GnRH analogues and uterine leiomyomas. Effect of hormone replacement therapy on cell proliferation.

Cell proliferation in uterine leiomyomas treated preoperatively with either nafarelin (400 microg/day) for 3 months (7 patients) or nafarelin plus hormone (oestradiol + norethisterone) add-back therapy (6 patients) was investigated by automatic image analysis of frozen tissue sections using immunohistochemistry with anti-proliferating cell nuclear antigen antibody. GnRHa therapy decreased cell proliferation in leiomyomas to a level corresponding to the situation previously seen in postmenopausal leiomyomas. However, there was no consistent correlation between cell proliferation and shrinkage of leiomyomal size. The hormone add-back therapy moderated the influence of GnRHa on cell proliferation and completely blocked a decrease in size of leiomyomas in our patients.

Demonstration of Chlamydia trachomatis in Papanicolaou-stained gynecological smears.

A fluorescent antibody staining method was developed to detect Chlamydia trachomatis elementary bodies in Papanicolaou-stained cervical smears. Twenty-five known chlamydia-positive and 12 chlamydia-negative smears were correctly identified using this method. Smears from individuals with culture-positive chlamydia infections showed a high density of elementary bodies. Among 64 routine cervical smears, 27% (6/22) of smears that showed inflammatory changes were positive by fluorescent antibody staining for chlamydia, compared to 2.4% (1/42) of smears that were negative for inflammatory changes. This method should facilitate detection of chlamydia infections in populations undergoing cytological screening.

Zoladex (goserelin acetate) and the anemic patient: results of a multicenter fibroid study.

OBJECTIVE: To compare the effects of goserelin acetate treatment with or without iron with iron alone. DESIGN: Multinational, multicenter, prospective, randomized, double-blind study. PATIENTS: Premenopausal women with menorrhagia or metrorrhagia and anemia associated with uterine leiomyomata awaiting hysterectomy. INTERVENTION: Patients were randomized to one of three 12-week treatment groups namely goserelin acetate 3.6 mg once monthly plus placebo iron; 3.6 mg goserelin acetate once monthly plus 600 mg/d iron; or sham injection once monthly plus 600 mg/d iron. MAIN OUTCOME MEASURE: Preoperative hemoglobin concentration; preoperative uterine and fibroid volumes and operative blood loss. RESULTS: Considering the entry and preoperative hemoglobin concentrations, there was a difference in least square means of just over 1 g/dL between the goserelin acetate plus iron and iron only groups and 2.6 g/dL between the goserelin acetate plus iron and goserelin acetate only group. These differences were both statistically significant. Uterine and fibroid volumes were decreased in the goserelin acetate-treated patients by between 37% and 40% and 44% and 47%, respectively, compared with 7% decreases for both in the iron only group. The differences in absolute changes were statistically significant for both the goserelin acetate-treated groups versus the iron-treated group. The least square geometric mean operative blood loss was greatest in the iron only group. CONCLUSION: In the patient with uterine leiomyomata and anemia, goserelin acetate in combination with iron therapy has shown significant advantages over the iron alone in restoring hematologic normality, decreasing uterine and fibroid volumes, and reducing operative blood loss.

Comparison of the gonadotropin-releasing hormone agonist goserelin acetate alone versus goserelin combined with estrogen-progestogen add-back therapy in the treatment of endometriosis.

OBJECTIVE: To investigate whether the addition of low-dose estrogen-P combination hormone replacement therapy (HRT) to GnRH agonist (GnRH-a) treatment for endometriosis reduces the pharmacologic side effects of such treatment without reducing efficacy and to determine the endocrinologic changes during treatment. DESIGN: Prospective, randomized, double-blind, placebo-controlled, comparative study of two drug regimens: 3.6 mg goserelin acetate in a 28-day SC depot formulation once monthly for 6 months plus either a combination of 2 mg 17 beta-E2 and 1 mg norethisterone acetate (NET) 1 mg or matching placebo tablets once daily for 6 months. SETTING: Multicenter study in three tertiary referral centers at university teaching hospitals and two central hospitals. PATIENTS: Women with laparoscopically confirmed symptomatic endometriosis were included in the study. RESULTS: Of the total of 109 patients screened, 93 were recruited and 88 patients were randomized to either the HRT or the placebo group. Four women were withdrawn because of various medical reasons, and 76 patients were followed-up for a total of 12 months. In terms of efficacy, there was no difference between the two drug regimens for objective or subjective response. There were significantly less postmenopausal symptoms in the patients treated with goserelin plus HRT compared with those treated with goserelin plus placebo. CONCLUSION: Goserelin diminished significantly the symptoms and laparoscopic scores of endometriosis. The addition of HRT did not reduce the efficacy of goserelin but diminished the postmenopausal symptoms during treatment.

Decrease in symptoms, blood loss and uterine size with nafarelin acetate before abdominal hysterectomy: a placebo-controlled, double-blind study.

To evaluate the efficacy and safety of nafarelin before hysterectomy in a prospective placebo-controlled trial, we randomized 188 pre-menopausal women with uterine fibroids (n = 111), menometrorrhagia (n = 58) or pelvic pain (n = 19) to receive either nafarelin (200 micrograms twice daily as a nasal spray) or a placebo for 3 months before abdominal hysterectomy. The data analysis could be performed in 166 women, of whom 107 received nafarelin and 59 a placebo. Nafarelin led to a rise in blood haemoglobin (5.5 g/l) and to a decrease in uterine volume (23.7%). This, however, gave no objective benefit during surgery (similar operative durations and blood losses). The uteri from patients treated with nafarelin (255.5 +/- 12.6 g, mean +/- SD) were significantly lighter (P = 0.029) than those from patients treated with a placebo (346.2 +/- 35.7 g). Histological examination of the fibroids or uteri revealed changes typical for hypo-oestrogenism, but no specific histological pattern could be established. The endometrium was proliferative in 56% and showed mild hyperplastic features in 10% of patients given nafarelin, whereas the respective figures for the placebo group were 41 and 0%. Hot flushes were the most common side-effects, being reported by 61% in the nafarelin group and 35% in the placebo group. Nafarelin can be useful as a pre-surgical adjunct in a patient scheduled for abdominal hysterectomy if there is a need to raise the haemoglobin concentration or to reduce the size of the uterus.

Combined intraperitoneal interferon alpha-2b and mitoxantrone in refractory ovarian cancer.

In a non-randomized clinical trial, combined intraperitoneal therapy with recombinant interferon alpha-2b (20-50 MU) and mitoxantrone (20-50 mg) was studied for recurrent ovarian cancer with ascites. Altogether 19 patients were treated. After primary operation, all patients had received intravenous chemotherapy, 16 of which included cisplatin. One patient had complete response, seven patients partial response, four no change and seven progressive disease. The mean duration of the responses was 5+ months (range 1-12), and mean survival time 4.5+ months (range 1-14+). Eight patients had side effects (flu-like symptoms, dyspnea, abdominal pain, vomiting, diarrhea, fever and bowel obstruction). It was concluded that the formation of ascites in refractory ovarian cancer can be reduced with intraperitoneal administration of interferon alpha-2b and mitoxantrone, with tolerable side effects.

Inheritance of intrahepatic cholestasis of pregnancy in one kindred.

We report three sisters with intrahepatic cholestasis of pregnancy (ICP) and the pedigree of the family, including six generations. ICP was observed in five successive generations; most of the patients also had cholelithiasis. The uniform expression, the complete penetrance of the trait and the direct parent-to-child transmission support the Mendelian dominant mode of inheritance. Determination of HLA A, B and C haplotype was made in five ICP patients, without any findings of HLA type common to everyone. X-linked inheritance cannot be excluded in this study.

Monitoring of smooth muscle antibodies in hypertensive complications during pregnancy.

Smooth muscle antibodies (SMA) were monitored in terms of titer, immunoglobulin class and staining pattern by indirect immunofluorescence assay during the pregnancies of 32 women with pregnancy induced hypertension (PIH), 21 with essential hypertension (EH), and 43 with a normal pregnancy. The mean SMA titer was higher both in PIH and EH than in normal pregnancy. SMA were mainly of the IgG class and gave a "vessel wall" staining pattern in immunofluorescence. The tendency for the mean SMA titer to increase was observed in PIH, whereas a falling tendency was found in EH and normal pregnancy. These tendencies suggest that hypertension, the duration of which has been shorter in PIH, induces SMA production. The observed staining pattern suggests the same kind of non-actin specificity for SMA as in our previous study of complications in early pregnancy.

Detection of small for gestational age fetuses by the combination of clinical risk factors and ultrasonography.

Clinical risk factors of fetal growth retardation and targeted ultrasound examinations were combined to detect small for gestational age (SGA) fetuses below the 10th percentile weight for age in 1122 unselected singleton pregnancies, in which the true gestational age was confirmed by ultrasonography at 18 weeks. The prevalence of SGA infants was 6.0% in this population. A risk group of 236 (21%) mothers was referred for an ultrasound examination of fetal growth by the midwives of maternity welfare centers on the basis of low symphysis-fundal height or five other major maternal risk factors (pregnancy associated hypertension, loss of weight gain, a previous SGA infant, pre-pregnancy weight below 50 kg, any smoking during pregnancy). The sensitivity and positive predictive value of the clinical part of the study were 83.6 and 23.7%, respectively. Fetal growth was assessed by measuring both biparietal diameter (BPD) and transverse abdominal diameter. In the clinically selected risk group, 83.9% of the SGA fetuses could be detected by this method using a cutoff level of -1 standard deviation (SD). The two-step screening combining clinical and ultrasonographic methods in the detection of SGA fetuses in general population showed a sensitivity of 70.1%, a specificity of 95.5%, a positive predictive value of 49.5%, and a negative predictive value of 98.1%. After ultrasound examination, the definitive risk group for SGA was 8.5% of the total material of 1122.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of toremifene on clinical chemistry, hematology and hormone levels at different doses in healthy postmenopausal volunteers: phase I study.

Toremifene was given within the dose range of 3-680 mg as a single dose or on five consecutive days to 72 postmenopausal volunteers. Blood samples for clinical chemistry were taken hourly up to 7 h and 1, 2, 3, 7, 10 and 15 days after the last dose of toremifene. The concentrations of serum bilirubin, creatinine, amylase, free thyroxine, cortisol, prolactin, electrolytes and blood glucose remained unchanged at all dose levels. A statistically significant decrease was observed in liver enzymes (ASAT, ALAT, ALP) at the dose levels of 220-680 mg, whereas gamma-GT remained unchanged. A decrease in the concentration of LH and FSH was observed at the dose levels of 46 mg or higher and 220 mg or higher, respectively. These hormonal changes including the increase of SHBG at the dose levels of 220-680 mg and the decrease of antithrombin III (220-680 mg) may be attributed to a weak estrogen-like effect of toremifene. Side effects were minimal: pulse rate, blood pressure and ECG remained unchanged during the test period. Only two patients on 680 mg dose suffered from nausea and vertigo, and one of them discontinued the medication.

Pharmacokinetics of toremifene.

The pharmacokinetics of toremifene has been investigated in man after single and multiple oral doses. Toremifene was completely absorbed without first-pass metabolism. Peak concentration in serum was achieved in 4 h. Mean half-lives of distribution and elimination were 4 h and 5 days, respectively. Kinetics was linear in the studied dose-range of 10-680 mg. Toremifene was over 99% bound to plasma proteins and extensively metabolized. The main metabolites in serum were demethyl- and deaminohydroxytoremifene. In patients receiving multiple dosing of 60 mg/day serum steady-state level of toremifene was 0.8 microgram/ml on average. The level of demethyl metabolite was twice and that of deaminohydroxy metabolite was one tenth of toremifene.

Genital human papillomavirus infections in the male sexual partners of 45 female patients with papillomavirus infection.

Forty-five women with a confirmed genital human papillomavirus (HPV) infection and their regular male sexual partners were examined. The diagnosis of the women was based on the colposcopic examination with cytological and histological samples. The men were studied by using a similar microscopic technique. Penisscopic and histological examinations showed that 22 out of the 45 men had genital HPV infection although only 7 men showed visible condylomatous warts. In addition, nine men had clinical lesions highly suggestive to HPV infection in penisscopy but they had unspecific histological samples. 23 of these 31 men were symptom-free. These results further emphasize the importance of regular examinations of the male sexual partners of women with genital HPV infection in order to prevent recurrences and spreading of the infection.

Diagnostic problems associated with cystinuria.

To elucidate the role of the urinary cystine concentration for the formation of urinary stones, 190 stone-formers were evaluated in this prospective study. Seven patients (3.8%) were heterozygous and one patient (0.5%) was homozygous for cystinuria; only two (1%) of them were cystine stone-formers. Two patients with calcium stones were heterozygous for cystinuria. This study confirms the observation that elevated concentrations of urine cystine are relatively infrequent among patients with urinary stones.

Phase II evaluation of peroral carmofur, cyclophosphamide, and hexamethylmelamine as a second-line therapy in advanced epithelial ovarian carcinoma.

A prospective phase II study was performed to evaluate the effect and tolerability of a peroral combination chemotherapy consisting of hexamethylmelamine, cyclophosphamide, and carmofur in patients with epithelial ovarian cancer previously heavily treated by cisplatin-based chemotherapy but no longer responding to it. Of the 27 patients 1 showed a clinical complete remission lasting 15+ months and 4 a partial remission of 6+ to 21 months. A further 7 patients had an unchanged situation of 4 to 13+ months. The median survival of the nonresponders was 3 months. The side effects were tolerable, mostly nausea and vomiting. Only 4 of 27 patients suffered from severe vomiting causing discontinuation of the therapy. The peroral ambulatory chemotherapy prolonged markedly the overall survival of about one-half of the patients with ovarian cancer who previously failed to respond to cisplatin-based chemotherapy.

Routine ultrasound screening for early detection of small for gestational age fetuses.

A real-time ultrasound screening examination was performed in 3208 unselected singleton pregnancies at 18 and 34 weeks to detect small for gestational age (SGA) fetuses below the tenth percentile weight for age. Such cases accounted for 4.9% of this population. Biparietal diameter (BPD) was used at the first examination to confirm the true gestational age. The growth was measured at 34 weeks with a combination of BPD and transverse abdominal diameter. With a cutoff level of -1.5 standard deviations (SD), the sensitivity of a single measurement was 62.2%, the specificity was 93.2%, and the positive predictive value was 32.4%. With a cutoff level of -1 SD, the values were 76.3, 84.8, and 20.4%, respectively. The positive predictive value approached 48.7% before birth in the group that was rescanned before delivery. The simple method of a combined measurement of BPD and transverse abdominal diameter provided efficient antenatal screening for diagnosis of SGA fetuses in the general population. A somewhat low positive predictive value indicates a control examination of fetuses suspected of being SGA. Nonlinear methods, such as the measurement of abdominal circumference, appear suitable for ruling out false-positive cases.

Tamoxifen and natural progesterone as supplements to low-dose postmenopausal estrogen therapy.

Postmenopausal women received 1 mg estrone sulfate a day for 3 weeks in 12 sequences separated by a 7-day interval without medication and every second time by a 10-day treatment with natural progesterone, 100 mg 2 times daily (n = 16), or tamoxifen, 10 mg 2 times daily (n = 17). Both treatments alleviated climacteric symptoms, maturated the vaginal epithelium, and decreased follicle-stimulating hormone, luteinizing hormone, and prolactin concentrations while lipid metabolism remained unaltered. In the estrogen-progesterone group 4 women (25%) were persistently amenorrheic, 12 (75%) experienced 1-5 bleedings per year, and 4 women had proliferative endometrium after treatments. In the estrogen-tamoxifen group 11 women (65%) were amenorrheic, 6 (35%) had 1-4 bleedings per year, and 5 had proliferative endometrium. With the present treatment schedules, tamoxifen was more effective than natural progesterone in inhibiting estrogen stimulation of postmenopausal endometrium.

Isolated prolactin deficiency in a woman with puerperal alactogenesis.

Idiopathic PRL deficiency was detected in a parturient woman with otherwise normal pituitary function. This PRL disorder first became manifest postpartum when she had no milk production, and oral metoclopramide failed to raise her serum PRL levels. Her second pregnancy occurred spontaneously after 3 yr of attempts to conceive. During the pregnancy, her serum PRL concentration was very low, varying from 4.5-7.8 ng/ml, and the puerperium was again characterized by alactogenesis. During normal menstrual cycles and after iv GnRH, TRH, metoclopramide, and insulin tolerance tests, serum PRL was only rarely detectable by RIA, at very low concentrations. Bioassay results confirmed the PRL deficiency. The results confirm that PRL is necessary for puerperal lactation and suggest that it is needed for normal ovarian function. The present data also suggest that the maternal pituitary is the main source of serum PRL during pregnancy, and the decidua has only a minor contribution in this respect.

Cervical carcinoma complicated by malignant pericarditis.

Malignant pericarditis is a rare complication of cervical cancer. In the present case a metastatic pericardial disease developed in a patient who was initially treated by radiation therapy for stage IIb cervical carcinoma. Shortly after the first cycle of chemotherapy with cisplatin, VP-16 and hexamethylmelamine, a pericardial effusion was observed. After drainage of the pericardium and diagnosis of malignant metastatic disease the patient was successfully treated with the initial combination chemotherapy. The patient is still alive 12 months after pericardiotomy.