Effects of low-dose bisphenol AF on mammal testis development via complex mechanisms: alterations are detectable in both infancy and adulthood.

Despite growing concern about adverse effects of bisphenol AF (BPAF) due to its endocrine disrupting properties, there is a lack of toxicity data from low-dose studies and direct evidence linking its adverse effects to endocrine disrupting properties. Here, we investigated the effects of gestational and postnatal exposure to BPAF through drinking water (0.15-15 µg/mL, equivalent to the daily intake of ~ 50 and 5 mg/kg/day) on testis development in mice. We found that like mestranol, 5 mg/kg/day BPAF resulted in remarkable decreases in multiple male reproductive parameters in adulthood, such as the sperm number and serum testosterone level. Notably, 50 µg/kg/day BPAF also caused significant decreases in anogenital distance (AGD), the luteinizing hormone level and spermatocyte number, along with declining trends in sperm number and the serum levels of testosterone and follicle-stimulating hormone. In line with the adverse outcomes observed in adulthood, on postnatal day (PND) 9, we also observed BPAF-caused dose-dependent alterations, including reduced AGD, seminiferous tubule area and numbers of total germ cells, spermatocytes and Leydig cells, coupled with down-regulated expression of male-biased genes in testes. Even when exposure to 5 mg/kg/day BPAF as well as MES was initiated from PND 0, similar alterations in male reproductive parameters were also found on PND 9, along with a decrease in the GnRH content in the hypothalamus; moreover, testicular alterations and the reduction in AGD were partly antagonized by the estrogen receptor (ER) antagonist ICI 182,780, but the reduction of GnRH production was not done, showing that the effects of BPAF on testis development may be partially mediated by ER signaling. In conclusion, all the findings demonstrate that low-dose BPAF can partly disrupt mammal testis development and cause adverse testicular outcomes in adulthood, indicating a potential reproductive risk to mammals including humans. Importantly, our finding that developmental alterations elicited by BPAF have been detectable on PND 9 provides important motivation for the development of effective methods for early detection of adverse effects of estrogenic chemicals on testis development.

Effect of CYP2C9 Genetic Polymorphism in a Chinese Population on the Metabolism of Mestranol in vitro.

BACKGROUND: Mestranol is a widely used estrogen, which is converted into its active metabolite ethinyl estradiol by cytochrome P450 (CYP) 2C9. To comprehensively examine the enzymatic activity of reported CYP2C9 variants in Chinese individuals in response to mestranol, wild-type CYP2C9*1 and 35 allelic variants were highly expressed in Sf21 insect cell microsomes and used for the detection of their enzymatic values in vitro. These results showed that the majority of tested variants exhibited decreased clearance values compared to wild type, except for CYP2C9*40 and *36. METHOD: Insect microsomes expressing the 36 CYP2C9 variants were incubated with 0.25-8 µmol/l mestranol for 30 min at 37°C. Then, the production of the metabolite of mestranol, ethinyl estradiol, was analyzed using high-performance liquid chromatography. RESULTS: Most CYP-catalyzed reactions were sufficiently described by classical Michaelis-Menten kinetic parameters (e.g., Km and Vmax), while 9 variants exhibited atypical or non-Michaelis-Menten kinetic values, which were largely due to the self-inhibitory effect in response to mestranol. CONCLUSION: This is the first report of these rare alleles for mestranol metabolism, which provides fundamental data for further clinical studies on CYP2C9 alleles for mestranol metabolism.

Occurrence and photochemical degradation of 17alpha-ethinylestradiol in Acushnet River Estuary.

17alpha-Ethinylestradiol (EE2), a major constituent of common contraceptive pills, and three other estrogenic hormones, estrone (E1), 17beta-estradiol (E2) and mestranol (MeEE2) have been determined in Acushnet River Estuary seawater using a GC-MS technique. Among three estrogenic compounds detected, EE2 has the highest concentration, up to 4.7 ng/l, at which EE2 may affect lobster and other fish abundance in the coastal seawater due to its high biological activity on fish feminization. Two natural estrogenic hormones, E1 and E2 have also been found in the estuary at concentrations up to 1.2 ng/l and 0.83 ng/l, respectively. Although EE2 is persistent to microbial degradation, it can undergo a rapid photodegradation in estuarine seawater under natural sunlight irradiation, with a half-life of less than 1.5 days in spring sunny days.

Properties of the estrogen receptor in the human oviduct and its interaction with ethinylestradiol and mestranol in vitro.

Biochemical properties of estrogen binding are investigated in the cytosol and nuclear fractions of the human Fallopian tube. Sucrose density ultracentrifugation and dextrancoated charcoal adsorption techniques are used for characterization of [3H]estradiol uptake in the human oviduct. There is indirect evidence for the presence of protease which can be inhibited by diisopropylfluorophosphate (DFP). When DFP is present in buffer of low ionic strength, the cytosol receptor sediments at 8S and 4S peaks. In the absence of DFP, the 4S peak alone is demonstrated. The proteolytic inhibitor does not alter the estrogen-binding capacity in the human oviduct. The dissociation constant (Kd) for [3H]estradiol in cytosol is 2 X 10(-10) M without DFP and 1.5 X 10(-10) M with DFP. The presence of protease in cytosol of human oviducts is confirmed by hydrolysis of benzoyl-arginine nitroanalide. The enzymatic activity is inhibited by DFP. Nuclear estrogen receptor sediments at 4S after extraction with 0.4 M KCL buffer. A rapid nuclear accumulation of [-3H]estradiol is seen at 25 C, with reciprocal depletion of cytoplasmic receptor in human oviduct tissue minces. The synthetic estrogens ethinylestradiol (17 alpha-ethynyl-1,3,5-estratriene-3,17 beta-diol) and mestranol [3-methoxy-17 alpha-ethinyl-1,3-5(10)-estratiene-17 beta-OL] are competitors for the estrogen receptor in the human Fallopian tube. Inhibition of oviductal estrogen binding is 500 times greater with ethinylestradiol than with mestranol (ki = 0.75 X 10(-9) M for ethinylestradiol; Ki = 3.74 X 10(-7) M for mestranol). The estrogen receptor in the human Fallopian tube shows properties similar to those of the estrogen receptor of the human uterus. However, the determination of the number of binding sites in the oviduct is not influenced by proteolytic enzyme activity.

PIP: The biochemical properties of estrogen binding are investigated in the cytosol and nuclear fractions of the human fallopian tube. Sucrose density ultracentrifugation and dextrancoated charcoal absorption techniques are used for characterization of estradiol uptake in the human oviduct. There is indirect evidence for the presence of protease which can be inhibited by (DFP) diisopropylfluorophosphate. When DFP is present in buffer of low ionic strength, the cytosol receptor sediments at 8S and 4S peak. In the absence of DFP, the 4S peak alone is demonstrated. The proteolytic inhibitor does not alter the estrogen-binding capacity in the human oviduct. The presence of protease in cytosol of human oviducts is confirmed by hydrolysis of benzoyl-arginine nitroanalide. The enzymatic activity is inhibited by DFP. Nuclear estrogen receptor sediments at 4S after extraction with 0.4M KCL buffer. A rapid nuclear accumulation of estradiol is seen at 25 C, with reciprocal depletion of cytoplasmic receptor in human oviduct tissue minces. The synthetic estrogens ethinyl estradiol (17alpha-ethynyl-1,3,5-estratriene-3,17 beta-diol) and mestranol (3-methoxy-17alpha-ethinyl-1,3,5(10)-3stratriene-17beta-OL) are competitors for the estrogen receptor in the human fallopian tube. Inhibition of oviductal estrogen binding is 500 times greater with ethinyl estradiol than with mestranol. The estrogen receptor in the human fallopian tube shows properties similar to those of the estrogen receptor of the human uterus. However, the determination of the number of binding sites in the oviduct is not influenced by proteolytic enzyme activity.

The interaction between St John's wort and an oral contraceptive.

OBJECTIVES: The popular herbal remedy St John's wort is an inducer of cytochrome P450 (CYP) 3A enzymes and may reduce the efficacy of oral contraceptives. Therefore we evaluated the effect of St John's wort on the disposition and efficacy of Ortho-Novum 1/35 (Ortho-McNeil Pharmaceutical, Inc, Raritan, NJ), a popular combination oral contraceptive pill containing ethinyl estradiol (INN, ethinylestradiol) and norethindrone (INN, norethisterone). METHODS: Twelve healthy premenopausal women who were using oral contraception (>3 months) received a combination oral contraceptive pill (Ortho-Novum 1/35) for 3 consecutive 28-day menstrual cycles. During the second and third cycles, the participants received 300 mg St John's wort 3 times a day. The serum concentrations of ethinyl estradiol (day 7), norethindrone (day 7), follicle-stimulating hormone (days 12-16), luteinizing hormone (days 12-16), progesterone (day 21), and intravenous and oral midazolam (days 22 and 23) were determined in serial blood samples. The incidence of breakthrough bleeding was quantified during the first and third cycles. RESULTS: Concomitant use of St John's wort was associated with a significant (P <.05) increase in the oral clearance of norethindrone (8.2 +/- 2.7 L/h to 9.5 +/- 3.4 L/h, P =.042) and a significant reduction in the half-life of ethinyl estradiol (23.4 +/- 19.5 hours to 12.2 +/- 7.1 hours, P =.023). The oral clearance of midazolam was significantly increased (109.2 +/- 47.9 L/h to 166.7 +/- 81.3 L/h, P =.007) during St John's wort administration, but the systemic clearance of midazolam was unchanged (37.7 +/- 11.3 L/h to 39.0 +/- 10.3 L/h, P =.567). Serum concentrations of follicle-stimulating hormone, luteinizing hormone, and progesterone were not significantly affected by St John's wort dosing (P >.05). Breakthrough bleeding occurred in 2 of 12 women in the control phase compared with 7 of 12 women in the St John's wort phase. The oral clearance of midazolam after St John's wort dosing was greater in women who had breakthrough bleeding (215.9 +/- 66.5 L/h) than in those who did not (97.5 +/- 37.2 L/h) (P =.005). CONCLUSION: St John's wort causes an induction of ethinyl estradiol-norethindrone metabolism consistent with increased CYP3A activity. Women taking oral contraceptive pills should be counseled to expect breakthrough bleeding and should consider adding a barrier method of contraception when consuming St Johns wort.

Tryptophan metabolism in women using steroid hormones for ovulation control.

PIP: This is an extension of work recently reported by Rose regarding young women using a combination of progesterone and estrogen for ovulation control. The 10 subjects studied had an abnormal xanthurenic acid excretion after a loading dose of tryptophan. After treatment with 2.5 mg norethynodrel and .1 mg mestranol (Enovid-E) from Days 5 to 24 of the the cycle, 24-hour urine specimens were collected before and after administration of 2 gm of L-tryptophan. They were then given 25 mg of pyridoxine hydrochloride 4 times a day during the 48 hours required to repeat the tryptophan loading test. Controls were 18 healthy women not taking drugs. Metabolites of trytophan determined were indican, anthranilic acid glucuronide, 0-aminohippuric acid, kynurenic acid, acetylkynurenine, kynurenine, 3-hydroxykynurenine, xanthurenic acid, and N-methyl-2-pyridone-5-carboxamide. Urine specimines were analyzed for these and for 4-pyridoxic acid taking usual precautions to avoid dietary factors or drugs which might vitiate the results. At first the ingestion of the steroid had no significant effect on the basal excretion of urinary tryptophan metabolites. However, after the loading dose of tryptophan, the subjects taking Enovid E- excreted a mean level of 697 micro-moles of xanthurenic acid compared with a mean level of 29.8 micro-moles in controls. Some of the other metabolites were also excreted in increased quantities: 3-hydroxykynurenine, kynurenine, kynurenic acid, and acetylkynurenine. The others were excreted in normal quantities. When experimental subjects were given 100 mg/day of supplemental pyridoxine hydrochloride, tryptophan metabolism was essentially normal. These results should be considered in human metabolic studies of pyridoxine-requiring enzyme systems.^ieng

Synthesis and estrogenic properties of 17-epi-ethynylestradiol and its ether derivatives epimestranol and epiquinestrol.

The synthesis of 17-epi-ethynylestradiol (10), the 17 beta-ethynyl-17 alpha-ol epimer of the well-known orally active estrogen, ethynylestradiol (1), was achieved by LiA1H4 reduction of epoxide 9, as well as by demethylating epimestranol (11) with CH3MgI. Compound 11 was obtained by the unusual 17 beta-ethynylation of estrone 3-methyl ether 22 under equilibrating conditions. The in vitro estrogen receptor-binding affinity and the oral estrogenicity in the rat for the 17-epi compounds 10, 11 and 20 (epiquinestrol) was evaluated. Despite moderate estrogen receptor-binding affinity, compound 10 was devoid of measurable estrogenicity at 10 mg/kg or antiestrogenicity at 3 mg/kg.

Effects of neomycin on the biliary excretion and enterohepatic circulation of mestranol and 17beta-oestradiol.

PIP: The continued circulation of free steroids depends on their resorption from the gut following the hydrolysis of biliary conjugates. In this study, the bile duct of female Wistar albino rats was cannulated. Animals receiving labeled steroids or labeled bile intraductally also had the duodenum fitted with a cannula connected with a dosing syringe. In neomycin-treated rats, recirculation was impaired up to 50%. The deconjugation of mestranol and estradiol biliary conjugates was shown in vitro uponiincubation with rat caecal microorganisms, and the inhibition of such hydrolysis by neomycin was observed in vitro. Neomycin pretreatment reduced the biliary excretion of mestranol and estradiol after intraductal administration. It was thought that suppression of the gut microflora by neomycin was a major factor in the impairment of the intrahepatic circulation of mestranol and estradiol metabolites. This effect may be important regarding the half-life of estrogenic compounds of the contraceptive pill.^ieng

Biotransformation of mestranol to ethinyl estradiol in vitro: the role of cytochrome P-450 2C9 and metabolic inhibitors.

Mestranol, the estrogen component of some oral contraceptive formulations, must be demethylated to its active metabolite, 17 alpha-ethinyl estradiol, to produce estrogenic activity. To investigate the transformation of mestranol to ethinyl estradiol, an in vitro assay was used with human liver microsomes from four different donors. Incubation of a fixed concentration of mestranol (3 mumol/L) with varying concentrations of CYP inhibitors revealed strong inhibition of ethinyl estradiol formation by sulfaphenazole, a specific CYP2C9 inhibitor, with an average inhibitor concentration at one half of Emax (IC50) of 3.6 mumol/L (range, 1.8-8.3 mumol/L) and an average maximal inhibitory capacity (Emax) of 75% (range, 60-91%). Troleandomycin (a CYP3A3/4 inhibitor) and quinidine (a CYP2D6 inhibitor), however, produced no substantial inhibitory activity. alpha-Naphthoflavone (a CYP1A1/2 inhibitor only at concentrations < 2 mumol/L and a CYP2C9 inhibitor at higher concentrations) had a weak inhibitory effect on ethinyl estradiol formation (< 20% decrease in mestranol demethylation activity). Of the three antifungal azoles tested, miconazole strongly inhibited mestranol demethylation, with an average IC50 of 1.5 mumol/L (range, 0.7-3.2 mumol/L) and an average Emax of 90% (range, 77-100%), whereas fluconazole displayed relatively weak inhibition only at the highest concentration of 50 mumol/L (mean reduction in demethylation activity was 29%). Itraconazole produced no meaningful inhibition. Strong inhibition of ethinyl estradiol formation by sulfaphenazole suggests a major contribution of CYP2C9 to this reaction.

Variation of ethinylestradiol blood levels among healthy women using oral contraceptives.

Data concerning ethinylestradiol (EE) blood levels among 93 healthy women using oral contraceptives are presented. Seventy-two per cent of the observed variation in EE blood levels was unexplainable on the basis of time since ingestion of the last oral contraceptive, day of menstrual cycle, race, age, weight, height, blood pressure, cigarette consumption, alcohol consumption, diurnal variation, or lifetime use of oral contraceptives.

PIP: This 2-fold investigation studied 1) the extent to which women vary in blood levels of ethinylestradiol (EE) after ingesting oral contraceptives (OCs) containing similar amounts of EE or mestranol (ME), which is metabolized to EE; and 2) whatever variations might be accountable on the basis of physical, behavioral, or other characteristics. 93 healthy OC users were given either OCs with 50 mcg of ME (84 subjects) of 50 mcg of EE (9 subjects). Linear regression was used to determine relevance of variation in EE blood levels based on hours since pill ingestion, day of menstrual cycle, or any other variables. Hours since OC showed the strongest relationship to log EE, accounting for 25% of the variation. Another 3% could be accounted for by day of menstrual cycle. The remaining 72% of observed variation in EE levels could not be explained in terms of time since ingestion of last OC, day of menstrual cycle, race, age, weight, height, or use-duration of OCs.

Danazol binding to rat androgen, glucocorticoid, progesterone, and estrogen receptors: correlation with biologic activity.

Danazol was found to possess androgenic and glucocorticoid activity in rat bioassays. In contrast, danazol displayed no significant estrogenic activity. In support of these findings, danazol bound to the 8 S androgen receptor of rat prostate cytosol and to the glucocorticoid receptor of rat liver cytosol, but danazol did not bind well to the estrogen receptor of the rat uterus. Finally, danazol bound to the progesterone receptor of the rat uterus, but controversy continues as the whether danazol possesses progestational, antiprogestational, or no progestational effects.

Metabolism of 2-3H- and 4-14C-17alpha-ethynylestradiol 3-methyl ether (mestranol) by women.

A mixture of 2-3H and 4-14C-mestranol was administered orally to five women and 2-3H-mestranol alone to one woman. Reactions involving position 2 were extensive as judged by liberation of 3H into body water (14-45% of the dose). 17alpha-Ethynylestradiol, 2-hydroxy-17alpha-ethynylestradiol, 2-methoxy-17alpha-ethynylestradiol, 2-hydroxy-17alpha-ethynylestradiol 3-methyl ether and 16geta-hydroxy-17alpha-ethynylestradiol were measured in the "glucuronide" and pH1 fractions and mestranol, D-homoestrone-17a and D-homoestradiol-17abeta were also measured in the "glucuronide" fraction frum the urine to two of the women by reverse isotope dilution. Radioactive 2-methoxyestradiol accounted for less than 0.011% of the 14C dose in the "glucuronide" fraction of one of the women, consistent with the extent of de-ethynylation previously reported (Steroids, 25, 343 (1975).

PIP: The metabolism of 2-tritium- and 4-carbon-14-17alpha ethynylestradiol 3-methyl ether (mestranol) by women was investigated. A mixture of tritiated and carbon-14 mestranol was administered orally to 5 women and tritiated mestranol alone to 1 woman. Reactions involving position 2 were extensive as determined by liberation of tritium into body water (14-45% of the dose). Urinary metabolites (17alpha-ethynylestradiol, 2-hydroxy-17alpha-ethynylestradiol, 2-methoxy-17 alpha ethynylestradiol, 2-hydroxy-17alpha-ethynylestradiol 3-methyl ether and 16beta-hydroxy-17alpha-ethynylestradiol) were measured by addition of authentic steroids to both the "glucuronide" and pH1 fractions and reisolation by countercurrent distribution, derivative formation and thick layer chromatography. 2-methoxyestradiol accounted for less than .011% of the carbon 14 dose in the "glucuronide" fraction of 1 woman, which is consistent with the extent of deethynylation previously reported.

Metabolism of radioactive 17alpha-ethynylestradiol by women.

PIP: Data on the urinary excretion and subsequent fractionation of radioactivity derived from 6,7-tritiated-17alpha-ethinyl estradiol (tritiated EE) are presented. Tritiated EE was administered orally to 9 women. 17alpha-ethinyl estradiol 2-methoxy-17alpha-ethinyl estradiol, 2 -hydroxy-17alpha-ethinyl estradiol 3-methyl ether, and D-homoestradiol-1 7abeta were identified as urinary metabolites by reverse isotope dilution. The extent of D-homoannulation was much less than that reported previously with rabbits.^ieng

Metabolism of 4-3-H- and 4-14-C-17alpha-ethynylestradiol 3-methyl ether (mestranol) by women.

A mixture of 4-3-H and 4-14-C-mestranol was administered orally to four women. Reactions involving position 4 were no greater than 1.7-3% of the dose as measured by liberation of 3-H into body water. The extent of de-ethynylation in vivo was no greater than 1-2% of the dose as measured by urinary estrone metabolites. Mestranol (0.7 and 0.32% of the dose), 17alpha-ethynylestradiol (6.6 and 11.3%) and 2-hydroxy-17alpha-ethynylestradiol (0.64 and 0.7%) were identified as metabolite aglycons by reverse isotope dilution after Ketodase hydrolysis of the urine from two of the women.

The influence of thiamin deficiency on the metabolism of the oral contraceptive mestranol [3-methoxy-17-ethynyl-1,3,5(10)-estratrien-17 beta-o1] by female rat liver enzymes.

Hepatic microsomes from female rats fed a thiamin deficient diet for three weeks had approximately three times the capacity to metabolize mestranol as microsomes from similar rats fed a diet rich in thiamin. The incremental addition of thiamin to the diet depressed mestranol O-demethylation, NADPH cytochrome c reductase, and cytochrome P-450 content in a dose related manner up to 2 microgram thiamin per gram of feed. Pair-feeding experiments indicate that thiamin ingestion is responsible for the depression of mestranol O-demethylation and NADPH cytochrome c reductase activity while carbodhydrate ingestion is responsible for the decrease in cytochrome P-450. The absorbance spectra generated by the binding of ethylisocyanide to microsomes yield data which suggest that there are no qualitative alterations in cytochrome P-450 due to diet.

PIP: The effect of thiamin deficiency on the metabolism of the oral contraceptive mestranol by female rat liver enzymes was determined. Rats were fed a diet for 3 weeks containing 0, .3, .7, 2.0, or 20 mcg thiamin/gm food before decapitation and extraction of liver microsomes. Mestranol was incubated with 1 ml microsomes from 250 mg liver and the metabolic reaction started by addition of cofactors and NADPH. Liver microsomes from rats fed a thiamin-deficient diet had 3 times the capacity to metabolize mestranol as microsomes from rats fed a thiamin-rich diet. The incremental addition of thiamin to the diet depressed mestranol 0-demethylation, NADPH cytochrome c reductase, and cytochrome P-450 content. Pair-feeding experiments indicate that the carbohydrate portion of the food is responsible for decrease in cytochrome c, while thiamin levels are responsible for changes in the other 2.

Steroid contraceptives in non-human primates (II). Metabolic fate of synthetic estrogens in the baboon after exposure to oral contraceptives.

PIP: The metabolism of isotopically labeled ethinyl estradiol (EE) and mestranol (ME) was studied in 3 baboons before and after the simultaneous injection of a norethindrone-mestranol contraceptive formulation. 6 days after the administration of tritiated-EE and carbon-14-ME, the mean urinary excretion of labeled-EE was 38.3-40.8% of the dose, while the excretion of labeled-ME was 17.8-19.8% of the dose. Plasma levels of tritiated-EE did not differ markedly between the follicular and luteal phases of the cycle. 24 hours after injection, plasma levels of tritiated-EE remained at levels more than 7% of the dose, which was considerably higher than recorded before administration of norethindrone-mestranol. In contrast, carbon-14-ME levels 24 hours after injection did not differ markedly from those found before treatment with norethindrone-mestranol. The results suggest that orally administered ME is demethylated to EE in primates.^ieng

Molecular biology and oral contraception.

Recent developments in knowledge of sex hormone receptors and steroid analogue metabolism allow a rational selection of oral contraceptive steroids from among the numerous available products. Dose related metabolic effects of synthetic estrogens have been demonstrated. Many of these estrogenic actions are antagonised by norgestrel but not by any other commercially available progestogen. Generalised activation of lysosomal enzymes can be demonstrated in oral contraceptive users and is shown to be related to the total steroid dose per cycle, rather than to particular products. These findings suggest that the lowest dose combination of ethynylestradiol and d-norgestrel is the product of choice. Clinical results with such a product are described.

[Comparison of effects of ingestion of Si on the content of Ca and Mg of different tissues of female rats normal or receiving oral oestrogen-gestogens (author's transl)]. / Comparaison des effets de l'ingestion de Silicium sur la teneur en Ca et en Mg de différents tissus de rattes normales ou traitées par des oestroprogestatifs.

In the adult normal the ingestion of silicon modifies the concentration of Ca and Mg of plasma and tissues most often opposite ways according to the mineral (silicate Na) or organic form (SMTO) of the administration. In the female adult under oestroprogestative traitment the organic Si is more active than the silicate to suppress the calcico-magnesic modifications caused by both oestroprogestatives (Norethisterone, Mestranol).

Human metabolism and steroid contraceptives. Part 1.

Metabolic activation of mestranol and certain progestagens is necessary before combination with their specific receptors. This process is subject to inhibition by other drugs. It is suggested that it is preferable to use agents not requiring metabolic activation. Widespread variation of human metabolic parameters is induced by oral contraceptives. A dose related effect of synthetic oestrogens on the synthesis and release of liver-derived plasma proteins is a major cause of this variation. The changes induced may be modified by norgestrel but not by other available progestagens. Changes in various specific plasma proteins, carrier proteins, enzymes and coagulation factors are discussed.

[Cellular estrogen receptors]. / Receptory komórkowe estrogenów.

PIP: The mechanism of hormone activity, especially that of estrogens presents an important link in the body of knowledge concerning the cyclical changes in a woman's life. The understanding of the individual stages of this mechanism is especially interesting in relation to hormonal therapy. This paper presents a review of actual knowledge in the field of cell response and cellular receptors of estrogen. The effect of estrogen activity on the tissues is discussed. The effect of estrogens can be well-demonstrated in hormone dependent cells and tissues (target cells and tissues). (Author's modified)^ieng