[Experience with a sequential oral contraceptive].
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In man both basal gonadotrophin levels and the pituitary responses to LHRH remained relatively constant throughout life. In women the pituitary sensitivity varied in the menstrual cycle due to the typical cyclic variation of oestradiol and progesterone. The max delta LH increase to 100 mug LHRH was observed in the periovulatory period (183 +/- 41 mU/ml); it was also significantly higher in the luteal (49 +/- 7 mu/ml) than in the early follicular phase (18 +/- 3 mU/ml). The effect of exogenous sex steroid hormones taken as contraceptive drugs was then studied in 15 women. Significantly lower LH and FSH basal values as well as responses to LHRH were observed in 8 normal women under oral combined contraceptives. Conversely, in 7 women under oral sequential contraceptives, basal LH and FSH remained in the normal range. The LH-FSH responses were increased and delayed when these tests were performed during the period of estrogen treatment. Thus, with combined oral contraceptives, constant and high levels of estrogens and progesterone not only inhibit the LH peak, but also decrease the basal LH-FSH levels and responses to releasing hormone. Conversely, with sequential oral contraceptives, the low level of estradiol does not inhibit these responses and even enhances them. In menopausal women both basal and gonadotrophin responses to LHRH were increased indicating an important pituitary reserve. In menstruating women a significant estradiol increase is observed 2 and 4 hours after a 100 mug LHRH injection, both during the follicular and the luteal phases whereas progesterone increases only in the luteal phase. In men, testosterone was found to increase 4 hours after a 100 mug LHRH injection. These studies show that in normal subjects, sex steroid hormones are important regulators of the sensitivity of the pituitary responsiveness to releasing hormone.
Six patients who took oral contraceptive agents for 5 to 18 years developed endometrial neoplasia. Endometrial adenocarcinoma occurred in 4 of these patients and severe adenomatous hyperplasia occured in 2. Five of the 6 patients took sequential agents; 1 patient used a combined agent. An additional patient who took Premarin and Provera sequentially developed adenocarcinoma of the endometrium. Eighteen cases of endometrial adenocarcinoma and 7 cases of adenomatous hyperplasia in patients with long-term sequential oral contraceptive use have previously been reported by others. Progestogens may not be completely protective against the endometrial cancer-causing potential of the estrogens, especially in the sequential regimens.
A prospective study was made to investigate the carbohydrate metabolic effects of the sequential-type oral contraceptive in form of a weekly pill with 0.6 mg ethinylestradiol-sulfonate soft gelatin capsules and 10 mg norethisterone acetate. Blood glucose and plasma insulin levels were measured during an intravenous glucose tolerance test in 17 nondiabetic healthy women. Each woman was tested before and after twelve months of drug use. There were no changes neither in average fasting blood glucose nor in glucose assimilation after intake of ethinylestradiol-sulfonate. At twelve months there were significant elevations of basal as well as reactive insulin levels.
Hormone formulation and estrogen/progestin potency were evaluated in relation to triglyceride and cholesterol concentrations in total plasma and lipoprotein fractions and in relation to lipid composition among a random sample of female telephone company personnel. Triglyceride concentrations in whole plasma, very low-density lipoprotein, and high-density lipoprotein (HDL) were elevated in response to increasing estrogen potency as were triglyceride concentrations in low-density lipoprotein (LDL). LDL cholesterol rose with increasing estrogen potency in contraceptive users but was slightly lower in postmenopausal estrogen-treated women. Plasma HDL cholesterol varied according to estrogen and progestin levels. The LDL cholesterol/triglyceride ratio was reduced for all combination oral contraceptives examined. Sequential oral contraceptives of postmenopausal estrogens did not significantly alter the cholesterol/triglyceride ratio in any lipoprotein fraction. Potential arteriosclerotic risk from sex hormone use may vary among oral contraceptive formulations.
Forty 3-hour oral glucose tolerance tests (OGTTs) were performed in 10 assumedly healthy female volunteers 19 to 30 years old, each serving four times as her own control. Each subject was taking a sequential type oral contraceptive containing either 50 microgram of ethinylestradiol or 80 microgram of mestranol alternatingly in four consecutive treatment cycles. The OGTTs were performed on the 6th day of each cycle, during pure estrogen medication. Blood glucose and serum insulin values did not differ significantly under either estrogen as tested by the t-test for paired observations. Our results do not support the findings of others that mestranol has a more pronounced or even exclusively adverse effect on glucose tolerance as compared with ethinylestradiol.
Serum vitamin vitamin B12 levels were determined in 199 women who were on a regimen of oral contraceptives of either the combination or sequential type and in a control group of 196 women. The group using oral contraceptive agents (OCA) had significantly lower serum levels of vitamin B12 vitamin as compared to those of the control group. A total of 19 women using OCAs had serum vitamin B12 levels that were lower than normal values. However, the Schilling test and urinary methylmalonate excretion in this group were normal. The OCA group had a significantly lower total serum vitamin B12 binding capacity, a lower total transcobalamin I level, and a higher transcobalamin III level. Our study suggests that the fall of serum vitamin B12 in OCA users is due to the changes in vitamin B12 binders of serum and does not represent vitamin B12 deficiency. Therefore, according to our data, there is no justification for vitamin B12 supplementation in users of oral contraceptives.
One hundred and fifty-one nulligravid women and 63 parous women stopped taking low-dose sequential oral contraceptives in order to become pregnant. During the first post-Pill cycle, 39% of the nulligravid and 54% of the parous women conceived. These figures have been compared with data from the Royal College of General Practitioners survey in England, in which 13% of nulligravid and 17% of parous women conceived in the first cycle after ceasing to take combined oral contraceptives. The percentage of nulligravid women not pregnant six months after withdrawal of low-dose sequential formulations was 19% compared with 32% after withdrawal of combined oral contraceptives. The corresponding figures for parous women were 5% and 21%. Available data suggest that after withdrawal of low-dose sequential oral contraceptives, the incidence of post-Pill infertility is lower than that after withdrawal of combined oral contraceptives. The extent of this difference is 16% three months after withdrawal of the Pill and 10% six months after attempting pregnancy.
Cell-mediated immunity was measured in women on hormonal contraceptives using the 2,4-dinitrochlorobenzene (D.N.C.B.) sensitisation test. Three groups of women were studied: forty-eight women were taking oral contraceptives of combined oestrogen/progestogen (thirty-seven of them had used oral contraceptives for a year or longer); twelve women were using a sequential pill (ethinyloestradiol and megestrolacetate); and sixteen women had received intramuscular injections of medroxyprogesterone acetate. The results were compared with those of a control group of twenty-nine age-matched women not taking contraceptive steroids. In women on the combined contraceptive pill and those who had received intramuscular progesterone, mean D.N.C.B. reactivity was significantly increased. The results were even more striking in women who had used combined contraceptive pills for more than one year. These results do not accord with the previously reported decrease in cell-mediated immunity in women on hormonal contraceptives.
A case-control study was conducted in Los Angeles County, California, of 127 endometrial cancer cases aged 45 years or less at diagnosis, to investigate the role of fertility, obesity and exogenous oestrogens in the development of the disease in young women. Use of sequential oral contraceptive (SOCs) or oestrogen replacement therapy (ERT) for greater than or equal to 2 years was strongly associated with increased risk of endometrial cancer. After excluding these cases, since the SOC or ERT use was probably the cause of their disease, we were left with 110 case-control pairs for further study. Among these remaining case-control pairs increasing parity was strongly associated with decreased risk (relative risk of 0.12 for women of parity 3 compared to nulliparous women, P less than 0.001). Current weight was associated with increased risk (relative risk of 17.7 for women weighing greater than or equal to 190 lbs compared to women weighing less than 130 lbs, P less than 0.001). Combination oral contraceptive (COC) use was associated with a decreased risk, which decreased with duration of COC use (relative risk of approximately 0.28 at 5 years of use, P less than 0.001), but the estimate of the protective effect was reduced and became statistically non-significant when allowance was made for weight and parity. The protective effect of COC use was only clearly evident in women who had less than 3 live-births and weighed less than 170 lbs. These results provide further support for the "unopposed" oestrogen hypothesis of the aetiology of endometrial cancer.