Estrogen profiles in young women: effect of maternal history of breast cancer.

To examine the hypothesis that familial breast cancer risk is related to estrogen metabolism, we analyzed urines of daughters of breast cancer patients and their matched controls for estrone (E1), estradiol (E2), and estriol (E3). From this, we computed estriol proportions (E3/E1 + E2 + E3). "Patient-daughters" and the matched controls showed no differences in estriol proportions. Our results failed to support the hypothesis that high-risk women (those with a family history of breast cancer) have relatively lower estriol proportions, and we concluded that whatever family history contributes to breast cancer risk, that risk is not likely to be transmitted by the estrogen profile.

PIP: A study designed to test the hypothesis that daughters of breast cancer patients would have "less favorable" estriol proportions than would a group of otherwise similar controls is reported. Urinary estrogen profiles of 46 daughters born to 45 women who later developed breast cancer and of 46 controls were examined. Computed estriol proportions (estriol/estrone plus estradiol plus estriol) revealed no differences in "patient-daughters" and the matched controls. It is concluded that whatever family history contributes to breast cancer risk, that risk is not likely transmitted by the estrogen profile.

Socioeconomic status, urine estrogens, and breast cancer risk.

Urine estrogens were measured in 46 women students, ages 15-18, at a middle-class high school in Athens and in 40 women of the same age residing at one of three orphanages in the same city. The lower socioeconomic status (SES) of the latter group was documented by their lower mean height (by 5.2 cm) and weight (by 5.3 kg) relative to the high school students. Both in follicular and luteal phases of the menstrual cycle, the women with lower SES had 50% higher estriol ratios (ratio of the concentration of estriol to the sum of the concentrations of estrone and estradiol). In luteal specimens the concentration of all three major estrogens was higher in the group with low SES than in the women in the other group, but the concentration of estriol was most increased. There was also an indication of less frequent anovular cycles among the women with low SES. These findings are consistent with hypotheses linking either the estriol ratio or the frequency of anovular cycles to breast cancer risk.

PIP: Urine estrogen levels were measured in 46 women students, ages 15-18, at a middle-class high school in Athens, Greece and in 40 women of the same age residing at 1 of 3 orphanages in the same city. The lower (SES) socioeconomic status of the latter group was documented by their lower mean height (by 5.2 cm) and weight (by 5.3 kg) relative to the high school students. Both in follicular and luteal phases of the menstrual cycle, the women with lower SES had 50% higher estriol ratios (ratio of the concentration of estriol to the sum of the concentrations of estrogens and estradiol). In luteal specimens, the concentration of all 3 major estrogens was higher in the group with low SES than in the women in the other group, but the concentration of estriol was most increased. There was also an indication of less frequent anovulan cycles among the women with low SES. These findings are consistent with hypotheses linking either the estriol ratio or the frequency of anovular cycles to breast cancer risk.

Metabolism of estrogens in breast cancer.

PIP: This extensive literature compilation reviews major studies on estrogen metabolism in cancer, studies which have led to proposed possible etiological roles of estrogens in human breast cancer. Urinary and plasma estrogen excretion patterns and profiles in women with breast cancer are the topics of part 1. Studies of estrogen profiles in women who are at high-risk for breast cancer are critiqued. The estriol hypothesis is presented and criticised in a chapter. The effects of endocrine ablation on urinary estrogen profiles in breast cancer patients are compiled. Production and metabolism of estrogens in women with breast cancer are rendered, including in vivo biotransformation rates and in vitro transformation data. And the search for estrogen metabolites in women with breast cancer is reviewed. In conclusion it is obvious that the question of whether breast cancer patients have an abnormal metabolism of estrogen has not been answered, but further investigations of estrogen metabolism in breast cancer should be continued because: 1) the possibility that estrogens are carcinogenic has not been ruled out; 2) receptors have been discovered which do correlate with hormone dependency of tumors; 3) present evidence suggests that neoplasm may induce abnormal estrogen metabolism; 4) directional changes of estrogen metabolism that occur in pregnancy may also occur in women with target tissue neoplasia; 5) hepatic tissue's relationship to breast cancer has not received attention; and 6) the role of peripheral aromatization in the pathogenesis of mammary cancer is not yet understood.^ieng

Hormone levels during prostaglandin F 2 infusions for therapeutic abortion.

PIP: This study determines the effect of prostaglandins (PGs) on fetal-placental hormone production or luteal steroidogenesis early in pregnancy by measuring plasma levels of unconjugated estrone, 17-beta estradiol, estriol, progesterone, 17-hydroxyprogesterone, human chorionic gonadotropin (HCG), and human chorionic somatomammotropin (HCS) in 7 healthy women aged 15-30 years receiving PGF2alpha for therapeutic abortion. The patients were 7-20 weeks pregnant and were all from the Clinical Research Unit of the Yale-New Haven Hospital. 5 patients participated in a dose-response tolerance study in which the drug was given over a 12-hour period at predetermined dose levels from 25-200 mcg/minute. The remaining 2 patients received 50 mcg for 12 consecutive hours, and 2 6-hour periods respectively. Heparinized blood samples were collected prior to the beginning of the infusion, at least hourly during the infusion, and also 24 hours after the beginning of the study. Transabdominal and transcervical catheters were used to monitor intrauterine pressures. A definite decline in estradiol levels (from 50-70% of initial levels) was observed during the PGF2alpha infusions. Plasma levels of unconjugated estriol were found to decline earlier and more markedly than the estradiol levels. 17-hydroxyprogesterone was undetectable in all but 1 patient who was 7 weeks pregnant. There were no significant changes in HCG levels in 4 patients until abortion and or curettage was performed. HCS levels gradually declined in 3 patients during the infusion process. This study shows that PGF2alpha does not exert a luteolytic effect in terminating pregnancy from 7-20 weeks gestation, confirming the study of Wiqvist et.al. Further study of the 1st few weeks of gestation should be done before ruling out the possibility of luteolysis in humans.^ieng

Oestrone, oestradiol-17beta and oestriol levels in human foetal plasma during gestation and at term.

PIP: Marked rises in both unconjugated and sulphoconjugated estrone, estradiol-17-beta and estriol were observed in human fetal plasma between midgestation and term. Significant arterio-venous differences were found in the umbilical cord plasma. No consistent arterio-venous differences were found in the umbilical cord plasma. This indicates that all 3 estrogens are secreted from the placenta into the fetal circulation in the unconjugated form. Mean unconjugated estrogen (estrone + estradiol-17-beta + estriol) levels rose from 22.7 ng/ml at 17-20 weeks of gestation to 108.9 ng/ml at term in umbilical venous plasma and from 4.3 ng/ml to 23.3 ng/ml in umbilical arterial plasma. This represents a secretion rate of approximately 30 mg estrogen/day into the umbilical vein at term. Mean estrogen sulphate levels rose from 128 ng/ml to 313 ng/ml in the cord plasma during the same period. Of the 3 estrogens measured, estriol was quantitatively the major estrogen in fetal plasma. It consistently represented about 78% of the unconjugated fraction and 95% of the sulphate fraction at all stages of gestation. The method of delivery did not have a significant effect on the estrogen levels in uncomplicated pregnancies. Similar estrogen levels were found in fetal heart blood after either hysterotomy at spontaneous abortion at 16-20 weeks of gestation, and no significant differences were found for estrogen levels in cord plasma after elective Caesarean section at 38-39 weeks when compared with estrogen levels after normal delivery at term. A significant rise in fetal unconjugated estrogens at a time when fetal corticosteroids are increasing may be of physiological importance for fetal maturation in women.^ieng

Plasma concentrations of oestrone, oestradiol, oestriol and progesterone during mechanical stretch-induced abortion at mid-trimester.

Plasma levels of unconjugated oestrone, oestradiol, oestriol and progesterone were serially studied in six uncomplicated patients in the mid-trimester of pregnancy before and during abortion induced by purely mechanical stretching of the uterus by laminaria and rubber balloon. Variability of these hormonal levels among patients was significant before the treatment. In four cases where the fetus was aborted alive, the plasma value of these hormones remained at a high level during the treatment with the exception of oestriol level in one case. In two early mid-trimester cases the fetus died during the treatment and plasma oestriol dropped significantly, while the level of the other hormones remained raised until fetal delivery. In these two cases the apparent onset of labour was noted before fetal death. It was concluded that the onset and progress of labour by mechanical stretching of the uterus is probably unrelated to the steroid hormones estimated in the present study.

In vitro and in vivo interactions of [3H]dimethylstilbestrol with the estrogen receptor.

PIP: The binding of an antiestrogen with the uterine estrogen receptor (R) has been studied directly in vitro using tritiated dimethylstilbestrol (DMS). The affinity of DMS for R as determined at equilibrium was similar to that of estradiol-17beta (E2) (K(D) approximately .3 nN) when taking into account the higher nonspecific binding of DMS. The number of DMS binding sites was constantly found to be inferior to that of E2. The fact that the DMS binding entity specifically bound estrogen and antiestrogen, was destroyed by pronase, displayed an 8S sedimentation constant, and interacted in vitro with DNA, strongly suggested that DMS interacted directly with R. The association of DMS to R was a simple 2nd-order reaction while its dissociation was a 1st-order reaction with 2 slopes. The association and dissociation rate constants of the R-DMS complex were, respectively, slower and higher than those of the R-E2 complex. The rapid dissociation rate of DMS could be responsible for its inability to protect the receptor binding sites against thermo-inactivation. Tritiated DMS was able in vivo to induce the nuclear translocation of the receptor. However, as with other short-acting antiestrogens and contrary to Nafoxidine, the time of nuclear retention of R was short. These results are in agreement with the assumption that the length of the nuclear retention of R is determinant in explaining the weak agonist activity of this compound.^ieng

Contraceptive mechanism of microdose norethindrone.

PIP: To determine how microdose progestogens exert their contraceptive mechanism, 5 normal 20-40 year old women (each acting as her own control) were studied during a normal menstral cycle followed by a cycle in which each received orrally 350 mcg norethindrone per day beginning on Cycle Day 1 for 30 days. Results indicated that all control cycles were ovulatory. In the treated cycle, endometrial morphology was altered. There was also significant suppression of preovulatory FSH and LH peaks, alteration of urinary estrogens (either increase or decrease), and marked suppression of progesterone production during the luteal phase. Cervical mucus properties and sperm penetration were inhibited during the treatment cycle. These findings suggest that at least 3 different factors were involved in the contraceptive mechanism of microdose norethindrone: 1) alteration of ovulation and progesterone production by the corpus luteum, 2) cervical mucus changes and inhibition of sperm transport, and 3) endometrial changes.^ieng

A new rapid assay of oestrogens in pregnancy urine using the substrate native fluorescence.

A simple and rapid method is described for the quantitative determinations of free and conjugated oestrogens in pregnancy urine. The oestrogens are precipitated with ammonium sulphate and freed from non-oestrogenic compounds by solvent extraction. The conjugated oestrogens are hydrolysed by a beta-glucuronidase from Escherichia coli, and the total free oestrogens are extracted into ether and their fluorescence intensity at 310 nm in this solvent is determined. The method is rapid and precise for oestrogen levels at concentrations greater than 2 mug/ml (7 mumol/1). It is proposed that this method, which measures oestradiol and oestriol levels, be applied routinely to monitor feto-placental function in pregnancy. It offers advantages over other currently used assays in that less manipulative and technical skill is required to give a high level of precision and accuracy. An accurate estimate can be produced within 30-60 min of receipt of a 24-h uring specimen. Two variations of the method are also described. In one the ammonium sulphate precipitation step is omitted so as to give an even quicker assay procedure which determines conjugated oestrogens in the urine, and in the other oestriol only is determined.

PIP: A simple and rapid method for the measurement of free and conjugated estrogens during pregnancy is described. The method can give an accurate estimation within 30-60 minutes when estrogen concentrations are greater than 2 mcg/ml. Conjugated estrogens are hydrolysed by a beta-glucuronidase from Escherichia coli and free estrogens are extracted into ether and their fluorescence intensity at 310 nm is determined. The method has application in the routine monitoring of feto-placental function in pregnancy. 2 variations of the method, 1 which eliminates the ammonium sulphate precipitation step, are described.

Identification of conjugated estrogen metabolites in dog plasma following administration of estriol-2,4,6,7-3H.

Following the constant infusion of 2,4,6,7-3H-estriol in male dogs for a period of 90 minutes, the radioactive metabolites present in arterial plasma were separated by solvent partition, DEAE-Sephadex, Celite partition and thin layer chromatography. The identities of the individual estrogens and estrogen conjugates were confirmed by specific activity determinations after chromatography in several different solvent systems, enzyme hydrolysis and chromatography of the unconjugated steroids and their derivatives.

PIP: Conjugated estrogen metabolites in arterial plasma were identified in male dogs by solvent partition, DEAE-Sephadex, Celite partition, and thin layer chromatography following constant infusion of tritiated-2,4,6,7-estriol for 90 minutes. Identification was confirmed by specific activity assessment in various solvent systems, enzyme hydrolysis and chromatography of the unconjugated steroids and their derivatives. All unconjugated and radioactivity after infusion was identified as free estriol, and 5 conjugated metabolites were isolated. 3 of these were identified as estriol-3-glucosiduronate, estriol-16alpha-glucosiduronate, and estriol-3-sulfate. 2 polyconjugates of estriol appeared to be estriol-3-sulfate-16alpha glucosiduronate and an estriol diglucosiduronate.

An assay for urinary estriol-16 alpha-glucuronide based on antibody-enhanced chemiluminescence.

An immunoassay for estriol-16 alpha-glucuronide in pregnancy urine is described that utilizes antibody-enhanced chemiluminescence. The steroid glucuronide was covalently conjugated with the chemiluminescent marker aminobutyl-ethyl-isoluminol. The light yield of this conjugate upon oxidation was augmented by specific antibody, and this effect was inhibited by addition of the homologous steroid glucuronide (10-100 pg) in a dose-dependent manner. The assay does not require separation of bound and free ligand and proved satisfactory with respect to sensitivity, precision and accuracy. Assay results obtained by radioimmunoassay and chemiluminescence immunoassay were in good agreement (r = 0.98; n = 25).

PIP: An immunoassay for estriol-16 alpha-glucuronide in urine, for pregnancy determinations, that uses antibody-enhanced chemiluminescence is described. Glucuronide was convalently conjugated with amino butyl-ethyl-isoluminol, a chemiluminescent marker. A specific antibody was used to augment the light yield of this conjugate upon oxidation, and this effect was inhibited by addition of the monologous steroid glucuronide (10-100 pgm) dose-dependently. The assay does not require separation of bound and free ligand, and its sensitivity, precision, and accuracy were satisfactory. Good agreement was found between assay results obtained by radioimmunoassay and the chemiliminescence immunoassay (r=.98; n=25).

Biliary metabolites of estriol in the rat.

Following the subcutaneous administration of estriol-6,7-3H to rats, biliary metabolites were identified and quantitated. Approximately 70% of the metabolites were excreted in the form of "glucosiduronate" conjugates. 3,17beta-Dihydroxy-2-methoxy-1,3,5(10)-estratrien-16-one was the major metabolite in this conjugate fraction. Significant amounts of 3,17beta-dihydroxy-1,3,5(10)-estratrien-16-one and 2,3,17beta-trihydroxy-1,3,5(10)-estratrien-16-one, as well as smaller quantities of 1,3,5(10)-estratriene-2,316alpha,17beta, tetrol and 2-methoxy-1,3,5(10)-estratriene-3, 16alpha, 17beta-triol, were also found. In 17alpha-ethinylestradiol-treated animals, the rate of excretion of radioactivity and the proportion of 16-oxo-17beta-ol metabolites found in the "glucosiduronate" fraction were reduced.

PIP: The biliary metabolites of tritiated-6,7-estriol were identified following the administration of the estrogen to rats. Glucosiduronate conjugate fraction constituted approximately 70% of the excreted metabolites. The primary metabolite found in this conjugate fraction was 3,17beta-dihydroxy-2-methoxy-1,3,5(10)-estratrien-16-one. There were also significant amounts of 3,17beta-dihydroxy-1,3,5,(10-estratrien-16-one and 2,3,17beta-trihydroxy-1,3,5(10)-estratrien-16-one. Smaller amounts of 1,3,5(10)-estratriene-2,3,16alpha,17beta-terol and 2-methoxy-1,3,5(10)-estratriene-3,16alpha,17beta-triol were also present. The administration of 17alpha-ethinyl estradiol reduced the rate of excretion of radioactivity and the proportion of 16-oxo-17-beta-ol metabolites in the glucosiduronate fraction.

Pharmacokinetics of oestrogens and progestogens.

There are large inter- and intra-individual variations in the serum concentrations of natural and synthetic sex steroids irrespective of the route of administration. Oral ingestion of steroids has a stronger effect on hepatic metabolism than parenteral administration, as the local concentration in liver sinusoids are 4-5 times higher during the first liver passage. Oestradiol and oestrone are interconvertible, dependent on the local concentrations in liver and target organs, and oestrone sulphate serves as a large reservoir. The oestrone/oestradiol ratio has no physiological significance, as oestrone is only a weak oestrogen. Oestrone is both a precursor and a metabolite of oestradiol. Oestriol is extensively conjugated after oral administration. Therefore, the oestriol serum levels are similar after oral intake of 10 mg and after vaginal application of 0.5 mg oestriol resulting in similar systemic effectiveness. Conjugated oestrogens can easily enter the hepatocytes but are hormonally active only after hydrolyzation into the parent steroids. Ethinylestradiol which exerts strong effects on hepatic metabolism and inhibits metabolizing enzymes, should not be used for hormone replacement therapy. Among the progestogens, the progesterone derivatives have less effects on liver metabolism than the norethisterone derivatives (13-methyl-gonanes and 13-ethyl-gonanes). The highly potent 13-ethyl-gonanes are effective at very low doses, because of a slow inactivation and elimination rate due to the ethinyl group.

15alpha-Hydroxyoestriol and other polar oestrogens in pregnancy monitoring.

Although oestriol measurements are well established for the assessment of 'at risk' pregnancies, there are a number of other oestrogens, excreted during pregnancy, which contain additional hydroxyl groups and might be more sensitive indicators of the condition of mother or fetus. Some of these result from the action of hydroxylases possibly present only in the fetus and others from maternal hydroxylations. We review the evidence for the biosynthesis of these polar oestrogens, summarise methods of measurement, and compare values obtained in normal and pathological pregnancies. There is as yet insufficient evidence to enable their potential value to be confirmed.

PIP: Attempts to assess "at-risk" pregnancies may be aided by measuring a number of polar estrogens excreted during pregnancy which contain additional hydroxy groups. 2 hydroxy groups show promise as sensitive indicators of maternal or fetal condition: 15-hydroxylations which appear to be predominantly fetal reactions, and 18-hydroxylations which can take place in both the fetus and adult. Excretion rates of the 15- and 18-hydroxy compounds were compared with known estriol excretion rates; in normal pregnancies the levels of estriol and 15 alpha-hydroxyestriol (15 alpha) in maternal blood and urine closely paralleled. In the pathological pregnancies, little indication that 15 alpha measurements are valuable in prediction of fetal morbidity or death was discovered; though in preeclamptic toxemia patients, 15 alpha levels became subnormal 1 day-several weeks before death, and urinary levels of 15 alpha were often low when birth weights were low. During measurement of several estriols throughout pregnancy, a good correlation between 18-hydroxyestriol and 15 alpha was shown; however, measurements from 20 at-risk pregnancies did not show such a correlation.

[Concentration of estrone, estradiol and estriol in the blood of pregnant sheep after induction of estrus with chlormadinone acetate and medroxyprogesterone acetate]. / Chlormadinonacetátom a medroxyprogesterón-acetátom

The radioisotopic method of 131J-labelled albumin was employed to determine the distribution of acidic proteinase activity in some organs and tissues of chickens. The highest enzymatic activities were found in intestine wall, in pancreas, and in liver. Considerably lower activities were ascertained in kidneys, brain, lungs, and heart. The different proportions of these enzymes in homogenates and supernatant fractions (106 000 g) testify to a lack of uniformity in the solubility of cathepsins in the organs tested. The tested organs, with the exception of pancreas, did not show any enzymatic activity of neutral proteinases.

PIP: Estrus was artificially induced in 10 Merino sheep by a vaginal swab administration of 30 mg of chlormadionone acetate (in 5 animals for 13 days) or of 60 mg of medroxyprogesterone acetate (in 5 animals for 17 days), both on a background administration of 750 IU pregnant mare's serum gonadotropin. After impregnation in this condition, the levels of esterone, estradiol, and estriol were determined. A progressive increase was found in the levels of all 3 of these hormones over the course of the pregnancy, in both groups. Comparison of estrogen concentrations showed that the use of the 2 progesterone derivatives did not affect the endocrine ciruclation of the mother and the fetus during pregnancy.

Practical uses of steroids and gonadotropins in obstetrics and gynecology.

PIP: Several steroid and gonadotropin determinations that are available to practicing physicians are discussed and their practical uses are emphasized. Before undertaking a workup of a patient who appears to have an endocrine abnormality a physician should know the availability and benefits of such tests, the time and expense involved, and the interpretation of laboratory reports. Estrogens are phenolic steroids secreted by the ovaries, adrenal glands, testicles, and the fetal-placental unit and are found in over 20 metabolites in the urine; the most important are estrone, estridiol, and estriol. Total or fractional determinations of urinary estrogens are expensive and may require 7 days. Human gonadotropin determinations are expensive and require 2 weeks. Contraceptive medications, tranquilizers, and sedatives interfere with secretion of this hormone. Clinical usefulness is of value only when dterminations are extremely high or repeatedly ver y low. Culdoscopic findings may be of more value than either estrogen or gonadotrpin determination. Estrogen determinations can be of value in male patients with gynecomastia, in suspected fetal distress or fetal death in utero (a drop of 50% in the normal 1000-fold increase of pregnancy indicates need for delivery of infant), and when an indication of size of infant is needed to determine elective repeat ceasarean sectton. Ther is no practical value of pregnanediol determination in pregnancy or in the amenorrheic female. The clinical use of 17-hydroxycorticoids is related to its value as a screening procedure for adrenal disorders. Patient stress and several drugs may interfere with accurate tests. The 17-ketosteroids are used primarily for the sam e purpose. Progesterone determinations are useful to differentiate ovarian from adrenal pathology. Urinary testosterone increase may be present in some ovarian tumors. Human chorionic gonadotropin (HCG) detection is used for pregnancy tests; a sensitive technique may obtain a positive test day Day 30 of the menstrual cycle or 16 days after conception. These tests are also used in the diagnosis of hydatidiform mole, choriocarcinoma, and to guide care of trophoblastic disease. Of newer methods the competitive protein binding technique for estrogen, progesterone, and testosterone is rapid, accurate, and sensitive. Radioimmunoassay for FSH, LH, and other trophic hormones is complex but promising. Conversion studies are complex but may be of use.^ieng

[Urinary estrogen profile in consecutive phases of menstrual cycle in young healthy women]. / Profile estrogenów w moczu w kolejnych fazach cyklu zdrowych kobiet

PIP: Urinary estrogen profiles were made on 6 women, aged 26-30 years. Mean values of excreted estrone (E1) were the highest values in the 1st half of the cycle: 10.15 in the follicular phase and 10.23 mcg/24 hours in midcycle. In the 2nd half of the cycle the level of E1 decreased: 8.78 in the early luteal phase and 8.36 in the late luteal phase. Estradiol (E2) showed its highest mean level in the midcycle, 4.53 mcg, 2.80 in the follicular phase, 3.95 mcg in the early luteal phase, and 3.38 mcg in the late luteal phase. Estriol (E3) showed its lowest levels in the follicular phase at 13.78 mcg and in the late luteal phase at 14.12 mcg/24 hours. The highest E3 levels were 17.59 mcg in midcycle and 17.33 mcg/24 hours in the early luteal phase. The mean quotient ratio of E3/E1+E2 (R) showed high estriol proportions of 1.1, 1.2, 1.4, and 1.2 in all consecutive cycle phases. These are noted to be higher than those of English women (.70 and 1.21 in the 1st and 2nd phases). The racial and geographical factors involved in this are examined.^ieng

[Some steroid hormone excretion in the urine during gestagen therapy]. / Wydalanie niektórych hormonów sterydowych z moczem w przebiegu leczenia gestagenami.

PIP: The urinary excretion of certain steroid hormones, estrone, estradiol-17(EZ), estriol (E3), 17-ketosteroids and pregnanediol was studied from the vaginal smears of 23 women using gestagens (Anovular and Lyndiol 2.5) as treatment for menstrual disorder, functional sterility, secondary amenorrhea, and endometriosis. The reactivity of women treated with gestagens for genital problems was different from that of women using gestagens as contraceptives. This difference is related to the initial state of the endocrine secretion prior to the therapy. The KI was depressed during the course of the treatment and returned to its normal levels after discontinuation of the drug. Increased urinary excretion of estrogens (especially E2 and E3) was accompanied by low KI values and vice versa. Evaluation of the endocrine activity should be based on both cytologic smears and urinary steroid tests in order to estimate the doses and duration of the therapy.^ieng

[Radioimmunoassay, its value in clinical use: LH, FSH, progesterone, estrone, estradiol, estriol]. / Radioimmunoassays, ihr Wert in der klinischen Anwendung: LH, FSH, Progesteron, Oestron, Oestradiol, Oestriol

PIP: The clinical value of hormone determinations and functional tests is presented. In regard to cyclical disruptions, foremost the anovulatory cycle with secondary amenorrhea primarily in mind, the important evaluation is that of the estrogen-gestagen test, followed by a determination of the plasma gonadotropins. For ovarian insufficiency, differential diagnosis between the hypothalamus, hypophysis, or disruptions in the feedback systems are most important. The clomisphene test is the primary means of radioimmunological evaluation of amenorrhea. This test enables one to determine which of the 3 functions above are showing a negative response to chemical stimuli. These tests are of great value in diagnostics and are also useful in evaluating the effectiveness of therapy. The main polemic is over whether it is most useful to evaluate the total estsrogens or the individual fractions. The same problem exists for progesterone. The main indication for the determination of total estogens, or fractions of estrone, estradiol, as well as progesterone is developmental control of medical ovulation release. The therapy of sterility cases also falls into this category. The exact determination of estrogen contents is not always possible, however, making reliability questionable. But the varied nature of their functions and the cost factors involved must remain important in evaluating them.^ieng

Serum unconjugated estriol levels in the third trimester and their relationship to gestational age. II.

The purpose of this study was to further validate a preliminary report concerning the clinical usefulness of serum unconjugated estriols as a marker of gestational age. Serial estriol values from 50 women with uncertain dates were plotted on semilogarithmic graphs and the gestational age predicted from the timing of the abrupt surge in estriol values which normally occurs between 35 and 36 weeks. The gestational age at birth, as determined by careful neonatal examination, agreed with the age predicted by the estriol surge within +/- 1 week.

PIP: To further confirm a preliminary report regarding the clinical usefulness of serum unconjugated estriols as a marker of gestational age, 50 patients with uncertain menstrual dates and in whom uterine size and fundal height growth were inconsistent with estimated gestational age were studied. 6 weekly venous blood samples were taken beginning at the estimated 32nd week. Serum was kept frozen until analyzed for unconjugated estriol. All samples were analyzed at the same time. Results show that the surge point can be used as a significant marker for gestational age. 48 of the 50 patients showed the expected surge which at the infants' births matched the developmental age within 1 week. The 2 patients who did not demonstrate the surge phenomenon had blood samples obtained too late in gestation for adequately plotting the regression line. No surge occurred if labor started prior to the 36th week. The surge in estriol production occurs at approximately the 36th week and continues until the 38th week when it plateaus until term. The 36-week surge point may be used in patients who are 1st seen in the 3rd trimester as an aid in decreasing the number of amniocenteses in evaluating those who may require repeat Caesarean section. The oxytocin-challenge test may be avoided in those who continue past the expected date of confinement. The information may enable one to predict lung maturation since the surge occurs after the time when the increase in pulmonary surfactant production in the fetal lungs would normally have taken place. The surge is thought to be a function of fetal adrenal maturity.