Cell surface coatings and membrane potentials of malignant and nonmalignant cells.

A positive surface potential indicating a cell coating is common to malignant cells, lymphocytes, and normal and malignant trophoblastic cells. This characteristic was not generally found for other normal cell types tested by microelectrode penetration.

Pituitary-thyroid function in trophoblastic disease.

Pituitary-thyroid function was assessed in 12 patients with trophoblastic disease (4 hydatidiform mole, 3 invasive mole, and 5 choriocarcinoma). Thyroid-stimulating activity was detectable, by means of the McKenzie bioassay, in 6 patients (Group 1) but not in the other 6 patients (Group 2). In Group 1 serum thyrotropin (TSH) determined by radioimmunoassay was mostly undetectable and did not respond to the administration of thyrotropin-releasing hormone (TRH) determined by radioimmunoassay was mostly undetectable and did not respond to the administration of thyrotropin-releasing hormone (TRH), while in Group 2 basal TSH was detectable in half of the patients and responded to TRH in all cases. Serum concentrations of total thyroxine (T4) (18.7 +/- 2.0 mug/100 ml, mean +/- SE), free T4 (4.9 +/- 0.04 ng/100 ml), total triiodothyronine (T3) (352 +/- 72 ng/100 ml), and free T3 (0.57 +/- 0.11 ng/100 ml) in Group 1 were statistically greater than those in Group 2 (total T4, 9.2 +/- 1.0 mug/100 ml, free T4, 2.0 +/- 0.2 ng/100 ml; total T3 156 +/- 20 ng/100 ml, and free T3 0.23 +/- 0.03 ng/100 ml). Free T4 and T3 fractions were within normal limits in both groups. After treatment of 5 patients in Group 1, the thyroid stimulating activity determined by bioassay dropped to undetectable levels, the serum concentrations of thyroid hormones decreased to normal limits, and TSH response to TRH became positive. These findings indicate that an abnormal thyroid stimulator, derived from the trophoblastic tissue, stimulated the thyroid hormone secretion from the thyroid gland and in turn suppressed TSH response to TRH in some patients with trophoblastic disease.

Persistent nonmetastatic gestational trophoblastic disease.

The management of GTD has developed as a result of an accurate and sensitive serologic marker, effective chemotherapeutic agents, and the judicious treatment of patients with evidence of persistence. Treatment and intervention guidelines are well established and will lead to a successful outcome for nearly all patients. Reproductive potential can be preserved and chemotherapy toxicity has been made quite manageable in the minority of patients requiring its administration. However, as demonstrated in the patient whose case is presented, violation or deviation from these guidelines for monitoring and intervention can lead to the unnecessary sacrifice of reproductive capability and the administration of potentially toxic multiagent chemotherapy regimens.

The role of hCG in regulation of the thyroid gland in normal and abnormal pregnancy.

There is strong evidence that at least some forms of hCG can interact with and stimulate the thyroid both in vitro and in vivo. Changes in thyroid tests are sufficiently common in normal pregnancy for us to regard them as physiologic. The evidence that hCG is the agent responsible for these changes remains largely circumstantial but is now supported by an increasing body of evidence from laboratory studies. Trophoblastic tumors secrete variant forms of hCG that can stimulate the thyroid, but we do not know if they have any role in the extreme examples of thyroid stimulation encountered in normal pregnancy. Preparations of hCG from pregnancy urine bind to thyroid membranes from a wide variety of species, but they do not activate adenylate cyclase in all assay systems. The enzyme in human thyroid cells or membranes is, at best, only weakly stimulated by hCG. There are ample in vitro data that hCG can stimulate the thyroid, but studies using human thyroid cells have yielded conflicting results. The most direct evidence comes from the study of thyroid tests in normal pregnancy. In early pregnancy, when hCG concentrations are highest, free thyroid hormones are increased and serum TSH concentration is decreased. An inverse correlation exists between serum hCG and TSH concentrations, but hCG generally correlates poorly with individual thyroid tests. An activity in pregnancy serum related to hCG is able to stimulate FRTL-5 cells and may account for the changes in thyroid function observed in pregnancy. Structural considerations, along with data from biologic assays and sensitive thyroid function tests, suggest that hCG has significant thyroid-stimulating activity. This information suggests that the thyroid may be under dual control from both hCG and TSH in early pregnancy.

Correlation of uterine hemodynamics with chemotherapy response in gestational trophoblastic tumors.

OBJECTIVE: To assess the uterine hemodynamics in gestational trophoblastic tumors and to correlate them with response to chemotherapy. METHODS: Using transvaginal color Doppler ultrasound, we measured the peak systolic velocity and the resistance index (RI) of the uterine arteries in 23 women with gestational trophoblastic tumors before each course of chemotherapy. Fifty-five nonpregnant women and another 15 women who had uneventful molar evacuation were enrolled as controls. Two-tailed Student t test was used for statistical analysis. RESULTS: A hyperdynamic uterine circulation was noticed at diagnosis in all gestational trophoblastic tumors, manifested as higher peak systolic velocity (mean +/- standard deviation 57.5 +/- 20.4 cm/second) of the uterine arteries compared to nonpregnant (28.3 +/- 3.41 cm/second; P < .0001) and uneventful post-mole uteri (26.8 +/- 3.08 cm/second; P < .0001). The RI values of the uterine arteries in gestational trophoblastic tumors at diagnosis ranged from 0.21-0.80. However, the mean value (0.56 +/- 0.19) was lower than those of nonpregnant (0.80 +/- 0.05; P < .0001) and post-mole uteri (0.75 +/- 0.06; P < .0001). A higher pre-treatment uterine artery RI (mean 0.71 +/- 0.09) was noted in ten patients with gestational trophoblastic tumors requiring fewer than five courses of chemotherapy, compared with the mean in 13 patients requiring longer courses of treatment (0.47 +/- 0.14; P < .0001). There was a marked decrease of peak systolic velocity during the first three courses of treatment in the former group (54.2 to 23.6 cm/second; P < .001), in contrast to no change in the latter group (60.1 to 60.5 cm/second). CONCLUSION: Uterine hemodynamic characteristics assessed by color Doppler ultrasound might predict and monitor the response to chemotherapy in gestational trophoblastic tumors.

High-risk metastatic gestational trophoblastic disease.

The clinical course of 61 patients with high-risk metastatic gestational trophoblastic disease was reviewed. Currently, 34 patients (56%) are alive and in complete remission. The survival rate after full-term pregnancy was significantly worse than after any other type of antecedent pregnancy. Analyzing survival by individual high-risk criteria revealed significantly improved survival for those patients with elevated beta-human chorionic gonadotropin titer alone when compared with all other high-risk criteria. Fifty-eight percent of patients (14 of 24) primarily treated with alternating-sequential therapy consisting of methotrexate and actinomycin-D experienced a complete remission. Of those patients primarily treated with methotrexate, actinomycin-D, and cyclophosphamide, 63% (20 of 32) achieved a complete remission. Treatment with second-line chemotherapy was largely unsuccessful. Aggressive early treatment is warranted in this group of patients, using multiagent chemotherapy. A search for newer more effective regimens should continue.

Human chorionic gonadotropin and the thyroid: hyperemesis gravidarum and trophoblastic tumors.

There is abundant evidence that human chorionic gonadotropin (hCG) is a weak thyrotropin (TSH) agonist. In FRTL-5 rat thyroid cells, hCG increases cyclic adenosine monophosphate (cAMP), iodide transport, and cell growth. hCG has thyroid-stimulating activity in bioassays in mice and in clinical studies in man. In cultured cells transfected with the human TSH receptor, hCG increases generation of cAMP. Molecular variants of hCG with increased thyrotropic potency include basic molecules with reduced sialic acid content, truncated molecules lacking the C-terminal tail, or molecules in which the 47-48 peptide bond in the beta-subunit loop is nicked. In normal pregnancy, when hCG levels are highest at 10 to 12 weeks gestation, there is suppression of serum TSH levels, presumably due to slight increases in free thyroxine (T4) concentration. In twin pregnancies, hCG levels tend to be higher and suppressed TSH levels are more frequent. Hyperemesis gravidarum, defined as severe vomiting in early pregnancy that causes 5% weight loss and ketonuria, is usually associated with increased hCG concentration. A high proportion of patients with hyperemesis gravidarum, about one-third to two-thirds in different series, have evidence of increased thyroid function. Only a small proportion of these patients have clinical hyperthyroidism, termed gestational thyrotoxicosis. These patients probably secrete a variant of hCG with increased thyroid-stimulating activity. Trophoblastic tumors, hydatidiform mole, and choriocarcinoma often cause hyperthyroidism because they secrete very large amounts of hCG. When the serum hCG exceeds about 200 IU/mL, hyperthyroidism is likely to be found. There is a correlation between the biochemical severity of hyperthyroidism and the serum hCG in these patients. Removal of the mole or effective chemotherapy of the choriocarcinoma cures the hyperthyroidism. In conclusion, hCG has thyroid-stimulating activity that influences thyroid function early in pregnancy when hCG levels are high. Excessive hCG secretion may cause hyperthyroidism in patients with hyperemesis gravidarum or trophoblastic tumors.

Thyroid function in gestational trophoblastic tumors.

Thyroid function was assessed in a total of 15 cases, 7 of whom had choriocarcinoma and 8 hydatidiform mole, by measuring free T3, free T4, thyroxin-binding globulin (TBG), basal thyroid-stimulating hormone (TSH) and after the thyrotropin-releasing hormone test (delta TSH). Free T3, free T4 and TBG were investigated in the same number of healthy women within the first three months of pregnancy. Only 13.4% of the cases presented elevated levels of free T3 and T4 and TBG; TSH and delta TSH were within normal limits. Both thyroid hormones and TBG returned to within normal limits when beta-human chorionic gonadotropin became undetectable. One patient was found to be hypothyroid. Comparison with the control group showed no significant differences except in TBG levels, which were higher in controls. A significant, direct correlation was found between levels of free T3 and T4 and TBG and the pattern of human chorionic gonadotropin.

Changes in gestational trophoblastic tumors over four decades. A Korean experience.

OBJECTIVE: To review changes that occurred in gestational trophoblastic tumor (GTT) patients treated over four decades and to identify factors leading to the changes. STUDY DESIGN: A retrospective study of 287 cases treated during 1961-1967, 1975-1979, 1980-1986 and 1990-1994. The method of diagnosis, incidence and outcome in each decade and factors that may have had an influence, on incidence, outcome or both, were reviewed. RESULTS: Diagnosis shifted from pathologic (1960s) to clinical (1990s). The incidence per 1,000 births decreased from 4.4 (1960s) to 1.6 (1990s). The incidence showed a 26-fold increase in women aged 40 and over and 13.4-fold increase in women para 3 and over. The obstetric population showed a decrease in the high-risk group of greater age and higher parity. Assessment by the 1983 World Health Organization prognostic score showed an increase in low-risk and decrease in high-risk disease. Prognostic score changes are related to a decrease in GTT in older women, increase in GTT with a short interval and increase in nonmetastatic disease. Overall mortality decreased from 32.6% to 2.6%. CONCLUSION: The decreased incidence and improved outcome of GTT in Korea are related to improved medical care and to social, economic and educational changes.

Reproductive status in GTD treated with etoposide.

OBJECTIVE: To investigate the mechanism and degree of ovarian dysfunction in gestational trophoblastic disease (GTD) patients treated with etoposide alone. STUDY DESIGN: Forty-seven patients with low-risk GTD were treated with etoposide alone, and pituitary-ovarian function was evaluated by measuring basal serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol and progesterone and by recording basal body temperature. Moreover, the responses of LH and FSH to the administration of LH-releasing hormone (LHRH) and the responses of prolactin to thyrotropin-releasing hormone (TRH) were analyzed after the completion of etoposide treatment. RESULTS: Increased basal LH and FSH levels were found in approximately 50% of patients, especially those over 40 years old. Although the LH and FSH responses to LHRH were exaggerated in patients with high basal FSH levels, the prolactin responses to TRH were normal. Ovulation resumed within 121 days after the cessation of chemotherapy in women under 39 years. However, five of nine patients over 40 years remained anovulatory during the follow-up period. CONCLUSION: Ovarian function was impaired in approximately 50% of patients treated with etoposide at the time of LHRH study, though pituitary function was preserved. This complication is age related but not related to the amount of etoposide exposure. Therefore, we must consider the possibility of permanent anovulation when we treat patients 40 years old and older.

Recent advances in gestational trophoblastic disease.

Recent advances have increased our understanding of gestational trophoblastic disease, and epidemiologic studies have demonstrated that there are important differences in risk factors for complete and partial mole. Complete moles are now increasingly being diagnosed in the first trimester, affecting their clinical presentation and pathologic characteristics. While important advances have been made in chemotherapy, it is now recognized that etoposide is associated with a risk of second tumors. Several studies have advanced understanding of the molecular biology of gestational trophoblastic disease, and this is important for the eventual development of new and innovative therapy.

[Effects of ACM sequential chemotherapy on ovarian function in trophoblastic tumors].

OBJECTIVE: To study the changes of ovarian function during and after ACM sequential chemotherapy on trophoblastic tumors. METHODS: 17 patients with trophoblastic tumors, received totally 48 cycles of ACM chemotherapy. Of these, 7 underwent hysterotomy and focal ectomy and ovarian biopsy. Changes of menstruation and BBT were observed. beta-hCG, E2, FSH and LH were assayed and histological and immunohistochemical studies in ovaries biopsied were made. RESULTS: Amenorrhea and anovulatory BBT were predominant at the onset of chemotherapy and high level of beta-hCG. Following chemotherapy and decrease of beta-hCG, menstruation recovered with less amount and BBT transformed into ovulatory types with shorter luteal phase. The E2 level appeared to be lower and the FSH and LH level higher. The different kinds of follicles were decreased, but estrogen receptors unchanged. Follow-up showed that ovarian function of 12 of the 17 patients returned to normal in one year. CONCLUSION: ACM chemotherapy suppresses ovarian function mildly and temporarily. Trophoblastic tumor also affects ovarian function. ACM chemotherapy seems to be suitable for young patients with trophoblastic tumors who desire child-bearing.

[Hysterotomy and focal ectomy of malignant trophoblastic tumor].

Hysterotomy and focal ectomy were performed on 25 patients with malignant trophoblastic tumor during 1979-1991, owing to the patients and their husbands desiring strongly to have reproductive function preserved. Each of the foci of malignant trophoblastic tumor was found to be single nodule with 1-4 cm in diameter and located within the myometrium. The incision of uterus was sutured interuptly with "2-0" catgut. The pregnant rate was 80% among the patients who had received this surgical therapy. The results showed that hysterotomy and focal ectomy were an effective management for some patients without children.

[Adrenal cortex function in trophoblastic disease]. / Funktsional'noe sostoianie kory nadpochechnikov pri trofoblasticheskoi bolezni.

In 100 patients with trophoblastic tumors the functional activity of the adrenal cortex was examined before and after chemotherapy. Androgen-producing function of the adrenal cortex was found to be reduced as well as the absolute number of excreted 17-ketosteroids separate fractions and their ratio. The glucocorticoid function of the adrenal cortex shows a monotonous character. Only in patients having uterine chorion-epithelioma with metastases a reliable reduction of the fraction of 11-hydroxy-17-ketosteroids is noted before and after chemotherapy, while the per cent content of free 17-oxy-corticoid fraction is increased with regard to their total amount. Successful chemotherapy, associated with a lower titre of chorionic gonadotropins up to its complete disappearance, does not result in normalization of values characterizing the functional activity of the adrenal cortex.

[Function of the hypophyseal-ovarian-adrenal system in trophoblastic disease]. / Funktsional'noe sostoianie gipofizarno-ovarial'no-nadpochechnikovoi sistemy pri trofoblasticheskoi bolezni.

Hyperproduction of chorionic gonadotropin was shown to be the first link in the chain of hormonal disturbances involved in trophoblastic disease, which induced changes of pituitary gonadotropic function. Ovarian function is affected by disturbances in trophoblastic and pituitary gonadotropic functions and depends on the extension and severity of the disease. This makes a case for corrective hormonal therapy in chorionepithelioma patients resistant to cytostatic or substitution therapy with sex hormones and in whom ovaries have been removed during combined treatment.

[Gestational trophoblastic disease--literature review].

Gestational trophoblastic disease is characterized by abnormal proliferation of pregnancy-associated trophoblastic tissue with malignant potential. Gestational trophoblastic disease covers a spectrum of conditions including hydatidiform mole, invasive mole, choriocarcinoma and placental site trophoblastic tumour. It is very important to understand the pathophysiology and natural history of the disease in order to achieve faster recognition and effective treatment. The presence and course of the disease can be monitored with quantitative levels of human chorionic gonadotrophin in all cases. Clinical signs and symptoms are usually insufficient to diagnose and predict the extent of disease. Nowadays, gestational trophoblastic diseases are the best treated gynaecological malignancy thanks to modern technology. This review covers various aspects of gestational trophoblastic disease: its development, epidemiology, aetiology and pathogenesis, as well as its classification, clinical manifestations and diagnostic methods.