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The effects of ampicillin on oral contraceptive steroids in women.

1 Thirteen women taking long term oral contraceptive steroids were studied while taking ampicillin (500 mg three times daily) and compared to a control cycle while not taking ampicillin. 2 There were no significant changes in the plasma concentrations of ethinyloestradiol, levonorgestrel, follicle stimulating hormone or progesterone, although lower concentrations of ethinyloestradiol were noted in two women. 3 We conclude that most patients taking oral contraceptive steroids do not need to take alternative contraceptive precautions while taking ampicillin.

Adult↗

Anti-inflammatory steroids, lysosomal stabilization and parachor.

Parachor is an additive constitutive property of a molecule and is related to the molar volume and the surface tension. The parachor of a steroid can be calculated from its constituent atoms and bonds. The parachor of a biologically active molecule is related to the ability of that molecule to permeate hydrophobic regions of cells, especially cellular membranes. An examination of the parachor values of a large number of steroids shows that these values are correlated with a number of different biological activities, from independent sources. The ability of steroids to release lysosomal enzymes from isolated lysosomes in vitro is inversely related to the parachor of the steroid. A similar relationship holds for the release of lysosomal beta-glucoronidase (EC 3.2.1.31) from isolated lysosomes of rat preputial gland following in vivo administration of steroids. The relative anti-inflammatory potencies of steroids by several assay methods are directly proportional to their parachors. The relative ability of corticosteroids to uncouple oxidative phosphorylation and to swell isolated mitochondria in vitro show a direct proportionality with the steroidal parachor. The percutaneous absorptions of steroids show good correlation with parachors, stratum corneum-water partition coefficients and amylcaproate-water partition coefficients; but not with hexadecane-water partition coefficients. The application of parachor as a structure-activity correlation parameter in drug design is likely to yield useful information. The advantages and limitations of the calculated parachor method are discussed.

Androgens↗

Influence of sex difference and oral contraceptives on forearm reactive hyperemia.

Experiments were performed on normal male and female subjects to compare blood flow responses following release of an arterial occlusion (reactive hyperemia). Additionally, the effects of oral contraceptive therapy on the reactive hyperemia reaction were studied in female subjects. Forearm blood flow was measured with a strain-gauge plethysmograph, heart rate with an electrocardiograph, and mean arterial pressure was measured by auscultation. Blood flow was determined before and after circulatory arrest of 1, 3, and 5 min. Blood serum levels of 17 beta-estradiol, progesterone, luteinizing hormone (LH), and follicle stimulating hormone (FSH) were measured by radioimmunoassay. The mean resting forearm blood flow was similar in males and females (approximately 4 ml/100 ml/min). There were no significant changes in systemic mean arterial pressure or heart rate during the experiments. Following 1 min of arterial occlusion, the peak blood flow responses were similar in males and females. The peak blood flow responses following release of arterial occlusion were lower in males than in untreated females at occlusion intervals of 3 and 5 min. Females receiving oral contraceptives showed reduced peak blood flow responses after circulatory arrest of either 3 or 5 min as compared to untreated females. There were no significant differences in the recovery times of the hyperemic responses between males and females following any of the periods of occlusion. The peak blood flow responses following 3 min of arterial occlusion were significantly correlated with the blood serum levels of 17 beta-estradiol, LH and FSH, but not with the blood serum levels of progesterone. These results suggest that: (1) sex difference has a marked effect on the blood flow response following arterial occlusion, and (2) hormonal changes influence vascular responsiveness in the female.

Blood Pressure↗

Estrogen and progestin regulation of the progesterone receptor concentration in human endometrium.

The concentration of the progesterone receptor (PR), both cytosol and nuclear, has been measured in the endometrium of 31 normal menstruating women during the 2 phases of their menstrual cycle and compared with the plasma 17 beta-estradiol and progesterone concentrations. There was no relationship between PR concentrations and the plasma steroid levels when the 2 phases of the cycle were considered; however, a statistically significant correlation (r = 0.70; P less than 0.005) was observed between PR concentration and plasma 17 beta-estradiol when only the follicular phase was considered. PR was then measured in the endometrium of 14 postmenopausal patients treated with ethinylestradiol at increasing doses with or without association of chlormadinone acetate. Ethinylestradiol was shown to increase PR concentration (P less than 0.05), and chlormadinone acetate was found to prevent this increase. These data suggest that in humans, as in other mammalian species, the endometrial PR concentration is under estrogen and progestin control.

Chlormadinone Acetate↗

Effects of an antiprogesterone (RU486) on the hypothalamic-hypophyseal-ovarian-endometrial axis during the luteal phase of the menstrual cycle.

The impact of the antiprogesterone RU486 [17 beta-hydroxy-11 beta-(4-dimethylaminophenyl) 17 alpha-(1-propynyl)estra- 4,9-dien-3-one] on the hypothalamic-pituitary-ovarian-endometrial axis was examined in normal cycling women during the mid (MLP)- and late (LLP) luteal phases. During the MLP, 10 women received 3 mg/kg RU486 for 3 days. During the LLP, a single dose of 600 mg RU486 was administered to 4 women, and in another 4 women a single dose of 3 mg/kg was given during corpus luteum rescue by hCG. Longitudinal studies with daily and frequent blood samples (every 10 min for 10 h) were conducted during 3 consecutive cycles (control-treatment-recovery). During the MLP, RU486-induced uterine bleeding occurred in all 10 women 36-72 h after the first dose. No histological evidence of endometrial breakdown was found in endometrial biopsies taken 12-24 h before the onset of bleeding. Significant decreases in LH secretion (P less than 0.001) and LH pulse amplitude (P less than 0.006) and blunted pituitary responses to GnRH (P less than 0.01) were evident by the last treatment day, but LH pulse frequency did not change. Complete luteolysis occurred in 2 of the 10 women. Incomplete luteolysis occurred in 8 women and was associated with an initial decline of serum estradiol (P less than 0.001), but not progesterone levels, followed by rebound increases (P less than 0.001) in LH, estradiol, and progesterone levels 3 days later, which may have reversed the luteolytic processes and prolonged corpus luteum function. Spontaneous luteolysis ensued 3-5 days later with the onset of second episodes of uterine bleeding. For serum FSH, an early rise occurred during the luteal phase in advance of the onset of the second episodes of uterine bleeding. This rise may have resulted in early follicle recruitment and accounted for the shorter duration of the follicular phase during recovery cycles. During the LLP, the single RU486 dose resulted in significant decreases in LH pulse amplitude (P less than 0.03), frequency (P less than 0.05), and secretion (not significant) within 12 h. The recovery cycle was entirely normal. Corpus luteum rescue with incremental doses of hCG did not prevent uterine bleeding after RU486 treatment. These findings indicate that RU486 operates at multiple sites and implies that progesterone is important in the control of luteal function. Further, our data provide a basis for exploring the potential use of RU486 as a once a month birth control agent.

Adrenocorticotropic Hormone↗

The effect of RMI 12, 936 synthetic antiprogestional steroid, on ovarian steroidogenesis in the rat.

A series of physiochemical investigations confirmed that the product of chemical and enzymatic isomerization of RMI 12,936 was 7alpha-methyltestosterone. The total activity per pair of ovaries of delta5 3-ketosteroid isomerase in vitro was unchanges by RMI 12,936 pretreatment or by advancing pregnancy, significant changes in ovarian weight being accompanied by reciprocal changes in enzyme activity/mg tissue. The initial rate of isomerization of RMI 12,936 was approximately five times greater than the corresponding rate of delta5-progesterone isomerization at equal substrate concentrations. It is concluded that RMI 12,936 does not inhibit progesterone biosynthesis by alteration of delta5 3-ketosteroid isomerase activity, but that it may do so by acting as an alternative substrate for this enzyme.

Androstenols↗

Levels of follicle-stimulating hormone, luteinizing hormone, oestradiol-17 beta and progesterone, and follicular growth in the pseudopregnant rat.

Throughout a period of pseudopregnancy the peripheral blood levels of progesterone, oestradiol-17 beta, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), as well as the size-distribution of ovarian antral follicles were estimated in the rat. The progesterone concentrations, as measured by a competitive protein-binding technique, exceeded metoestrous values (25 ng/ml plasma) from day 3 of pseudopregnancy onwards. The highest levels were found on days 6 and 8 (91 ng/ml). From day 8 onwards the levels decreased gradually but were still above metoestrous values on the day of pro-oestrus after pseudopregnancy. Concentrations of oestradiol-17 beta, as measured by radioimmunoassay, were within the range of those at metoestrus (about 5 pg/ml plasma) until day 10. Thereafter levels increased to a value of 57 pg/ml. Concentrations of FSH, measured by radioimmunoassay, were within the range of metoestrous values until day 10 (about 100 ngNIAMD-rat-FSH RP-1/ml serum), but declined to a level of 33 ng/ml on day 12. Concentrations of LH, measured by radioimmunoassay, were generally within the wide range of metoestrous values (9-60 ng NIAMD-rat-LH RP-1/ml serum), but concentrations found on days 4, 8 and 10 were significantly lower than those found on preceding or subsequent days. Histological determination of the number of follicles present in various volume-classes, showed an increase in antral follicles on days 1 and 2, comparable to the increase observed during metoestrus and dioestrus 1 of the normal cycle. There was no change in the follicles between days 3 and 10 and they resembled those of early dioestrus. Preovulatory growth had occurred by day 12. Injection of human chorionic gonadotrophin (HCG) on days 2, 4 or 6 showed that ovulation could be induced only in some of the larger follicles. On the basis of these results it is suggested that during pseudopregnancy the high progesterone levels present result in a decreased plasma LH level which is insufficient to cause full maturation of the follicles and to stimulate oestrogen secretion to the levels required for induction of an ovulatory surge of LH release.

Animals↗

Midtrimester intra-aminotic administration of prostaglandin F2alpha in combination with an hyperosmolar urea solution: effect upon plasma levels of estradiol, progesterone, and human placental lactogen (HPL).

A study was undertaken in order to investigate the clinical observation that patients who underwent midtrimester abortion using intra-amniotic PG F2alpha in combination with hyperosmolar urea, always aborted a dead fetus. Ten Caucasian primigravidae, aged between 16 and 22 years old and whose pregnancies ranged between 14 and 23 weeks in duration, were studied. The patients were randomly divided into two equal groups. The one group received urea and PG F2alpha intra-amniotically whereas the other received PG F2alpha alone. Blood was drawn for measurement of plasma estradiol, progesterone and human placental lactogen (HPL) prior to injection of the abortifacients and at regular intervals thereafter for a period of 120 min. The five patients who received the combination regime of treatment (urea + PG F2alpha) showed a rapid decline in the plasma concentrations of these hormones and induction of abortion was followed by fetal death within 35 min in all cases. In contrast, the five patients who received intra-amniotic PG F2alpha alone, did not (with a single exception), demonstrate this rapid decline in the plasma concentrations of the placental hormones measured. Also with the same single exception, these fetuses, although stillborn, were alive two hours after inducing abortion.

Abortion, Induced↗

Progesterone levels before and after laparoscopic tubal sterilization using endotherm coagulation.

Tubal sterilization can be performed by several surgical methods. It has often been reported that menstrual disorders appear after the operations, probably caused by hormonal disturbance. However, there is no published systematic study of the ovarian hormonal status after sterilization. In the present prospective study therefore, the plasma progesterone level has been determined during one menstrual cycle before and one after endotherm tubal laparoscopic coagulation. Plasma progesterone was chosen as normal levels of this hormone during the luteal phase reflect ovulation and an adequate corpus luteum. The endotherm coagulation method does not appear to cause any progesterone malfunction in the ovary.

Adult↗

Drug control of steroid metabolism by the hepatic endoplasmic reticulum.

In this review evidence is provided for the interaction between various drugs and steroid hormones in man and between drugs and progestogens in experimental animals. The mechanism by which these drug interactions occur are of fundamental biochemical and pharmacological interest. The importance of practical clinical considerations of drug-steroid interactions has also been discussed. In particular, considering the present tendency to lower the dose of progestogen and estrogen in most contraceptive preparations, any factor that reduces the bioavailability of the steroid hormones becomes very important. Other drugs and environmental chemicals may interact with these steroids and thereby diminish their efficacy. Clinical studies have reported that the most important interfering drugs are some anticonvulsants and antibiotics, and the antituberculosis compound rifampicin. Anticonvulsants and antituberculotics affect microsomal enzyme induction in the liver or interfere with enzyme systems in the gut wall. The action of antibiotics is connected with the pharmacokinetics of contraceptive steroids by an interaction with their enterohepatic circulation. Some environmental factors such as smoking, alcohol, and other dietary variations, and concurrent hepatic disease may modify the disposition of circulating endogenous steroids and exogenous contraceptive steroids. These effects may alter their response accordingly. In our studies drug treatments of rats reduced serum progesterone level irrespective of whether a potent inducer (phenobarbital, 4-methylcoumarin) or a hepatotoxin (carbon tetrachloride, coumarin, alpha-naphthylisothiocyanate) was administered. These treatments affected hepatic progesterone content. Phenobarbital and carbon tetrachloride reduced serum level, but the hepatic incorporation was enhanced by phenobarbital and reduced by carbon tetrachloride. The opposite actions were selective; phenobarbital raised the oxidative pathway of progesterone metabolism but did not modify the reductive pathway. This drug also enhanced progesterone 16 alpha-, 6 beta-, and 20 alpha-hydroxylase, but did not alter delta 4 - 5 alpha-reductase. In contrast, carbon tetrachloride inhibited hydroxylase and enhanced reductase activities. The effects of these test compounds on progesterone-metabolizing enzymes in isolated microsomes in vitro were similar to the in vivo results. It is concluded that the action of various drugs on serum and liver progesterone levels and metabolism is probably related to changes manifest in the function of the hepatic endoplasmic reticulum.

Animals↗

[Comparison of chemical and radiochemical methods in determination of steroid hormones].

While in some cases steroids can be measured directly in serum or plasma by radioimmunoassay (RIA), in other cases, especially when analyses are carried out in urine, the samples must be processed before RIA can be performed. The operations involved in the preparation of urinary or blood extracts suitable for the RIA of steroid hormones are examined and compared in terms of practicability with the analytical procedures currently used for the chemical determination of the same steroids or their metabolites.

17-Hydroxycorticosteroids↗

Intrauterine release of progesterone: changes in RNA patterns of endometrium.

The changes induced in the relative concentrations of the different species of RNA (messenger, ribosomal, transfer and heterogenous) which regulate the metabolic behavior of tissues were studied in the endometrium of normal women and in women wearing a progesterone T IUD for 6-12 months. It was observed that the intrauterine release of progesterone is accompanied by a significant decrease in the content of total RNA (from 78 +or- 8.4 to 64 +or- 6.7 mcg/mg of protein) and in the RNA/DNA ratio (from 0.85 +or- 0.10 to 0.73 +or- 0.08). Although the protein decreased significantly (from 102 +or- 11 to 82 +or- 14 mg/g wet wt.), the DNA content and the Prot/DNA ratio were not altered. Using the affinity chromatography technique in poly(u)Sepharose it was found that the relative concentrations of RNA types were in general drastically modified: mRNA and rRNA decreased (from 2.6 +or- 0.31 to 1.28 +or- 0.15 and from 65.5 +or- 8.0 to 54.8 +or- 6.7 mcg/mg of protein respectively). tRNA content was increased (from 6.2 +or- 0.9 to 11.0 +or- 1.3) while hRNA was unchanged. The probable inhibitory effects of these changes in relation to the normal hormonal stimulation of the human endometrium, as a possible explanation of the mechanism of action of this device, are discussed.

Biology↗

[Steroidogenic function of the intra-arterial trophoblast in the rat. Ultrastructural, histoenzymologic and biochemical data].

The ultrastructural study of the intra-arterial trophoblast has revealed in the pregnant Rat a steroidogenic activity which has been confirmed by histoenzymologic observations (presence of delta 5-3 beta-HSDH and 17 beta-HSDH). At the 15th day postcoitum an in vitro investigation upon the metabolism of steroid hormone precursors suggests that the steroids (oestrogens, progestogens and androgens) secreted by the intra-arterial trophoblast have a local action upon the wall of the uterine placental arteries and are actively concerned with an important part upon the utero-placental hemodynamic as a whole.

Androstenedione↗