Antti Kauppila

Placebo-controlled comparison of danazol and high-dose medroxyprogesterone acetate in the treatment of endometriosis.

A prospective, double-blind, placebo-controlled study was designed to evaluate the clinical efficacy and tolerance of danazol and high-dose medroxyprogesterone acetate (MPA) in the treatment of mild-moderate endometriosis. After laparoscopical confirmation of endometriosis, 59 patients were randomized to receive danazol (200 mg 3 times daily), MPA (100 mg daily) or placebo for 6 months. Clinical examinations were done before and 1, 3, 6 and 12 months after the beginning of the study, and a 2nd laparoscopy 6 months after termination of the medication. Eighteen patients in the danazol group, 16 in the MPA group and 17 in the placebo group completed the trial. Total or partial resolution of peritoneal implants was observed in 60% of the patients receiving danazol and in 63% of the patients receiving MPA. In the placebo group, resolution was observed in 18%, while the size of the implants was estimated to be increased in 23% of the patients. In relation to placebo, danazol and MPA significantly alleviated endometriosis-associated pelvic pain, lower back pain and defecation pain, but they did not differ from each other in these actions. The appearance of acne, muscle cramps, edema, weight gain and spotting bleeding complicated MPA treatment. The present results indicate that because of good efficacy and tolerance, high-dose MPA is a useful alternative in the hormonal treatment of endometriosis.

Estrogen and progestin receptors in endometriosis lesions: Comparison with endometrial tissue

Cytosol estrogen (ER) and progestin (PR) receptors were quantified in 47 endometriosis lesions from 41 patients and compared with receptor measurements in the endometrial tissue of nine of these patients. Half of the specimens of endometriosis tissue contained PR only, in concentrations that were significantly lower than in the endometrium. Only 30% of the specimens of endometriosis tissue contained the two receptors simultaneously, and levels of ER were very low compared with those in the endometrium. Levels of PR in the specimens of endometriosis tissue were highest at the periovulatory period, whereas concentrations of ER tended to be highest at the beginning and close to the end of the cycle. These results suggest that regulation of these receptors is dissimilar in endometriosis lesions and endometrium. It remains to be seen whether differences in receptor distribution in the lesions of individual patients could explain differences in the course of this disease, and have therapeutic implications. The presence of PR in the majority of the endometriosis lesions is in accord with the favorable therapeutic response often obtained with progestin treatment of this disease.

Placebo-controlled comparison of danazol and high-dose medroxypro-gesterone acetate in the treatment of endometriosis after conservative surgery

To evaluate the clinical value of postoperative hormone therapy in endometriosis, 60 patients with advanced disease were randomized to receive in a double-blind study danazol (200 mg, 3 times daily), medroxyprogesterone acetate (MPA) (100 mg daily) or placebo post-operatively for 6 months. Treatment efficacy was evaluated clinically and at laparoscopy 6 months after medication. In relation to placebo, danazol and high-dose MPA treatments, which did not differ from each other in efficacy, significantly alleviated pelvic pain. In addition, the peritoneal endometriosis lesions found at 6-months laparoscopy were significantly smaller in the MPA and danazol groups than in the placebo group. Breakthrough bleeding, weight gain and acne complicated danazol treatment but only breakthrough bleeding complicated MPA treatment. These data suggest that postoperative treatment of advanced endometriosis with high-dose MPA or danazol is clinically beneficial.

Oral administration and distribution of melatonin in human serum, saliva and urine.

In order to evaluate for future physiological and pharmacological studies the extent to which orally administered melatonin is found in human serum and saliva and excreted into urine we measured serum, saliva and urine concentrations of melatonin by radioimmunoassay after oral administration of 100 mg melatonin. Elevated melatonin concentrations were observed with peak values of 435 nmol/l in serum and 241 nmol/l in saliva at 60 min. Elimination was monophasic following first-order kinetics. The half-lives for serum and saliva melatonin were 41 and 38 min, respectively. The results suggest that melatonin is passively secreted into saliva which reflects closely the changes in serum melatonin. Saliva sampling is thus useful in studies on peripheral melatonin both in physiological and experimental conditions. Urinary excretion of melatonin was 0.01 % of the amount of melatonin ingested. In high-performance liquid chromatography urine extracts were found to contain also a minor unknown immunoreactive component which we suggest to be some unknown metabolite of melatonin.

Steroidal regulation of endometriosis tissue: lack of induction of 17β-hydroxysteroid dehydrogenase activity by progesterone, medroxyprogesterone acetate, or danazol

Cytosol and nuclear estrogen receptors were detected in 73% and 89% of untreated endometriosis specimens, respectively. The corresponding figures for cytosol and nuclear progestin receptors were 94% and 100%, respectively. Compared with the endometrium, the concentrations in endometriosis tissue were low. The anatomic site, the severity of the disease, and the phase of the menstrual cycle had no significant influence on receptor concentrations in endometriosis tissue. The activities of 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) did not increase during the luteal phase. Danazol for 1, 3, 7 to 11, and 18 to 30 days, or medroxyprogesterone acetate for 5 days, had no effect on receptor concentrations or 17 beta-HSD activity in endometriosis tissue. The frequent presence of the receptors suggests that endometriosis lesions are under the control of steroid hormones. The lack of effect by progesterone and progestins on 17 beta-HSD shows that this regulation is different in endometriosis tissue and in the endometrium.

Lead and cadmium concentrations in maternal and umbilical cord blood, amniotic fluid, placenta, and amniotic membranes.

The lead and cadmium concentrations in maternal and umbilical cord blood and amniotic fluid were determined in 19 parturient women at delivery. Six placental and amniotic membrane tissue specimens were also investigated. The mean lead concentrations (mean +/- SD) in maternal (40.4 +/- 18.2 ng/ml) and umbilical cord (37.1 +/- 13.5 ng/ml) blood were similar and correlated significantly with each other (r = 0.77, p less than 0.001). The lead concentration in amniotic fluid (59.6 +/- 8.3 ng/ml) was significantly higher than in maternal or umbilical cord blood. Cadmium concentrations in maternal blood (1.1 +/- 0.9 ng/ml) and amniotic fluid (1.0 +/- 0.2 ng/ml) were significantly higher (p less than 0.001) than in umbilical cord blood (0.4 +/- 0.2 ng/ml) and there was no significant correlation among these values. The highest concentrations of cadmium (35.1 +/- 24.2 ng/gm of wet weight) and lead (87.3 +/- 154.2 ng/gm of wet weight) were found in the amniotic membranes. Our results show that lead and cadmium accumulate in amniotic fluid and amniotic membranes and that the distribution of lead and cadmium is different in the human maternal-fetoplacental unit. The fetal exposure to lead is similar and that to cadmium, lower, compared with maternal exposure. The inability of the placenta to totally prevent the fetus from exposure to lead and cadmium suggests that pregnant women should avoid occupations where exposure to these toxic elements is possible.

Evidence of Founder Mutations in Finnish BRCA1 and BRCA2 Families

This study was supported by the University of Oulu, Oulu University Hospital, the Finnish Cancer Society, the Cancer Foundation of Northern Finland, and the Finnish Breast Cancer Group. We also wish to thank Ake Borg, Arto Mannermaa, Jarmo Korkko, Helena Rahja, and Kari Mononen.

Transdermal estrogen with a levonorgestrel-releasing intrauterine device for climacteric complaints: Clinical and endometrial responses☆

OBJECTIVE Our purpose was to study the effects of intrauterine release of a daily dose of 20 micrograms levonorgestrel by an intrauterine device on climacteric symptoms, bleeding pattern, and endometrial histologic features in postmenopausal women receiving transdermal estrogen replacement therapy. STUDY DESIGN Forty parous postmenopausal women were randomly allocated into two groups for 1 year: 20 women receiving a continuous transdermal daily dose of 50 micrograms of estradiol had a levonorgestrel-releasing intrauterine contraceptive device inserted, and the control group of 20 women received a continuous oral dose of 2 mg of estradiol valerate and 1 mg of norethisterone acetate daily. The climacteric symptoms, bleeding patterns, endometrial thickness, and endometrial changes in biopsy samples were analyzed. Serum levels of estradiol in both groups and levonorgestrel levels in the intrauterine device group were also determined. RESULTS Both treatment regimens effectively relieved climacteric symptoms. Spotting was more common in the intrauterine contraceptive device group than in the oral therapy group for the first 3 months. After that, the proportion of women without any bleeding was similar in both groups. Two patients in each group dropped out because of bleeding. CONCLUSION These preliminary findings suggest that the levonorgestrel-releasing intrauterine contraceptive device is a useful alternative mode of progestin administration for certain selected women receiving estrogen replacement therapy.

Cytosol estrogen and progestin receptors in endometrial carcinoma of patients treated with surgery, radiotherapy, and progestin. Clinical correlates

Cytosol progestin (PR) and estrogen receptor (ER) concentrations were measured in 114 endometrial carcinoma specimens from 109 patients; these levels were correlated with clinical and histopathologic characteristics, and with clinical outcome in 44 patients followed for at least two years after the primary therapy consisting of surgery, irradiation and adjuvant administration of progestin. Eighty percent of all specimens were simultaneously PR‐ and ER‐positive (≥6 fmol and ≥3 fmol/mg protein, respectively) whereas 10% were both PR‐ and ER‐negative. Early clinical stages (I and II) were more often receptor‐positive, and the receptor concentration in these tumors was higher than in advanced or recurrent disease. The same was the case for superficial as compared with deeply invasive lesions. Both PR and ER concentrations in well or moderately differentiated tumors were higher than in anaplastic carcinomas. PR and ER concentrations did not correlate with the age or menopausal status, body weight or carbohydrate metabolism of the patients. In the patient group followed up for two years or more, the receptor‐poor tumors tended to behave more aggressively than did receptor‐rich malignancies in relation to patient survival. The measurement of PR and ER concentrations in advanced endometrial carcinoma has been proved useful in the selection of hormonal or cytotoxic chemotherapy. The current results advocate their use as prognostic risk factors which might be useful in selection of the most efficient treatment modalities for individual patients.

LH(hCG) Receptor in Benign and Malignant Tumors of Human Ovary

LH(hCG) receptors were identified with [125I]hCG in 38 benign and 26 malignant ovarian tumors of the human ovary. Eighteen per cent of all the benign and 27% of all the malignant tumors were LH(hCG) receptor‐positive. Four of 12 benign serous tumors and 3 of 17 benign mucinous tumors displayed definitive binding of [125I]hCG. Two Brenner tumors failed to bind [125I]hCG. Six of 21 malignant epithelial tumors displayed definitive binding of [125I]hCG. Only one out of 4 malignant granulosa cell tumors bound [125I]hCG, while the other sex cord stromal tumors as well as one dysgerminoma failed to bind [125I]hCG. LH(hCG) receptor content in the benign and malignant receptor‐positive tumors was low compared with the normal ovarian tissue. The presence of LH(hCG) receptors in certain benign and malignant ovarian tumors may be a sign of the gonadotropic control of these tumors. The possible applications of these findings for the diagnosis and treatment of human ovarian tumors is discussed.