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PubMed1976

Placental sulfatase deficiency: a case study.

A pregnancy with placental sulfatase deficiency was suspected when a 36-year-old patient at 41 weeks of gestation was found to have extremely low urinary estriol excretion and an otherwise normal prenatal course. The maternal plasma levels of estriol and estradiol 17-beta (E2) were extremely low and estetrol (E4) was undetectable (less than 40 pg/ml), whereas dehydroepiandrosterone sulfate (DS) was normal. THE AMNIOTIC Fluid DS concentration was 22-fold higher than the mean of normal pregnancy, while that of dehydroepiandrosterone (D) and androstenedione (A) was normal. Following intravenous infusion of 50 mg DS, no rise of plasma E2 was noted and plasma E4 levels remained undetectable. At 42 weeks of pregnancy, after induction of labor failed, a healthy male infant was delivered by cesarean section. The umbilical vein (UV) and umbilical artery (UA) levels of DS were extremely high, and those of E2 and E4 were subnormal. The UA level of A was normal and the levels of D and testosterone were slightly elevated. In vitro studies of placental microsomes and the 10,000 x g supernantant confirmed the diagnosis of placental sulfatase deficiency. The infant at 6 months of age had normal growth and development and normal peripheral plasma DS concentration.

Adult↗
PubMed1984

[The metabolism and conjugation of estrogens in the human fetus].

Although several studies have been reported on the synthesis of steroids in the fetus, the metabolism and conjugation of estrogens in the fetus is not completely known. In this study serum levels of estetrol (E4), estetrol glucosiduronate (E4-G), estriol (E3) and estriol-16-glucosiduronate (E3-16-G) were measured by R.I.A. in maternal peripheral vein blood (MPV), umbilical artery blood (UA) and umbilical vein blood (UV) at delivery. The same steroids were also measured in various fetal organs (liver, kidney, intestine, adrenal, lung and placenta) in the second-trimester. After 4-14C-E2, 4-14C-E3 and 6, 9 (n)-3H-E4 were incubated with homogenates of various human fetal organs, the metabolites were analyzed with an authentic sample. 15, 15-D2-estradiol-17 beta (d2-E2) was incubated with human second-trimester fetal liver and the metabolites were analyzed with GC-MS. It was concluded that: 1) E3-16-G was higher in UA and UV than in MPV, suggesting active glucosiduronation in the fetus. 2) Higher levels of E4 and E4-G in UA and UV than in MPV suggest the production of E3 and E3-16-G in the fetus. 3) Levels of E4 and E4-G were higher than those of E3 and E3-16-G in various fetal organs in the second-trimester. 4) E4 and E4-G were especially high in fetal liver and intestine, and E3 and E3-16-G were high in fetal kidney, liver and intestine. 5) The level of E3-16-G was higher than that of E3 in these organs. 6) The second-trimester fetal liver conjugated E2, E3 and E4 to each glucosiduronate. 7) The second-trimester fetal kidney conjugated E2 and E4 to each sulfate, but E3 to E3-16-G. 8) 15-Hydroxylation of d2-E2 was demonstrated in the incubation with homogenate of second human fetal liver. 9) The active glucosiduronation of E3 in the fetus was thought to inactivate a large amount of E3 transported from the placenta.

Estetrol↗
PubMed1989

Hyperreninemia and hypertension observed during Kaufmann therapy of patients with gonadal dysgenesis and hypopituitarism.

Cyclic replacement therapy using estrogen and progesterone was instituted in 28 patients with gonadal dysgenesis and 13 patients with hypopituitarism. When estriol was given at a dose of 2 mg per day, 10 patients (9 gonadal dysgenesis and 1 hypopituitarism) developed hyperreninemia and 3 of the 10 patients (all gonadal dysgenesis) were associated with hypertension. These side effects subsided within 6 months when the therapy was discontinued or the dose of estriol was decreased to 1 mg per day in addition to beta-blocker. Hypercholesterolemia was observed in 8 patients, but not related to high blood pressure. Attention should be paid to plasma renin activity and blood pressure when estrogen and progesterone are given for the development of genitalia in patients with gonadal dysgenesis.

Adolescent↗
PubMed1980

Evaluation of an enzyme-immuno-assay for the determination of total serum estrogens in pregnancy.

We have evaluated a new diagnostic kit for the determination of total estrogens in serum or plasma of pregnant women by means of an enzyme-immuno-assay. Within-run precision had a coefficient of variation of 4.7-4.9% for total estrogen concentrations of 400 to 2000 nmol/l. For the same range of concentrations, day-to-day precision was found to be 5.9-8.9%. Mean analytic recovery of unconjugated estriol was 102%. Enzymatic hydrolysis of different estrogen conjugates was shown to be virtually complete. The antiserum used in the assay has the same affinity for estrone, estradiol and estriol. Preliminary clinical studies included 14 pregnant women. The results suggest that the determination of total estrogens in pregnancy plasma can be used to monitor fetoplacental function in much the same way as urine total estrogens are used.

Estradiol↗
PubMed1976

Estrogens in maternal plasma following intraamniotic injection of (3H)-dehydroepiandrosterone-sulfate in midpregnancy.

In 4 patients with normal pregnancies between the 18th and 20th week of gestation (3H7alpha)-dehydroepiandrosterone-sulfate ([H]-DHEA-S) was injected intraamniotically. Maternal venous blood was drawn before and at regular intervals for 240 minutes after DHEA-injection. Thereafter, legal abortion was performed by intraamniotic instillation of prostaglandine. The conjugated steroids were hydrolyzed enzymatically and the total steroids were isolated and identified. The following labelled metabolites were determined quantitatively: Estriol (e3, estradiol-17beta (E2-17beta), estrone(E1), 16alpha-hydroxy-estrone, (16alpha-OH-DHEA), ALPHA4-androstenedione (AD) and testosterone (T). The maximal increase of all estrogen fractions in matermal plasma occurred 120-180min after intraamniotic injection of the precursor. The most prominent rise of the C18-steroids could be shown for estriol. 60-70% of all metabolites were C16-hydroxylated.

Amnion↗
PubMed1986

Estrogen screening in evaluation of fetal outcome and infant's development.

In an unselected obstetric population of 869 women serial determinations of estriol in serum and urine were performed from the 28th week of pregnancy until delivery. Clinical management was based on ultrasound and nonstress/contraction stress tests only. Data on the development of the infants were available after 1 year in 759 cases (89%) and after 2 years in 661 cases (78%). Serum free estriol (E3) screening during weeks 28-34 of pregnancy revealed a significantly increased risk for reduced Apgar scores, growth retardation and postnatal complications in pregnancies with decreased levels (p less than 0.001). The development of the children was disturbed by a higher incidence of childhood diseases, retardation in speech and bowel and bladder control. The urinary estrogen determinations (UE) during this period of pregnancy showed only a vague connection with birth weight and Apgar scores (p less than 0.05) and no connection to the infant's development. Serial determinations of E3 after the 35th week of pregnancy increased the significance for all parameters tested. If the estrogen concentration was determined in the last 2 weeks before delivery, 50% of the SGA and 60% of the endangered cases could be diagnosed. After reduced E3 serial levels neurological sequelae, reduced body weight, retarded speech and late development of bowel and bladder control were significantly more frequent at age two than after normal E3 levels. The differences obtained by serial UE determinations were less evident. Considering cost-benefit-calculations, an E3 screening of every pregnant woman cannot recommended. In pregnancies at risk serial E3 determinations allow better prognostication of fetal well-being. In the case of reduced E3 values maximum post partum care should be made available for all newborns. Special support should be given to the early infant's development after reduced E3 values have been observed.

Apgar Score↗
PubMed1980

Incorrect diagnosis of placental insufficiency in a patient with pre-eclampsia.

A case of pre-eclampsia is described where suspicion of placental insufficiency arose due to low estriol levels and a positive oxytocin challenge test (OCT). The cause, however, of these findings was later proven to be strictly fetal. It is concluded that low estriol levels and a positive OCT may be caused by a decreased placental capacity but specific tests of placental function, as for instance estimations of HPL in plasma and/or a DHAS-test, should be used to verify or rule out a suspicion of placental insufficiency.

Adult↗
PubMed1984

Low maternal but normal fetal prolactin levels in cigarette smoking pregnant women.

In the 36th week of pregnancy, levels of serum prolactin (PRL) (p less than 0.01) and estriol (p less than 0.05) were significantly lower in 101 consecutive women smoking 10 cigarettes or more per day, compared with a control group of 104 non-smoking pregnant women. Cord serum PRL was not related to maternal smoking habits, whereas estriol was significantly (p less than 0.05) lower in the infants of smokers, compared with the control group. The lower PRL levels in cigarette-smoking pregnant women may be due either to a direct effect of nicotine or secondary to lower estrogen levels, and the finding may be of clinical importance in relation to lactation.

Adolescent↗
PubMed1991

A health care program for the investigation and treatment of elderly women with urinary incontinence and related urogenital symptoms.

The assessment and treatment of urinary incontinence and related urogenital symptoms using an algorithm model was evaluated in 364 elderly women complaining of urinary incontinence. The women (age 72.1 +/- 1.5 years, range 65-84 years) were assessed by a 48-hour pad test, a cough provocation test, micturition lists and a gynecological examination which included a smear test, measurement of vaginal pH and bacterial cultures. The diagnosis of urinary incontinence was confirmed in 346 women (stress 26.3%; urge: 32.7%; mixed: 41.0%). Women suffering from stress incontinence were younger (p less than 0.05) and had experienced a larger number of deliveries (p less than 0.05) than women with urge incontinence. All the women were treated with oral estriol, 3 mg daily for 4 weeks followed by 1-2 mg daily. The total urinary leakage per 48 hours (p less than 0.01) and maximum single leakage (p less than 0.05) were reduced in women with mixed incontinence, while the frequency of micturition decreased (p less than 0.05) in women with urge incontinence after 12 weeks treatment with oral estriol. There were no significant changes in any of the objective micturition parameters in women with stress incontinence following treatment. Karyopyknotic index and the presence of lactobacilli were increased (p less than 0.001), and vaginal pH decreased (p less than 0.001) following treatment in women with all types of incontinence. More than 70% of all the women treated in this algorithm model judged themselves to be improved, much improved or cured.

Aged↗
PubMed1993

Urinary incontinence and related urogenital symptoms in elderly women.

The aims of this study were to investigate the prevalence of urinary incontinence (UI), urinary tract infections (UTI) and related urogenital symptoms (UGS) in a representative sample of elderly women (Papers I & II), and to investigate factors (Papers II & III) influencing the prevalence of UI in these women. The effects of treatment with oral estriol and placebo on the vaginal bacterial flora, vaginal cytology and urogenital symptoms in elderly women suffering from the urogenital estrogen deficiency syndrome were compared (Paper IV). A health care programme, based on an algorithm model, for the investigation and treatment of elderly women suffering from UI and related UGS, was designed and applied to a large group of elderly women (Paper V). The prevalence of UI increased in a linear fashion from 12% in the 1940 birth cohort to 25% in the 1900 birth cohort (Papers I & II). There was similar increase in the prevalence of UTI from 14% in the 1920 birth cohort to 23% in the 1900 birth cohort. In contrast, the reported prevalence of UGS such as vaginal discomfort, discharge and pruritus did not increase with age. The prevalence of UI increased with increasing parity and after hysterectomy, but was unaffected by the duration of previous oral contraceptive usage. There was no evidence to suggest that the prevalence of UI increased at the time of the last menstrual period. Neurological illnesses were an uncommon cause of UI in women < or = to 75 years of age (Paper III). Oral estriol (3 mg/day for 4 weeks followed by 2 mg/day for a further 6 weeks) had a positive influence on vaginal pH, cytology and the vaginal bacteria flora, and on UGS in elderly women suffering from the urogenital estrogen deficiency syndrome (Paper IV). Using objective techniques of evaluation (Paper V) it was possible to demonstrate successful treatment of elderly women with urge and mixed incontinence using a simple health care programme. There was however no evidence of improvement in women suffering from stress incontinence when using the same treatment regime. Women with all types of incontinence, treated according to this algorithm model, displayed an improvement in vaginal pH, vaginal cytology and the vaginal bacterial flora.

Administration, Oral↗
PubMed1997

In vivo effects of estrogens on c-erbB-2 oncoprotein levels in chorionic villous tissue and maternal serum.

The c-erbB-2-encoded oncoprotein p185 (HER2) is overexpressed in the fetal epithelium, the placenta and several carcinomas. Elevated serum levels of the released ectodomain (p105) were found in cancer patients and pregnant women at term. In cultured breast cancer cells estradiol inhibited p185 expression and induced growth arrest. These results prompted us to investigate the in vivo influence of serum estradiol and estriol on c-erbB-2 protein levels in pregnancy. We examined chorionic villous tissue extracts and maternal sera obtained from six legal abortions in the first trimester and 20 vaginal deliveries at term. For quantification of c-erbB-2 protein we employed an ELISA. In the first trimester maternal p105 serum levels were significantly (p < 0.0001) lower and p185 tissue levels significantly (p < 0.05) higher than in the third trimester. The highest p105 values were found in additionally examined cord blood. Interindividual regression analyses yielded inverse correlation between estradiol concentrations and placental p185 expression in the first (r = -0.58) and third trimester (r = -0.38) as well as p105 serum levels in the first trimester (r = -0.83). Estriol was correlated positively with p105 values in maternal and umbilical serum but not with placental p185 expression. We conclude that estradiol down-regulates p185 expression in pregnancy whereas the level of maternal p105 depends on the total amount of fetoplacental p185.

Chorionic Villi↗
PubMed1983

Evidence for hormonal imbalance after methadone treatment in pregnant and pseudopregnant rats.

The effects of methadone (METH) on the plasma estriol level and hormonal target tissues' cyclic nucleotides (cAMP and cGMP) were investigated in pregnant and pseudopregnant rats. In the pregnant animals, METH (5 mg/kg/day), given once daily from Days 6 to 15 of gestation, significantly reduced the maternal body weight gain in association with an increase in the number of dams bearing resorptions (56%) and a significant reduction in fetal body weight (33%). An inhibition of the plasma estriol level by METH was observed on Day 9 of gestation. Stimulation of the sympatho-adrenal axis and hypothalamo-pituitary axis by acute METH administration was observed and correlated with a significant increase in the levels of cyclic nucleotides in the uterus and adrenal glands of pregnant rats. However, tolerance to METH effects on cyclic nucleotide levels developed by Day 15 of gestation. METH also depressed the fetal cyclic nucleotide levels on Days 12 and 15 of gestation. These findings suggest that METH had pronounced effects on hormonal secretion during pregnancy, and hormonal transport to or hormonal production by the fetuses. In contrast, METH did not exhibit any adverse effects on the hormonal and cyclic nucleotide levels of pseudopregnant rats with deciduoma formation; a model for the maternal compartment. These latter findings may reflect METH's adverse effects on the fetal compartment, and suggest the use of pseudopregnancy as a model to distinguish adverse drug effects between these compartments.

Adrenal Glands↗
PubMed2001

Low-dose estrogen therapy ameliorates experimental autoimmune encephalomyelitis in two different inbred mouse strains.

It has been proposed that homeostatic levels of estrogen can enhance female susceptibility to autoimmunity, whereas the heightened levels of estrogen associated with pregnancy are protective. This hypothesis was tested using the mouse model of experimental autoimmune encephalomyelitis (EAE). Diestrus (<100 pg/ml in serum) levels of 17beta-estradiol were found to significantly reduce the clinical manifestations of active EAE in both male and female mice. Estriol was also effective but at doses below those previously established for pregnancy. The reduction in disease severity was accompanied by a coincident reduction in the number and size of inflammatory foci in the CNS of estrogen (17beta-estradiol or estriol)-treated mice. Recipients of encephalitogenic T cells from low-dose estrogen-treated mice developed less severe paralysis than mice receiving T cells from placebo-treated mice. A modest shift in Th1/Th2 balance suggested that low dose estrogen therapy could bias the immune reaction toward a protective anti-inflammatory cytokine response. However, estrogen treatment at the onset of active EAE failed to reduce disease severity, a result that is consistent with the hypothesis that naive cells are more sensitive to sex hormones than differentiated effector cells. These data suggest that treatment with low doses of estrogen can reduce the capacity of developing myelin-reactive T cells to initiate disease and challenges the idea that increased susceptibility to autoimmunity in females is dependent on homeostatic levels of estrogen.

Adoptive Transfer↗
PubMed1975

Hormone profiles in hormone-dependent cancers.

Studies on the relationship of urinary excretion of androgen metabolites and estrogens to the natural history of breast cancer are reviewed. The importance of distinguishing between "within-population" studies (i.e., cancer patients versus normal controls) and "between populations" studies (i.e., low-risk versus high-risk populations) is emphasized, and it is pointed out that "qualitative" agreement (i.e. the same direction of differences) between the two types of studies must be present in order to implicate a hormonal parameter as a determinant of the natural history of breast cancer. For reasons detailed in this paper, it is concluded that the reported relationship of low urinary androgen metabolite excretion to increased risk of developing breast cancer and poor response to adrenalectomy or hypophysectomy and the validity of the "estriol hypothesis," namely, that a high urinary ratio of estriol to estrone-plus-estradiol in early life is protective against subsequent development of breast cancer, are both dubious. A new hypothesis concerning the relationship of estrogens to breast cancer risk is presented: "A period of of time, prior to age 30, during which the amount of biological availability of active estrogens' (i.e., estrone and estradiol) is diminished, protects against subsequent development of cancer." This hypothesis is shown to be compatible with the epidemiological and biochemical data. Reports concerning the influence of nutrition on endocrine parameters are reviewed. Inanition and obesity have been shown to alter steroid metabolism but it is not known whether nutritional "microdifferences" (i.e., differences between populations or individuals that are due to cultural, geographic, or socioeconomic factors, but that fall within the range of "normal" or adequate nutrition) can also alter steroid metabolism.

Adrenalectomy↗
PubMed1975

Oxytocin challenge test in monitoring high-risk pregnancies.

Eighty-nine pregnancies, at risk for placental insufficiency, were monitored with serial oxytocin challenge tests (OCT) and estriol determinations on 24-hour urine collections. Intraamniotic catheters were used to accurately record intrauterine pressure in 63% of the tests; 114 of the 116 tests (98%) were adequate for interpretation. Thirteen positive tests were recorded; however, in only 2 cases did the positive OCT predict a dysmature-postmature infant when estriol determinations were normal. Prompt delivery following a positive OCT can significantly reduce the incidence of fetal wastage.

Apgar Score↗
PubMedDate not supplied

Utility of the triple test in the detection of abnormalities of the feto-placental unit.

INTRODUCTION: The objective of the study was to examine the relationship between the concentrations of maternal serum AFP, total beta-hCG and uE3 and the presence of various pathologies of the feto-placental unit. MATERIAL AND METHODS: The triple test was performed in the group of 882 pregnant women between the 14th and 21st week of gestation. The control group consisted of 863 pregnant women with unburdened obstetric anamnesis with an uneventful singleton pregnancy. The examined group consisted of 19 pregnant women with fetal aneuploidies and other pathologies of the feto-placental unit (oligohydramnios, vacuolization of the trophoblast). In the maternal sera concentrations of AFP, total beta-hCG and unconjugated estriol were determined. The risk of fetal trisomy 21 was calculated using DOWNS and PRISCA 3.0 software (cut-off 1: 295), Ulm Index was also calculated (cut-off 8.1). RESULTS: In the group of pregnant women with fetal chromosomal aneuploidies no significant changes of the examined parameters were established. In the cases of oligohydramnios AFP concentrations significantly increased, in the cases of fetal triploidy the concentrations of all examined parameters decreased. In the cases of vacuolization of the trophoblast concentration of the total beta-hCG increased. CONCLUSION: Oligohydramnios, fetal triploidy and vacuolization of the trophoblast caused significant changes of the concentrations AFP, total beta-hCG and unconjugated estriol in maternal sera.

Aneuploidy↗
PubMedDate not supplied

Potential test systems for drugs against prostatic cancer.

A number of chemotherapeutic agents have been tested in two systems which could be useful as models in the search for effective drugs for cancer of the prostate. One system involved the effects of the administered drugs on rat prostatic 5 alpha-reductase and arginase activities. Since both enzymic systems are androgen dependent and essential for prostatic function and anatomy, the effectiveness of a drug in these systems could be indicative of its value in the treatment of prostatic cancer. Michaelis constants were obtained with Lineweaver-Burk plots and the conclusions are based on a comparison of these plots with those of the controls. Thus, the following results were obtained: (a) isophosphamide, bleomycin, and procarbazine produced definite inhibition of 5 alpha-reductase in either or both the ventral and dorsolateral glands of the rat; (b) 5-fluorouracil, vincristine, bleomycin, procarbazine, adriamycin, and hexamethyl-melamine inhibited arginase activity significantly in both glands; (c) streptozotocin and 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide (NSC-45388) produced inhibition of arginase in the ventral gland only; (d) in contrast to the noncompetitive or uncompetitive inhibition of most of the drugs, particularly in the ventral gland, procarbazine, hexamethylmelamine, bleomycin, adriamycin, and NSC-45388 produced competitive inhibition of arginase in the dorsolateral gland; and (e) seven of the drugs led to an activation of 5 alpha-reductase (5-fluorouracil, vincristine, NSC-45388, hexamethylmelamine, CCNU, streptozotocin, and diglycolaldehyde). The second model system utilized the deposition of labeled estriol and testosterone in the dog prostate and the effects of drug therapy as a possible index of effectiveness in prostatic cancer. Streptozotocin and procarbazine definitely interfered with the deposition of both estriol and testosterone. On the basis of the data obtained, the model systems investigated by us could potentially serve as reliable indicators for the clinical use of drugs against cancer of the prostate.

Animals↗
PubMed1979

Effect of catechol estrogens on rat mammary tumors.

The effect of 1,3,5(10)-estratriene-3, 16 alpha, 17 beta-triol (estriol), 1, 3, 5(10)-estratriene-2,3-diol-17-one (2-hydroxyestrone), and 1,3,5(10)-estratriene-2,3,17 beta-triol (2-hydroxyestradiol) on the growth of dimethylbenz(a)anthracene-induced mammary tumor and of R3230AC-transplantable mammary tumor was compared with that produced by estradiol benzoate treatment. Estriol showed minimal inhibition of tumor growth in dimethylbenz(a)anthracene-induced tumor and no effect on R3230AC tumor while 2-hydroxyestrone showed no effect of tumor inhibition. On the other hand, 2-hydroxyestradiol showed appreciable inhibition of tumor growth in both tumors studied. That 2-hydroxyestradiol has been found to bind to estrogen receptors in mammary tumors and is uterotropic suggests that the inhibition of tumor growth by 2-hydroxyestradiol may be similar to the mechanism of inhibition of mammary tumors by high concentrations of estradiol.

9,10-Dimethyl-1,2-benzanthracene↗