Measurement of the Beta - Subunit of Chorionic Gonadotrophin in Uncomplicated, Complicated, and Molar Pregnancies

Summary: The beta-subunit of chorionic gonadotrophin (HCG-β) was measured in serum by radioimmunoassay in patients with uncomplicated, complicated, and molar pregnancies. In normal pregnancy, HCG-β was just detectable at levels of less than 10 ng per ml at 4 weeks of amenorrhoea; the levels increased rapidly to a peak mean value of 135.1 ng per ml at 9–10 weeks. Serum levels in patients with abortion or tubal ectopic pregnancy were much lower for the period of amenorrhoea, and results were negative for all patients who were not found to be pregnant. Serum levels were greatly elevated, often exceeding 1,500 ng per ml, in patients with hydatidiform mole. The majority of patients with molar pregnancies showed levels exceeding 750 ng per ml, whereas the highest level in patients with normal pregnancy was 325 ng per ml. The use of serial HCG-β levels provides a sensitive means of follow-up of hydatidiform mole, being able to distinguish the disease undergoing spontaneous regression from residual or metastatic disease.     

Gestational trophoblastic diseases: the ratio of choriogonadotropin to specific pregnancy protein, hCG/SP1, provides useful diagnostic and prognostic evidence

Serum levels of human chorionic gonadotropin (hCG), specific pregnancy protein (SP1), and hPL were measured in 675 samples from women with uneventful pregnancy, and serially from the time of presentation in 125 patients with hydatidiform mole (HM), 43 with invasive mole (IM), and 34 with choriocarcinoma (CC). In HM serum levels of hCG and SP1 declined steadily from presentation to remission; when gestational age at the time of molar evacuation was shorter than 11 weeks, hCG declined to the normal range later than SP1 (57% patients), and when the age was longer--at the same rate as SP1 (26% patients) or earlier (17% patients). Serum levels of either marker were higher in IM than in HM and tended to increase, and in CC were either lower or higher than in IM. Treatment was followed by parallel decline of either marker, although SP1 declined to the normal range later than hCG in 12% of patients with IM and in 10% with CC. The hCG/SP1 ratios in normal pregnancy declined exponentially between the beginning and 23rd week of gestation and stayed level thereafter. The ratios calculated for the gestational age at the time of initial evacuation of the uterus or delivery were close to those of normal pregnancy in 80%, slightly increased in 20% of patients with spontaneously regressing HM, and markedly increased in 70% of patients with IM and in 74% of patients with CC. The ratios tended to increase during chemotherapy. An increase in the hCG/SP1 ratio seemed to be a characteristic sign of malignant change when compared with this ratio in normal pregnancy and hydatidiform mole. Determination of SP1 for monitoring therapy seemed redundant, and hPL assay was useful for discrimination between relapse and pregnancy.     

Evaluation of leukemia inhibitory factor as a marker of ectopic pregnancy

OBJECTIVE: Our purpose was to determine the utility of measuring serum leukemia inhibitory factor, a cytokine expressed in the process of pregnancy implantation, for the diagnosis of ectopic pregnancy. STUDY DESIGN: Serum samples from 40 patients with positive serum quantitative beta-human chorionic gonadotropin levels were used for leukemia inhibitory factor determination. The serum leukemia inhibitory factor concentration was determined by enzyme-linked immunosorbent assay in the following 4 groups: (1) normal intrauterine pregnancies, (2) threatened abortions, (3) spontaneous abortions, and (4) ectopic pregnancies. RESULTS: All patients had detectable concentrations of leukemia inhibitory factor in serum, ranging from 2.44 to 8.25 pg/mL. Mean leukemia inhibitory factor concentrations for ectopic pregnancy were significantly lower (P <.05) than those of both the spontaneous abortion and threatened abortion groups by 1-way analysis of variance. When a cutoff point of serum leukemia inhibitory factor <6.2 pg/mL is assigned as diagnostic of ectopic pregnancy, leukemia inhibitory factor in patients with ectopic pregnancies versus all other groups predicted ectopic pregnancy with a sensitivity of 73%, specificity of 72%, positive predictive value of 50%, and negative predictive value of 88%. CONCLUSION: Serum leukemia inhibitory factor concentration is lowest in patients with ectopic pregnancy. A cutoff point of 6.2 pg/mL maximizes the sensitivity and specificity of the test; however, it is not sufficiently discriminatory to be used clinically for the diagnosis of ectopic pregnancy.     

Serum alpha-fetoprotein in hydatidiform mole, choriocarcinoma, and twin pregnancy.

Serum alpha-fetoprotein (AFP) levels in patients with hydatidiform mole, choriocarcinoma, and twin pregnancy were studied by radioimmunoassay. Serum AFP was absent in seven of seven patients (100 per cent) with choriocarcinoma and 10 of 13 (76.9 per cent) with hydatidiform mole. However, low concentrations (below 8 ng. per milliliter) of AFP were detected in two patients (15.4 per cent) and 105 ng. per milliliter in one (7.7 per cent) with hydatidiform mole. In 10 of 14 patients (71.4 per cent) with twin pregnancy serum AFP levels were significantly above the normal range for single pregnancy and approximately twice as high as the average value in pregnancy. It was concluded from these findings that abnormal levels of serum AFP during pregnancy suggest the presence of various complications such as hydatidiform mole, choriocarcinoma, or twin pregnancy and that the determination of serum AFP is valuable for prenatal diagnosis. The origin and significance of elevated AFP in patients with hydatidiform mole are now being investigated.     

Serum testosterone and dihydrotestosterone in patients with trophoblastic disease.

Serum testosterone (T) and dihydrotestosterone (DHT) were measured by radioimmunoassay in 14 patients with unaborted hydatidiform mole and in 16 patients with normal pregnancy of similar gestational age. Serum human chorionic gonadotropin (hCG) was measured by the radioreceptor assay in patients with hydatidiform mole. Serum T ranged from 0.27 to 5.39 ng/ml with a mean +/- SE of 2.21 +/- 0.45 ng/ml in patients with hydatidiform mole mole and from 0.20 to 2.40 ng/ml with a mean +/- SE of 0.80 +/- 0.14 ng/ml in patients with normal pregnancy, the difference being statistically significant (P = less than 0.005). Similarly, patients with molar pregnancies had a significantly higher (P = less than 0.005) serum DHT (range: 0.09 to 0.62 ng/ml; mean +/- SE: 0.29 +/- 0.05 ng/ml) than patients with normal pregnancies (range: 0.04 to 0.28 ng/ml; mean +/- SE 0.12 +/- 0.02 ng/ml). There was no significant correlation between uterine size or serum hCG and serum T or DHT. The possible sources of the elevated serum T and DHT and the lack of hirsutism or virilization in patients with trophoblastic disease are discussed.     

Serum specific protein 1 and beta-human chorionic gonadotropin concentrations in patients with suspected ectopic pregnancies

To determine the predictive value of serum specific protein 1 (SP1) and beta-human chorionic gonadotropin (beta-hCG) in the diagnosis of ectopic pregnancy, blood was sampled from 82 patients referred for suspected early extrauterine pregnancies. Serum concentrations of SP1 and beta-hCG were determined by EIA and RIA. All patients with early pregnancies had detectable SP1 and beta-hCG levels. An intrauterine pregnancy was found in six patients, and an ectopic pregnancy was confirmed by surgical explorations in 32 of these women. The remaining 40 women had other non-pregnancy related complaints. In all pregnant patients, the beta-hCG RIA and SP EIA determinations were also found positive. This study demonstrates the high predictive value of serum SP1 and beta-hCG determinations with an acceptable sensitivity and specificity in the diagnosis of suspected early ectopic pregnancies. In addition, the practicability and the easy performance of the enzymoimmunometric SP1 determination renders this test superior over the radioimmunoassay for beta-hCG determination.     

检测妊娠区带蛋白临床意义的研究

采用血清妊娠区带蛋白（ＰＺＰ）单向免疫扩散法时７０８例正常妊娠孕妇，２０７例异常妊娠孕妇及１８８例妇科肿瘤患者进行测定。结果表明：正常妊娠孕妇血清ＰＺＰ含量在妊娠第５周即可测出，其含量随孕周的增加而增加，至妊娠４０周达高峰；先兆流产预后佳者，８１．５％分布在正常范围内；妊高征、胎儿宫内生长迟缓、无脑儿、异位妊娠时，ＰＺＰ多在正常范围内；５１．６％恶性葡萄胎患者血清ＰＺＰ含量低于正常范围，绒毛膜癌低值者占８０．０％，在妇科肿瘤中，卵巢癌患者血清ＰＺＰ明显高于卵巢瘤（Ｐ＜０．０１），子宫内膜癌和宫颈癌高于子宫肌瘤（Ｐ＜０．０１）。本研究认为，测定血清ＰＺＰ含量可作为判定先兆流产预后，鉴别滋养细胞肿瘤及妇科良恶性肿瘤的一项重要参考指标。     

Overdiagnosis of complete and partial hydatidiform mole in tubal ectopic pregnancies.

Partial or complete hydatidiform mole (HM) affects approximately 1 in 500 to 1,000 pregnancies. Previous small series suggest that histopathologic diagnosis of HM may be difficult in tubal ectopic pregnancies. The histopathology database of a regional Trophoblastic Disease Unit was searched to identify cases with a referral diagnosis of tubal HM, and the histopathologic findings were reviewed. During the study period (1986-2004 inclusive), there were 132 cases. After central review by specialist histopathologists, the final diagnosis was ectopic partial mole in two, ectopic complete mole in five, and ectopic hydatidiform mole (not otherwise specified) in one. The final diagnosis of definite hydatidiform mole was made in eight (6%) cases, significantly less than in referred uterine curettage specimens, in which approximately 90% have a confirmatory diagnosis of HM (Z = 12.9; p < 0.0001). No cases in this series developed persistent gestational trophoblastic disease, the human chorionic gonadotropin concentration spontaneously returning to normal. Ectopic pregnancies, where managed surgically, should be submitted for histopathologic examination; however, the pathologist should be aware that the degree of extravillus trophoblastic proliferation may appear more florid compared with evacuated uterine products of conception. Molar pregnancy should only be diagnosed when strict criteria regarding morphologic abnormalities previously described in uterine evacuation material are applied.     

Circulating levels of placental protein 5 in normal and abnormal pregnancies

Serum concentrations of PP5 were measured by radioimmunoassay in 219 women with normal pregnancies and 163 women whose pregnancies were complicated. PP5 in serum disappeared rapidly after delivery, with a half-life of 5-10 min in the first 10 min. Serum PP5 levels were higher in uterine than in antecubital venous blood. In normal pregnancies, PP5 was detectable at 7-8 weeks of gestation; its mean concentration rose gradually to a maximum of 17.8 +/- 10.2 ng/ml at 34-35 weeks of gestation. Elevated serum PP5 concentrations were noted in patients whose pregnancies were complicated by toxemia of pregnancy with appropriate-for-date baby or by twin pregnancy. Low serum PP5 concentrations tended to be found in patients whose pregnancies were complicated by abortion, intrauterine fetal death, and hydatidiform mole. Marked abnormal PP5 levels were not found in patients with maternal diabetes and placenta previa. These findings suggest that the assay of serum PP5 concentrations can be a useful parameter in determining the prognosis of abnormal pregnancies.     

Serum human chorionic somatomammotropin in unaborted hydatidiform mole.

Serum human chorionic somatomammotropin (hCS) was measured in 35 patients with intact unaborted hydatidiform mole by a rapid radioimmunoassay using 70% dioxane in water to separate the bound from unbound fraction. Serum hCG was measured by a hemagglutination inhibition method. Serum hCS ranged from 250 to 5900 ng/ml, while serum hCG ranged from 60 IU/ml on unaborted molar pregnancies. Serum hCS in hydatidiform mole increases from a mean +/- SE of 650 +/- 88.5 ng/ml at 7 to 9 weeks' gestation to 1986.7 +/- 859.3 ng/ml at 22 to 25 week's gestation. There was a significant correlation between uterine size and serum hCS in molar pregnancies (correlation coefficient r = +0.5183; P = 0.0025). There was no significant correlation between serum hCS and serum hCG. Serum hCS in a patient with molar pregnancy who subsequently developed choriocarcinoma was not significantly different from that in patients who did not. The findings indicate: 1) that peripheral hCS increases with increased gestational age in molar pregnancies, 2) that the amount of peripheral serum hCS is related to the mass of molar tissue present and not dependent on serum hCG level, and 3) that the serum hCS level in unaborted hydatidiform mole was a poor index for predicting malignant sequelae.     

Hydatidiform mole and fetus with normal karyotype: support of a separate entity

Repetitive hydatidiform mole was observed in four pregnancies. The pregnancies presented with heavy bleeding and vomiting, but the post-evacuation courses were uncomplicated, with rapid regression of serum hCG levels. Cytogenetic investigations, analyses of restriction fragment length polymorphisms, and flow cytometry in three pregnancies were consistent with diploid, biparental conception as the origin of fetal tissue and molar and nonmolar villi. In one pregnancy, the analyses of cytogenetic markers suggested the coexistence of two different cell lines of dizygotic, biparental origin, whereas DNA analysis was consistent with a single conception. With incomplete genetic information, a hydatidiform mole with coexistent normal fetus is generally considered to result from dizygous twinning comprising an androgenetic complete mole and a normal conception. In the present gestations, the results based on several techniques applied on numerous samples from different tissues render this possibility unlikely. Some of the contradictions between histologic and cytogenetic classifications of hydatidiform mole may be explained by diploid, biparental partial mole, which seems to constitute a separate subgroup within hydatidiform mole. Following chorionic villus sampling or amniocentesis, continued pregnancy may be considered, depending on prenatal diagnosis including genetic marker analysis.     

Diagnostic reliability of simultaneous measurements of beta human chorionic gonadotropin and pregnancy-specific beta-1-glycoprotein in serum of patients with trophoblastic disease

Serum levels for beta-human chorionic gonadotropin (beta-hCG) and pregnancy-specific beta 1-glycoprotein (SP1) in patients with trophoblastic disease were measured by radioimmunoassay and enzyme-linked immunosorbent assay. The beta-hCG:SP1 ratios were below 1.0 in all 22 cases of complete hydatidiform mole and in 8 of 9 cases of partial hydatidiform mole. Two (10.5%) of 19 cases of invasive mole involving metastasis had ratios that rose above 1.0 during chemotherapy. Ratios ranged from 1.6 to 29 in 11 of 15 cases of choriocarcinoma before chemotherapy. The remaining 4 cases, diagnosed within 3 months of antecedent pregnancy, had ratios below 0.99. Thus, the difference between choriocarcinoma and nonchoriocarcinoma beta-hCG:SP1 ratios may be due to trophoblastic differentiation based on the developmental stage and with trophoblast age, or due to the mass and potential activity of trophoblastic cells.     

Serum estradiol as an aid in the diagnosis of ectopic pregnancy.

The value of serum beta-hCG measurement in the diagnosis of ectopic pregnancy is well established, and there have been recent studies on the use of serum progesterone levels. However, we have been unable to find any reports on the potential application of serum estradiol (E2) assays in the diagnosis of ectopic pregnancy. We therefore concurrently measured serum E2, progesterone, and beta-hCG in 100 women with ectopic pregnancies, as well as in 69 controls with normal intrauterine pregnancies and 36 women with threatened abortion. The mean (+/- standard deviation) E2 levels for ectopic-pregnancy patients, the normal controls, and the women with threatened abortion were 281.1 +/- 115.6, 788.2 +/- 45.5, and 788.8 +/- 40.6 pg/mL, respectively; the mean levels in the ectopic group were significantly different (P less than .0001) from those of the other two groups. All but one of the ectopic pregnancies had values below 650 pg/mL for E2 and 23 ng/mL for progesterone, and all but one of the normal intrauterine pregnancies had values above these levels. Our data suggest that the addition of the estradiol assay, with or without progesterone, to the early evaluation of patients suspected of having an ectopic pregnancy may be helpful in diagnosis.     

Serum human placental lactogen (HPL) levels in patients with intact hydatidiform mole.

Serum human placental lactogen (HPL) levels in forty cases of intact hydatidiform mole were measured by radioimmunoassay. The HPL values were generally lower than normal pregnancies of the corresponding period of gestation. However, normal and occasionally higher than normal values were observed in a few cases. Serum HPL level alone is of some clinical use in the diagnosis of hydatidiform mole. When combined with human chorionic gonadotropin (HCG), a low HPL/HCG ratio for the corresponding period of amenorrhoea is a useful index in the diagnosis of hydatidiform mole.     

Serum SP1 and hCGβ-subunit (hCGβ) levels in choriocarcinoma, invasive mole, and hydatidiform mole—Clinical significance of ratio

Serum SP₁ (pregnancy-specific β₁, glycoprotein) levels in patients with choriocarcinoma, invasive mole, and hydatidiform mole were radioimmunoassayed and compared with simultaneously measured serum hCGβ-subunit (hCGβ) levels in order to evaluate the clinical significance of SP₁ determination. Serum SP₁ levels at the time of admission ranged from 6.4 to 1660 ng/ml in choriocarcinoma patients, 16.3 to 540 ng/ml in invasive mole, and 720 to 58,000 ng/ml in hydatidiform mole. ratios were under 1.0 in choriocarcinoma (0.3 ± 0.2, mean ± SD), over 1.0 in hydatidiform mole (10.9 ± 8.3), and intermediate in invasive mole (1.5 ± 0.3). In normal pregnancy, the ratio increases as pregnancy progresses, that is, from 15.25 in 7-week gestation to 14,090.90 in 40-week gestation. The mean ratio differs significantly among choriocarcinoma, invasive mole, and hydatidiform mole. ratio is likely to represent the degree of differentiation of trophoblastic cells. The ratio may be useful in differentiating between choriocarcinoma and invasive mole.     

Levels of placenta growth factor in gestational trophoblastic diseases

OBJECTIVE: The aim of the current study was to investigate levels of placenta growth factor in the tissues and sera of the patients with gestational trophoblastic disease and to determine its usefulness for the treatment of gestational trophoblastic disease. STUDY DESIGN: Placenta growth factor concentrations were measured in the tissue homogenates of 12 normal placentas, 33 complete hydatidiform moles, and 6 gestational choriocarcinomas. Serum placenta growth factor levels were determined in 59 women with normal pregnant course, in 30 women with complete hydatidiform mole, in 36 women with persistent gestational trophoblastic disease, and 100 nonpregnant healthy volunteers. RESULTS: Serum and tissue placenta growth factor levels in the patients with mole tended to be decreased compared with the levels in normal pregnancy; the levels were increased significantly in patients with choriocarcinoma. When serum placenta growth factor levels were >20 pg/mL (normal upper limit in nonpregnant women), placenta growth factor-to-human chorionic gonadotropin ratios were increased significantly in patients with persistent gestational trophoblastic disease. CONCLUSION: Serum placenta growth factor levels are not of any predictive value in patients with hydatidiform mole. However, elevated serum placenta growth factor levels with increased placenta growth factor-to-human chorionic gonadotropin ratios are suggestive of persistent gestational trophoblastic disease.     

Maternal serum CA125 levels in early intrauterine and tubal pregnancies

Summary Using an immunoradiometric assay, serum CA125 levels were measured in 13 women with a normal pregnancy, 9 with a spontaneous abortion, 3 with a hydatidiform mole, and 15 with a tubal pregnancy. Serum CA125 levels were high in patients with a normal pregnancy (154±169 U/ml; mean±S.D.), a spontaneous abortion (244±258 U/ml), or a hydatidiform mole (54±16 U/ml). In contrast, CA125 levels in patients with a tubal pregnancy (33±25 U/ml) were low, and almost all of those without uterine bleeding (25±9 U/ml) were within the normal range for non-pregnant women (<35 U/ml). The difference between serum CA125 levels with intrauterine pregnancy and with tubal pregnancy may be ascribed to the difference of the amount of decidual tissues at the site of trophoblastic invasion.     

Radioimmunoassay of serum SP 1 and HPL in normal and abnormal pregnancies.

Serum concentrations of the pregnancy-specific beta 1-glycoprotein (SP 1) and human placental lactogen (HPL) were measured by radioimmunoassay in 372 blood samples obtained from 40 women in the second half of a normal singleton pregnancy. The mean level of SP 1 steadily increased from 40 micrograms/ml in the 22nd week of pregnancy to 168 micrograms/ml in the 36th week of gestation and thereafter reached a plateau. The half-life of SP 1 during the first week after delivery was about 39 h. The clinical value of SP 1 in comparison to HPL estimations was assessed in a prospective study of a few high risk pregnancies. There were no significant differences between serum SP 1 and HPL levels in pregnancies complicated by preeclampsia with or without intrauterine growth retardation and in twin pregnancies. Serum HPL and SP 1 levels were equally effective in predicting placental insufficiency with fetal growth retardation.     

Androgenetic complete mole coexistent with a twin live fetus.

OBJECTIVE: The aim of this study was to evaluate the clinical course and the management policy of complete mole coexistent with a twin live fetus confirmed with DNA polymorphism in a single hospital. METHODS: From 1981 to 1995, six patients with androgenetic complete hydatidiform mole coexistent with a twin live fetus were diagnosed by DNA polymorphism analysis. The clinical course of these six patients was analyzed. RESULTS: Two patients chose to terminate pregnancies and four patients desired to continue the pregnancy. However, the pregnancy had to be interrupted in two patients because of severe preeclampsia and sudden intrauterine fetal death. In two patients, fetuses were growing unremarkably and normal babies were delivered at term. The development of persistent trophoblastic tumor (PTT) in these rare pregnancies was higher (50.0%: 3/6) than that of single complete mole. In three patients, serum hCG titers during pregnancy were monitored. Although serum hCG levels progressively decreased during pregnancy in one patient without PTT, hCG levels initially decreased, but subsequently increased or showed a plateau with advancing gestational age in two patients with PTT. CONCLUSIONS: In patients with complete mole coexistent with a live fetus, the pregnancy may be allowed to continue when the fetal karyotype and development are normal and serum hCG titers are constantly falling with advancing gestational age.     

Serum relaxin in patients with hydatidiform mole

Human chorionic gonadotropin (hCG) is considered to be one of the factors that regulates relaxin secretion in humans. However, the secretory pattern of relaxin has not been evaluated in pregnancy complicated by hydatidiform mole, where circulating hCG levels are higher than in normal pregnancy. In the present study, relaxin, progesterone, and hCG levels were determined by radioimmunoassay in patients with hydatidiform mole before and after evacuation of the mole. Serum immunoreactive relaxin and progesterone levels in patients with hydatidiform mole were similar to those in normal women at corresponding weeks of pregnancy before evacuation of the mole, though hCG levels were significantly higher. The fall of relaxin levels after evacuation of the mole was slower than that of hCG or progesterone. This finding may reflect a continued stimulation of the corpus luteum by lower, but still effective, hCG levels persisting after evacuation of the mole. An extraluteal source of relaxin cannot be excluded.