966
Communications
Table I. Increase estrogen therapy*
April
in brief
in plasma
Am. J, Obstet.
estrogen
levels after
DOS?
Cm&W
N
0.3 0.625 1.25
6 4 11
Oral 47.7 + 5.0t 103.0 2 16.41 125.3
-r- 20.19
N 6 5 14
Vaginal
-0.7 + 9.0t 35.8 * 7.0$ 93.7 c 11.76
*All values are means (?SEM) after 1 week of estrogen therapy with one oral tablet or one vaginal application daily, at each dose level (in pg/ml). TSignificantly different: p < 0.001. #Significantly different: p < 0.005. $Significantly different: p < 0.03. administration fi-om oral to vaginal, substantially lower blood levels can be achieved. At a daily dose level of 0.3 mg vaginally, systemic absorption appears to be completely eliminated. It may be difficult or impossible to control certain of the reputed risk factors for endometrial carcinoma such as obesity, hypertension, or diabetes. However, this investigation has shown that blood levels of one of the alleged etiologic agents, the exogenous estrogen to which the endometrium is exposed, can be minimized by lowering the dose and/or by administering the drug vaginally. The importance of the blood estrogen level is further underscored by two reports in 1979, in which a higher incidence of endometrial carcinoma was associated with an increasing dosage of exogenous estrogens. Furthermore, studies in this laboratory, in 1976, demonstrated an association between elevated endogenous estrogen levels and endometrial carcinoma. Investigations are currently underway in our laboratory to expand the study reported here, both quantitatively and qualitatively. This is being done by (1) studying a larger number of patients, (2) treating the same patients sequentially with oral and vaginal estrogens so that each case subject acts as her own control, (3) evaluating the differential blood estrogen levels obtained by the oral versus the vaginal route of administration as a function of time, (4) measuring various estrogen fractions (estradiol, estrone and, hopefully, equilin estrogen), and (5) correlating the clinical results with the dosages, methods of administration, and plasma levels, so as to determine the lowest exogenous amount of estrogen required to achieve the desired clinical result.
15, 1981
Gynecol.
Use of a rapid radioimmunoassay for pregnancy-specific beta-l glycoprotein in gynecologic emergencies: Comparison with routine urinary pregnancy test and a rapid radioimmunoassay for human chorionic gonadotropin JON E. SIITERI, B.Sc.* RIITTA KOISTINEN, M.Sc. TAP10 RANTA, M.D. ULF-HAKAN STENMAN, M.D. MARKKU SEPP;iLa, M.D. Department I of Obstetrics and Gynecology, University Central Hospital, and Department of Bacteriology and Immunology, University ?f Helsinki, Helsinki, Finland PREGNANCY TESTS have been introduced for the detection of human chorionic gonadotropin (hCG) in patients with gynecologic emergencies. L-s In a previous report4 we analyzed the use of highly sensitive radioimmunoassays (RIA) for hCG and pregnancy-specific beta- 1 glycoprotein (SPl) in patients with ectopic pregnancy and found that both were equally effective. The conventional RIA method is unsuitable for the examination of a single sample from an emergency patient. Recently, we reported the use of a rapid hCG RIA for this purpose which showed that, while the test is highly effective, some false positive and false negative results do appear, causing inappropriate clinical action.3s 4 With this in mind we have examined the use of a rapid test for SPl in such patients and now report our results on 141 women with gynecologic emergencies. Serum samples were obtained from 141 women of reproductive age with lower abdominal pain or vaginal bleeding (Table I). The RIA for SPI was principally the same as described in our previous report,¶ but we used only one standard (100 yl), consisting of pregnancy serum diluted with normal female serum to give an SP 1 concentration of 20 pg/L. Serum (100 ~1, undiluted) was incubated with anti-SPI antiserum (100 ~1) diluted to yield 30% binding in zero standard and 1251-SP1 (100 ~1, 10,000 cpm) at 37” C for 3 hours. Antibody-bound material was precipitated with 200 ~1 of 1: 20 diluted anti-rabbit gamma globulin serum and 0.5 ml of 16%
SUPERSENSITIVE
REFERENCES
1. Martin, P. L., Yen, S. S. C., Burnier, S. M., and Herman, H.: Systemic absorption and sustained effects of vaginal estrogen creams, JAMA 242:2699, 19’79. 2. Englund, D. E., and Johannson, E. D. B.: Plasma levels of estrone, estradiol and gonadotropins in postmenopausal women after oral and vaginal administration of coniueated equine estrogens (PreGarin), Br. J. Obstet. G;naecol. 85:957, 1978.
Supported by the Research Council for Medical Sciences, Academy of Finland, and the Foundation for Gynecological Research, Helsinki, Finland. Reprint requests: Prof. M. SeppHlH, M.D., Department of Obstetrics and Gynecology, University Central Hospital, 00290 Helsinki 29, Finland, *Research Fellow at University of Helsinki. Present address: 543 McClay Road, Novato, California 94947. 000%9378/81/080968+03$00.30/0
@ 1981 The C. V. Mosby Co.
Communications
Table I. Serum in 141 patients
SP 1, hCG, and urinary with acute gynecologic
pregnancy test (positive emergencies Rapid
Positive (A20 pgIL)
Diagnosis
SPI test
and negative Urina?
Negative (cc!0 NIL)
results)
pregnancy
Positive (>I,000 IUIL)
in relation
to clinical
test
Rapid
Negative (
in brief
Positive (>251.!JlL)
969
findings
hCG
test
Negative (c25IUIL)
Proved ectopic pregnancy Other evidence of present or past pregnancy Cyst or endometriosis Infection Abnormal bleeding Nonspecific lower abdominal pain
10 13*
7 8
3 3
10 8
17 16*
0 0 1 0
19 27 16 38
0 0 0 0
4 23 9 24
0 0 1 0
19 29 16 38
Total
26
115
6
78
34
107
*There tThere
were were
five two
cases in which cases in which
the only the only
evidence evidence
was a decidual was a decidual
Table II. Clinical evaluation of the rapid SPl RIA relative patients with gynecologic emergencies Parameter Sensitivity
k%
(%)
SPl RIA
pregnancy Urinary
pregnancy
test and the rapid test
Rapid
hCG RIA in hCG RIA 87
97
100
99
88
100
97
TP (No.) FP (No.) TN (No.) FN (No.)
23 3 100 15
6 0 64 14
33 1 102 5
Total
141
True
(%)
to the urinary
30
Predictive
(&j
of the endometrium. of the endometrium.
61
Specificity
TP:
Rapid
reaction reaction
0 5t
value
(fi]
(%)
(No.) positive;
FP: false
positive;
TN:
true
negative;
FN:
(w/v) polyethylene glycol. The result was judged positive if the radioactivity in the precipitate was less than that in the reference tube. The results were compared with those of a routine urinary pregnancy test (Pregnosticon All-In, Organon, sensitivity 1,000 U/L) and the rapid serum hCG beta subunit RIA3 (sensitivity 25 U/L). Clinical and/or histologic evidence of complicated intrauterine or ectopic pregnancy was obtained in 38 patients (27%). The rapid SPl RIA gave a positive result in 18% of all patients; the rapid hCG RIA was positive in 24%, and the urinary pregnancy test was positive in 7% of the cases studied (Table I). Ectopic pregnancy was verified in 17 patients; 59% had a positive SPI RIA test; 23% had a positive urinary test, and all had a positive serum hCG RIA test. Twenty-one other patients had histologic evidence of a pregnancy-related disorder. The SPl RIA gave a positive result in 62% of these cases; the urinary test was positive in 27%, and the hCG RIA was positive in 76%. These unexpectedly low figures are due to inclusion of seven patients in whom the only evidence was a decidual reaction of the
84 false
141
negative.
endometrium; five of them had a negative result for both the SPl RIA and the hCG RIA. In clinical terms of sensitivity, specificity, and predictive value5 the best figures were obtained for the rapid hCG RIA (Table II). The urinary pregnancy test gave no false positive results but far too many false negative results, and results of the SPl RIA lay between these two. In the present set of patients a combination of hCG and SPl RIAs did not increase the efficacy of the hCG RIA alone (Table III). A practical test for gynecologic emergencies should be rapid and simple. We have achieved this for both hCG and SPI RIAs by using a short incubation time, a single standard instead of a standard curve, and instant precipitation of antibody-bound radioactivity. Our methods enable us to test economically a single serum sample with the result available in 3 to 4 hours. We originally hoped that the SPl test would provide additional evidence of pregnancy in those cases where the hCG test was positive without clinical evidence of pregnancy. This did not turn out to be the case, as the
970
Communications
April Am. J. Obstet.
in brief
Table III. Clinical evaluation of combined use of rapid SPl and hCG RIA tests in patients with gynecologic emergencies Both positive/ either or both negative
Parameter Sensitivity Specificity Predictive
(%) (%) value
(%)
TP (No.) FP (No.) TN (No.) FN (No.)
Either or both positive/ both negative
61 100 100
87 96 89
23 0 103 15
33 4 99 5
only sample with a false positive hCG test was SPl negative. However, in two cases in which the only clinical evidence of pregnancy was a decidual reaction of the endometrium, the occurrence of both markers strongly suggested that there was a pregnancy-related disorder. On the basis of our previous results with a highly sensitive SPl RIA” it would seem that, had a lower cutoff level been selected, a higher proportion of patients with ectopic pregnancy would have been SPl positive. Indeed, examination of the same samples by a highly sensitive RIA would have increased the positive rate of the SPl to 94% (result not shown), but this would have occurred at the cost of a considerable increase in the number of false positive results. In the present unselected material the hCG test gave a 100% positive rate in ectopic pregnancy, and the number of false positive results was quite acceptable. Our results clearly demonstrate the value of supersensitive tests in the detection of pregnancy-related disorders in patients with gynecologic emergencies. These tests are superior to the routine urinary pregnancy test, and the rapid hCG RIA is more efficient than the SPl RIA. REFERENCES 1. Braunstein, G. D., Karow, W. G., Gentry, W. G., Rasor, J., and Wade, M.: First-trimester chorionic gonadotropin measurements as an aid in the diagnosis of early pregnancy disorders, AM. J. OBSTET. GYNECOL. 131:25, 1978. 2. Saxena, B. B., and Landesman, R.: Diagnosis and management of pregnancy by the radioreceptorassay of human chorionic gonadotropin, AM. J. OBSTET. GYNECOL. 131:97, 1978. 3. Seppala, M., Tontti, K., Ranta, T., Stenman, U.-H., and Chard, T.: Use of a ranid hCG-beta-subunit radioimmunoassay in acute gynaecological emergencies, Lancet 1:165, 1980. 4. Seppala, M., Venesmaa, P., and Rutanen, E.-M.: Pregnancy-specific beta- 1 glycoprotein in ectopic pregnancy, AM. J. OBSTET. GYNECOL. 136: 189, 1980. 5. Gordon, Y. B., Lewis, J. D., Pendlebury, D. J., Leighton,
15, 1981 Gynecol.
Transformation of endodermal sinus tumor to dysgerminoma following chemotherapy GUNTER
DEPPE,
ALLAN
J.
LIANE
DELIGDISCH,
CARMEL
M.D
JACOBS, J.
COHEN,
M.D.* M.D. M.D.
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, and Department of Pathology, The Mount Sinai Hospital and The Mount Sinai School of Medicine, New York, New York IN 1977, DiSaia and associates’ described the conversion of malignant teratomas to histologically benign, although metastatic, teratomas following the administration of combination chemotherapy. All patients remained well on long-term follow-up. We have observed a different type of chemotherapy-related conversion, which we wish to report. The patient, a 13-year-old, nulligravid girl, presented to her private physician in June, 1979, with abdominal distention. A cystic, enlarged 6 by 8 cm ovary was removed. It contained a mixed germ cell tumor with predominantly endodermal sinus tumor histology (Fig. 1) but with some choriocarcinoma elements and a few areas of dysgerminoma. The tumor was confined to the ovary. At our institution, metastatic workup, laparoscopy, and washings were negative and alpha fetoprotein and human chorionic gonadotropin tests were negative. For
the next 24 weeks vincristine
was given every 2 weeks, while
actinomycin D and cyclophosphamide weeks. In January, 1980, second-look formed. Tumor masses, each less than found on the anterior peritoneum and inal aorta. A 6 by 6 cm retrosigmoid encountered. These were resected and lignant dysgerminoma (Fig. 2). The platinum, bleomycin, and vinblastine evidence of disease.
were given every 4 laparotomy was per1 cm in diameter, were anterior to the abdom-
tumor mass was also all contained pure mapatient is receiving cisand is without clinical
Conversion of teratomas from malignant to benign histology following chemotherapy has been reported in the testis2 as well as in the ovary. In male subjects, every known type of germ cell tumor has converted to benign teratoma following the use of a wide variety of chemotherapeutic agents. Eleven of twelve patients remained well with secondary chemotherapy, but a death from progressive, histologically benign teratoma was reported.z Thus, the literature shows that redifferentiation of germ cell tumors in association with
L
M., and Gold, J.: Is measurement of placental function and maternal weight worth while? Lancet l:lOOl, 1978.
Reprint
requests: Gunter
Obstetrics and Gvnecolonv. Ave., New York,‘New Y&k
Deppe, Mount 10029.
M.D., Department
Sinai
Hosnital. I
’ 1176
of Fifth
*Present address: Department of Obstetrics and Gynecology, University of Nebraska College of Medicine, Omaha, Nebraska 68 105. 0002-9378/81/0809’70+03$00.30/0
0
1981 The
C. V. Mosby
Co.