High Estrogen Concentrations Research Articles

Drug interactions with oral contraceptive preparations.

Oral contraceptives (OCs) should be used with additional caution in combination with other drugs in certain disease states. This discussion focuses on only those interactions which are due to identifiable pharmacokinetic processes. Pharmacological interactions between OCs and other compounds may be of 2 kinds: drugs may impair the effectiveness of the OCs to cause breakthrough bleeding or to allow pregnancy to occur; and OCs may interfere with the metabolism of other componds. In general interactions of the 1st kind are due to interference with the absorption metabolism or excretion of estrogens and interactions of the 2nd kind are due to competition for metabolic pathways. It is difficult to obtain estimates of the frequency of interactions but it seems likely that as low-dose preparations become more widely used interactions of the 1st type will become more common and those of the 2nd type less common. Although it is probably only those women with low plasma hormone concentrations who are at risk that other drugs may interfere with contraceptive efficacy and women with high plasma concentrations of estrogen who are at risk of side-effects and that OCs may interfere with other drugs there is no way of detecting women in either category. Consequently it is safer for the present to assuume that all women who take OCs might be at risk of some form of interaction. Significant drug interactions in which contraceptive efficacy is reduced are more likely to occur in the early part of the cycle when circulating hormone concentrations are of critical importance. It is well known that infective diarrhea can induce OC failure by increasing gastrointestinal motility and reducing hormone absorption. Thus any drug which reduces gut transit time and causes diarrhea is potentially likely to reduce circulating concentrations of OCs. The sulphation of ethinl-estradiol in the gastrointestinal wall has been shown to be a site of interaction for the enhancement of the activity of OCs. Ascorbic acid also undergoes sulphate conjugation in the gut wall and acts as a competitive inhibitor for sulphation of estrogens. The most clinically significant group of interactions occurs with other drugs that are metabolized by the same hepatic microsomal pathways as is estrogen. Most of the anticonvulsant drugs are inducers of microsomal enzymes. Rifampicin is known to be a potent inducer of hepatic microsomal enzymes and has been shown to increase the rate of metabolism of both estrogeens and progestogens. A recent report has suggested that the antifugal drug griseofulvin may cause a clinically important interaction with OCs. There are numerous well documented clinical reports of women who have taken OCs without missing a dose who have become pregnant while taking a variety of antibiotic agents such as ampicllin and tetracycline. Estrogens are inhibitors of hepatic microsomal enzymes. In this way they may show the metabolsim of other drugs thus increasing their plasma and tissue concentrations and increasing the risk of side-effects. These interactions might be expected to become less common as the concentration of estrogen in OCS decreases.

Beta Adrenergic Receptors in Human Cavernous Tissue

Beta adrenergic receptor binding was performed with 125I iodocyanopindolol on human cavernous tissue membrane fractions from normal tissue and transsexual procedures obtained postoperatively, as well as from postmortem sources. Isotherm binding studies on normal fresh tissues indicated that the receptor density was 9.1fmoles/mg. with a KD of 23 pM. Tissue stored at room temperature for 4 to 6 hours, then at 4C in saline solution for 19 to 20 hours before freezing showed no significant changes in receptor density or affinity, and provided evidence for the stability of postmortem tissue obtained within the same time period. Beta receptor density of 2 cavernous preparations from transsexual procedures was not significantly different from normal control tissues, and showed that high concentrations of estrogen received by these patients had no effect on beta adrenergic receptor density. Displacement of 125iodocyanopindolol by 5 beta adrenergic agents demonstrated that 1-propranolol had the greatest affinity followed by ICI 118,551, zinterol, metoprolol and practolol. When the results of these displacement studies were subjected to Scatfit, non-linear regression line analysis, a single binding site was described. Based on the relative potency of the selective beta adrenergic agents it appears that these receptors were of the beta 2 subtype.

Estrogen and progesterone receptors in the uterus of the vervet monkey.

Experimental conditions for the optimal measurement of estrogen (ER) and progesterone (PR) receptors in normal vervet monkey (Cercopithecus aethiops pygerythrus) uteri are described. The uteri of this primate were found to contain relatively high concentrations of both ER and PR. Levels of ER ranged from 151 to 822 femtomoles per mg protein (mean for group assayed is 327 +/- 165 femtomoles per mg protein). PR assays were performed on the same cytosols and the levels ranged from 444 to 2267 femtomoles per mg protein (mean of 1285 +/- 511 femtomoles per mg protein). Mean Kd values for the ER- and PR-ligand complexes were found to be 3.15 +/- 1.4 X 10(-10)M and 2.38 +/- 0.2 X 10(-9)M respectively, within the group analysed (n = 21). The ratio of PR to ER varied between 1.1 and 13.1 with a mean of 4.5 +/- 2.4. Ligand specificity studies revealed that [3H]-17 beta-estradiol binding to the ER could only be inhibited by estrogens or estrogen analogues. The PR however exhibited an affinity for a wider range of ligand types. In low ionic strength buffers both ER and PR sedimented as approximately 8S type molecules in the presence or absence of 10mM sodium molybdate. Both receptors dissociated into smaller components, following a short exposure to 0.4 M KCl and subsequent centrifugation in a gradient containing 0.4 M KCl.

Biphasic modulation of pituitary sensitivity to GnRH by oestrogens: the effects of A- and D-ring substitution on LH release in cultured pituitary cells.

The sensitizing effect of oestrogens on GnRH-stimulated LH release was evaluated in pituitary cells from adult female rats, cultured for 2 days in the presence of 10(-13) to 10(-6) M concentrations of oestradiol and selected A- and D-ring modified oestrogens. With almost all steroids tested, bell-shaped dose-response curves with comparable LH-maxima but different ED max values were obtained for the LH response to a submaximal GnRH stimulus (5 X 10(-10) M). Maximal LH response to 5 X 10(-10) M GnRH were found at the following oestrogen concentrations: oestradiol and 4-hydroxyoestradiol = 10(-11) M; 2-methyloestradiol = 10(-9) M; 2-hydroxyoestradiol = 10(-8) M; with 4-methyloestradiol no significant maximum was observed. When cells were pretreated with 10(-13), 10(-11) and 10(-9) M oestradiol, or 4-hydroxyoestradiol, or 2-hydroxyoestradiol, and exposed to increasing concentrations of GnRH (10(-11) to 10(-7) M), an almost 10-fold decrease in the ED50 for GnRH was observed after pretreatment with 10(-11) M oestradiol and 4-hydroxyoestradiol. With 2-hydroxyoestradiol at this concentration, the sensitizing effect was much less pronounced. Increasing the steroid concentration to 10(-9) M slightly decreased the effect of oestradiol and 4-hydroxyoestradiol, whereas it increased the effect of 2-hydroxyoestradiol. Thus, at the target cell 4-hydroxyoestradiol has the same potency as oestradiol, while 2-hydroxyoestradiol is significantly less active. The sensitizing effect of oestradiol is only slightly decreased by the presence of a methyl group in position 2, but is markedly reduced by a methyl group in position 4. Our results also demonstrate the high sensitivity of the pituitary to oestrogen-induced enhancement of GnRH-stimulated gonadotrophin release, as well as the decrease of the positive effect at high oestrogen concentrations. The bell-shaped dose-response curves for oestrogen action should be taken into account when evaluating the effects of oestrogens and their derivatives upon gonadotrophin release from the pituitary gland.

Application of Synovex-H in veal calves: steroid release and residues.

Four experiments were carried out with veal calves which were implanted subcutaneously with Synovex-H. Testosterone in blood plasma and also total oestrogens in plasma, urine and faeces during the trial and in liver, kidney and muscle after slaughter (62-75 days after implantation) were determined. Prepurification methods and radioimmunoassays for faeces and tissue samples were elaborated and validated. Variables between or within the trials were the sex, the dose (four pellets versus eight pellets; 25 mg testosterone propionate + 2.5 mg 17 beta-oestradiol-3-benzoate per pellet) and the implantation site (either on the base of the ear or on the middle of the pinna). Results from the blood plasma and the excreta showed that using four pellets implanted in the middle of the pinna guaranteed a continuous release in order that oestrogen levels were maximally doubled in comparison to controls. On the other hand, application of the same dose at the base of the ear was characterized by an accentuated burst during the first three days (10-fold elevation over controls). In plasma and excreta of male controls, higher oestrogen concentrations were measured as compared to the corresponding substrates of females. Comparing all groups, untreated males showed the highest testosterone levels. In all animals, residues of total oestrogens were of the same order of magnitude (kidney and liver 0.1-1.5 ng/g; muscle 0-32 pg/g) with somewhat higher means in the treated groups. Since all results are within the physiological scope, no risk for the consumer is visible after correct use of Synovex-H.

Binding of the glycosaminoglycan [3H]heparin to bovine granulosa cells varies with size and estrogen content of ovarian follicles.

Bovine ovarian follicles were individually aspirated to obtain granulosa cells and follicular fluid, and estrogen concentrations in fluid were measured with a radioimmunoassay. Granulosa membranes were harvested by centrifugation and were pooled from follicles containing statistically high or low estrogen. Granulosa cell concentrations were estimated by comparing their protein content to cell standards. Results showed that cell numbers increased with increasing follicle size, and follicles with high estrogen concentrations possessed more granulosa than follicles with low estrogen. Specific binding of [3H]heparin decreased with advancing follicle size and was higher to granulosa harvested from follicles containing low estrogen.

Early menarche, a risk factor for breast cancer, indicates early onset of ovulatory cycles.

The associations between age at menarche and the hormonal patterns of adolescent menstrual cycles were investigated to obtain information as to why early menarche is an important risk factor for breast cancer. An initial group of 200 schoolgirls, 7-17 yr old, was investigated longitudinally 3 times at 1.5-yr intervals. A serum progesterone concentration in the latter part of the cycle exceeding 6.4 nmol/liter (2.0 ng/ml) was considered to signify an ovulatory cycle, and a concentration less than 1.6 nmol/liter (0.5 ng/ml) an anovulatory cycle. The frequency of ovulation depended significantly on both the time since menarche and the age at menarche (P less than 0.001 for both variables). Early menarche was associated with early onset of ovulatory cycles. The times from menarche until 50% of the cycles were ovulatory were about 1, 3, and 4.5 yr when the ages at menarche were less than 12.0, 12.0-12.9, and more than or equal to 13.0 yr, respectively. Girls with a menarcheal age below 12.0 yr had higher serum estradiol but lower testosterone and dehydroepiandrosterone concentrations than subjects with later menarche. The estradiol to dehydroepiandrosterone ratio was already higher before menarche in subjects who displayed early menarche during follow-up. These findings show that the increase in adrenal androgen secretion was mainly related to chronological age and was not affected by the time of menarche. The demonstration of early ovulation after early menarche is in conflict with the estrogen-window hypothesis suggesting a longer duration of anovulatory cycles to explain the increased risk of breast cancer after early menarche. Other theories should therefore be considered, among them the following: 1) high serum progesterone concentration in association with normal or high serum estradiol at puberty increases the risk, 2) only the early and relatively high estrogen concentrations are important, or 3) the estrogen to androgen ratio is the critical factor, with androgens having a protective effect.

High Fetal Estrogen Concentrations: Correlation with Increased Adult Sexual Activity and Decreased Aggression in Male Mice

In the house mouse (Mus musculus), fetuses may develop in utero next to siblings of the same or opposite sex. The amniotic fluid of the female fetuses contains higher concentrations of estradiol than that of male fetuses. Male fetuses that developed in utero between female fetuses had higher concentrations of estradiol in their amniotic fluid than males that were located between other male fetuses during intrauterine development. They were also more sexually active as adults, less aggressive, and had smaller seminal vesicles than males that had developed between other male fetuses in utero. These findings raise the possibility that during fetal life circulating estrogens may interact with circulating androgens both in regulating the development of sex differences between males and females and in producing variation in phenotype among males and among females.

Etiology of DES-induced uterine tumors in the Syrian hamster.

This paper describes a new experimental model system for the induction of endometrial adenocarcinoma in hamster uterus following diethylstilbestrol (DES) treatment of the newborn female. We propose that DES acts as an initiator during early development and that other estrogens act as promoters to stimulate tumor development in the adult uterus. DES directly affects the uterus as was shown by the failure of neonatal ovariectomy to prevent early DES-induced uterine growth. Subsequently, ovarian estrogen secretion from anovulatory, polyfollicular ovaries modifies the DES-altered uterus starting between 20 and 30 days of age and continuing into adult life. Early DES effects on the uterus include stimulation of endometrial cellular differentiation and progesterone receptor production. Permanent changes in uterine collagen, DNA and progesterone receptor content were noted, but the responsiveness of the DES-altered uterus to estrogen and progestin action was not impaired. Morphogenetic changes included an increase in extracellular connective tissue elements and striking alterations in endometrial cell composition such as hyperplasia of luminal and glandular epithelia and a massive inflammatory response in the stroma. Endometrial adenocarcinomas occurred in DES-treated animals in association with exposure to either endogenous estrogen from anovulatory ovaries or exogenous estrogen treatment of the ovariectomized animal. Endometrial tumors had relatively high concentrations of estrogen and progesterone receptors, suggesting a sensitivity to hormone action. Thus, these studies (a) demonstrate the utility of this animal model for the preparation of experimental endometrial tumors, and (b) suggest that DES acts as an initiator to transform uterine cells during early development, and estrogen exposure later in life acts as a promotor to stimulate growth and proliferation of DES-transformed cells.

Effect of estrogen on the mixed lymphocyte reaction in normal individuals and prostatic cancer patients.

Lack of initial response or relapse to hormones in advanced prostatic cancer may be due to an adverse effect of estrogen on host immune function. This study investigated the effect of diethylstilbestrol diphosphate (DES-P) on the normal mixed lymphocyte reaction (MLR) and on the MLR in prostatic cancer patients before and during treatment with DES-P. These data showed that the normal MLR was suppressed by high concentrations of estrogen in vitro, but physiologic levels of DES-P were not suppressive. Therapeutic doses of DES-P did not suppress the spontaneous MLR of prostatic cancer patients compared with previous treatment. Estrogens did not significantly impair the immunologic responsiveness of normal individuals or prostatic cancer patients.

Estrogen receptors of the rat uterus during pregnancy and lactation

Uterine estrogen receptors (ER) of the rat during pregnancy and postpartal lactation were assayed. Both the cytoplasmic and nuclear ER were determined by the controlled pore glass (CPG) method as previously described in detail. The cytoplasmic ER level slightly decreased as pregnancy advanced and then increased remarkably during postpartal lactation, with a tendency to decrease at 5 weeks of lactation when the estrous cycle could have recurred despite the nursing behavior of the rats. On the other hand, no remarkable difference in nuclear ER was noted during pregnancy and lactation. A high concentration of plasma progesterone could have reduced the translocation of the cytoplasmic ER to the nucleus and the replenishment of the cytoplasmic ER, despite a high concentration of plasma estrogen during pregnancy. In order to keep an environment of a high plasma concentration of estrogen similar to that of pregnancy, a long-acting estrogen (estradiol dipropionate) was injected in to the proestrous rats. The cytoplasmic ER rapidly translocated to the nucleus, followed by a prolonged maintenance of a low cytoplasmic and a high nuclear ER level until 7 days, with a gradual replenishment of the cytoplasmic Er and a gradual decline of the nuclear ER thereafter. A translocation of the cytoplasmic Er to the nucleus, similarly seen in the hysterectonized-adult rats treated with estradiol, was noted in the rats injected with estradiol at 3 weeks of lactation. In general, low estrogen and high prolactin may be held in plasma during lactation. These results indicate that the fluctuation of uterine ER simply depends on the plasma level of estrogen during pregnancy and postpartal lactation in rats.

LIVER CIRRHOSIS AND OESTROGEN METABOLISM – PERFUSION STUDIES WITH CIRRHOTIC RAT LIVERS

1. Radioactive oestrone and oestradiol-17 beta were perfused through normal and cirrhotic livers of rats. Liver cirrhosis had been induced by a combined application of carbon tetrachloride and azathioprine. 2. The hepatic uptake of both oestrogens by cirrhotic livers was reduced; the uptake of oestrone was more affected than that of oestradiol-17 beta. 3. The pattern of oestrogen metabolites indicated a reduction of the sulphotransferase activity in cirrhotic livers. The activity of other enzymes of oestrogen metabolism were similar in normal and cirrhotic livers. 4. The amount of oestrogen glucuronides excreted into the bile was significantly less in cirrhotic livers although the bile volume was larger in cirrhotic than normal livers. 5. The release of oestrogen metabolites into the circulating medium was considerably higher during perfusion of cirrhotic livers. From the findings presented here it is concluded that the turnover of oestrogens is slower in cirrhotic than in normal livers. Moreover, it may be speculated that the distribution volume of the oestrogen metabolites is smaller in rats with liver cirrhosis, due to a disturbed enterohepatic circulation. This results in higher oestrogen concentrations in extracellular fluids, thus supporting the concept of hyper-oestrogenism in liver cirrhosis.

Role of pituitary LH and placenta in luteal progesterone production and maintenance of pregnancy in the rat.

It is now well-established that neutralization of circulating LH using specific antiserum leads to termination of pregnancy in the rat (1–3). In our extensive investigations, we demonstrated that LH antiserum is effective when administered from day 1–8 or any day between 8 and 11 (1,3). Neutralization of LH is effective even at midnight of day 11, but not at 10 a.m. on day 12, indicating a sharp ‘cut off’ point. The observed termination of pregnancy is accompanied by profuse vaginal bleeding 36 to 48 hrs after antiserum administration. Plasma progesterone levels drastically fall within a short period of neutralizing LH (4). This indicates that LH is essential for production of progesterone at this time of pregnancy. The effects of LH antiserum on pregnancy have been amply confirmed by other investigators (5–7). Morishige and Rothchild (5) extended these studies to earlier period of pregnancy and demonstrated that LH dependency sets in between day 6 and 8, simultaneously with the loss of dependency on pituitary prolactin. To investigate the mode of action of LH, Gibori et al utilized the LH antiserum treated rat model system (8). They demonstrated that testosterone implants can maintain pregnancy, in such rats. Further Gibori and Keyes have provided significant evidence that testosterone administered is converted to estrogen, which in turn maintains progesterone production in the pregnant rat. The rat corpus luteum contains high concentrations of estrogens during pregnancy (9, 10) and exogenous estrogen stimulates luteal growth and progesterone secretion in hypophysectomized-hysterectomized pregnant rats (11, 12). Intraovarian bursal estrogen implants also seem to maintain luteal functionality as judged by progesterone secretion, during days 10 and 11 of pregnancy (13). Thus at the present time it seems that the luteal progesterone production becomes dependent on pituitary LH and placental luteotropin by day 8 of pregnancy. The present series of investigations were undertaken to elucidate the contribution of the placenta and its potential to sustain steroidogenesis in the absense of LH.KeywordsProgesterone ProductionLuteal FunctionProgesterone SecretionSynthetic ProgestinSerum Progesterone LevelThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Endogenous Estrogen Production in the Young

Only in human pregnancy is the fetus exposed to high concentrations of estrogens throughout gestation, owing to the unique interplay of steroidogenesis between fetus, placenta, and mother. It is well recognized that both the fetal and maternal adrenal glands contribute to placental estrogen synthesis by secretion of steroidal precursor androgens.1 The principal estrogen of human pregnancy, estriol, is produced in disproportionately large quantities because of the extensive 16α-hydroxylation of fetal dehydroepiandrosterone sulfate (DHEAS) in fetal liver and other tissues. 16α-Hydroxy DHEAS is directly converted to estriol within the placenta by the abundant sulfatase, 3β-hydroxysteroid dehydrogenase-isomerase, and aromatase enzymes contained therein. Thus, the fetus is the source of most of the estriol precursor during pregnancy. Fetal and maternal DHEAS secretion contribute roughly one half of the precursor for placental estradiol synthesis late in pregnancy. Although most of the placental estrogen is secreted into the maternal circulation, a large quantity is delivered to the fetus via the umbilical vein. Table I lists the approximate concentrations of free estrone, estradiol, and estriol, as well as progesterone, in umbilical venous and arterial plasma as compared with the concentrations found in the maternal circulation at term of normal pregnancy. It can be seen that the concentration of estriol is approximately ten times that of estradiol and five times greater than that of estrone entering the fetus. The level of estradiol in the fetal circulation (5 to 6 ng/ml at term) is 10 to 20 times higher than that found in the normal adult female just prior to the midcycle gonadotropin surge.

Foetal and maternal plasma concentrations of 13, 14-dihydro-15-oxo-prostaglandin F in the mare during late pregnancy and at parturition.

The concentrations of 13, 14-dihydro-15-oxo-prostaglandin F(PGFM), the stable metabolite of prostaglandin F, were measured in the plasma of catheterized mares and foetuses and non-catheterized thoroughbred mares and ponies during the last months of gestation. The plasma concentration of PGFM increased gradually towards term in all groups of animals. During the operation for insertion of catheters, maternal and foetal concentrations of PGFM were high, but the values fell to basal levels 24--48 h after the operation. It was found the preoperative starvation (24 h) led to a rise in the concentration of PGFM in the maternal plasma. The raised concentrations of PGFM during the operation were associated with low progestogen and high oestrogen concentrations in umbilical venous plasma. The subsequent survival period of the catheterized foal was inversely related to the maximum concentration of PGFM were studied during normal parturition in thoroughbred mares, during oxytocin-induced delivery in non-catheterized ponies and during premature delivery or abortion in the catheterized animals. The greatest increase in the concentration of PGFM was seen in the thoroughbred animals during second-stage labour; oxytocin also resulted in a very rapid rise in the level of PGFM, which remained high until delivery. In the catheterized animals, the birth of live foetuses was associated with a rise in the concentration of PGFM in both foetal and maternal plasma during the last 2 h before delivery. Less consistent changes were found during abortion.

Human Endometrial Cells in Primary Tissue Culture: Estrogen Interactions and Modulation of Cell Proliferation*

Human endometrium, obtained from premenopausal women after hysterectomy, was dissociated into cells and placed in culture in order to examine estrogen responsiveness in a model in vitro system. Experiments which utilized cell proliferation as an index of responsiveness spanned at least 7 days and were performed in Dulbecco's modified Eagle's medium supplemented with 10% steroid-depleted serum from castrate-adrenalectomized calves. The addition of 2 × 1(10−7 M 17β-estradiol (E2) or diethylstilbestrol (DES) resulted in a 2- to 5-fold optimal acceleration in the rate of proliferation, with stimulation first being detected at 2-4 days. Ten-fold higher or lower concentrations of E2 or DES resulted in little stimulation, and high (2 × 10−5 M) concentrations of either estrogen stopped cell proliferation. The addition of E2 or DES (2 × 10−8−2 × 10−6 M) to cultures of a putative nontarget cell line (Detroit- 98) derived from human sternum failed to elicit any increase in the rate of proliferation, although high E2...

ESTROGEN EFFECT ON CALCIUM UPTAKE BY BONE

Cord blood plasma has high concentrations of estrone (E1), estradiol (E2) and estriol (E3). E2 causes hypocalcemia in newborn rats and in parathyroidectomized (PTX) adults. Since kidney and intestine have been excluded as sites of this action, bone is the presumptive locus of calcium (Ca) sequestration. Uniform discs from the calvaria of newborn rats and young mice were incubated in Krebs' solution. The addition of E2 to the medium or prior E2 injection of the donors increased Ca uptake by 60-100%. Nitromiphene, a competitive blocker of estradiol, prevented this effect and eliminated hypocalcemia after E2 in vivo. Discs from donors injected with parathyroid extract (PTE) showed decreased Ca uptake; when both PTE and E2 were given, uptake equalled that of uninjected controls. Since E2 lowers Ca in PTX rats. Its effect on bone must be independent of, as well as opposite to, that of parathyroid hormone. E1, thought to be active only after hepatic conversion to E2, caused hypocalcemia in vivo but not in vitro. E3 was inert both in vivo and in vitro. These findings suggest that the high plasma estrogen concentrations present in the neonate may contribute to hypocalcemia through a direct effect on bone.

EFFECT OF OESTRADIOL-17β AND PROGESTERONE ON THE METABOLISM OF TESTOSTERONE BY HUMAN PROSTATIC TISSUE

SUMMARY The metabolism of testosterone in vitro by normal benign hyperplastic and carcinomatous prostatic tissues has been compared. 5α-Dihydrotestosterone was the predominant metabolite followed by 3α- and 3β-androstanediol. No difference in the pattern of metabolism, either quantitatively or qualitatively, was found in normal, benign hyperplastic and welldifferentiated carcinomatous prostatic tissue. In poorly differentiated carcinomatous tissue there was less formation of all 5α-reduced metabolites. Treatment of patients with carcinomata with diethylstilboestrol resulted in greatly decreased activity of prostatic 5α-reductase with a considerable proportional increase in 17β-dehydrogenase activity. The addition of oestradiol-17β or stilboestrol in vitro also inhibited the formation of 5αdihydrotestosterone and androstanediols by all types of prostatic tissue, but only when high concentrations of oestrogen were used and there was no increase in 17β-dehydrogenase under these conditions. In contrast, progesterone was a much more effective inhibitor of 5α-reductase in vitro than was oestrogen.

Estrogen Excretion in High-risk Pregnancy: A Comparison of Two Assay Procedures

To assess the clinical significance of acid-labile estrogens in high-risk pregnancy, urinary excretion of estrogen in 197 patients was measured by the Cohen ammonium sulfate precipitation method and by the Brown acid hydrolysis technic and the results were compared. The methods gave parallel results and both had essentially the same predictive value in assessing impairment of function of the fetoplacental unit. There was no evidence of an abnormally high concentration of acid-labile estrogens in the urines of 24 diabetic patients in this series.

CIRCULATING LEVELS OF OESTRADIOL-17 DURING EARLY PREGNANCY IN THE ALASKAN FUR SEAL SHOWING AN OESTROGEN SURGE PRECEDING IMPLANTATION

Circulating levels of estradiol-17beta during early pregnancy in the Alaskan fur seal (Callorhinus ursinus) were studied to determine whether an estrogen surge coincided with the period of blastocyst growth immediately before implantation. Blood samples were obtained from 38 adult female seals during the period of blastocyst dormancy and early postimplantation. An estrogen surge (35 pg/ml) occurred immediately before the time of blastocyst reactivation and accelerated growth leading to implantation. A prolonged period (almost 2 months to return to lowest levels of 11 pg/m1) of high estrogen concentration followed ovulation. A return to high levels was characteristic of postimplantation. It is concluded that the Alaskan fur seal, having obligatory delayed implantation, has an estrogen surge near the end of that delay period.