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Endometrial abnormalities occurring in young women on long-term sequential oral contraception.

Recently the occurrence of adenocarcinoma of the endometrium has been reported in young women exposed to sequential oral contraceptive agents for long periods of time. Twelve young women who had been using Oracon for periods of from 13 to 93 months were subjected to office endometrial aspirations. Tissue specimens showed endometrium which varied in diagnosis from proliferative endometrium to severe atypical adenomatous endometrial hyperplasia bordering on endometrial carcinoma in situ. Adenomatous endometrial hyperplasia is though by many investigators to be a precancerous condition. The progression of endometrial changes from benign proliferation to cystic hyperplasia and adenomatous hyperplasia accompanied by varying degrees of anaplasia in young women exposed to Oracon for long periods of time is significant. It is not surprising, therefore, that adenocarcinoma of the endometrium has been reported in these women at an age where this condition had been relatively uncommon prior to the use of sequential oral contraceptives.

Adenocarcinoma

The effect of sequential oral contraceptive pill (Fysioquens) administration on carbohydrate and lipid metabolism.

The aim of this study was to investigate the effect of a new sequential oral contraceptive pill, Fysioquens, (7 tablets containing 0.05 mg ethinylestradiol and 15 tablets containing 0.05 mg ethinylestradiol plus 1 mg lynestrenol) on carbohydrate and lipid metabolism. In our investigation we found slight changes in the carbohydrate metabolism during and after treatment with Fysioquens but it was chiefly the changes in plasma insulin response during glucose tolerance tests that were significant. We could not find any significant changes in mean fasting serum cholesterol and triglyceride values.

Adult

Adenocarcinoma of the endometrium in women taking sequential oral contraceptives.

Abnormal bleeding while taking oral steroidal contraceptives has been managed by changes in pill or addition of estrogen or progestin moieties. Diagnostic procedures, classically indicated, are universally not undertaken or postponed. Three cases of adenocarcinoma of the endometrium in relatively young patients using sequential oral contraceptives for cause are presented to reiterate the need for tissue diagnosis when abnormal bleeding occurs as a common side-effect of contraceptive therapy.

Adenocarcinoma

Lower esophageal sphincter pressure in women using sequential oral contraceptives.

Lower esophageal sphincter pressure, basal gastric pH, and fasting plasma gastrin were measured sequentially in female volunteers who were using oral contraceptives. No difference in basal gastric pH or fasting plasma gastrin was observed during any of the three selected periods studied. Lower esophageal sphincter pressure was the same during menses (20.8 +/- 1.7) when the volunteers took no medication during the phase of the cycle when the volunteers were ingesting ethinylestradiol (18.3 +/- 1.7). Lower esophageal sphincter pressure decreased significantly (P less than 0.01) to 9.4 +/- 1.2 during the phase of the cycle when the volunteer took the progestation agent, dimethisterone, as well as ethinylestradiol. It is therefore proposed that the progessive rise in plasma progesterone alone or in combination with estrogens that occurs during the course of pregnancy might be responsible for the increased incidence of symptomatic heartburn in pregnant women.

Adult

Accumulation of ethinylestradiol in blood and endometrium of women taking oral contraceptives: the sequential therapy.

A radioimmunoassay to quantitate ethinylestradiol (EE-2) in both plasma and endometrium is described. In 29 women under sequential oral contraceptive therapy (chlormadinone acetate, 2 mg, plus mestranol, 80 microgram) for 6 to 84 months, a single blood sample and a single endometrial sample were simultaneously obtained on different days of the pseudomenstrual cycle. In 24 women under 40 years of age the mean plasma EE-2 concentrations were similar during the first (989 +/- 94 pg/ml) and the second half of the cycle (1053 +/- 186 pg/ml) (P greater than 0.05). A similar finding was observed with regard to mean endometrial EE-2 concentrations (3.55 +/- 2.1 and 5.89 +/- 1.7 microgram/gm of wet tissue, respectively). On the other hand, five women over 40 years of age had plasma EE-2 concentrations similar to those of the previous group, but the mean endometrial EE-2 concentrations was 0.9 +/- 0.6 microgram/gm of wet tissue (P less than 0.05). Although plasma follicle-stimulating hormone and luteinizing hormone did not show midcycle peak values, complete suppression of both gonadotropins was not observed. These results show that endometrium has a great ability to concentrate EE-2, and this ability seems to be greater in women below age 40 than above. Whether or not this observation might be related to the known higher incidence of endometrial cancer in women less than 40 years old who have been under chronic sequential oral contraceptive therapy cannot be disclosed from this limited number of determinations.

Adolescent

[Results of in vitro sperm penetration tests in cervical mucus under takings of the sequential oral contraceptive ovanon and sequilar (author's transl)].

The in vitro penetrability of cervical mucus by sperm was investigated in women who were taking Ovanon or Sequilar. Measurements were made under constant experimental conditions on every day of the cycle. The depth of penetration differed strikingly between women with normal menstrual cycles and women taking the sequential hormonal contraceptives. The penetration depth was substantially less when Sequilar or Ovanon was used. The Sequilar induced cervical sperm barrier during the entire cycle was almost as strong as that observed when combined preparations are used. During the proliferative phase of the cycle the penetration depth allowed by Ovanon was less than that observed during normal cycles but greater than that seen with Sequilar. During the secretion phase no appreciable differences in the penetrability of cervical mucus between the two contraceptives was observed. The hypothetical relationship between these data and the problem of cervical carcinoma was described.

Cervix Mucus

Histology of the endometrium in long-term use of a sequential oral contraceptive.

Non-atypical adenomatous hyperplasia was found in 13.5% of 111 biopsies obtained from long-term, predominantly black, users of Oracon. An association between length of time of use (95 cycles for those with adenomatous hyperplasia versus 73 for those without) and the development of adenomatous hyperplasia was noted, but there was no association with hypertension or obesity. Cystic glandular dilatation was seen in 63% but was not thought to represent hyperplasia. No more advanced lesions were seen.

Contraceptives, Oral

[Effect of the steroid sex hormones on the LH and FSH responses to LHRH in the normal subject].

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.

Contraceptives, Oral, Combined

Endometrial carcinoma and oral contraceptive agents.

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.

Adenocarcinoma

Comparison of ethinylestradiol and mestranol in sequential-type oral contraceptives in their effects on blood glucose and serum insulin in oral glucose tolerance tests.

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.

Adult

The effect of oral contraceptives on vitamin B12 metabolism.

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.

Absorption

Post-pill infertility.

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.

Contraceptive Devices

Dinitrochlorobenzene sensitisation test in women on hormonal contraceptives.

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.

Adolescent

Potencies of oral contraceptives.

Oral contraceptives are combinations of estrogens and progestogens or, in the case of the mini-pills, progestogens alone. With specific test procedures in laboratory animals or human subjects, it is possible to assign potency evaluations to the components relative to the progestational, estrogenic, or antiestrogenic activities of the progestogen or to the estrogenic potencies of the estrogenic component. It might even be possible to quantify the synergistic effects of the estrogen on the progestational agent. Unfortunately, however, it is impossible now to amalgamate such assay results into single estimates of the potencies of the combinations (either the combination products per se or the combination tablets of sequential products). For example, an over-all estrogenic potency of a combination preparation would involve the integration of contributions form the estrogen itself plus the estrogenic products of metabolism of the progestogen minus the antagonistic effect of the progestational agent, if any. These factors cannot now be quantified independently, much less merged into a single figure of clinical significance. Further, even if it were possible to produce such an estimate, it is unlikely that the evaluation would be meaningful in relation to any putative side effect or adverse reaction, i.e., the alleged thrombogenic effects of oral contraceptives cannot currently be related directly to any measure of potency that will allow prediction of these clinical conditions from laboratory models. Any evaluation of the potential of a given contraceptive to produce a specific side effect will depend upon data generated with specific regard to that adverse reaction and the individual product in question.

Contraceptives, Oral

[Serum level of thyroxin-binding globulin under oral contraception (author's transl)].

The use of oral contraceptives results in an increase in thyroid-binding-capacity in conformity with a change of results by T3/T4-tests. Using Laurell-electrophoresis and an anti-serum produced by Behringwerke the determination of the thyroid-binding-globulin (TBG) in serum is easy to handle. TBG was determined in serum from 137 women using oral contraceptives for more than 3 months. The apllication of oral contraceptives is followed by a statistically significant increase in the TBG level in serum. Thereby oral contraceptives change the TBG-level in a different degree. Preparations with a marked estrogen potency on the average effect a higher TBG-concentration than those with progesterone activity derived by menses-delay test. The difference of TBG-level is statistically significant. According by the increase of TBG-concentration in serum is caused by estrogen, the extent of the increase is modified by the progesterone component.

Adolescent