, or thyroid autoantibodies. We categorized our patients' infertility according to standard clinical criteria. Ovulatory dysfunction was suspected from a clinical history of amenorrhea or irregular menses. This diagnosis was confirmed if the basal body temperature showed a prolonged (:::!21 days) follicular phase or a monophasic pattern accompanied by a decreased «3 ng/ml) serum progesterone concentration or if an endometrial biopsy specimen showed proliferative endometrium. A luteal phase defect was not considered an ovulatory disorder. Serum from all patients' blood samples were assayed for thyroxine and thyrotropin ("regular" immunoradiometric assay) in the automated radioimmunoassayhigh technology instrument (Becton Dickinson Immunodiagnostics, Salt Lake City, Utah).2 The triiodothyronine resin uptake assay (Nuclear Diagnostics, Troy, Mich.) was performed on all samples and the results were used to calculate the FTI = (thyroxine) x [T3(RU)/30], where FTI = free thyroxine index, T3 = triiodothyronine, and RU = resin uptake. Prolactin concentration was determined with the TandemR prolactin kit (Hybritech Inc., San Diego, Calif.). Patients (n = 8) with subclinical hypothyroidism were asymptomatic but had an increased thyrotropin concentration (mean thyrotropin ± SD = 8.3 ± 2.7 mIU/L; range, 5.3 mIU/L to 12.3 mIU/L) and thyroxine, triiodothyronine resin uptake, and free thyroxine index values within the normal reference range for these analytes established in our laboratory. It has been previously shown that an increased (5.2 mIU/L < [thyrotropin] < 10.4 mIU/L) thyrotropin concentration in euthyroxinemic patients is commonly associated with abnormal thyrotropin-releasing hormone test results suggestive of subclinical hypothyroidism.' At a thyrotropin cutoff value of 5.2 mIU /L (i.e., the upper limit of the normal reference range for thyrotropin concentration established in our laboratory), diagnostic sensitivity and specificity were 71 % and 96%, respectively. Ovulation disorders were found in seven of the eight
Letters 263
Volume 163 Number 1, Part 1
(87%) patients with an increased thyrotropin concentration and in 55 of the remaining 202 (27%) women who had a normal thyrotropin concentration, By X2 analysis, these distributions were significantly different (p < 0.001). Conversely, the incidence of subclinical hypothyroidism in dysovulatory women (n = 62; seven with an increased thyrotropin concentration and 55 with a normal thyrotropin concentration) was 11.3%. Prolactin concentrations were normal (mean prolactin ± SD = 6.6 ± 2.3 ng/ml; normal range, 0 ng/ml to 20 ng/ml) in serum samples from all eight patients who had an increased thyrotropin concentration. Patients with subclinical hypothyroidism are generally asymptomatic and produce suboptimal levels of thyroid hormones that are compensated for by increased output of thyrotropin to maintain euthyroxinemia" This disorder has been estimated to occur in up to 7% of the adult population 5 and is generally considered an innocuous disease, although it has been linked to hypercholesterolemia and impaired cardiac systolic time intervals. 3 In our population of infertile women the incidence of subclinical hypothyroidism was only 3.8%, but in the subset of women with ovulatory dysfunction the incidence increased threefold to 11.3%. If the diagnostic sensitivity and specificity of a test and the prevalence of disease in a population are known, the positive or negative predictive value of this test can be calculated. 6 With the use of the sensitivity (71 %) and specificity (96%) of the thyrotropin test (at a thyrotropin cutoff concentration of 5.2 mIU /L) to predict subclinical hypothyroidism and the prevalence (3.8%) of this disease in our population of infertile women, the positive predictive value is only 41 % (i.e., 59% of all patients with an increased thyrotropin concentration will not have subclinical hypothyroidism). However, among dysovulatory women the positive predictive value of the thyrotropin test increased to 68%. We conclude that in a population of infertile women, subclinical hypothyroidism may be observed occasionally; however, the prevalence of this disease in this group of women is probably no greater than the prevalence in the general population. Even if the diagnostic sensitivity and specificity of the thyrotropin test were increased by use of currently available "sensitive" thyrotropin assays,2 the low prevalence of subclinical hypothyroidism in infertile women suggests that it may not be cost effective to routinely screen this group of women for this disease. However, in our population of dysovulatory women the prevalence of subclinical hypothyroidism increased threefold. Wilansky and Greisman have proposed "systematic study of thyroid function" in women with menorrhagia. Similarly, our data suggest that it may be prudent to screen dysovulatory women for subclinical hypothyroidism with a thyrotropin measurement. Daniel M. Strickland, MD, and Wayne A. Whitted, MD Department of Obstetrics and Gynecology, Wilford Hall, USAF Medical Center, Lackland AFB, TX 78236-5300
Frank H. Wians, Jr., PhD Department of Pathology, Wilford Hall, USAF Medical Center, Lackland AFB, TX 78236-5300
The opinions or assertions contained herein are the p~vate views of the authors and are not to be construed as offiCial or as reflecting the views of the Department of the Air Force or the Department of Defense.
REFERENCES l. Bohnet HG, Fiedler K, Leidenberger FA. Subclinical hy-
pothyroidism and infertility [Letter). Lancet 1981;2:1278. 2. Wians FH Jr, JacobsonJM, Dev J, HealdJI, Ortiz G. Thyrotroph function assessed by sensitive measurement of thyrotropin with three immunoradiometric assay kits: analytical evaluation and comparison with the thyroliberin stimulation test. Clin Chern 1988;34:568-75. 3. Brietzke SA, Wians FH Jr, Jacobson JM, Ortiz G. Clinical significance of a slightly increased thyrotropin concentration. J Clin Immunoassay 1989;12:224-8. 4. Evered DC, Smith PA, Hall R, Bird T. Grades of hypothyroidism. Br MedJ 1973;1:657-62. 5. Tunbridge WM, Evered DC, Hall R, et al. The spectrum of thyroid disease in a community: the Whickham survey. Clin Endocrinol 1977;7:481-93. 6. Galen RS. Application of the predictive value model in the analysis of test effectiveness. Clin Lab Med 1982;2:685-99.
Reply To the Editors: We thank Dr. Strickland and colleagues for sharing with us their important and significant observation on subclinical hypothyroidism in persons with infertility, and in particular those with ovulatory dysfunction. We were particularly interested to be informed of the 11 % prevalence of hypothyroidism in the ovulatory dysfunctional group and the suggestion to screen dysovulatory women for subclinical hypothyroidism. I wonder whether Dr. Strickland and colleagues have had an opportunity to note the response to L-thyroxine administration in these dysovulatory patients with subclinical hypothyroidism. The endocrine literature has characterized subclinical hypothyroidism as occurring in two phases. The later phase is that in which there is random thyrotropin elevation. The earlier phase is identified only after administration of thyrotropin-releasing hormone. We showed that whereas within the normal reference range serum thyroxine levels are significantly lower in the early phase than in a control population. If Dr. Strickland's group wished to maximize their recognition of subclinical hypothyroidism a modified thyrotropinreleasing hormone test might be desirable. In some persons with subclinical hypothyroidism, the diagnosis will be missed because the random thyrotropin elevation in early hypothyroid states may be intermittent, similar to the gonadotropic hormone elevation in early ovarian failure. Finally, because we are talking about clinical manifestation of so-called subclinical hypothyroidism, we wonder whether this term continues to be appropriate. We have suggested the term early hypothyroidism to replace such terms as triiodothyronine euthyroidism, compensated hypothyroidism, and subclinical hypothyroidism. Furthermore, we believe that this term may stimulate efforts to clarify the clinical significance of these important phases of developing hypothyroidism. Douglas L. Wilansky, MD, and Bernard Greisman, MD The Etobicoke General Hospital, I 0 I Humber College Blvd., Rexdale, Ontario, Canada M9V IR8
Letters
lular sodium over the course of their pregnancy." Given that the authors found elevated levels of endoxin in the hypertensive group, it would be interesting to learn the intracellular values of sodium in subjects with significantly elevated endoxin values. Robert C. Goodlin, MD City and County of Denver, Denver General Hospital, 77 Hancock St., Denver, CO 80204-4507
REFERENCES I. Tranquilli AL, Brandis S, Rabini RA, et al. Altered cation transport in gestational hypertension. 1. The significance of intracellular sodium. Clin Exp Hypertens 1988;B7: 11-22. 2. Weissberg PL, Weaver J, Woods KL, West HJ, Beevers DG. Pregnancy-induced hypertension: evidence for increased cell membrane permeability to sodium. Br Med J 1983; 287:707-11.
Reply To the Editors: Although increased circulating endoxin may be expected to inhibit sodium-potassium adenosine triphosphatase activity and thereby reduce intracellular sodium levels, our data do not support this. However, our findings are consistent with a previous report that chronic exposure to digoxin does not result in reduced sodium pump activity or increased intracellular sodium levels, although short-term treatment does result in these effects. 1 In addition, we found that both plasma endoxin and erythrocyte sodium-potassium adenosine triphosphatase activity exhibit significant increases during pregnancy! Further, there is a significant positive correlation between the two (r = 0.72) rather than the expected inverse relationship, suggesting that the sodium-potassium adenosine triphosphatase exhibits an adaptive response to the high endoxin levels. 2Thus, these data further support the finding that increased endoxin levels in patients with preeclampsia does not result in a chronic suppression of sodium-potassium adenosine triphosphatase activity and thereby an increase in intracellular sodium levels. James R. Sowers, MD, and Michael B. Zemel, PhD Wayne State University School of Medicine, Department of Medicine, Division of Endocrinology, UHC, 4201 St. Antoine, Detroit, M1 48201.
REFERENCES 1. Cumberbatch M, Zarcian K, Davidson C, Morgan DB, Swamini S. The early and late effects of digoxin treatment on the sodium content and Na+,K+-ATPase of erythrocytes. Br J PharmacoI1981;1l:565. 2. Sowers JR, Zemel MB, Walsh MF, et al. Effects of normal pregnancy on cellular cation metabolism and peripheral vascular resistance. AmJ Hyperten 1990;3:16-22.
Screening infertile women for subclinical hypothyroidism To the Editors: Wilansky and Greisman reported an association between menorrhagia and an abnormal thyroliberin (thyrotropin releasing hormone) stimulation test (Wilansky DL, Greisman B. Early hypothyroidism in patients with menorrhagia. AM J OBSTET GYNECOL 1989;160:673-7). Administration of L-thyroxine re-
July 1990 Am ] Obstet Gynecol
sulted in elimination of menorrhagia. Bohnet et al. 1 reported that subclinical hypothyroidism was found in 20 of 150 infertile women with anovulation or luteal insufficiency. Thus, it is common practice to screen infertile women with the use of thyroid function tests (thyroxine, thyrotropin, triiodothyronine resin uptake, and free thyroxine index). However, a cursory review of thyroid function test results of infertile women at our institution suggested a low prevalence of abnormal thyroid function test results from such screening. Therefore, we performed a survey to determine the prevalence of subclinical hypothyroidism in a population of infertile women and to ascertain whether routine screening of this population for subclinical hypothyroidism with thyroid function tests, especially thyrotropin measurement, is justified. We reviewed the records of 210 patients enrolled in our infertility clinic during a I-year period. None of these patients had clinical or laboratory findings consistent with the presence of overt thyroid disease, thyroid enlargement, or thyroid autoantibodies. We categorized our patients' infertility according to standard clinical criteria. Ovulatory dysfunction was suspected from a clinical history of amenorrhea or irregular menses. This diagnosis was confirmed if the basal body temperature showed a prolonged (:::!21 days) follicular phase or a monophasic pattern accompanied by a decreased «3 ng/ml) serum progesterone concentration or if an endometrial biopsy specimen showed proliferative endometrium. A luteal phase defect was not considered an ovulatory disorder. Serum from all patients' blood samples were assayed for thyroxine and thyrotropin ("regular" immunoradiometric assay) in the automated radioimmunoassayhigh technology instrument (Becton Dickinson Immunodiagnostics, Salt Lake City, Utah).2 The triiodothyronine resin uptake assay (Nuclear Diagnostics, Troy, Mich.) was performed on all samples and the results were used to calculate the FTI = (thyroxine) x [T3(RU)/30], where FTI = free thyroxine index, T3 = triiodothyronine, and RU = resin uptake. Prolactin concentration was determined with the TandemR prolactin kit (Hybritech Inc., San Diego, Calif.). Patients (n = 8) with subclinical hypothyroidism were asymptomatic but had an increased thyrotropin concentration (mean thyrotropin ± SD = 8.3 ± 2.7 mIU/L; range, 5.3 mIU/L to 12.3 mIU/L) and thyroxine, triiodothyronine resin uptake, and free thyroxine index values within the normal reference range for these analytes established in our laboratory. It has been previously shown that an increased (5.2 mIU/L < [thyrotropin] < 10.4 mIU/L) thyrotropin concentration in euthyroxinemic patients is commonly associated with abnormal thyrotropin-releasing hormone test results suggestive of subclinical hypothyroidism.' At a thyrotropin cutoff value of 5.2 mIU /L (i.e., the upper limit of the normal reference range for thyrotropin concentration established in our laboratory), diagnostic sensitivity and specificity were 71 % and 96%, respectively. Ovulation disorders were found in seven of the eight
Letters 263
Volume 163 Number 1, Part 1
(87%) patients with an increased thyrotropin concentration and in 55 of the remaining 202 (27%) women who had a normal thyrotropin concentration, By X2 analysis, these distributions were significantly different (p < 0.001). Conversely, the incidence of subclinical hypothyroidism in dysovulatory women (n = 62; seven with an increased thyrotropin concentration and 55 with a normal thyrotropin concentration) was 11.3%. Prolactin concentrations were normal (mean prolactin ± SD = 6.6 ± 2.3 ng/ml; normal range, 0 ng/ml to 20 ng/ml) in serum samples from all eight patients who had an increased thyrotropin concentration. Patients with subclinical hypothyroidism are generally asymptomatic and produce suboptimal levels of thyroid hormones that are compensated for by increased output of thyrotropin to maintain euthyroxinemia" This disorder has been estimated to occur in up to 7% of the adult population 5 and is generally considered an innocuous disease, although it has been linked to hypercholesterolemia and impaired cardiac systolic time intervals. 3 In our population of infertile women the incidence of subclinical hypothyroidism was only 3.8%, but in the subset of women with ovulatory dysfunction the incidence increased threefold to 11.3%. If the diagnostic sensitivity and specificity of a test and the prevalence of disease in a population are known, the positive or negative predictive value of this test can be calculated. 6 With the use of the sensitivity (71 %) and specificity (96%) of the thyrotropin test (at a thyrotropin cutoff concentration of 5.2 mIU /L) to predict subclinical hypothyroidism and the prevalence (3.8%) of this disease in our population of infertile women, the positive predictive value is only 41 % (i.e., 59% of all patients with an increased thyrotropin concentration will not have subclinical hypothyroidism). However, among dysovulatory women the positive predictive value of the thyrotropin test increased to 68%. We conclude that in a population of infertile women, subclinical hypothyroidism may be observed occasionally; however, the prevalence of this disease in this group of women is probably no greater than the prevalence in the general population. Even if the diagnostic sensitivity and specificity of the thyrotropin test were increased by use of currently available "sensitive" thyrotropin assays,2 the low prevalence of subclinical hypothyroidism in infertile women suggests that it may not be cost effective to routinely screen this group of women for this disease. However, in our population of dysovulatory women the prevalence of subclinical hypothyroidism increased threefold. Wilansky and Greisman have proposed "systematic study of thyroid function" in women with menorrhagia. Similarly, our data suggest that it may be prudent to screen dysovulatory women for subclinical hypothyroidism with a thyrotropin measurement. Daniel M. Strickland, MD, and Wayne A. Whitted, MD Department of Obstetrics and Gynecology, Wilford Hall, USAF Medical Center, Lackland AFB, TX 78236-5300
Frank H. Wians, Jr., PhD Department of Pathology, Wilford Hall, USAF Medical Center, Lackland AFB, TX 78236-5300
The opinions or assertions contained herein are the p~vate views of the authors and are not to be construed as offiCial or as reflecting the views of the Department of the Air Force or the Department of Defense.
REFERENCES l. Bohnet HG, Fiedler K, Leidenberger FA. Subclinical hy-
pothyroidism and infertility [Letter). Lancet 1981;2:1278. 2. Wians FH Jr, JacobsonJM, Dev J, HealdJI, Ortiz G. Thyrotroph function assessed by sensitive measurement of thyrotropin with three immunoradiometric assay kits: analytical evaluation and comparison with the thyroliberin stimulation test. Clin Chern 1988;34:568-75. 3. Brietzke SA, Wians FH Jr, Jacobson JM, Ortiz G. Clinical significance of a slightly increased thyrotropin concentration. J Clin Immunoassay 1989;12:224-8. 4. Evered DC, Smith PA, Hall R, Bird T. Grades of hypothyroidism. Br MedJ 1973;1:657-62. 5. Tunbridge WM, Evered DC, Hall R, et al. The spectrum of thyroid disease in a community: the Whickham survey. Clin Endocrinol 1977;7:481-93. 6. Galen RS. Application of the predictive value model in the analysis of test effectiveness. Clin Lab Med 1982;2:685-99.
Reply To the Editors: We thank Dr. Strickland and colleagues for sharing with us their important and significant observation on subclinical hypothyroidism in persons with infertility, and in particular those with ovulatory dysfunction. We were particularly interested to be informed of the 11 % prevalence of hypothyroidism in the ovulatory dysfunctional group and the suggestion to screen dysovulatory women for subclinical hypothyroidism. I wonder whether Dr. Strickland and colleagues have had an opportunity to note the response to L-thyroxine administration in these dysovulatory patients with subclinical hypothyroidism. The endocrine literature has characterized subclinical hypothyroidism as occurring in two phases. The later phase is that in which there is random thyrotropin elevation. The earlier phase is identified only after administration of thyrotropin-releasing hormone. We showed that whereas within the normal reference range serum thyroxine levels are significantly lower in the early phase than in a control population. If Dr. Strickland's group wished to maximize their recognition of subclinical hypothyroidism a modified thyrotropinreleasing hormone test might be desirable. In some persons with subclinical hypothyroidism, the diagnosis will be missed because the random thyrotropin elevation in early hypothyroid states may be intermittent, similar to the gonadotropic hormone elevation in early ovarian failure. Finally, because we are talking about clinical manifestation of so-called subclinical hypothyroidism, we wonder whether this term continues to be appropriate. We have suggested the term early hypothyroidism to replace such terms as triiodothyronine euthyroidism, compensated hypothyroidism, and subclinical hypothyroidism. Furthermore, we believe that this term may stimulate efforts to clarify the clinical significance of these important phases of developing hypothyroidism. Douglas L. Wilansky, MD, and Bernard Greisman, MD The Etobicoke General Hospital, I 0 I Humber College Blvd., Rexdale, Ontario, Canada M9V IR8
