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.     

Radioimmunoassay of maternal serum -fetoprotein associated with pregnancy

Alpha fetoprotein (AFP) was measured by radioimmunoassay of urine and serum of pregnant women at various stages of gestation and postpartum; sera of patients with hydatidiform mole and choriocarcinoma were also measured. Concentrations below 5 ng/ml were considered negative. Nonpregnant and early pregnancy levels of AFP did not differ significantly. At 14 weeks of gestation, serum AFP showed an initial increase which increased progressively throughout pregnancy, reaching its maximum 35-38 weeks postconception. Average serum AFP was 232.6 ng/ml at 35 weeks, 253.3 at 36 weeks, 222.3 at 37 weeks, and 185.7 at 38 weeks. At term, serum AFP leveled off slightly, averaging 108.7 ng/ml at 40 weeks, 86.5 at 41 weeks, and 80.8 at 42 weeks. Serum AFP decreased rapidly after delivery and was almost negligible by 20 days postpartum. Average AFP half-life was 3.9 days. AFP was also detected in serum from 1 patient with hydatidiform mole (105 ng). AFP was found in urine of 1 patient with marked albuminuria but not in normal pregnancy. Results indicated that AFP in serum may be partly of maternal origin. It is speculated that the inhibition against the repressor-operator gene system which was responsible for AFP synthesis was accelerated in pregnancy by unknown factors, probably of placental origin, resulting from maternal AFP production.     

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.     

Serum progesterone and serum human chorionic gonadotropin in gestational and nongestational choriocarcinoma.

Serum progesterone was assayed by the competitive protein-binding technique in 20 cases of gestational choriocarcinoma and one case of nongestational choriocarcinoma. Serum human chorionic gonadotropin (HCG) was simultaneously measured from the same blood samples by the hemagglutination-inhibition technique. Serum progesterone in choriocarcinoma ranged from 1.3 to 182.9 ng. per milliliter with a mean +/- standard error of the mean of 36.2 +/- 10.2 ng. per milliliter. Serum HCG ranged from 0.6 to 1,280 I. U. per milliliter. In 11 patients with choriocarcinoma, serum progesterone levels were indistinguishable from values obtained during the luteal phase of the normal menstrual cycle; six patients had values similar to those found in early normal pregnancy and four patients with postmolar villous choriocarcinoma had elevated serum progesterone. There was a significant correlation between serum HCG and serum progesterone (r = + 0.5652, p = 0.005). The significance of these findings is discussed with reference to the likely source of progesterone in choriocarcinoma.     

Differential production of human chorionic gonadotropin and free subunits in gestational trophoblastic disease

Serum levels of human chorionic gonadotropin (hCG) and its free subunits (alpha hCG and beta hCG) were determined by means of highly sensitive and specific monoclonal and antipeptide-based monoclonal immunoradiometric assays. During normal pregnancy, the beta hCG to hCG ratio appears constant at approximately 0.5% after 5 weeks of gestation. In contrast, gestational choriocarcinoma was characterized by absolute serum beta hCG levels varying from three to 280 times greater than the maximum values observed during pregnancy and by exceedingly high beta hCG to hCG ratios. In complete hydatidiform mole, this ratio was intermediate between normal pregnancy and choriocarcinoma. The ratios of free beta hCG to hCG will distinguish normal from complete molar pregnancy (p less than 10(-8)), hydatidiform mole from choriocarcinoma (p less than 10(-4)), and choriocarcinoma from normal pregnancy (p less than 10(-8)) with high probability. Finally, it was found by means of the high sensitivity hCG immunoradiometric assays (less than 0.02 ng/ml) that this assay predicted very early tumor recurrence in patients with gestational choriocarcinoma.     

Serum SP1 and hCG beta-subunit (hCG beta) levels in choriocarcinoma, invasive mole, and hydatidiform mole--clinical significance of SP1/hCG beta 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. $\text{SP}{}_1\text{hCGβ}$ 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 $\text{SP}{}_1\text{hCGβ}$ ratio differs significantly among choriocarcinoma, invasive mole, and hydatidiform mole. $\text{SP}{}_1\text{hCGβ}$ ratio is likely to represent the degree of differentiation of trophoblastic cells. The $\text{SP}{}_1\text{hCGβ}$ ratio may be useful in differentiating between choriocarcinoma and invasive mole.     

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.     

Human chorionic gonadotropin and its subunits in hydatidiform mole and choriocarcinoma.

Serum human chorionic gonadotropin (hCG) was measured by a radioreceptorassay (RRA) and radioimmunoassay (RIA) and serum hCG-beta and hCG-alpha by RIA in 10 patients with intact mole, 3 patients with choriocarcinoma, and 4 patients with hydatidiform mole during treatment. hCG levels by RRA were higher in 5 of 10 molar pregnancies and ranged from 20,900 to 100,000 ng/ml and from 30,000 to 100,000 ng/ml by RIA. hCG levels by RRA and RIA paralleled one another closely during treatment of hydatidiform mole. hCG-alpha was higher than hCG by RRA and RIA and hCG-beta in molar pregnancies, in the uterine venous blood draining a uterine choriocarcinoma, and during chemotherapy of choriocarcinoma. In 2 of 3 choriocarcinoma patients who eventually developed cerebral metastases, hCG-alpha increased while hCG and hCG-beta were declining or negative. hCG-beta was usually lower than hCG or hCG-alpha in all the cases studied. These results demonstrate the production of free alpha and beta subunits in trophoblastic disease. Further, due to the biospecificity, simplicity, and rapidity, the RRA of hCG is a sueful diagnostic aid during treatment of trophoblastic neoplasia until the levels fall to within the sensitivity range of the assay. Finally, the RIA of hCG, hCG-beta, and hCG-alpha, which requires several days, should be performed until they become negative or fall within normal range.     

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.     

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.     

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.     

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.     

Radioimmunoassay of placental protein 12: levels in amniotic fluid, cord blood, and serum of healthy adults, pregnant women, and patients with trophoblastic disease

A radioimmunoassay for placental protein 12 (PP12) is described and the levels in amniotic fluid, cord blood, and serum of nonpregnant individuals, pregnant women, and patients with trophoblastic disease are presented. During pregnancy, the highest PP12 levels were found at 22 to 23 weeks (mean +/- SD, 169 +/- 123 ng/ml), and there was a transient decline at 32 to 33 weeks (63 +/- 23 ng/ml). In amniotic fluid, the levels were 100 to 1,000 times higher than in maternal serum. In cord blood at birth, the values were of the same magnitude as in maternal serum. Also healthy nonpregnant women and men had PP12-like immunoreactivity in serum. Nonpregnant women (9 to 47 ng/ml) had higher levels than men (undetectable to 21 ng/ml). Elevated levels up to 84 ng/ml were occasionally observed in trophoblastic disease, both hydatidiform mole and choriocarcinoma, but they bore no correlation with the human chorionic gonadotropin levels. On the basis of these results PP12 is not a suitable marker for trophoblastic disease. PP12 values in normal pregnancy provide the basis for the evaluation of PP12 levels in abnormal pregnancy.     

Methotrexate for prophylaxis of choriocarcinoma

The malignancy rate in 580 cases of hydatidiform mole in Singapore was 14.8 per cent. An attempt was made to reduce this rate by giving patients with moles 3 courses of prophylactin oral methotrexate totaling 150 mg. after removal of the mole. In a study involving 380 patients, including control subjects, the treatment achieved a slight reduction in malignancy rate from 8.7 to 4.5 per cent, but it produced considerable toxicity and a significantly increased mortality rate (2.2 per cent compared with 0.5 per cent in controls). However, the tumors which developed subsequent to prophylactic methotrexate were sensitive to the same drug given in larger doses. Choriocarcinomas which were recognized within a year of hydatidiform mole were highly sensitive to chemotherapy, and a 100 per cent survival rate can be expected if close follow-up and carefully supervised treatment are instituted. There was an 80 per cent mortality rate among 5 cases of choriocarcinoma which were detected later. It is suggested that closer supervision of follow-up programs, parenteral chemotherapy, a careful, decisive rotation of chemotherapeutic agents, and selective use of radiotherapy in cases of cerebral choriocarcinoma may improve the survival rate in the late cases. Routine prophylactic chemotherapy for hydatidiform mole is not recommended.     

Circulating placental proteins (hCG, SP1 and PP5) in trophoblastic disease

Summary. Scrum human chorionic gonadotrophin (hCG), pregnancyspecific β₁-glycoprotein (SP₁) and placental protein 5 (PP5) levels have been measured by radioimmunoassay in 20 patients (116 samples) with hydatidiform mole, one patient (nine samples) with invasive mole and 10 patients (103 samples) with choriocarcinoma. Measurement of both serum SP₁ and hCG are useful in the monitoring of these diseases. The presence of PP5 in hydatidiform mole and its absence in choriocarcinoma support the hypothesis that PP5 is closely associated with the invasive activity of malignant trophoblast.     

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.     

Evaluation of serum progesterone during treatment of malignant trophoblastic disease.

Serial assays of serum progesterone and serum human chorionic gonadotropin (HCG) were performed in eight cases of choriocarcinoma before and during treatment of the disease. Serum progesterone was measured by the competitive protein-binding technique and serum HCG was measured by the hemagglutination inhibition method. Serum HCG gives a better index of response of the tumor to treatment when compared to serum progesterone. In cases where the ovaries are still present serum progesterone does not disappear completely when the disease is eradicated and fluctuates cyclically, thus reflecting ovarian activity. However, in most cases with pulmonary secondaries, serum progesterone was elevated in spite of undetectable serum HCG. With widespread metastases serum progesterone rose to pregnancy levels and remained persistently high. Cerebrospinal fluid progesterone in a case of choriocarcinoma with cerebral metastasis was 5 ng. per milliliter, which was very much higher than in normal pregnant subjects. The findings of serum progesterone in comparison to serum HCG during therapy of choriocarcinoma are discussed.     

Clinical and laboratory correlates of molar pregnancy and trophoblastic disease.

From January 1, 1970 to July 1, 1976, 128 women had hydatidiform moles evacuated at the Los Angeles County-University of Southern California Women's Hospitals. Of the 121 patients with follow-up, persistent trophoblastic disease (TD) was diagnosed in 32 (26.4 per cent). Remission was achieved in all treated patients. The frequency of TD was significantly increased in pregnancies large for dates (47.8 per cent), with a uterus greater than 20 weeks' gestational size (45.0 per cent) or with theca-lutein cysts greater than 5 cm. in diameter (50.0 per cent). A normal regression curve for serum beta-human gonadotropin as measured by radioimmunoassay has been constructed as an aid to the early recognition of postmolar TD (invasive mole and choriocarcinoma).     

Study of serum SP1 levels in early normal and abnormal pregnancies

The pregnancy-specific beta 1 glycoprotein (SP1) levels in the serum of normal and abnormal pregnancies were determined by radioimmunoassay in the first trimester. The results indicated that serum SP1 levels of normal pregnancies increased with the advancing gestational week; 67% of threatened abortions with low SP1 levels would finally abort and only 7% of those with normal SP1 levels would abort. Serum SP1 levels were of lower values in ectopic pregnancy and hydatidiform mole. Serum SP1 might be taken as a better index for estimating the fetal prognosis in threatened abortion and an auxiliary diagnostic means for ectopic pregnancy and hydatidiform mole.     

Maternal serum alpha-fetoprotein screening for open neural tube defects in twin pregnancies.

Data on maternal serum alpha-fetoprotein (AFP) levels at 13-24 weeks' gestation in 46 twin pregnancies with open neural tube defects (22 with anencephaly, 24 with open spina bifida) and 169 unaffected twins were used to estimate the detection and false-positive rates associated with different cut-off levels. Using the conventional cut-off level of 2.5 multiples of the median (MoM) for unaffected singleton pregnancies of the same gestation and laboratory, the detection rate in twins was 99 per cent for anencephaly and 89 per cent for open spina bifida, with a false-positive rate of 30 per cent. Using a 5.0 MoM cut-off level to maintain a similar false-positive rate to that found among singleton pregnancies at 16-18 weeks' gestation (about 3 per cent), the detection rate was 83 per cent for anencephaly and 39 per cent for open spina bifida. Estimates are provided of the odds of having an affected twin pregnancy given a positive AFP result as well as the odds for individual women with a raised AFP level.