Prediction of clinical outcome with estrogen and progestin receptor concentrations and their relationships to clinical and histopathological variables in endometrial cancer.

Concentrations of cytosol estrogen (ERC) and cytosol progestin (PRC) receptors were assayed in malignant tissue specimens of 230 patients with endometrial cancer, and those of nuclear estrogen and nuclear progestin receptors, and 17 beta-hydroxysteroid dehydrogenase activities in about 100 specimens. Endometrial cancer was at an early stage in 205 and advanced in 25 patients. As a supplement to surgical and radiation therapy, all patients received p.o. medroxyprogesterone acetate (100 mg a day) for 2 years. The follow-up time varied from 12 to 96 months (median, 42 months). Concentrations of ERC, PRC, nuclear estrogen, and nuclear progestin receptors in endometrial cancer tissue were significantly lower in clinical stages III-IV than in clinical stage I. In clinical stage I, ERC and PRC appeared in significantly lower concentrations in anaplastic than in moderately and well differentiated malignancies. The concentrations of these receptors were increased in obese patients, and the activity of 17 beta-hydroxysteroid dehydrogenase was increased in patients younger than 50 years, suggesting that endogenous female steroid hormones modify the pattern of female steroid receptors in malignant endometrium. In clinical stage I, 13 of 153 patients with adequate therapy contracted a recurrent disease. Poor prognosis was predicted by anaplastic structure of the malignancy (P less than 0.001), low tissue concentrations (0-30 fmol/mg protein) of ERC alone (P = 0.006), PRC alone (P = 0.010), and ERC and PRC simultaneously (P = 0.004). All 101 patients who simultaneously had ERC and PRC in concentrations higher than 30 fmol/mg protein remained disease free for 2 years, whereas all recurrences in patients with receptor-poor tumors appeared during the 2 years of medroxyprogesterone acetate treatment. In clinical stage II, with 30 patients, no prognosis indicators predicted the clinical outcome, whereas in clinical stages III + IV, with 25 patients, low ERC concentrations were associated with a worsened prognosis (P = 0.045). Conclusively, cytosol and nuclear estrogen and nuclear progestin receptor concentrations and 17 beta-hydroxysteroid dehydrogenase activity give valuable information about the endocrine associations in endometrial cancer. Cytosol estrogen and cytosol progestin receptors appeared to be useful predictors of recurrent disease. They also have the potential to distinguish between patients expected to benefit from adjuvant progestin therapy and those expected to be unresponsive to the same treatment.

Estrogen receptor in human myoma tissue.

The occurrence and characteristics of an estrogen receptor in the cytosol of myoma samples from human uteri were investigated employing dextran-coated charcoal and density gradient centrifugation techniques. Receptor binding site concentrations in 24 myoma specimens ranged from 23 to 515 fmol/mg cytosol protein (98+/-108, mean+/-S.D.). In one myoma sample no receptor was found. The apparent equilibrium dissociation constant (Kd) was 1.3 X 10(-10) mol/l for estradiol-17beta. On sucrose density gradient centrifugation, [3H]estradiol was bound by macromolecules with sedimentation rates of 4 and 8 S. The latter component was specific for estrogens, whereas the former contained specific and nonspecific binding sites. Ligand specificity studies were carried out utilizing 30 different steroidal compounds. A good correlation was found between the in vitro binding affinity and the in vivo estrogenic potency of the compounds tested. The cytosol estrogen receptor from myoma had a ligand specificity which closely resembled that of the corresponding receptor in normal human myometrium and endometrium as well as in human breast carcinoma. The myoma estrogen receptor level was compared to that in normal myometrium and endometrium in 13 uterine specimens. The receptor concentrations in cytosol fractions from myoma and myometrium correlated significantly (P less than 0.05), whereas no correlation existed between the receptor levels in endometrial and myoma cytosols. Furthermore, the estrogen receptor content in myoma samples did not correlate to estradiol-17beta levels in the myoma cytosol or serum of the same patient.

Response of pituitary-adrenal axis on partal stress.

The circulating level of ACTH (by radioimmunoassay) and cortisol (by competitive protein binding) were determined at 1- to 2-hour intervals during spontaneous labor (N=8) and induced labor (N=28) and after delivery. There were no differences in ACTH levels between primiparous and multiparous women. The primiparous women displayed a higher level of cortisol throughout labor than the multiparous women, but not after delivery. After spontaneous onset of labor, ACTH levels were always lower than after elective induction of labor, while there were no differences in the levels of cortisol. The hypertensive complications of pregnancy did not affect the secretion of ACTH. In normal pregnancy the rise of cortisol during labor and after delivery was significant, but it was not significant in the group of patients with hypertensive complications.

Grand grand multiparity and birth weight.

OBJECTIVE: To evaluate the association between birth weight and birth order in grand grand multiparous women (i.e., those who have had at least ten deliveries). METHODS: The longitudinal population consisted of 96 grand grand multiparous women with 1098 singleton deliveries. Two birth cohorts formed the cross-sectional reference populations: one from 1966 with 7564 deliveries and one from 1985-1986 with 5691 deliveries. In each population, birth weight was compared in four birth-order groups: first, second to fifth, sixth to ninth, and tenth to 12th born. RESULTS: The birth weight increased with birth order in each population, especially in the longitudinal one. The association remained even after adjusting for gestational age, sex of the newborn, maternal diabetes mellitus, and body mass index. Children born tenth to 12th were 83 g (95% confidence interval [CI] 29, 137) heavier than those born sixth to ninth; these in turn were 29 g (95% CI -27, 85) heavier than children born second to fifth, and those born second to fifth were 169 g (95% CI 54, 283) heavier than first born infants. Further indirect adjustment for the secular trend decreased these contrasts somewhat. CONCLUSION: Birth order is an independent determinant of birth weight even until the tenth delivery.

Adrenocortical function of female endurance runners and joggers.

The aim of the present study was to investigate the long-term effects of endurance exercise on the function of the adrenal cortex of 18 female runners, 12 control subjects, and 13 joggers and their 11 control subjects by measuring the serum concentrations of cortisol and dehydroepiandrosterone sulfate and the responses of cortisol to intravenous ACTH injection. All of the participants were studied over one menstrual cycle, during a light training period in the autumn and a hard training period in the spring. There were no significant between-group differences in the concentrations of cortisol in the autumn or the spring. However, the mean spring vs autumn concentrations of cortisol were significantly increased in runners during the follicular and luteal phases of the menstrual cycle. The concentrations of cortisol in the ACTH response test were also increased at 30 and 60 min in runners and all the time in joggers in spring, in relation to the respective values in the autumn. The absolute and relative rises of cortisol in response to ACTH did not differ between the groups, but the relative spring vs autumn increase of cortisol was significantly higher at 60 min in the runners and lower at 30 min in the control subjects of the joggers. There were no differences in the serum concentrations of dehydroepiandrosterone sulfate between the groups, or between spring and autumn values in any group. In conclusion, chronic endurance exercise per se did not appear to alter the function of the adrenal cortex, while an undefined spring-associated factor, possibly the high luminosity, appeared to induce an increase in cortisol secretion in female runners.

Serum lipids and lipoproteins in postmenopausal women receiving transdermal oestrogen in combination with a levonorgestrel-releasing intrauterine device.

OBJECTIVES: To compare the effects of a non-oral combination of a transdermal oestradiol patch (50 micrograms daily) and an intrauterine device (IUD) releasing 20 micrograms of levonorgestrel daily on the serum pattern of lipids and lipoproteins with an established oral regimen of a daily dose of 2 mg of estradiol and 1 mg of noretisterone acetate. METHODS: An open, randomized study comprised of 40 healthy, early postmenopausal women. RESULTS: During 1 year the concentration of total cholesterol decreased 5.0% in the LNg-IUD group and 10.6% in the oral therapy group; HDL cholesterol decreased 10.9% and 12.8%, respectively, and HDL2 cholesterol decreased 18.1% and 26.9%, respectively. LDL cholesterol values did not change in the LNg-IUD group, whereas a 10.3% decrease was observed in the oral therapy group. Triglyceride values did not change in either group. There were no significant differences in the serum lipoprotein changes between the groups during the treatment. CONCLUSIONS: The use of a non-oral regimen of hormone replacement therapy has been advocated to minimize the effect of steroids on the liver. Its effects on the serum pattern of lipids and lipoproteins, however, did not differ significantly from those induced by a continuous oral treatment regimen.

STEROIDAL DRUGS IN ENDOMETRIOSIS.

Progestins, including medroxyprogesterone acetate (MPA), danazol and gestrinone, are used in the medical management of endometriosis. Danazol and gestrinone, by inducing progestin-like effects, closely resemble MPA in their actions on intrauterine endometrium. Ectopic endometrium, on the other hand, does not respond to these hormonal stimuli (as determined by estrogen and progestin receptor assays and 17ß-hydroxysteroid dehydrogenase activity measurements), indicating that the therapeutic effects of steroidal drugs may not be entirely due to an action on the endometrium. At therapeutic doses, these drugs also prevent the midcycle elevation in gonadotropic hormone secretion and suppress ovarian activity (as evidenced by follicular arrest and low and stable estrogen and progesterone secretion). These indirect actions of progestins are probably more important than their direct actions on the endometrium in the treatment of endometriosis. These steroidal drugs also have androgenic effects, though the increase in the free androgen index caused by danazol is significantly larger than that induced by gestrinone or by MPA. In a study involving treatment with danazol (200 mg three times a day), high-dose MPA (100 mg/day) or placebo for 6 months, danazol and MPA were found to have equal clinical efficacy (as judged by relief of symptoms and disappearance of lesions). Danazol therapy, however, caused more androgenic and metabolic side-effects. Those patients who were infertile were also examined at 30 months. The cumulative pregnancy rate in these patients over the duration of the trial was danazol 33%, MPA 42% and placebo 46%, with no significant difference between treatments. Hormonal therapy delayed conception by approximately 8 months. Steroidal drugs of this type, which are useful in the treatment of both the lesion and symptoms of endometriosis, are not in general the treatment of choice for infertility associated with endometriosis.

A shift from a male to a female majority in newborns with the increasing age of grand grand multiparous women.

In this longitudinal study, we investigated the relationship of birth order and the age of mother and father to the gender of 1795 newborns (mean +/- SD 12.5 +/- 1.6 per mother) of 143 grand grand multiparous (i.e women who have had >10 deliveries). The frequency of boys was 52.2% in the group of 1st to 9th paras and 46.2% in the group of 10th to 20th paras (P = 0.022). Mothers aged > or =35 years had 7.0% more female than male newborns (P = 0.024). The respective figure for fathers was 5.6% (P = 0.023). The interpregnancy interval evaluated for 96 mothers with 1091 deliveries had no correlation with the gender of the infants. In the stepwise logistic regression analysis, the age of the mothers remained the only significant independent factor for the shift from a male to a female majority in the newborns (P = 0.0389). The present data thus indicate that the age of the mother is the factor which explains why grand grand multiparous women deliver more girls than boys.

Steroidal drugs in endometriosis.

Progestins, including medroxyprogesterone acetate (MPA), danazol and gestrinone, are used in the medical management of endometriosis. Danazol and gestrinone, by inducing progestin-like effects, closely resemble MPA in their actions on intrauterine endometrium. Ectopic endometrium, on the other hand, does not respond to these hormonal stimuli (as determined by estrogen and progestin receptor assays and 17 beta-hydroxysteroid dehydrogenase activity measurements), indicating that the therapeutic effects of steroidal drugs may not be entirely due to an action on the endometrium. At therapeutic doses, these drugs also prevent the midcycle elevation in gonadotropic hormone secretion and suppress ovarian activity (as evidenced by follicular arrest and low and stable estrogen and progesterone secretion). These indirect actions of progestins are probably more important than their direct actions on the endometrium in the treatment of endometriosis. These steroidal drugs also have androgenic effects, though the increase in the free androgen index caused by danazol is significantly larger than that induced by gestrinone or by MPA. In a study involving treatment with danazol (200 mg three times a day), high-dose MPA (100 mg/day) or placebo for 6 months, danazol and MPA were found to have equal clinical efficacy (as judged by relief of symptoms and disappearance of lesions). Danazol therapy, however, caused more androgenic and metabolic side-effects. Those patients who were infertile were also examined at 30 months. The cumulative pregnancy rate in these patients over the duration of the trial was danazol 33%, MPA 42% and placebo 46%, with no significant difference between treatments. Hormonal therapy delayed conception by approximately 8 months.(ABSTRACT TRUNCATED AT 250 WORDS)

Maternal hormone levels during Na 872 infusion in late pregnancy.

In order to assess the effects of Na 872 infusion on maternal endocrinology during late pregnancy, we measured serum estradiol, estriol, progesterone, human placental lactogen, follicle simulating hormone, prolactin, cyclic adenosine monophosphate, cortisol and insulin before, during and after Na 872 infusion (bromhexine 2 mg/min for one hour) in ten mothers. As compared to six control mothers, no changes could be observed. This suggests that the claimed maturing effect of Na 872 on the fetal lungs is not mediated by the hormonal changes measurable in maternal blood.

Antipyrine metabolism and liver function in patients treated with high-dose medroxyprogesterone.

The effect of high-dose medroxyprogesterone acetate (MPA, 250 mg intramuscularly for six days) on hepatic drug-metabolism and liver function was investigated in eleven females with endometrial carcinoma. Antipyrine plasma clearance, an index of hepatic drug-metabolizing ability, improved significantly during this treatment, and the serum total bilirubin level was lowered, whereas other liver function tests, including alkaline phosphatase, and albumin values in the serum, remained unchanged. The results demonstrate that therapy with MPA has an inducing effect on hepatic enzyme activity and antipyrine metabolism. The findings may be of importance when prescribing drugs for females receiving large doses of MPA.

PIP: The effects of high doses of medroxyprogesterone acetate (MPA) on liver metabolism were investigated by determining the plasma antipyrine clearance rates for a group of 11 patients with endometrial cancer both before and during use of MPA in therapy. MPA dosage was 250 mg, intramuscularly, for 6 days. The antipyrine half-life was prolonged in 4 patients. MPA treatment had an inducing effect on antipyrine metabolism; the plasma half-life of the drug was shortened and apparent clearance rate increased; however, no change occurred in the apparent volume of distribution of the drug. Significant decreases in bilirubin were also seen (P .01), but no other liver function tests showed significant differences. When the patients were divided into 2 groups according to age over or under 60 years, there was a significant difference (P .05), with the younger group having a half-life of 8.1 hours and the older group evincing a half-life of 13.6. These half-lives were reduced by MPA treatment to 7.5 and 11 hours, respectively. The results indicate that MPA therapy has an inducing effect on hepatic enzyme activity and antipyrine metabolism.

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.

PIP: The purpose was to study the effects of intrauterine release of a daily dose of 20 mcg levonorgestrel by an IUD on climacteric symptoms, bleeding pattern, and endometrial histologic features in postmenopausal women receiving transdermal estrogen replacement therapy. 40 parous postmenopausal women were randomly allocated into 2 groups for 1 year. They were required to be parous, to have an intact uterus, and to have had amenorrhea for at least 6 months but less than 5 years. 20 women received a combination of 50 mcg of estradiol per 24 hours delivered transdermally from a patch, and received estrogen pretreatment for 1 month to make insertion of a levonorgestrel-releasing IUD (Levonova), which was installed a month later, easier. This combination was continued for 1 year. The control group of 20 women received an established form of continuous oral estrogen and progestin with a daily dose of 2 mg of estradiol, and 1 mg of norethindrone acetate also administered for 1 year. Checkup visits were scheduled at 3, 6, and 12 months. The climacteric symptoms, bleeding patterns, endometrial thickness, and endometrial changes in biopsy samples were analyzed. The increase in estradiol concentration was similar in both groups, and the mean concentrations of levonorgestrel in the IUD group were 216 +or- 25 pg/ml at 3 months, 209 +or- 11 pg/ml at 6 months, and 212 + 10.5 pg/ml at 12 months. Both treatment regimens effectively relieved climacteric symptoms. The IUD group experienced more days of bleeding, primarily spotting, during the first 3 months than did the oral therapy group but the differences between the groups had disappeared by 6 months. Both treatments resulted in an atrophic endometrium developing from a proliferative one. Two patients in each group dropped out because of bleeding. The levonorgestrel-releasing IUD is a useful alternative mode of progestin administration for certain selected women receiving estrogen replacement therapy.