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.

Evaluation of antimicrobial efficacy of Trachyspermum ammi (Ajwain) oil and chlorhexidine against oral bacteria: An in vitro study.

INTRODUCTION: Plaque removal is of utmost importance for control of dental caries and other associated diseases of oral cavity. However, various natural agents have proven their efficacy over chemotherapeutic agents in terms of antibacterial activity against various microorganisms. The effect is mainly due to polyphenol as its major constituent. AIM: In this in vitro study, we aimed to determine the antibacterial efficacy of Trachyspermum ammi oil at different concentrations against five oral bacteria. HYPOTHESIS: Herbal compound, T. ammi oil is effective in reducing five oral plaque-forming bacteria. MATERIALS AND METHODS: We determined the antimicrobial activity of T. ammi oil (test material) against chlorhexidine (gold standard). Pure cultures of Streptococcus mutans MTCC No 497, Streptococcus oralis MTCC No. 2696, Lactobacillus acidophilus MTCC No. 10307, Lactobacillus fermentum MTCC No. 903, and Candida albicans MTCC No. 183 were obtained and grown in selective culture media. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of both materials were evaluated by serial dilution and disc diffusion method, respectively. RESULTS: Our results revealed that T. ammi oil moderately inhibits bacterial growth with mean MIC of 250, 125, 250, 125, and 250 µg/ml, respectively. Mean MBC for T. ammi oil obtained was 18.60 ± 0.65, 11.60 ± 1.14, 14.10 ± 0.55, 11.50 ± 0.61, and 15.10 ± 0.74 mm. The MIC and MBC values were higher as compared to chlorhexidine gluconate and it was statistically significant. CONCLUSION: T. ammi (ajwain) can serve as a potential, natural, nontoxic, and economical therapeutic antiplaque agent.

Parallel Solid-Phase Synthesis using a New Diethylsilylacetylenic Linker and Leading to Mestranol Derivatives with Potent Antiproliferative Activities on Multiple Cancer Cell Lines.

BACKGROUND: RM-133 belongs to a new family of aminosteroid derivatives demonstrating interesting anticancer properties, as confirmed in vivo in four mouse cancer xenograft models. However, the metabolic stability of RM-133 needs to be improved. After investigation, the replacement of its androstane scaffold by a more stable estrane scaffold led to the development of the mestranol derivative RM-581. METHODS: Using solid-phase strategy involving five steps, we quickly synthesized a series of RM-581 analogs using the recently-developed diethylsilylacetylenic linker. To establish structure-activity relationships, we then investigated their antiproliferative potency on a panel of cancer cell lines from various cancers (breast, prostate, ovarian and pancreatic). RESULTS: Some of the mestranol derivatives have shown in vitro anticancer activities that are close to, or better than, those observed for RM-581. Compound 23, a mestranol derivative having a ((3,5-dimethylbenzoyl)- L-prolyl)piperazine side chain at position C2, was found to be active as an antiproliferative agent (IC50 = 0.38 ± 0.34 to 3.17 ± 0.10 µM) and to be twice as active as RM-581 on LNCaP, PC-3, MCF-7, PANC-1 and OVCAR-3 cancer cells (IC50 = 0.56 ± 0.30, 0.89 ± 0.63, 1.36 ± 0.31, 2.47 ± 0.91 and 3.17 ± 0.10 µM, respectively). CONCLUSION: Easily synthesized in good yields by both solid-phase organic synthesis and classic solution-phase chemistry, promising compound 23 could be used as an antiproliferative agent on a variety of cancers, notably pancreatic and ovarian cancers, both having very bad prognoses.

Effects of estrogen in the regulation of nitric oxide pathway during development of hypertension in rats.

A down-regulation of nitric oxide (NO) synthesis has been involved in the genesis of cardiovascular complications associated with hypertension. This study was designed to assess the role of estrogen in the modulation of the pressor response elicited by N-methyl-L-arginine (L-NMA) in conscious spontaneously hypertensive (SHR) rats before and after ovariectomy. Four-week-old female SHR (n = 6) and age matched Wistar-Kyoto (WKY; control n = 7) rats were treated with mestranol (50 micrograms/100 g BW) twice a week for 8 weeks. At week 12, SHR and WKY were instrumented with catheters in the femoral artery and vein. L-NMA (30 mg/kg, i.v.) was infused over 1 min in SHR and WKY rats prior to and 3 weeks following ovariectomy. Results were compared to control rats, non-estrogen treated female SHR (n = 6) and WKY (n = 6). Our data show that the pressor response induced by L-NMA in estrogen-treated SHR was similar to estrogen-treated WKY (29 +/- 4 vs 25 +/- 2 mmHg). As compared to intact SHR and WKY, our data demonstrate that 3 weeks following ovariectomy, baseline blood pressure increased by 15% in SHR but remained unchanged in ovariectomized WKY. Furthermore, the magnitude of the L-NMA-induced pressor effect was significantly decreased in ovariectomized SHR and WKY. Our data support the concept that estrogen treatment does not play a significant role in the modulation of NO pathway in female SHR, whereas the presence of an intact ovaria modulates the NO pathway in female WKY.

FSH and ovarian response: spontaneous recovery of pituitary-ovarian activity during the pill-free period vs. exogenous recombinant FSH during high-dose combined oral contraceptives.

OBJECTIVE: Compare spontaneous recovery of pituitary-ovarian activity during the pill-free period following the correct use of low-dose oral contraceptives and subsequent ovarian function during the administration of exogenous recombinant FSH (recFSH) after switching to continued Lyndiol (2.5 mg lynestrenol + 0.05 mg ethinyl-oestradiol) medication. DESIGN: Prospective, randomized, group-comparative, single-centre study. Following the monitoring of the pill-free period (week 1) and subsequent treatment with Lyndiol (for a total of 5 weeks), all subjects were randomly allocated to one of four groups receiving daily FSH injections for 1 week [75, 150, 225 IU recFSH or 150 IU purified urinary FSH (uFSH)] during the fourth week of Lyndiol use. PATIENTS: Thirty-six healthy volunteers aged 18-39 years, prestudy oral contraceptive use for at least 3 months, cycle length between 24 and 35 days. MEASUREMENTS: Serum FSH, LH and oestradiol (E2) concentrations as well as transvaginal ultrasound assessment of the number and diameter of follicles > 2 mm were used to monitor pituitary ovarian function. RESULTS: At the start of the pill-free period following the prestudy contraceptive medication, 67% of the women presented with LH and FSH levels < 1 IU/l and only one follicle > 10 mm was observed. Initial levels of LH and FSH correlated (P < 0.05) with the extent of pituitary-ovarian activity during the pill-free period. At the end of the pill-free period a follicle > 10 mm had emerged in one subject only. During the first 3 days of Lyndiol use, seven women (19%) eventually showed at least one follicle > 10 mm. During combined exogenous FSH and Lyndiol administration, LH levels remained completely suppressed (< or = 0.5 IU/l) in all women studied. FSH levels and number and size of follicles increased with increasing doses of exogenous FSH in a dose-dependent manner. E2 levels remained low in all groups (< 150 pmol/l). During the week following FSH administration, FSH levels and E2 levels decreased gradually while the number of follicles > 10 mm still increased. CONCLUSIONS: We have confirmed that dominant follicles > 10 mm are present at the end of the pill-free period and during the first days after resumption of pill intake. Once follicles > 10 mm arose at the end of the pill-free period, continued use of Lyndiol did not reduce follicle diameters. One week of Lyndiol reduces pituitary-ovarian activity to levels observed after 3 weeks of low-dose pills. FSH administration during Lyndiol resulted in dose-dependent follicle growth despite extremely low LH levels. E2 secretion (56 +/- 51 pmol/l) occurred to a limited and variable extent along with extremely low serum LH concentrations. Recovery of pituitary-ovarian activity at the end of the pill-free period is comparable to FSH levels and follicle dynamics following 7 days of 75-150 IU/l recFSH.

Rhesus macaque model for ovarian cancer chemoprevention.

PURPOSE: The objective of the study reported here was to explore whether a nonhuman primate model could be developed for chemoprevention of ovarian cancer. METHODS: An initial feasibility trial was done with three monkeys to determine tolerance for these drugs and for acquisition of surgical ovarian biopsy specimens. In the study, 19 female adult Macacca mulatta (rhesus macaques) were given fenretinide (4HPR) oral contraceptive (OCP), the combination of 4HPR+OCP, or no medication for three months. Laparotomy was performed before and after drug administration, and ovarian biopsy specimens were obtained to evaluate the potential for this animal as a model for ovarian cancer chemoprevention, as well as evaluating fluorescence spectroscopy and other potential biomarkers for ovarian cancer prevention studies. RESULTS: The monkeys tolerated the drugs, surgeries, and acquisition of multiple ovarian biopsy specimens with resultant minimal morbidity. On initial data analysis, fluorescence spectroscopy was the marker that appeared the most promising. CONCLUSIONS: On the basis of results of this study, this model merits further investigation. The rhesus monkey is an excellent candidate for a nonhuman primate model for ovarian cancer chemoprevention.

Histological changes induced by tibolone and estrogen/glucocorticoid on aging skin.

OBJECTIVE: The aim of this study was to investigate the oral effects of tibolone and mestranol plus paramethasone on the skin of postmenopausal women. A second purpose was to determine endometrial thickness with transvaginal ultrasound. MATERIALS AND METHODS: This randomized study was carried out in 39 healthy postmenopausal women. Skin biopsies were obtained from the thigh area by a single punch, before and after treatment, and the sections were evaluated. Current characteristics of both groups were measured at follow-up. RESULTS: No gross differences were observed in size, distribution or imaging of collagen, elastic or reticular fibers. Statistically significant changes were found in the papillar dermis thickness. There were no statistically significant differences in the sonographic measurements. CONCLUSION: The estrogen/glucocorticoid combination provides a way to evaluate in parallel the cellular metabolism effects on the irreversible aging process. The current results encourage widening these observations of the possible advantage of this combination, in order to alleviate the cellular degenerative process.

Oral contraceptives elevate core temperature and heart rate during exercise in the heat.

It is generally believed that the elevated progesterone levels seen during the luteal phase of the menstrual cycle alter thermoregulatory function during exercise. We hypothesized that oral contraceptives (OCs) that contain synthetic progestogen would alter thermoregulation during exercise in a manner similar to that seen during the luteal phase. To test this hypothesis 10 healthy women currently taking OCs were recruited. Subjects performed a 1 h exercise bout in the heat (30 degrees C, 50% relative humidity; RH) at 60% of their maximum oxygen uptake on two occasions: once while on OCs and once during a control trial when the subjects were off OCs. Core temperature, skin temperatures, heart rate, skin blood flow and sweat rate were measured at rest and every 20 min during both exercise bouts. OCs significantly increased core temperature and heart rate over that seen during the control condition. Specifically, after 1 h of exercise, OCs caused a mean 0.3 degrees C and an 8-bpm increase in core temperature and heart rate respectively. Additionally, the differences in core temperature and heart rate during the two trials became more exaggerated as exercise duration increased, as evidenced by significant treatment-by-time interactions. These results suggest that OCs alter thermoregulatory and cardiovascular function during exercise in the heat. Furthermore, the changes in core temperature and heart rate seen during exercise while taking OCs are similar in direction and magnitude to those observed during the luteal phase of the menstrual cycle.

Effect of the separate and combined administration of mestranol and phenobarbital on the development of altered hepatic foci expressing placental form of glutathione S-transferase in the rat.

The stages in the carcinogenesis process include initiation, promotion and progression. Although many characteristics of tumor promotion and promoting agents have been reported, relatively few studies on the effects of combinations of promoting agents have been detailed. For study of the combined effects of phenobarbital (PB) and mestranol (MS) in multistage rat hepatocarcinogenesis, an initiation-promotion protocol was developed. Female rats were injected i.p. at 5 days of age with either diethylnitrosamine (DEN) (10 mg/kg) or the solvent tricaprilyn. At weaning, approximately 10 rats from both the DEN-initiated and the solvent control groups were provided basal diet alone, PB (10, 100 or 500 mg/kg diet), MS (0.02 or 0.2 mg/kg diet) or various combinations of both PB and MS in the basal diet. At 8 months of age, the rats were killed and the livers removed, sectioned and fixed in ice-cold acetone. Sections of 5 microgram thickness were stained for placental glutathione S-transferase (PGST) expression, and the volume fraction of liver occupied by altered hepatic foci was determined by stereology. In addition, incorporation of bromodeoxyuridine into nuclei of PGST-expressing (focal) and non-PGST-expressing (non-focal) hepatocytes was determined. Administration of the highest dose of PB resulted in a significant decrease in non-focal hepatocyte labeling index, with a 4-fold differential between the focal and non-focal hepatocyte labeling index. Administration of 0.2 mg/kg diet MS resulted in effective promotion. The non-focal labeling index was increased and the focal labeling index was further enhanced (3-fold) relative to the non-focal index by this dose of MS. Combination of the lower MS dose with PB resulted in at least an additive promoting effect; however, a lower volume fraction was noted for the combination of low MS dose plus the highest PB dose. Combination of the higher MS dose with PB resulted in an elevation of volume fraction only for the middle PB dose. These findings indicate that the potency of promotion by mixtures is modulated by the dose of each component as well as by pharmacodynamic and pharmacokinetic properties of each component of the mixture.

Inverted skin changes induced by estrogen and estrogen/glucocorticoid on aging dermis.

To evaluate hormone replacement therapy effects at the peripheral level, the present trial explored the oral effects of mestranol (80 micrograms/day for 10 days) and mestranol plus paramethasone (80 micrograms + 6 mg/day for 10 days) on the skin of postmenopausal women. This double-blind study included 13 patients. Skin biopsies were obtained from the thigh area by a single punch, 5 mm in diameter, before and after treatment, and the sections, six per sample, were micrometrically evaluated. Various features of the epidermis and dermis layers were stained using the hematoxylin and eosin, Masson, Verhoeff's and Gomori techniques. Statistically significant changes were found in the papillar dermis thickness; mestranol reduced it and mestranol plus paramethasone increased it. The current results encourage widening these observations of the possible advantage of this estrogen/glucocorticoid combination, in order to alleviate the cellular degenerative process.

[Effect of mestranol on pharmacokinetics of phenazone in the rabbit]. / Wplyw mestranolu na farmakokinetyke fenazonu u królic.

There was studied the influence of mestranol on the pharmacokinetics parameters of phenazone. There was proved the decrease AUC abridgement the period of semi duration for elimination phase and increase total clearance. On the base of these experiments there was able to make a conclusion that estrogens influence on the phenazone's pharmacokinetic probably by induction of microsomal enzymes of liver.

Effects of estrogen and progesterone on plasma platelet-activating factor-acetylhydrolase activity and low-density lipoprotein cholesterol concentration in men.

OBJECTIVE: We examined the effects of estrogen and progesterone on the plasma platelet-activating factor (PAF)-acetylhydrolase activity and lipoprotein concentrations in men. METHOD: Ten healthy men received 6 days of oral mestranol (0.24 mg/day) followed by 6 days of oral norethisterone (20 mg/day). The PAF-acetylhydrolase activity and lipoprotein profiles were determined in each subject prior to and following mestranol loading and following norethisterone administration. RESULT: The mestranol caused a significant decrease in both the plasma PAF-acetylhydrolase activity and the low-density lipoprotein (LDL) cholesterol concentrations of 26.4% and 26.9%, respectively; norethisterone appeared to revert the PAF-acetylhydrolase activity and LDL cholesterol concentrations to the levels observed prior to mestranol loading. In addition, the plasma PAF-acetylhydrolase activity was positive correlated with the LDL cholesterol concentration (r = 0.58, P < 0.001). CONCLUSION: The results of this study indicate that mestranol and norethisterone exert an effect on the plasma PAF-acetylhydrolase activity in men, possibly by influencing plasma LDL cholesterol concentrations.

Tamoxifen inhibits hepatoma cell growth through an estrogen receptor independent mechanism.

BACKGROUND/AIMS: Tamoxifen has previously been shown to prolong the survival of patients with advanced stages of hepatocellular carcinoma and it has been suggested that it inhibits the growth of hepatoma cells through an estrogen receptor-dependent mechanism. We have studied the effects of the synthetic estrogen, mestranol, and the antiestrogen, tamoxifen, on the growth regulation of hepatoma cells in vitro. METHODS: Cells were maintained under fully estrogenized conditions and were deprived of estrogen shortly before conducting experiments. RESULTS: In the human hepatoma cell line Hep 3B, tamoxifen inhibited cell growth in a concentration and time-dependent manner with effective concentrations ranging from 0.1 microM to 10 microM. Mestranol inhibited cell growth at a concentration of 10 microM and had an additive effect with tamoxifen on growth inhibition. Expression of estrogen receptors in hepatoma cells was not detected by enzyme immunoassay, Northern blot analysis or reporter gene expression assay. Furthermore, the introduction of estrogen receptors into Hep 3B cells did not alter the effect of tamoxifen and mestranol on cell growth. CONCLUSIONS: This study suggests that tamoxifen inhibits the growth of Hep 3B hepatoma cells through an estrogen receptor-independent mechanism.

The co-mitogenic effects of various estrogens for TGF-alpha-induced DNA synthesis in cultured female rat hepatocytes.

The synthetic estrogens ethinyl estradiol (EE) and mestranol (M) are weak complete hepatic carcinogens and potent tumor promoters. In vivo, EE and M cause a rapid but transient increase in liver growth. However, studies in cultured female rat hepatocytes indicate that EE is not a strong complete hepatic mitogen but rather enhances epidermal growth factor (EGF)-induced DNA synthesis and is thus classified as a co-mitogen (Yager, J.D., Zurlo, J. and Ni, N. (1991) Proc. Soc. Exptl. Biol. Med., 198, 667-674). The endogenous estrogen 17 beta-estradiol (E2) also exhibits co-mitogenic activity, enhancing the fraction of hepatocytes undergoing DNA synthesis induced by both EGF and transforming growth factor alpha (TGF-alpha) (Ni, N. and Yager, J.D. (1994) Hepatology, 19, 183-192). The objectives of the study reported here were: (1) to determine whether the co-mitogenic effects of EE and E2 extend to other synthetic estrogens including mestranol and diethylstilbestrol, and to alpha-zearalanol, a natural product with estrogenic activity; (2) to compare the co-mitogenic effects of endogenous estrogens including E2, estrone, estriol and the catechol metabolites 2- and 4-hydroxy-estradiol; and (3) to determine whether the conditioned medium from E2-treated hepatocytes has co-mitogenic activity. Female rat hepatocytes in primary culture were exposed to the various estrogens +/- TGF-alpha and DNA synthesis was determined by measuring [3H]thymidine incorporation into extracted DNA. The results show that the co-mitogenic effects previously observed with EE and E2 also extend to all of these estrogens and to the E2 catechol metabolites. Although the co-mitogenic potency of these estrogens does not correlate with their reported affinities to the estrogen receptor, their estrogenicity appears necessary since the non-estrogenic metabolite 2-methoxy-estradiol lacks co-mitogenic activity. In addition, enhancement of TGF-alpha-induced DNA synthesis by conditioned medium from E2-treated cells supports the notion that a metabolite mediates its co-mitogenic effect.

Modulatory influence of oral contraceptives on mammary growth pattern of normal and ovariectomised mice.

The present study reports the modulatory influence of oral contraceptive formulations, Ovral (0.05 mg ethinylestradiol plus 0.5 mg norgestrel per pill), Noracycline (0.05 mg ethinylestradiol plus 0.1 mg lynestrenol per pill), Pearl (0.03 mg ethinylestradiol plus 0.30 mg norgestrel) and Centchroman (30 mg), on the growth and developmental pattern of murine mammary epithelium in normal as well as ovariectomised mice. Oral treatments of ovariectomised mice for 15 days with doses D1 (1/5th of a pill) and D2 (1/10th of a pill) of Ovral, Noracycline and Pearl enhanced the diameter of the terminal end buds (TEBS) and lateral buds (LBS) significantly. The increase in the diameters of TEBS and LBS on treatment with similar doses of Centchroman were not much significant. Hence, it may be concluded from the present study that the growth and development pattern of mammary epithelium can be modulated by treatment with oral contraceptives Oral, Noracycline, Pearl and Centchroman which is indicated by the increase in the diameters of TEBS and LBS.

PIP: In India, researchers at Jawahar Lal Nehru University in New Delhi compared data on 80 bilaterally ovariectomized 4-5 week old virgin mice with data on 10 nonovariectomized age- and sex-matched controls to examine the modulatory influence of various combined oral contraceptives (OCs) on the growth and developmental pattern of mammary epithelium. The experimental groups of 10 mice each received either 20% or 10% of an OC pill administered orally for 15 days. The OC formulations included Ovral (.05 mg ethinyl estradiol [EE2]+ .5 mg norgestrel), Noracycline (.05 mg EE2 + .1 lynestrenol), Pearl (.03 EE2 + .3 norgestrel), and Centchroman (a nonsteroidal contraceptive, 30 mg). Ovral, Noracycline, and Pearl at both doses increased the diameter of the terminal end buds and lateral buds of ovariectomized and nonovariectomized mice (p .0000001). Even though Centchroman also enhanced the diameter of the terminal end buds and lateral buds, the increase was not significant. These findings show that combined OCs do modulate the growth and developmental pattern of mammary epithelium. They lead us to question whether OCs might also increase the risk of breast cancer. In fact, many epidemiological studies demonstrate an increase in the risk of breast cancer among OC users.

Effect of mestranol on pharmacokinetics of paracetamol.

The aim of this study was to investigate the effect of mestranol on pharmacokinetics of paracetamol. The study was carried out on 20 female rabbits. Paracetamol was administered to rabbits intragastrically at a dose of 50 mg/kg b.w. One group of animals was given mestranol intragastrically 0.1 mg once daily during 2 months. The method of Routh A. et al. was used to paracetamol concentration assay. Blood for the assays was collected within 24 hours after drug administration, prior to the study as well as 1 month and 2 months after continuous mestranol administration. The two compartment open model was used for calculations. The study revealed an increase in AUC and paracetamol half-life as well as decrease in the total body clearance. We conclude that there is an interaction between mestranol and paracetamol leading to a decrease in total body paracetamol clearance.

Seguridad, efectividad y control del ciclo menstrual de una preparación anticonceptiva oral monofásica con 75 mcg de gestodeno y 30 mcg de etinilestradiol / Safety, efficacy and cycle control of an oral monophasic contraceptive formulation containing gestodene 75 mcg de gestodeno y 30 mcg de etinilestradiol

Se estudió una formulación oral monofásica a base de 75 mcg de gestodeno y 30 mcg de etinilestradiol, con el objeto de probar su seguridad, eficacia y control del ciclo menstrual. En el estudio se incluyeron 67 mujeres sanas que acumularon 574 ciclos. Esta formulación mostró ser muy eficaz, ya que con el uso adecuado del método no se presentó ningún embarazo. los efectos secundarios observados fueron iguales o menores a los reportados con otros anticonceptivos hormonales orales. La administración de este nuevo preparado no modificó los parámetros hematológicos, bioquímicos o urinarios de las usuarias. Con respecto al control sobre el sangrado endometrial, las usuarias de mantuvieron dentro de un patrón menstrual considerado como acptable. En conclusión, se trata de un anticonceptivo oral que resultó ser eficaz, bien aceptado y cuyos efectos secundarios son semejantes o menores a los de otros anticonceptivos orales.

Long-term effect of low-dose combined steroid contraceptives on body iron status.

The present study was aimed to evaluate iron metabolism in active and healthy adult women having taken oral contraceptives (OC) long-term. Mean dietary iron intake in age-matched control and experimental groups was adequate. Serum ferritin used as a marker for body iron stores was marginal in both groups underlying a high prevalence of deficient-iron reserves among subjects. This parameter was not correlated to the iron content of the diet. The serum iron concentration was significantly higher in OC users than control subjects (p less than 0.001). Biochemical results commanded a discussion on the pertinence of evaluating the total dietary iron intake and on the sensitivity of biochemical methods used to assess the iron status.

Effects of norethisterone on pressor response to angiotensin II in men.

OBJECTIVE: We examined the effects of norethisterone and/or mestranol on the pressor response to angiotensin II in 20 healthy men. METHODS: Four study protocols were used: I) mestranol 0.08 mg/day for 6 days followed by mestranol plus norethisterone 20 mg/day for 6 days, II) mestranol 0.16 mg/day for 6 days followed by norethisterone alone 10 mg/day for 6 days, III) mestranol 0.24 mg/day followed by norethisterone 20 mg/day for 6 days, and IV) norethisterone 20 mg/day for 6 days. The angiotensin II dose to elicit a 20-mmHg rise in diastolic blood pressure was considered the effective pressor dose. This was determined before each protocol, at the end of the mestranol-alone portion, and at the end of the norethisterone portion. Subjects in study III also underwent measurement of plasma prostanoid levels, plasma renin activity and concentration, and estradiol and progesterone just before each angiotensin II infusion. Subjects in studies I and III underwent measurement of mean platelet volume, complete blood counts, liver function tests, and coagulation factors before each angiotensin II infusion. RESULTS: Whereas mestranol had no apparent effect on angiotensin II pressor response, norethisterone at a dose of 20 mg/day (with or without concurrent mestranol administration) caused a significant decrease in pressor responsiveness to angiotensin II. No changes in plasma prostanoids or renin could be found that would account for the change in pressor response. CONCLUSION: These findings indicate that the refractoriness to angiotensin II induced by norethisterone was related to its progestogenic properties.

Estrogen protection against atherosclerosis and synthetic estrogen production of cirrhosis in the rabbit.

Two artificial estrogens, ethinyl estradiol and mestranol, were found to cause cirrhosis in the rabbit liver during a study of atherosclerosis. These drugs showed protective effects against atherosclerosis in cholesterol-fed rabbits when administered orally (1 ppm in diet). These drugs and two naturally occurring estrogens, estrone and estradiol, were similarly effective when administered intramuscularly (1.5 mg per rabbit per week) to rabbits fed a diet lower in cholesterol. Reduction by estrogens of plasma cholesterol did not fully account for the reduction of extent of aortic atherosclerosis. Also, no differences in aortic or platelet eicosanoid production from exogenous arachidonic acid were found to explain the effect on atherogenesis. The 2 artificially modified estrogens, ethinyl estradiol and mestranol, caused portal fibrosis with biliary proliferation (even in rabbits not fed cholesterol). Estrone, estradiol, and testosterone were not injurious in this regard at the dosages used. Only the unmodified estrogens reduced atherosclerosis without damaging the rabbit liver.