Oral contraceptives and breast cancer.

PIP: Changes in endogenous hormones at various times in life (e.g., early menarche, birth of the 1st child at an advanced maternal age, and late menopause) increase the changes of developing breast cancer. It is reasonable then to expect oral contraceptive (OC) use to increase the risk of breast cancer. It is difficult, however, to prove OC exposure has this effect due to changed OC use patterns plus OCs consist of many different hormones at various doses and compositions. Yet, OC use in the past (even more than 15 years of OC use) had not increased the risk of breast cancer in women of all combined age groups. 3 research groups have identified a small increase in overall risk in low risk women, but unidentified sources of bias or confounding could account for this increased risk. Some recent studies indicate an increased risk of breast cancer with duration of OC use, but the risk depends somewhat on dose of either the estrogen or the progestin. Nonetheless, these findings were weak and inconclusive. Other research shows long-term OC use increases the risk of breast cancer in just young women (under 45 years old). Future epidemiologic studies thus need to address increased breast cancer risk in women under 45 years old who used OCs for a long time. They need to look at whether the risk is due to early use and continues into older age or to longterm use at any time in just young women. Some studies should include women with and without various biological markers of susceptibility. Other studies should measure blood levels of estrogens and progestins in women using the same OCs. BAsed on the information now available, it would be unwise for physicians to warn women against using the highly effective OCs because they do prevent unwanted pregnancy and are protective against ovarian and endometrial cancer.^ieng

Swedish studies link hormone use to higher breast cancer risk.

PIP: 2 more reports on heightened risk of breast cancer in certain subsets of oral contraceptive and menopausal estrogen-progestin users have appeared from Sweden, in addition to 3 studies published in early 1989 that prompted the U.S. F.D.A. to re-evaluate its warning labels on pill packages inserts. The 1st study on 10 cases among 23,244 women from Uppsala found that women who took hormone replacement therapy briefly for menopausal symptoms had a 10% increased risk of breast cancer, while those taking hormones for 9 years or more had a 70% higher risk. The report estimated that women using combined estrogen-progestins for 6 years or more had a 4.4-fold risk of breast cancer appearing in the pre- menopausal age group. Women who used pills 5 or more years before the age of 25 had a 5.3-fold risk of breast cancer. Those using for 8 or more years before the 1st pregnancy had a 2.0-fold risk. These data analyzed 174 pre-menopausal women diagnosed with breast cancer in the early 1980s, and included many women who began pills in the 1960s. The author noted that we have no studies yet on the modern, lower-dose oral contraceptive pills.^ieng

Effect of oral contraceptives on the mammary glands of Rhesus monkeys: a preliminary report.

PIP: To determine the relationship of oral contraceptive use and breast cancer, 96 rhesus monkeys were administered either Enovid-E (2.5 mg norethynodrel and .1 mg mestranol) or Ovulen (1 mg ethynodiol diacetate and .1 mg mestranol) cyclically for 5 years at doses of 1, 10 and 50 times the human dose. The animals' progress was compared with a control group of 32 monkeys. General physical and mammary gland examinations were conducted before treatment and monthly thereafter. During the 5 year study period none of the treated animals demonstrated clinical evidence of mammary gland lesions, no deaths from breast malignancy occurred, and no palpable breast nodules were found.^ieng

Effect of estrogen and progestin treatments on endometria from postmenopausal women.

PIP: This report describes experiments designed to answer several important questions about the biochemistry of estrogen-stimulated postmenopausal endometrium; in particular; how much estrogen enters the endometrium and the biological effectiveness of that estrogen in women receiving different forms of postmenopausal estrogenic therapy. To this end, nuclear and cytoplasmic estradiol receptor (ER) and cytoplasmic progesterone receptor (PR) were measured in curettage samples of endometria from women receiving, either sequentially or cyclically, Premarin, Harmogen, Progynova, or mestranol at either low or high doses. Cyclical treatment with estrogen alone was compared with sequential therapy with 3 weeks of estrogen plus 1 week of estrogen plus 1 week of estrogen plus northisterone. No difference in any of the receptor levels was found in samples obtained during the 3rd week of any of the 4-week treatment cycles. For 2-3 weeks of a treatment cycle, the receptor levels were similar to those seen in premenopausal, proliferative-phase endometrium, suggesting that postmenopausal endometrial cells are subjected to a very potent estrogenic stimulus for a considerable period. Norethisterone ingestion for 1 week decreased both the amount of nuclear ER and the percentage of total cellular ER that were in the nuclear fraction. Estradiol dehydrogenase was also induced by the progestin. The presence of this enzyme could result in lowered nuclear ER levels which were seen during the progestogenic phase of the treatment schedule. Nuclear ER was lower during Week 3 than Week 2 of estrogen treatment. In addition, PR was negatively correlated with nuclear ER in postmenopausal tissues obtained in Week 3 in contrast to positive correlations seen in premenopausal samples. Possibly a 3-week treatment with estrogen leads to a refractory condition. When receptor levels of normal, cystic hyperplastic, typical hyperplastic, and atypical hyperplastic tissues were compared, the endometria that had been returned to normal histology suggested that cells in atypical hyperplastic endometrial cells may be more estrogen sensitive than other types of endometrial tissues.^ieng

On the epidemiology of oral contraceptives and disease.

PIP: Adverse and beneficial effects, especially with regard to mortality rates, of oral contraceptives (OC) are reviewed. In 1980 approximately 80 million women used OCs worldwide. OCs were first marketed in the United States in the 1960's, but by the 1980's low-dose combination pills with less estrogen and progesterone content became widespread along with the minipill, injectable preparations depo- medroxyprogesterone DMPA, and norethindrone containing capsules. Relative disease risk estimates are based on cohort studies and case- control studies. The Royal College of General Practitioners RCGP Oral Contraceptive Study of 1974 involved 46,000 women aged over 15 (50% were OC users, 50% were nonusers) the Oxford Family Planning Association Contraceptive Study of 1976 recruited 17,032 women aged 25-39, 56% of whom used OCs, and the Walnut Creek Contraceptive Drug Study of 1981 studied 16,638 women aged 18-54 of whom 28% were OC users and 33% were former users. A somewhat elevated mortality among ever-users of OCs in the order of 20% seems to be indicated by these studies mostly attributable to diseases of the circulatory system. Current OC use is also a risk factor in thrombotic stroke of the order of 4 or 5, but former use of OCs lowers the risk to 2. The effect of OC dose and formulation, duration of use, and predisposing factors on hemorrhagic and thrombotic stroke appears to be inconclusive with varying data from different studies. There is evidence for some increase in ischemic heart disease among current OC users, and also a 2-fold increase of myocardial infarction (MI) when smoking, serum cholesterol, and hypertension is taken into account, moreover higher estrogen dosage also contributes to a higher incidence of MI. There is also a 5-fold increase of venous thromboembolism among OC users induced by duration of use and estrogen potency, as OCs seem to promote atherogenesis, although the roles of progesterone and estrogen are conflicting. combination pills reduce the rate of endometrial cancer, provided protection against ovarian cancer, and do not seem to increase breast cancer incidence, although the relative risk of cervical cancer is elevated. Mortality risks with older OCs outweigh the benefits.^ieng

A primer on the hormone-free interval for combined oral contraceptives.

BACKGROUND: The dosing, schedules, and other aspects of combined oral contraceptive (COC) design have evolved in recent years to address a variety of issues including short- and long-term safety, bleeding profiles, and contraceptive efficacy. In particular, several newer formulations have altered the length of the hormone-free interval (HFI), in order to minimize two key undesired effects that occur during this time: hormone-withdrawal-associated symptoms (HWaS) and follicular development. OBJECTIVE: This primer reviews our current understanding of the key biological processes that occur during the HFI and how this understanding has led to changes in the dosing and schedule of newer COC formulations. MAIN MESSAGE: In brief, HWaS are common, underappreciated, and a likely contributor to COC discontinuation; because of this, shortening the HFI and/or supplementing with estrogen during the progestin-free interval may provide relief from these symptoms and improve adherence. A short HFI (with or without estrogen supplementation) may also help maintain effective follicular suppression and contraceptive efficacy, even when the overall dose of estrogen throughout the cycle is low. CONCLUSIONS: Taken together, the available data about HWaS and follicular activity during the HFI support the rationale for recent COC designs that use a low estrogen dose and a short HFI. The availability of a variety of COC regimens gives physicians a range of choices when selecting the most appropriate COC for each woman's particular priorities and needs.

Patterns of serum LH and FSH in response to 4-hour infusions of luteinizing hormone releasing hormone in normal women during menstrual cycle, on oral contraceptives, and in postmenopausal state.

PIP: Patterns of serum luteinizing hormone (LH) and follicle stimulating hormone (FSH) in response to 4-hour infusions (1 mcg/min) of LH-releasing hormone in 16 normal women during the menstrual cycle, in 4 women on oral contraceptives (OCs), and in 3 postmenopausal women were investigated. A biphasic response of LH was observed in the follicular and luteal phases, with the response much larger in the latter (p .001). The largest LH response was observed during the periovulatory phase (p .001). Women on combined OCs studied between Cycle Days 11-14 showed a biphasic response intermediate in magnitude (p .05) between follicular and luteal phases with some blunting of the initial phase of secretion. FSH response was not clearly biphasic but was greatest in the periovulatory phase (p .001), intermediate in the luteal phase (p .01), and least in the follicular phase. In postmenopausal women, total output of LH was similar to the luteal phase and the output of FSH was equivalent to that at midcycle. These data support the concept that the biphasic response to LH to the prolonged infusion is present in women and that its magnitude and characteristics may be modulated by estradiol and progesterone levels.^ieng

Insulin receptors in circulating erythrocytes and monocytes from women on oral contraceptives or pregnant women near term.

Altered carbohydrate metabolism occurs in women during pregnancy and in those using oral contraceptives (OC). Insulin binding to circulating erythrocytes and monocytes was studied in 77 nonobese, healthy women volunteers; they were divided into 4 groups: 1) late pregnant (n = 19),2) OC users taking 50 microgram estrogen daily (OC-50; n = 19),3) OC users taking 35 microgram estrogen daily (OC-35; n = 18), and 4) a control group (n = 21). All nonpregnant volunteers were in the luteal phase (days 18-21) of the menstrual cycle. Oral glucose tolerance tests were normal in all groups. Fasting plasma insulin was higher (P < 0.001) in the pregnant group, and plasma insulin responses to the oral glucose tolerance test were higher (P < 0.05) in the pregnant, OC-35, and OC-50 groups compared to that in the control group. The percentage of specific binding of [125I]insulin to 1.2 x 10(7) monocytes/ml (and 4.4 x 10(9) erythrocytes/ml) was similar in all groups (mean +/- SE): pregnant, 6.85 +/- 0.48% (6.85 +/- 0.59%); OC-35, (6.85 +/- 0.40%); OC-50, 6.95 +/- 0.55% (6.73 +/- 0.59%); and control 6.66 +/- 0.64% (7.17 +/- 0.44%). No correlation was found between insulin binding to erythrocytes and monocytes. Average affinity profiles and binding sites per cell (70/erythrocyte and 50,000/monocyte, respesctively) were similar in all groups. Since insulin binding to monocytes in decreased during the secretory phase of the menstrual cycle, one could extrapolate from our data that pregnant women will have lower insulin binding compared to nonpregnant women in the proliferative phase of the cycle; such a report has appeared recently (Beck-Nielsen et al., J Clin Endocrinol Metab 49: 810, 1979). Differences in plasma levels of estrogen and progesterone between the secretory and proliferative phases of the cycle are much smaller than between the nonpregnant state and late pregnancy. Therefore, it remains to be seen whether these steroid hormones would cause, by the same mechanism, a decrease in insulin binding (and insulin resistance) during late pregnancy and in the secretory phase of the cycle.

PIP: This study of altered carbohydrate metabolism in pregnant women and oral contraceptive (OC) users measured insulin binding to circulating erythrocytes and monocytes in 77 nonobese healthy women volunteers. The 77 women were divided into 4 groups: 1) third trimester pregnant (n=19); 2) OC users using 50 mcg estrogen formulations (n=19; OC50); 3) OC users with 35 mcg formulations (n=18; OC35); and 4) controls (n=21). Nonpregnant participants in the study were between menstrual cycle Days 18 and 21 (luteal phase). Oral glucose tolerance tests were performed on all groups, and results were normal for all 4 groups. When fasting plasma insulin was tested, it was higher (P .001) in the pregnant group, and plasma insulin responses to oral glucose tolerance test were higher (p .05) in the pregnant, OC35, and OC 50 groups compared with controls. Specific binding of tritiated insulin to monocytes showed similar percentage in all 4 groups. There was no correlation between insulin binding to erythrocytes and monocytes. The average affinity profiles and binding sites per cell (70/erythrocyte and 50,000/monocyte) were similar in all groups as well.

The increase in plasma and saliva cortisol levels in pregnancy is not due to the increase in corticosteroid-binding globulin levels.

Total and free cortisol levels are significantly elevated in pregnancy, but the reasons for this are not clear. The relationships between the diurnal variation in saliva (free) cortisol and baseline levels of total cortisol, corticosterone-binding globulin (CBG), progesterone, and estrogens were studied in several groups of women (normal nonpregnant, taking a combined oral contraceptive pill, after superovulation therapy, during early and late pregnancy, and postpartum). Saliva cortisol levels were significantly elevated in late pregnancy throughout the day, with preservation of diurnal variation. Total cortisol and CBG levels were also significantly raised in pregnancy, but total cortisol levels were normal in women taking a combined oral contraceptive pill in spite of significantly elevated CBG. There was no relationship between saliva cortisol and progesterone levels, and it is unlikely that the increase in cortisol is due to displacement of cortisol from CBG by progesterone. Cortisol levels fell slowly postpartum over several days, making it improbable that the increase in cortisol is solely due to elevated CRH levels. It appears that increased free and total cortisol levels in pregnancy are related to resetting of the sensitivity of the hypothalamic-pituitary-adrenal axis and not merely to raised CBG, progesterone, or CRH levels.

The effect of posture and saline loading on plasma renin activity and aldosterone concentration in pregnant, non-pregnant and estrogen-treated women.

The effect of contraceptive ingestion and pregnancy on components of the renin-angiotensin-aldosterone system was compared in 17 non-pregnant women, 8 non-pregnant women taking oral contraceptives, and 11 pregnant women. Plasma renin substrate concentrations and the dynamic responses of plasma renin activity and aldosterone concentrations to upright posture and iv saline infusion were evaluated. Renin substrate was significantly higher in those women taking oral contraceptives and among the pregnant subjects than the other non-pregnant group. No significant differences in plasma renin activity or aldosterone concentrations were seen before or after postural stimulation among the 2 non-pregnant groups. After saline loading renin was higher and aldosterone lower in the contraceptive-treated group. In contrast, the pregnant group had significantly higher values at every point. The response to posture and saline among the pregnant subjects was similar in direction and magnitude to those of the non-pregnant groups. The urinary excretion of sodium before and after saline infusion was significantly lower in the pregnant group than in the non-pregnant groups. These observations suggest that estrogen-induced increases in renin substrate do not alone account for the increases in the renin-angiotensin-aldosterone system observed during pregnancy, but rather such increases appear to represent a physiological response to increased sodium need during pregnancy.

PIP: The effect of posture and saline loading on plasma renin activity (PRA) and aldosterone concentration in 11 pregnant, 17 nonpregnant, and 8 estrogen-treated women was investigated. Following saline loading, renin was higher and aldosterone lower in the contraceptive-treated group, while the pregnant group has markedly higher values at every point. The response to posture and saline was similar in direction and magnitude in all groups. The urinary excretion of sodium before and after saline infusion was singificantly lower (p less than .005) in the pregnant group than in the nonpregnant groups. The contraceptive group had a significantly higher (p less than .001) mean plasma renin substrate (PRS) than the nonpregnant group. The pregnant group had an even higher PRS when compared to those taking contraceptives (p less than .05). No marked differences in PRA or aldosterone concentrations were seen before or aft postural stimulation among the 2 nonpregnant groups. These results suggest that estrogen-induced increases in renin substrate do not alone account for the increase in the renin-angiotensin-aldosterone system observed during pregnancy, but rather such increases appear to represent a physiological response to increased sodium need during pregnancy.

Changes in insulin receptors during oral contraception.

Combined estrogen/progestagen oral contraceptives (OC) have been reported to be associated with a deterioration of glucose tolerance and a decrease in insulin sensitivity; thus, since it has been suggested that steroids affect insulin receptor properties, the influence of OC on insulin receptors was investigated. The study groups were composed of nine normal menstruating women (controls), nine pill users, and two healthy women on OC for the first time. Insulin receptors on monocytes were evaluated at 7-day intervals during the 28 days between menses. Insulin receptor concentration and/or affinity did not show any variation in pill users during the test period and did not differ from values observed in controls in the luteal phase; consequently, the insulin receptor concentration in pill users is lower than that during the follicular phase or in men. The physiological variation of insulin receptor concentration and the increase of receptor affinity in the midfollicular phase, which characterize the normal menstrual cycle, are therefore abolished by OC. This effect occurs rapidly because it was also evident in the two women on OC for the first time. No difference was observed in fasting blood glucose and serum immunoreactive insulin concentrations between control subjects and pill users. The present data appear to confirm that sex steroids affect the insulin receptor and lend further support to the concept that caution must be used in clinical studies of insulin receptors when women are included. In addition, the results suggest that insulin receptors may play a role in the glucose intolerance and insulin insensitivity which have been described in pill users.

PIP: Combined estrogen/progestagen (OC) oral contraceptives have been reported to be associated with a deterioration of glucose tolerance and a decrease in insulin sensitivity. Since it has been suggested that steroids affect insulin receptor properties, the influence of OCs on insulin receptors was investigated. The study groups were composed of 9 normally-menstruating women (controls), 9 pill users, and 2 healthy women on OCs for the 1st time. Insulin receptors on monocytes were evaluated at 7-day intervals during the 28 days between menses. Insulin receptor concentration and/or affinity did not show any variation in pill users during the test period and did not differ from values observed in controls in the luteal phase; consequently, the insulin receptor concentration in pill users is lower than that during the follicular phase or in men. The physiological variation of insulin receptor concentration and the increase of receptor affinity in the midfollicular phase, which characterize the normal menstrual cycle are therefore abolished by OCs. This effect occurs rapidly because it was also evident in the 2 women on OCs for the 1st time. No difference was observed in fasting blood glucose and serum immunoreactive insulin concentrations between control subjects and pill users. The present data appear to confirm that sex steroids affect the insulin receptor and lend further support to the concept that caution must be used in clinical studies of insulin receptors when women are included. In addition, the results suggest that insulin receptors may play a role in the glucose intolerance and insulin insensitivity which have been described in pill users.

Divergent effects of weight reduction and oral anticonception treatment on adrenergic lipolysis regulation in obese women with the polycystic ovary syndrome.

The influence of weight reduction and female sex hormones on the regulation of lipolysis was investigated in isolated abdominal sc adipocytes from 20 obese hyperandrogenic women with polycystic ovary syndrome (PCOS). Nine PCOS women were reinvestigated after 8-12 weeks of weight reduction therapy (WR) with a very low calorie diet, inducing a mean loss of 8 +/- 3 kg, and 8 PCOS women were reinvestigated after 12 weeks of treatment with combined oral contraceptives (OC), containing ethinyl estradiol and norethisterone; the remaining 3 subjects were drop-outs. Both WR and OC normalized hyperandrogenicity. WR caused a 50% reduction of basal lipolysis rate and a 5- to 7-fold increased noradrenaline and terbutaline sensitivity (P < 0.02); the latter could be ascribed to a 2-fold increased beta2-adrenoceptor density (P < 0.02) as determined with radioligand binding. There was no change with regard to dobutamine (beta1-adrenoceptor sensitivity) or clonidine, (alpha2-adrenoceptor sensitivity) or to beta1-adrenoceptor density. OC treatment did not influence the basal lipolysis rate or beta2- or alpha2-adrenoceptor sensitivity, but lowered the beta1-adrenoceptor sensitivity 7-fold (P < 0.03) without a reduction in beta1-adrenoceptor density. The OC treatment effect was not observed when forskolin and dibutyryl cAMP, acting on adenylate cyclase or protein kinase A, respectively, were used, suggesting a partial uncoupling of beta1-adrenoceptors. WR therapy, but not OC therapy, caused, in addition to changes in lipolysis function, improved in vivo insulin sensitivity and lower plasma noradrenaline levels. These findings suggest that factors other than hyperandrogenicity modulate lipolysis regulation in obese subjects with PCOS. Disturbances in sympathetic pathways could be of pathogenic importance.

Effects of a new oral contraceptive containing an antimineralocorticoid progestogen, drospirenone, on the renin-aldosterone system, body weight, blood pressure, glucose tolerance, and lipid metabolism.

Combined hormonal oral contraceptives (OCs) may lead to a mild rise in blood pressure and body weight. In rare instances, large increments in blood pressure are measured. We investigated the effect of a combination of ethinyl estradiol (EE) plus a progestogen with antimineralocorticoid, i.e. natriuretic, properties [Drospirenone (DRSP)] on body weight, blood pressure, the renin-aldosterone system, atrial natriuretic factor, plasma lipids, and glucose tolerance. It is anticipated that this will lead to the development of an OC that does not raise body weight or blood pressure. Four groups of 20 women each received 30 micrograms EE plus 3 mg DRSP (group A), 20 micrograms EE plus 3 mg DRSP (group B), 15 micrograms EE plus 3 mg DRSP (group C), and, as a control OC, 30 micrograms EE plus 150 micrograms levonorgestrel (Microgynon, Schering; group D) for 6 months. During the OC-free control cycles before and after treatment and throughout treatment, the target parameters were measured. Between the pretreatment cycle and the sixth treatment cycle, mean body weight fell by 0.8 to 1.7 kg in groups A, B, and C (P < 0.05 vs. D), whereas it rose by 0.7 kg in group D. Systolic and diastolic blood pressures fell by 1-4 mm Hg in groups A, B, and C (significant for A and C vs. D) and increased by 1-2 mm Hg in group D. Renin substrate rose equally in all groups (P < 0.05), whereas PRA and plasma aldosterone rose significantly only in the DRSP groups, presumably due to sodium loss. In the DRSP groups, high density lipoprotein cholesterol rose (P < 0.05), in contrast to group D. Low density lipoprotein cholesterol fell slightly (P > 0.05), whereas triglyceride levels showed a stronger increase in the DRSP groups (P < 0.05) than in group D. All groups attained good cycle control; group A had the best. Side-effects were minimal. To our knowledge, this is the first report on a combined OC that leads to a small decrease in body weight and blood pressure. It may be especially beneficial for women susceptible for a gain in weight and a rise in blood pressure.

PIP: The potential of a new oral contraceptive (OC) containing drospirenone (DRSP) to avert the moderate increases in body weight and blood pressure often associated with use of existing combined OCs was investigated in a study of four groups of 20 German women each. Group A received 30 mcg of ethinyl estradiol (EE) and 3 mg of DRSP, Group B was administered 20 mcg of EE and 3 mg of DRSP, Group C received 15 mcg of EE and 3 mg of DRSP, and Group D was given a standard OC containing 30 mcg of EE and 150 mcg of levonorgestrel. Between the pretreatment cycle and the last (sixth) treatment cycle, mean body weight fell by 0.8-1.7 kg in Groups A, B, and C, but rose by 0.7 kg in Group D. Systolic and diastolic blood pressures fell by 1-4 mm Hg in Groups A, B, and C and rose by 1-2 mm Hg in Group D. Renin substrate rose equally in all four groups, while plasma renin activity, plasma aldosterone, and high density lipoprotein cholesterol rose significantly only in the three DRSP groups and serum triglyceride levels were significantly higher in Group D than in the three DRSP groups. Glucose tolerance increases were similar in all four groups. Finally, all groups--but especially Group A--experienced good cycle control and there were no serious side effects. These findings suggest that a combined OC containing DRSP may be especially beneficial for women who have a tendency to gain weight or experience a rise in blood pressure while taking OCs.

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.

PIP: The effects of oral contraceptive treatment on the pituitary-adrenal axis were studied. Secretion rate and plasma concentration of the adrenocortical steroid cortisol was modified in subjects treated with estrogenic and/or progestational steroids. Concentrations of adrenocorticotropin (ACTH) and cortisol in plasma obtained at 0800-0900 hours from a group of women with normal cyclic menses (n=4) ranged from 78-120 pg/ml and 77-137 pg/ml, respectively. Although significant cyclic changes in plasma levels of luteinizing hormone (LH) follicle stimulating hormone (FSH), estradiol, and progesterone occurred during the ovarian cycle, no obvious cyclic fluctuations in plasma levels of ACTH or cortisol were observed. Plasma concentrations of women treated with Norinyl 1 + 80 (1 mg of norethindrone and .08 mg of mestranol) of LH, FSH, estradiol, and progesterone were significantly lower (P .001) than plasma levels of these hormones in normal women during the ovarian cycle. Mean daily plasma concentrations of ACTH were significantly lower ( P .001), whereas plasma cortisol levels were significantly higher (P .001) in women treated with oral contraceptives compared to the levels of these hormones in untreated ovulatory women.

Oral contraceptive and postmenopausal estrogen effects on lipoprotein triglyceride and cholesterol in an adult female population: relationships to estrogen and progestin potency.

PIP: A study of the prevalence of hyperlipidemia has been conducted among female telephone company employees using oral contraceptives (OCs) or estrogenic hormones. This paper relates hormone formulation and estrogen/progestin potency to striglyceride and cholesterol concentrations in total plasma and lipoprotein fractions and relative lipid composition. Changes in these lipid parameters are of interest because they may predict atherosclerosis risk. Results in 148 hormone users are compared with those in 306 nonhormone users. All data are adjusted for the effects of age, relative body weight, cigarette smoking, and alcohol intake. Triglyceride concentrations in whole plasma, very low density lipoprotein (VLDL), and high density lipoprotein (HDL) are elevated 1.5-2.5 fold with increasing estrogen potency. Low density lipoprotein (LDL) triglyceride concentration is elevated to a similar degree among OC users regardless of estrogen potency, but there is no significant effect of postmenopausal estrogen use on LDL triglyceride concentrations. The LDL cholesterol concentration shows an increasing trend with increasing estrogen potency in a random sample of OC-treated women, but is slightly lower than control in postmenopausal women treated with estrogen alone. The HDL cholesterol concentration in plasma is highest with hormones having the greatest estrogen potency and lowest with those having the greatest progestin potency. The VLDL cholesterol to triglyceride ratio adjusted for triglyceride concentration is significantly increased with the use of Ovral, a progestin-predominant contraceptive preparation. The LDL cholesterol to triglyceride ratio is reduced with the use of all OCs examined, except for Ovral, where the ratio is above average. The HDL cholesterol to triglyceride ratio is reduced for all combination OCs examined. The use of a sequential OC or postmenopausal estrogens is not associated with a significant alteration in the cholesterol to triglyceride ratio in any lipoprotein fraction. Knowledge of estrogen and progestin potency and kind of progestin are important in predicting the effect of OCs on plasma and lipoprotein lipids. On the basis of observed differences in lipoprotein lipid concentrations and relationships, the potential arteriosclerotic risk from sex hormones may vary among OC formulations.^ieng

Attenuation of mild hyperandrogenic activity in postpubertal acne by a triphasic oral contraceptive containing low doses of ethynyl estradiol and d,l-norgestrel.

The effect of a low dose triphasic oral contraceptive (OC) was evaluated during a 6-month treatment period in 41 patients (mean age, 25.4 +/- 0.7 yr) who had grade I-IV postpubertal acne and normal menses. The OC contained three dose levels of ethynyl estradiol and dl-norgestrel. Acne lesions were assessed, and serum androgen levels were measured during a control cycle and between days 17-21 of treatment cycles 1, 2, 3, and 6. Four patients dropped out after 3 months of treatment. Acne was significantly improved after the first OC cycle. After six cycles, the number of comedones had decreased by 79.6 +/- 3.2% (range, 50-100%) in 69.4% of the patients. Mean baseline levels of testosterone, 17-hydroxyprogesterone, and dehydroepiandrosterone sulfate were in the upper third of the normal range, with elevated individual values in 18.9%, 36.5%, and 26.8% of the women, respectively. Mean baseline levels of androstenedione, free testosterone (T), and 3 alpha-androstanediol glucuronide (3 alpha-diol-G) were above the normal range, with elevated individual values in 51.2%, 75.0%, and 85.4% of the patients, respectively. Sex hormone-binding globulin (SHBG) levels were below the normal range in 26.8% of the cases. At the end of the first OC cycle, there was a significant (P less than 0.01) decrease in all androgen precursors and a 2-fold increase in SHBG. Androstenedione and free T decreased into the normal range during OC intake. Serum 3 alpha-diol-G levels remained elevated, but had decreased by 34.5% at cycle 6 (P less than 0.05). These results show that the triphasic OC has significantly improved acne in postpubertal women for whom acne was the main manifestation of mild hyperandrogenic activity. The improvement in acne corresponded to a decrease in adrenal/ovarian androgens and free T, which led to a decreased metabolism to 3 alpha-diol-G, presumably by the sebaceous glands. The increase in SHBG is considered an estrogenic effect, and the triphasic formulation containing low dose dl-norgestrel is not androgenic but, rather, an estrogen-dominant formulation; as such, this product is recommended in women requiring contraception who also have idiopathic acne.

Anti-estrogens and plasma proteins. II. Contraceptive drugs and gestagens.

PIP: The effects of Ovral (.5 mg norgestrel and .05 mg ethinyl estradiol (EE), and Norlestrin (1 mg norethindrone acetate and .05 mg EE) in women; dydrogesterone alone and with EE in men; and norgestrel, chlormadinone, EE, cyproterone and 17-alpha-methyltestosterone in green monkeys, on plasma proteins and hormones were studied, in an attempt to reverse estrogenic changes. Both contraceptives, given for 2 cycles to 25 women, increased corticosteroid-binding globulin, cortisol, thyroxin, and plasminogen, and Norlestrin increased fibrinogen. 30 or 40 mg dydrogesterone with .01 mg EE did not block the changes induced by estrogen alone in 5 men. Plasma protein and hormone levels in monkeys, tabulated after 2.5 mcg EE, 2 mg norgestrel alone and with 2.5 mcg EE showed that the estrogen effects of EE on corticosteroid-binding globulin and haptoglobin could be reversed by norgestrel. Similarly, 12.5 mg chlormadinone blocked the action of EE on thyroxine. The experiment with cyproterone acetate and methyltestosterone did not yield significant results.^ieng

Insulin resistance, secretion, and metabolism in users of oral contraceptives.

Studies of insulin employing the oral glucose tolerance test demonstrate marked differences between the effects of different oral contraceptives, but provide little insight into the underlying disturbances. We investigated the metabolic basis of these disturbances by computer modelling of iv glucose tolerance test glucose, insulin, and C-peptide concentration profiles. Insulin resistance, secretion, and metabolism were evaluated in 296 oral contraceptive users and 95 nonusers. Four estrogen/progestin combinations, with similar estrogen but differing progestin contents, and 1 progestin-only formulation were studied. Effects on iv glucose tolerance test glucose, insulin, and C-peptide concentrations varied according to progestin content, with levonorgestrel-containing combinations having the greatest effect, followed by desogestrel and norethindrone. However, these formulations increased insulin resistance to a similar extent. The progestin-only formulation did not affect insulin resistance. Levonorgestrel combinations increased second phase pancreatic insulin secretion by 60-90%, but did not affect the insulin half-life. The desogestrel combination increased the insulin half-life by 28%, but did not affect insulin secretion. The effects of different combined oral contraceptives on glucose tolerance test glucose, insulin, and C-peptide concentration profiles appears to be due to a combination of estrogen-induced insulin resistance and progestin-associated changes in insulin half-life.

PIP: Results of intravenous glucose tolerance tests on glucose, insulin, and C-peptide in women using combined and progestin-only oral contraceptives were analyzed by several computer models to dissect the effects of the steroids on insulin resistance, secretion, ad clearance. 391 subjects used monophasic, triphasic, or progestin-only oral contraceptives containing ethinyl estradiol and levonorgestrel, desogestrel or norethindrone. They consumed 200 g carbohydrate daily for 3 days, then fasted 12 hours before being tested between pill cycle Day 15-21 or menstrual cycle Day 21-27. Results of IVGTTs were analyzed for net glucose elimination constant; minimal model of glucose disappearance, to estimate insulin resistance; minimal model of posthepatic insulin delivery, for 1st and 2nd phase insulin response, insulin elimination constant and half-life. Pancreatic insulin secretion modeling also gave the fractional hepatic insulin throughput index, and elimination constants for insulin and C-peptide. There were significant differences in duration of oral contraceptive use, parity and age among study groups. The levonorgestrel combination increased glucose, insulin and C-peptide areas, the desogestrel combination increased only glucose and insulin areas, and the norethindrone combination only the glucose area. All combined pills, but not the norethindrone progestin-only pill, reduced the glucose elimination constant. Combined pills reduced insulin sensitivity 30-40%. Desogestrel increased insulin concentrations at the zero and 20 minute points, while levonorgestrel raised insulin after 30-45 minutes lasting for the rest of the 180-minute test. Levonorgestrel combinations increased 2nd phase pancreatic insulin secretion 60-90%, but did not change insulin half-life. The desogestrel combination increased insulin half-life 28%, but did not affect insulin secretion. Orals did not affect the hepatic insulin throughput index. The results suggest that estrogen causes insulin resistance, while progestins modify the response. Thus, the effects of oral contraceptives on oral ad intravenous glucose tolerance is similar, while insulin half-life varies with the progestin. It may be prudent to look for better estrogens or alternative routes to prevent estrogen-associated insulin resistance in contraceptive users.

The effect of a desogestrel-containing oral contraceptive on glucose tolerance and leptin concentrations in hyperandrogenic women.

Ovarian hyperandrogenism can be associated with insulin resistance, hyperinsulinemia, glucose intolerance, and obesity. High levels of the lipostatic hormone, leptin, have also been reported in this condition. The purpose of the present study was to examine the effect of an oral contraceptive (OC) of low androgenicity containing desogestrel on glucose tolerance in hyperandrogenic women and the impact of changes in androgenic/estrogenic status on leptin concentrations. Sixteen nondiabetic hyperandrogenic women, aged 29 +/- 1 yr with a body mass index (BMI) of 36.8 +/- 1.8 kg/m2, underwent an oral glucose tolerance test before and after 6 months of therapy with the OC. Free testosterone decreased and sex hormone-binding globulin increased after therapy (P < 0.001). Glucose tolerance deteriorated significantly, and two women developed diabetes. Body weight, BMI, and leptin did not change significantly. Leptin correlated with BMI before (r = 0.56; P = 0.02) and after (r = 0.51; P = 0.04) treatment, but not with glucose, insulin, total and free testosterone, or sex hormone-binding globulin before or after treatment. In conclusion, 1) glucose tolerance should be monitored in hyperandrogenic women using OC, even those of low androgenicity; and 2) changes in androgenic/estrogenic status had no effect on the leptin concentration, suggesting that its sexual dimorphism is not related to sex steroids.

PIP: Ovarian hyperandrogenism can be associated with insulin resistance, hyperinsulinemia, and glucose intolerance--all of which, in turn, have been linked to high levels of the lipostatic hormone, leptin. This study investigated the effect of an oral contraceptive (OC) containing a progestin of low androgenicity on glucose tolerance and insulinemia in hyperandrogenic women and the impact of changes in androgenic/estrogenic status on plasma leptin levels. 16 nondiabetic hyperandrogenic US women (mean age, 29 years) with a mean body mass index of 36.8 kg/sq. m underwent oral glucose tolerance testing before and after 6 months of treatment with an OC containing 30 mcg of ethinyl estradiol and 150 mcg of desogestrel. Treatment was associated with significant decreases in free testosterone and increased sex hormone-binding globulin (p 0.001). Glucose tolerance deteriorated moderately but significantly. After 6 months of treatment, 5 women had normal glucose tolerance, 9 had impaired glucose tolerance, and 2 developed non-insulin-dependent diabetes mellitus. There were no significant changes in serum insulin concentrations, body weight, body mass index, or leptin, but leptin levels were highly correlated with body mass index both before and after treatment. The data suggest that the sexual dimorphism of leptin is not caused by differences in sex hormones. Even when OCs containing low androgenic progestins are prescribed, women at high risk for diabetes should receive regular glucose tolerance tests.

Oral contraceptive effects on methylprednisolone pharmacokinetics and pharmacodynamics.

OBJECTIVE: Oral contraceptive (OC) steroids alter the disposition of numerous drugs, including corticosteroids. We investigated the pharmacokinetics and pharmacodynamics of methylprednisolone. METHODS: Twelve women (six women used OC steroids and six women did not) received intravenous methylprednisolone (0.6 mg/kg ideal body weight). Methylprednisolone disposition was assessed from plasma concentrations. Pharmacodynamic parameters measured were plasma cortisol, whole blood histamine (reflecting basophils), and blood helper T lymphocytes. RESULTS: Methylprednisolone clearance was significantly decreased in the women who used OC steroids (0.298 versus 0.447 L/hr/kg), resulting in a longer elimination half-life (2.20 versus 1.72 hours). With use of indirect response models, significant differences were observed with the cortisol and basophil responses. A larger value for the concentration that inhibits the zero-order production rate by 50% (0.37 versus 0.11 ng/ml) was observed in the women who used OC steroids for suppression of cortisol secretion, indicating less sensitivity to the suppressive effects of methylprednisolone. Greater net suppression of basophils was observed in the users of OC steroids (area under the response curve, 694 versus 401 ng x hr/ml). No differences were observed for helper T-cell responses. CONCLUSION: OC steroids appear to inhibit methylprednisolone metabolism. However, mixed changes in several responses occur, indicating that women can probably receive similar doses of methylprednisolone irrespective of OC steroid use.

PIP: At the Buffalo General Hospital in New York, researchers randomly assigned 6 healthy, nonobese women, 30-36 years old and using a triphasic oral contraceptive (OC) (Triphasil 28, Wyeth-Ayerst Laboratories), to either the baseline phase group or the group receiving an intravenous bolus of methylprednisolone sodium succinate at a dose of 0.6 mg/kg ideal body weight during the 2-week period after ovulation (i.e., luteal phase). These women were compared with 6 other women who did not use OCs but did receive the same dose of methylprednisolone. The purpose was to determine whether the adrenosuppressive, anti-inflammatory, and immunosuppressive effects of methylprednisolone differ in OC users. OC users experienced slower clearance of methylprednisolone (33% slower) than controls. This slower clearance rate contributed to a longer elimination half-life for methylprednisolone (2.2 vs. 1.72 hours; p 0.05). OC users also had a rate of slower elimination of cortisol than controls (0.180 vs. 0.276 hr-1; p 0.05). They had higher mean cortisol levels than controls (136 vs. 65 ng/ml). Women who used OCs for suppression of cortisol secretion had a larger value for the concentration of cortisol that suppresses the zero-order production rate by 50% (0.37 vs. 0.11 ng/ml; p 0.05), suggesting a decreased sensitivity to the effects of methylprednisolone on cortisol suppression. OC users experienced a greater net suppression of basophils at drug effect than at baseline. Methylprednisolone appeared to have no effect on helper T-cell responses. These findings suggest that OCs inhibit methylprednisolone metabolism. Since there were inconsistent changes in several responses, women can likely receive similar doses of methylprednisolone irrespective of OC use.