Effects Of Contraceptive Steroids Research Articles

Radiation-induced mammary tumors in virgin and parous rats administered contraceptive steroids, 17alpha-ethinylestradiol and norethisterone.

Oral contraceptives are used among women worldwide, and radiation is being used increasingly for diagnosis or therapy. We have investigated the effects of contraceptive steroids on the risk of mammary tumors initiated by radiation. Virgin rats received whole-body irradiation with 2.6 Gy gamma-rays 1 month after the administration of low- or high-dose pellets of contraceptive steroids, such as 17alpha-ethinylestradiol (EE(2)) combined with 19-norethisterone (NET). The high-dose pellet was removed 1 month after irradiation, but administration of the low-dose pellet was continued for up to 1 year. The incidence (33.3%) of mammary tumors initiated with radiation was not modified by the long-term administration of the low-dose pellets. However, the incidence (58. 3%) was increased significantly by the irradiation during administration of the high-dose pellets, but no significant difference in the proportion of adenocarcinoma and fibroadenoma was observed. Meanwhile, parous rats were irradiated with 2.6 Gy gamma-rays at weaning, a period of greater susceptibility to radiation, and then were implanted with the low-dose pellets 1 month later. The highest incidence (90%) of mammary tumors was detected in the parous rats. The proportion of adenocarcinomas in the parous irradiated rats increased significantly on treatment with the low-dose pellets. The results suggest that administration of the high-dose pellets of EE(2)-NET, but not of the low-dose pellets, enhances susceptibility to the initiation by gamma-rays of mammary tumors in virgin rats, and that the low-dose pellets act as a tumor promoter in the mammary glands of parous rats irradiated at weaning.

Behavioral and neurobiological effects of estrogen replacement therapy and a history of triphasic oral contraceptive exposure.

The effects of contraceptive steroids and estrogen replacement therapy on behavior and neuroendocrine function were evaluated in adult female cynomolgus monkeys. During the 'premenopausal' phase of the experiment, the animals were assigned to either treatment with a triphasic oral contraceptive (OC) for 24 months or the untreated control group. The monkeys were then ovariectomized and half of each of the premenopausal groups were randomly assigned to either treatment with conjugated equine estrogens (ERT) or the untreated control group for 12 months (the 'postmenopausal' phase). All evaluations were completed during the postmenopausal phase of the experiment. Both types of exogenous steroid treatments appeared to increase cardiovascular and hypothalamic-pituitary-adrenal responses to stress in socially dominant but not socially subordinate females. A history of triphasic OC administration increased contact aggression received, and reduced the prolactin response to fenfluramine, suggesting reduced serotonergic activity, for at least a year following the cessation of triphasic OC treatment.

Assessment of endothelial function during oral contraception in women with insulin-dependent diabetes mellitus

The effects of contraceptive steroids on the expression of endothelial homeostasis were examined by direct and indirect measures in women with insulin-dependent diabetes mellitus (IDDM) in a prospective nonrandomized controlled study. Study subjects were 13 women with uncomplicated IDDM treated with a monophasic combination of 30 μg ethinyl estradiol and 75 μg gestodene for 12 consecutive cycles and 13 women of comparable diabetic status as control. During the study period, none of the participants developed increased renal albumin excretion, which was used as a direct measure of endothelial function. In the indirect assessment of endothelial function, we found a proportionate increase in plasma levels of thrombin-antithrombin III (TAT) complexes and D-dimer during treatment. Hormonal intake was followed by decreased antigen concentrations of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor (type 1 [PAI-1]), whereas the activities of t-PA and PAI-1 were unchanged. Plasma levels of plasminogen and histidine-rich glycoprotein (HRG) increased and decreased, respectively, whereas an increase in von Willebrand factor was observed in the treatment group. No significant changes in direct or indirect measures were observed in the control group during the observation period of 12 months. In conclusion, no adverse effect on endothelial function was demonstrated by direct measures, but our findings suggest that a procoagulant state, compensated by enhanced activity of the fibrinolytic system, is induced by hormonal treatment. Clinical and metabolic monitoring is recommended if the use of oral contraceptives in women with IDDM is extended.

Effects of contraceptive steroids on cardiovascular risk factors in women with insulin-dependent diabetes mellitus

We evaluated established cardiovascular risk factors within lipoprotein metabolism, hemostasis, and endothelial function in women with insulin-dependent diabetes mellitus who were using oral contraceptives. Twenty-five women with uncomplicated insulin-dependent diabetes mellitus, allocated to treatment with a monophasic combination of 30 micrograms ethinyl estradiol and 75 micrograms gestodene (treatment group, n = 12) or with nonhormonal contraception (control group, n = 13), were prospectively followed up for 12 months. Nonparametric methods were used for statistical evaluation. No statistical differences in the biochemical risk markers were noted between the two groups at the start of the study. In the treatment group serum levels of low-density lipoprotein cholesterol decreased, whereas the concentrations of total cholesterol, high-density lipoprotein cholesterol, very-low-density lipoprotein cholesterol, and triglycerides were unchanged. Within the coagulation system factor VII coagulant activity increased, while fibrinogen levels were unchanged. In the fibrinolytic system we found unchanged activities but decreased antigen concentrations of tissue plasminogen activator and plasminogen activator inhibitor. The concentration of von Willebrand factor increased, but no change in albumin excretion rates were found. In the control group no changes in any of the variables were observed. Intake of modern oral contraceptives does not deteriorate the cardiovascular risk profile in women with insulin-dependent diabetes mellitus, but our study indicates a risk of disturbances of the endothelial integrity, which needs further investigation.

Comparative Aspects of Contraceptive Steroids: Effects Observed in the Monkey

The use of the non-human primate in long-term studies of contraceptive steroids has been questioned because of time, expense and apparent lack of results predictive for humans. Controversies have arisen primarily over the occurrence of mammary nodules in studies of different contraceptive steroids and the occurrence of uterine tumors in 2 high-dose group monkeys in the Depo-Provera study. The long-term studies have been criticized because of the experimental design and the small number of monkeys per dose group. Individual studies by themselves did not reveal lesions other than those expected from an exaggerated pharmacologic response of target tissues; however, a pattern may emerge from reviewing and combining results of different studies that indicate the results of these studies are in agreement with the clinical findings in man. Effects of contraceptive steroids on the mammary gland and genital organs will be discussed. Data from 17 contraceptive steroid studies involving 264 untreated control and 733 treated non-human primates were available.

Kinetics of drug action in disease states. XXII. Effects of contraceptive steroids on the pharmacodynamics of ethanol in rats.

This investigation was designed to determine the effect of treatment with contraceptive steroids on the central nervous system depressant activity of ethanol. Adult female rats received oral doses of ethynyl estradiol (0.1 mg kg-1 day-1), ethynyl estradiol and norethindrone (0.1 and 10 mg kg-1 day-1), or vehicle only for 14 days. Ethanol was then infused slowly iv until the animals lost their righting reflex. The concentrations of ethanol at that time in serum and cerebrospinal fluid were statistically significantly higher in rats treated with the estrogen-progestin combination than in control animals. Ethanol concentrations in rats treated only with the estrogen were intermediate and did not differ significantly from control values. These results indicate that treatment with an estrogen-progestin combination is associated with a decreased sensitivity of the central nervous system to the hypnotic activity of ethanol. This evidence of a pharmacodynamic interaction between contraceptive steroids and ethanol in rats is consistent with a recent clinical report of significant contraceptive steroid-related improvement in tolerance to ethanol with no apparent effect on the pharmacokinetics of ethanol.

Effect of contraceptive steroids on creatine kinase activity in serum.

Administration of steroids has been reported to decrease creatine kinase (CK; EC 2.7.3.2) activity in sera of patients suffering from various diseases. Recently one of us reported a decrease in serum CK activity in healthy women of reproductive age taking a contraceptive steroid (Primovlar Schering) for 9 months. We continued to study to investigate the effect of another contraceptive steroid preparation (Ovulen Searle) on serum CK. CK activity was measured in sera of 10 healthy women of reproductive age 3 6 and 9 months after they started taking Ovulen and in 20 healthy women of comparable age (control group) as described earlier. The data were analyzed statistically by Students t-test. There was no significant difference (p>0.05) in the serum CK activity of control subjects and women taking Ovulen for 3 6 and 9 months. All the individual values were within the normal range. We conclude that the serum CK-lowering effect of contraceptive steroids depends on the specific steroids involved. Both Primovlar and Ovulen are estrogen/progestogen combinations but Primovlar contains 0.05 mg of ethinyl estradiol and 0.5 mg of norgestrel and Ovulen contains 0.1 mg of mestranol and 1.0 mg of ethynodiol diacetate. (full text)

Anti-estrogenic effects of contraceptive progestins on the dynamics of gonadotropin release.

The hypophysiotropic effects of ethinylestradiol (EE) alone and in combination with three different progestins at various doses were assessed in 39 normal women. The compounds were given orally for 7 to 21 days. Serum LH and FSH were measured before and after GnRH double stimulation (2 x 25 micrograms i.v. at a two-hour interval); the ratio between second and first response served as an index of gonadotropin-synthesis capacity. Compared to pretreatment early follicular phase controls (LH and FSH ratios of 1.3 and 1.4), administration of 40 and 50 micrograms of EE daily elicited a significant amplification of LH and FSH synthesis (LH ratios of 2.2 and 3.3; FSH ratios of 2.8 and 3.3). By contrast, 80 micrograms of EE daily caused little change. The EE-induced rise of pituitary responsiveness to GnRH could be counteracted by the addition of progestins. The degree of inhibition as dependent on the type and dose of the progestational compound. It is concluded that the standardization GnRH double stimulation technique may serve as a pharmacodynamic model to quantitate the estrogenic and anti-estrogenic effects of contraceptive steroids at the pituitary level.

Hormonal activity and hepatic effects of contraceptive steroids

Hormonal activity and hepatic effects of contraceptive steroids

Periportal sinusoidal dilatation, inflammatory bowel disease, and the contraceptive pill

Two women, aged 19 and 28 yr, who had been on the contraceptive pill for at least 18 mo, developed abnormal levels of circulating liver enzymes, minimal hepatomegaly, and elevated erythrocyte sedimentation rate. Liver biopsy in both women showed a sinusoidal dilatation sparing the perihepatic venous regions. The liver function abnormality resolved on stopping the pill. Both patients also had clinically mild inflammatory bowel disease. The possibility of both liver and bowel abnormalities being effects of contraceptive steroids is discussed.

Effect of contraceptive steroids on γ-aminobutyric acid metabolism and pyridoxal kinase activity in rat brain

Adult female albino rats were administered oral contraceptive steroids daily for 3 months and γ-aminobutyric acid (GABA) content as well as the GABA metabolizing enzyme(s) activity were assayed. GABA content of the brain was found to be elevated in both estrogenic and progestogenic hormone-treated animals. However, no significant change was observed either in glutamic acid decarboxylase (EC 4.1.1.15) activity or in γ-aminobutyric acid transminase (EC 2.6.1.19) activity of brain tissue in hormone-treated animals. Interestingly, parallel to the increase of GABA content, a concomitant elevation of pyridoxal kinase (PL-kinase) (EC 2.7.1.35) activity was observed. It seems that the increase in the GABA concentration by the contraceptive steroids might have been mediated through an elevated pyridoxal kinase activity of the brain. The possible mechanism and interrelationship between the metabolic activities is discussed.

Effects of contraceptive steroids on serum lipoproteins and cardiovascular disease scrutinized at workshop in Bethesda

A 2-day workshop was held at the National Institute of Health during May 1979 in an effort to assess the current status of the interrelationships between high density lipoprotein (HDL) levels and the incidence of ischemic heart disease and to delineate immediate needs for further research aimed at improved steroid contraceptive safety. Review of older and recent data gave little doubt as to the association between lipoprotein patterns and the incidence of heart disease. Less clear was the relationship between lipoprotein patterns and coronary heart disease (CHD) then is the relationship between oral contraceptive (OC) usage and lipoprotein patterns. Workshop participants did provide strong evidence that OC usage can modify these patterns. The final interrelationship discussed was that of OC usage and cardiovascular disease, particularly atherosclerosis. Along with considering the interactions among OCs, serum lipoproteins, and cardiovascular disease by epidemiologic approaches, workshop participants also considered the status of current studies bearing on the mechanisms by which these interactions may be mediated and the status of methodology for evaluating the interactions. During the general discussion at the end of the workshop, participants agreed that the apparent association between HDL levels and the incidence of cardiovascular disease dictates the need for vigorous research. It was agreed that at least some OC pills do lower serum HDL levels.

Effect of contraceptive steroids on mammary tumor development in experimental animals

Effect of contraceptive steroids on mammary tumor development in experimental animals

Pain relief in childbirth and its consequences for the infant

species. may stimulate development of mammary carcinoma in male and/or female animals. In treated rats. this is usually accompanied by higher (males) or lower (females) incidences of benign mammary tumors, as compared with the corresponding controls. The speciesspecific neuroendocrine system. i.e.. estrogen-dependent stimulation of PRL seLretion appears to be of great importance in the pathogenesis of mammary tumors in mice and rats. On the other hand, stimulation of mammary tumors in dogs by certain progestogens or progestogen-estrogen combinations seem to be related to high mammary proliferative activity of these compounds in the dog and their stimulatory effect on highly mammotrophic canine GH. In total contrast to the sittiation in mice and rats. !ong-term treatment of the dog with high doses of estrogens does not stimulate mammary tumor development in spite of their ability to stimulate PRL secretion in this species. Similarly, in the monkey and man certain sex steroids (high doses) may stimulate PRL secretion. However, in the monkey. steroid-related mammary tumors are not observed. even after long-term treatmr’nt wath high doses of estrogens. progestogt ns and their combinations. Moreover, cc Intraceptive use appears to decrease the rjsk OI benign breast tumors in women. and after two decades of extensive use of contraceptive steroids, the evidence weighs against an association of these preparations with human breast cancer. These findings indicate that, with regard to the develop rr,ent of mammary tumors as an undesirable effect of contraceptive steroids. not otlly the species-specific neuroendocrine s! stem (e.g. stimulation of PRL and/or GH secretion) but also the susceptibility of certain species, strains or individuals seems to play a great role. This clearly illustrates the hmitations inherent in the extrapolation to man of data on steroid-related mamman tumors in various experimental animals.

Plasma Levels of Adrenocorticotropin and Cortisol in Women Receiving Oral Contraceptive Steroid Treatment*

The secretion rate and plasma concentration of the adrenocortical steroid cortisol is modified in subjects treated with estrogenic and/or progestational steroids. The effects of contraceptive steroids on the secretion of ACTH are poorly documented, however, In the current investigation, we found that concentrations of ACTH and cortisol in plasma obtained at 0800--0900 h from a group of women with normal cyclic menses (n = 4) ranged from 78--120 pg/ml and 77--137 ng/ml, respectively. Although significant cyclic changes in the plasma levels of LH, FSH, 17 beta-estradiol, and progesterone occurred during the ovarian cycle, no obvious cyclic fluctuations in plasma levels of ACTH or cortisol were observed. In women treated with Norinyl 1 + 80 (1.0 mg norethindrone plus 0.08 mg mestranol), plasma concentrations of LH, FSH, 17 beta-estradiol, and progesterone were significantly lower (P less than 0.001) than plasma levels of these hormones in normal women during the ovarian cycle. The mean daily plasma concentrations of ACTH were significantly lower (P less than 0.001), whereas plasma cortisol levels were significantly higher (P less than 0.001) in women treated with oral contraceptive steroids compared to the levels of these hormones in the untreated ovulatory women.

Effect of contraceptive steroids on mammary gland of beagle dog and its relevance to human carcinogenicity

Differences in the inhibitory potentials against UDP-glucuronosyltransferase (UGT) between species have been reported only rarely, even though the information would be useful for the precise characterization of drug candidates. In this study, the inhibition potentials of nonsteroidal anti-inflammatory drugs (NSAIDs) against UGT-catalyzed estradiol 3β-glucuronidation (E3G) in the liver microsomes of rats, dogs, and humans were compared. Rat liver microsomes (RLMs) and human liver microsomes (HLMs) exhibited homotropic activation kinetics with S50 values of 22 and 12 µM, respectively. However, dog liver microsomes (DLMs), exhibited Michaelis–Menten kinetics with no activation. Among the NSAIDs investigated (diclofenac, diflunisal, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, mefenamic acid, niflumic acid, and sulindac), only niflumic acid and mefenamic acid inhibited E3G potently in all three species. The IC50 values of NSAIDs against E3G in RLMs and HLMs were within a threefold difference of each other, while those in DLMs was more than three times higher than the other two. In conclusion, RLMs showed an inhibitory pattern similar to that of HLMs, whereas DLMs presented a distinct pattern. These results indicate that a rat animal model would be useful for evaluating the inhibitory potentials of drugs against estradiol glucuronidation, but a dog model would not.

Mammary neoplasia in animals: pathologic aspects and the effects of contraceptive steroids.

The incidence of spontaneous tumors of the mammary gland varies greatly among the different mammalian species. Large domesticated animals have a very low frequency of the disease. Even though the cow has enormous mammary gland development and cows numbering in the millions are observed to an old age, less than 50 cases have been reported in the literature. Similarly, mammary tumors are equally rare in sheep, horses, pigs, and goats. In contrast, the incidence of mammary tumors in the dog exceeds that of women by a factor of 3 to 4, and the disease is common in the cat. Rats and mice have a high incidence of mammary tumors; however, they are less frequent in other species of small laboratory animals. Mammary neoplasms are apparently rare in the nonhuman primate, but interest in the disease in these animals remains high as they have a menstrual cycle comparable to women. This paper reviews some major aspects of spontaneous mammary tumors in mice, rats, cats, dogs, and nonhuman primates. Emphasis has been placed on the pathologic aspects of the neoplasms and the use of these species in the carcinogenic testing of contraceptive steroids. The literature contains a large number of excellent publications on mammary neoplasia in animals; only selected articles are cited. The reader is especially referred to the comprehensive review by Hamilton published in 1974 [32] and the review by STEWART published in 1976 [68] on the comparative pathology of animal neoplasia.KeywordsMammary GlandMouse Mammary Tumor VirusTubular AdenocarcinomaMammary NoduleContraceptive SteroidThese 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.

Effect of contraceptive steroids on arginine-stimulated glucagon and insulin secretion in women. III. Medroxyprogesterone acetate

The effect of medroxyprogesterone acetate (MPA) on basal circulating lipids, arginine-stimulated glucagon and insulin secretion, and glucose tolerance was studied in normal women. After 5 days of oral MPA treatment (10 mg/day), there was a small but significant decline in basal circulating triglycerides. No changes were observed in fasting plasma concentrations of cholesterol, free fatty acids, glucagon, insulin, or glucose; in the plasma glucagon, insulin, or glucose responses during L-arginine infusion; or in the plasma insulin or glucose responses during oral glucose tolerance tests. There was no correlation of any of these parameters with the observed decline in fasting plasma triglyceride concentrations. These results confirm previous reports of no consistent changes in lipid or glucose homeostasis in women using derivatives of 17α-acetoxyprogesterone derivatives for contraceptive purposes, and suggest that MPA may be a suitable alternative for those women who develop hyperlipemia or glucose intolerance when they use contraceptive agents which contain derivatives of ethinyl estradiol and nortestosterone.

Effects of oral and intrauterine administration of contraceptives on the uterus

Combined regimen contraceptive steroids produce precocious endometrial secretion, followed by involution leading to a suppressed endometrium with small tubular glands and failure of spiral arterioles to develop; decidua-like stromal changes are dose related as is dilatation of venules. Thrombosis of the latter, perhaps estrogen mediated, leads to local tissue infarction and is the proximate cause of “breakthrough bleeding”. Sequential regimen contraceptive steroids lead to retarded endometrial secretion, failure of spiral arterioles to develop, and a weak decidua-like stromal transformation. Contraceptive steroids occasionally produce polypoid lesions of the endocervix with atypical microglandular hyperplasia. There are conflicting reports about the effects of contraceptive steroids on the squamous epithelium of the exocervix, but they neither protect against cancer nor cause it in the usually accepted sense. Uterine leiomyomas may exhibit increased cellularity and bizarre, hyperchromatic nuclei or mutinucleation in women receiving contraceptive steroids. Both polyethylene and metal-containing intrauterine devices may initiate inflammatory responses in the endometrium varying from mild to severe, related to the time the device has been in contact with the mucosa. Salpingitis and ectopic pregnancy are increased in frequency in device users.

Effects of contraceptive steroids and pregnancy on bile composition and kinetics in the baboon

The effects of subcutaneous implants of ethinyl estradiol (EE) and norethindrone (NE) alone and in combination and pregnancy on bile composition and kinetics were studied in the baboon. Treatment with EE significantly (p less than .01) reduced biliary cholesterol; the addition of NE enhanced this effect. NE alone however produced a slight increase in biliary cholesterol. During the third trimester of pregnancy both biliary cholesterol and the lithogenic index were significantly (p less than .05) decreased. The chenodeoxycholic acid pool (CAP) size was significantly (p less than .05) decreased by EE and further decreased by EE plus NA (p less than .01). NET alone resulted in an increase in CAP size. CAP size was also reduced by pregnancy though the reduction was not significant (p less than .05) until the third trimester. EE plus NE significantly (p less than .05) increased deoxycholic acid pool (DAP) size though NE along could not sustain this increase. DAP size in pregnancy decreased during the third trimester. No net change in total bile acid pool size was observed during any of the periods of EE or EE plus NE though there was a significant (p less than .05) net decrease in total bile salt pool size during the third trimester of pregnancy. The relevance of the findings to the formation of gallstones in the human female is discussed.