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.     

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.     

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.     

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.     

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 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 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.     

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 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.     

Glycogen metabolism in vesicles of hydatidiform mole in vitro.

Glycogen content, glycogen synthetase, and glycogen phosphorylase were studied in placental tissue of normal pregnancy and in vesicles of hydatidiform mole. The glycogen content of placental tissue of normal pregnancy decreased significantly with increased gestational age: 6 to 10 weeks, 716.6 +/- 55.7 mg/100 gm wet weight (mean +/- standard error of the mean); 15 to 20 weeks, 216.1 +/- 11.2 mg/100 gm; and 37 to 41 weeks, 176.1 +/- 18.1 mg/100 gm. The decrease in placental glycogen content was accompanied by a corresponding decrease in the placental glycogen synthetase enzyme levels, whereas no remarkable change was found in the glycogen phosphorylase enzyme levels. The glycogen content of hydatidiform mole tissue from 10 patients (13 to 20 weeks of gestation) was 507.0 +/- 58.0 mg/100 gm and was significantly (P less than 0.005) higher than that of normal placental tissue with a corresponding period of gestation. A possible cause of this phenomenon may be the marked decrease in the glycogen phosphorylase enzyme level in hydatidiform mole tissue, which was about one-third that of the normal placental tissue.     

Placental isoferritin measured by a specific monoclonal antibody as a predictive marker for preterm contraction outcome

The serum levels of placental isoferritin and normal ferritin in 25 women with preterm contractions (mean +/- SE gestational age 28.8 +/- 4.7 weeks) were compared with those in 14 control women with uncomplicated pregnancies (29.1 +/- 7.3 weeks). The serum concentration of placental isoferritin in women with preterm contractions (15.3 +/- 6.2 U/mL) was significantly lower than that in normal pregnant women (87.6 +/- 22.6 U/mL) (P = .005). The level of normal ferritin in women with preterm contractions (30.6 +/- 4.16 ng/ml) was lower than that in women with normal pregnancies (67 +/- 9.6 ng/mL) (P = .01); however, both were within the normal range. Serum placental isoferritin levels correlated with pregnancy outcome; low placental isoferritin (up to 10 U/mL) was a sensitive (71.5%) indicator of preterm labor. Low placental isoferritin had a positive predictive value of 59% and a negative predictive value of 71%. These results suggest that placental isoferritin may serve as a predictive marker for the prognosis of preterm contractions.     

Recurrent gestational trophoblastic disease after hCG normalization following hydatidiform mole in The Netherlands

OBJECTIVES: To determine the risk for recurrent trophoblastic disease after spontaneous normalization of human chorionic gonadotropin (hCG) levels in patients with hydatidiform mole and to determine the risk for tumor relapse after apparent remission following chemotherapy in patients with low- and high-risk persistent trophoblastic disease. METHODS: From 1994 until 2004, 355 patients with hydatidiform mole were registered at the Dutch Central Registry of Hydatidiform Mole and were monitored by sequential hCG assays in serum at the department of Chemical Endocrinology of the Radboud University Nijmegen Medical Centre. HCG regression curves were analyzed together with clinical information collected from the Hydatidiform Mole Database. RESULTS: Among the 355 registered hydatidiform mole patients, 265 patients attained spontaneous normalization following evacuation. Of the 265 patients, one patient (0.38%) subsequently required chemotherapeutic treatment for recurrent trophoblastic disease (95% confidence interval 0.0% to 2.1%). HCG levels did not decline to normal (<2.0 ng/ml) spontaneously in 90 patients; those patients were subsequently treated. Relapse rates were 8.1% (6/74) and 6.3% (1/16) for the low- and high-risk category respectively. CONCLUSION: Our analysis indicates that relapse risk in hydatidiform mole patients with spontaneous normalization is extremely low (one in 265 patients) after two normal hCG levels (<2.0 ng/ml) are achieved. Our results support the suggestion that two subsequent normal hCG levels may be sufficient to ensure sustained remission after hydatidiform mole evacuation. In contrary, in order to assure sustained remission, the relapse rates after chemotherapy in the current study emphasize the need for surveillance of trophoblastic tumor patients even after complete remission has apparently been achieved.     

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.     

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.     

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.     

Immunosuppressive 30-kDa protein in urine of pregnant women and patients with trophoblastic diseases

Urine samples obtained from normal pregnant women and patients with trophoblastic diseases contain 30-kDa protein that suppresses phytohemagglutinin-induced T cell proliferation. The immunosuppressive protein was measured by a newly developed radioimmunoassay. The 30-kDa protein was demonstrated in almost all urine samples examined, fluid from hydatid vesicles and chorionic extracts, but not in any serum samples except at low levels in some sera from patients with choriocarcinoma. During pregnancy, the level of urinary 30-kDa protein was higher in the first (1625.5 ± 1212.0 ng/ml, mean ± S.D.) and second (1457.4 ± 1332.4 ng/ml) trimesters than in the third trimester (460.6 ± 419.0 ng/ml). The urinary 30-kDa protein/hCG ratios in patients with choriocarcinoma (8.3 ± 10.9) were significantly higher than those in patients with hydatidiform mole (0.67 ± 1.00, P < 0.01) and in all trimesters than those of normal pregnant women (0.54 ± 0.44 in the first trimester, P < 0.05; 0.63 ± 0.46 in the second trimester, P < 0.05; 0.24 ± 0.17 in the third trimester, P < 0.01). There is no significant difference between the ratios in hydatidiform mole and normal pregnancy. These findings and the fast disappearance of the 30-kDa protein from the circulation suggest that the 30-kDa protein plays a part in proliferation of trophoblastic cells in, or their invasion into the host by locally suppressing the immune reaction of the host and that the increase in the urinary 30-kDa protein level, in cases of choriocarcinoma, may be due to the malignant transformation of trophoblastic cells resulting in their rapid invasion.     

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.     

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.     

Application of the radioreceptor assay for human chorionic gonadotropin in pregnancy testing and management of trophoblastic disease.

A commercially prepared radioreceptor assay (RRA) for human chorionic gonadotropin (hCG) has been evaluated as a pregnancy test and in a quantitative assay to follow patients with hydatidiform mole. The RRA demonstrated almost 100% agreement in comparison with radioimmunoassay (RIA) and urinary hCG tests. In the quantitative assay, a limiting reliable concentration of 70 mIU/ml of hCG in serum could be obtained. Extremely good correlation was achieved between the RRA and RIA test for hCG in 2 patients with hydatidiform mole over a span of 3 months of followup after evacuation of the mole. The usefulness of the RRA as a replacement of RIA tests for hCG is discussed.     

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.