Comparative studies of the ethynyl estrogens used in oral contraceptives. VI. Effects with and without progestational agents on carbohydrate metabolism in humans, baboons, and beagles.

Human subjects, baboons, and beagles were given cyclic regimens of ethynylestradiol or mestranol; after a number of such cycles, concurrent administration of norethindrone acetate, dl-norgestrel, or megestrol acetate was introduced for a similar number of cycles. Carbohydrate tolerance was evaluated by oral glucose tolerance testing in the human subjects and by intravenous glucose tolerance testing in the baboons and beagles. In the human subjects, neither mestranol nor ethynylestradiol at daily doses of 50 to 100 microgram/day produced any effect on fasting glucose levels or on glucose tolerance even after six cycles of treatment. The addition of the progestational compounds also had no effect on these two variables. In baboons, ethynylestradiol and mestranol were bioequivalent and produced a dose-related decrease in the glucose disposal rate. All three progestational agents counteracted this effect in a comparable manner. In beagles, on the other hand, estrogens produced an increase in the glucose disposal rate, and the addition of progestational agents produced an initial fall and a subsequent return to pretreatment levels.

PIP: In a comparison of the glucose metabolic effects of certain estrogens and progestins, 163 normal females received either 50 or 80 mcg/day ethinyl estradiol or 50, 80, or 100 mcg/day mestranol for 21 days over 6 cycles. At the end of 6 cycles each group received additionally either 2.5 mg/day norethindrone acetate, 2 mg/day megestrol acetate, or .5 mg/day dl-norgestrel. Simulations of this regimen were carried out in beagles and baboons using lower dosages and treatment durations of 4 instead of 6 cycles. Glucose tolerance tests were administered orally to the humans and iv to the animals in the latter part of certain treatment cycles. In humans, no significant effects were found for type or dose of estrogen, cycle number, addition of progestin, or any of their interactions. In the animals, estrogen lowered fasting plasma glucose both in the baboons (p .05) and in the beagles (p .001), a trend which reversed spontaneously until control values prevailed at the end of the 4th estrogen-treatment cycle. Progestins had no effect. Glucose assimilation rates (K values) were significantly depressed over the first 4 cycles in baboons (p .001) but rose with the addition of progestins. In beagles, by contrast, the K values rose (p .001) and fell again with the introduction of progestin treatment. It is concluded that baboons and beagles are poor models for examination of human carbohydrate metabolism.

Comparative studies of the ethynyl estrogens used in oral contraceptives. VII. Effects with and without progestational agents on ultracentrifugally fractionated plasma lipoproteins in humans, baboons, and beagles.

Ethynyestradiol and mestranol, in doses ranging from 50 to 100 microgram/day, were given to women in 21-day cycles; baboons and beagle dogs received 1 and 4 microgram/kg/day in a similar regimen. After a number of such cycles, megestrol acetate, norethindrone acetate, or dl-norgestrel was given concomitantly. Protein, cholesterol, triglyceride, and phospholipid levels were determined in total plasma and in ultracentrifugally separated lipoprotein fractions. Over the dosage range studied, the effects of the two kinds of estrogen were indistinguishable. Except for human total plasma triglyceride, no dose-related differences were observed. The lowering of serum protein and the increase in cholesterol induced by estrogen were more pronounced in baboons and beagles than in human subjects. The cholesterol-depressing effect of progestational compounds observed in humans was very pronounced in baboons but absent in beagles. In all three species, estrogen increased the lipoprotein fraction cholesterol, except for human low-density lipoprotein cholesterol, which was decreased. Human plasma triglyceride and phospholipid increased on estrogen administration and were decreased by the progestins; in the two animal species, triglyceride is normally very low and the estrogen-induced changes were negligible; the phospholipid rose with estrogen but was unaffected by progestins. In sum, the two animal species show many similarities to, as well as important differences from, the human response of plasma lipids to various contraceptive steroids.

PIP: In this comparative study, ethinyl estradiol and mestranol (dose range, 50-100 microg/day) were given to women in a 21-day cycle; baboons and beagle dogs received 1 and 4 microg/kilog/day in a similar regimen. After a number of cycles, mestranol acetate, norethindrone acetate, or d,1-norgestrel was given concomitantly. Protein, cholesterol, triglyceride and phospholipid levels were determined in total plasma and in ultracentrifugally separated lipoprotein fractions. Effects of the 2 kinds of estrogens were indistinguishable over the dosage range studied. Except for human total plasma triglyceride (P .001), no dose-related differences were observed. Lowering of serum protein and increase in cholesterol induced by estrogen were more pronounced in the 2 animal species than in humans. The cholesterol-depressing effect of progestational compounds observed in humans was very pronounced in baboons but was absent in beagles. In all 3 species, estrogen increased the lipoprotein fraction cholesterol, except for human low-density lipoprotein cholesterol, which was decreased. Human plasma triglyceride and phospholipid increased on estrogen administration and were decreased by progestins. In beagles and baboons, triglyceride is normally very low and the estrogen-induced changes were negligible; phospholipid rose with estrogen but was unaffected by progestins.

Carbohydrate metabolism of Indian women taking steroid contraceptives.

Three parameters, serum glucose, insulin, and growth hormone levels, were used to measure carbohydrate metabolism in 25 women not using steroid contraceptives, 48 women using combination oral contraceptives, and 27 women using low-dose progestogen oral contraceptives. Women in the combination contraceptives group had significant modifications in the responses of all three parameters studied. A bias toward modification was also seen in the normal tests of the combination group. The low-dose progestogen, megestrol acetate, did not cause similar changes in glucose, insulin, and growth hormone values.

PIP: A study was undertaken to report the responses of serum glucose, insulin, and growth hormone levels to iv glucose injections in 48 women using a combination oral contraceptive (OC) (OVral), in 27 women on dialy progestogen alone (megestrol acetate), and in 25 non-OC users. Women taking combination OCs had significant modifications in the responses of all 3 parameters ( p less than .05). The normal tests of the combination OC group also exhibited a tendency toward modification. Changes in serum glucose, insulin, and growth hormone values were absent in the low-dose progestogen group. These studies indicate that the mechanisms whereby OCs modify carbohydrate metabolism are unknown. More research is necessary to provide information concerning metabolic effects of hormonal contraceptives.

Megestrol acetate concentrations in plasma and milk during administration of an oral contraceptive containing 4 mg megestrol acetate to nursing women.

PIP: An oral contraceptive containing 4 mg megestrol acetate + 50 mcg ethinyl estradiol was given to 5 fully lactating and nursing women, starting 2 months postpartum. Milk and blood samples were collected simultaneously to allow a comparison between plasma and milk levels of megestrol acetate. Megestrol acetate was estimated by radioimmunoassay. The plasma:milk ratio of megestrol acetate was found to be 100:80. About 2 mcg of megestrol acetate was calculated by be transferred with 600 ml of milk/day corresponding to about .1% of the given dose to the mother.^ieng

Invluence of oral contraceptives on circulating immune response. II. Effect of progestogenic and estrogenic components.

PIP: Female mice were treated with chlormadinone acetate (.25 mcg or 6.25 mcg), megestraol acetate (.25 mcg or 6.25 mcg), ethynodiol diacetate (.5 mcg or 12.5 mcg), norgestrel (.25 mcg or 6.25 mcg) or norethynodrel (2.5 mcg or 62.5 mcg) and studied to determine what effect these progestagens had on circulating tetanus antibody titers. None of the progesterones affected the immune response to tetanus toxoid. Mice given ethinyl estradiol or mestranol had enhanced circulating antibody titers. It is conlcuded that combination oral contraceptives act to diminish antibody response as a result of the combined potency of the estrogen and progesterone components.^ieng

The effect of various contraceptive hormonal therapies in women with normal and diabetic oral glucose tolerance test.

PIP: The effect of various contraceptive hormonal therapies was studied in 176 women with normal and diabetic oral glucose tolerance tests (OGTTs). 160 women showed normal and 16 showed diabetic patterns on the 14th day of a control cycle, during the 3rd and 6th months of contraceptive therapy, and 3 months after having stopped medication. The women were divided into groups and fitted with a Lippes loop, treated with low doses of chlormadinone acetate, lynestrenol, and megestrol acetate or with a sequential estrogen-progestogen contraceptive containing either ethinyl estradiol or mestranol. The only groups showing modifications of OGTTs were the sequential estrogen-progestogen groups, where the OGTT curves of the normal groups became abnormal while those of the diabetic group improved. The modifications disappeared 3 months after discontinuation of the medication which can be interpreted as a direct effect of the steroids on carbohydrate metabolism.^ieng

Multiple arterial occlusions and hypertension probably caused by an oral contraceptive: a patient in whom the development of renovascular hypertension has been followed.

An 18-year-old woman taking an oral contraceptive was admitted to hospital because of a stroke due to occlusion of three branches of the right middle cerebral artery. She later developed renovascular hypertension due to occlusion of one of two renal arteries on the right side. Occlusion of the ceoliac artery was also found. The circumstances suggest that the occlusions were caused by multiple emboli, the source of which could not be identified. The kidney with the circulatory disturbance was shown to have a persistent abnormal renin secretion three and six months after the stroke, but the peripheral renin level was lower at the second investigation. Cardiac function studies revealed an alarming degree of left ventricular hypertrophy, and satisfactory blood pressure control could not be maintained despite increasing antihypertensive therapy. Surgical corrrction of the circulatory disturbance promptly led to normotension without drugs, and the patient has remained normotensive during the postoperative observation period of twelve months. The oral contraceptive was probably responsible for precipitating the vascular occlusions, but no predisposing factors or warning symptoms were present to identify this patient as being at risk.

PIP: The case history of an 18-year-old patient, who had been taking oral contraceptives for 2 years (ethinylestradiol 50 mcg, megestrol acetate 4 mg) and who developed multiple arterial occlusions and hypertension, is reported. Occlusion of the ceoliac artery was also found. The circumstances suggest that the occlusions were caused by multiple emboli of unknown source. The affected kidney was shown to have an abnormal renin secretion 3 and 6 months after the stroke, but the peripheral renin level was lower at the 6 month investigation. A large degree of left ventricular hypertrophy was seen. Blood pressure was still uncontrolled despite antihypertensive therapy. Surgery was performed on the affected kidney and normal perfusion restored. The patient then became normotensive, and has remained so for a 12-month period. Oral contraceptives were probably responsible for precipitating the vascular occlusion. Predisposing factors or warning symptoms were absent in this patient.

Urinary steroid hormone patterns: III. Effect of continuous daily administration of low dose megestrol acetate.

PIP: The effect of megestrol acetate, administered in daily doses of .5 mg, on urinary steroid levels was studied before, during, and after therapy in 4 women volunteers. In each case, pregnanediol levels were reduced, though ovulatory biphasic patterns, as reflected in basal body temperature patterns, were apparent in the majority of the cycles, which suggests that corpus luteum function, but not ovulation, was impaired. 17-ketosteroid levels were significantly (p less than .001) increased either during or after treatment, while 17-hydroxycorticoid levels were reduced in 3 of the women. 2 subjects showed a marked reduction in levels of 17-ketogenic steroids and corticoid levels. Total estrogen levels seemed to correlate with the levels of corticoid excretion.^ieng

Low dosage megestrol acetate application as contraceptive.

PIP: A review of the development of low dose progesterone is presented. Continuous low-dose megestrol acetate therapy data from 43 patients is presented. When short cycle lengths, breakthrough bleeding, and amenorrhea occurred, a lower dose of megestrol acetate was substitute. 78% of the cycles varied between 21 and 38 days a breakthrough bleeding occurred in 19.6% cycles, and average flow was 5.2 days. There were no breakthrough pregnancies in this group. A majority of the cycles with megestrol acetate were ovulatory, but the cervical mucus was hostile and vaginal smears showed a definite progestational effect.^ieng

Megestrol acetate for estrus postponement in the bitch.

Megestrol acetate was given orally to 389 bitches in early proestrus, at a dosage of 2.2 mg/kg (1 mg/lb) per day for 8 days. Estrus was suppressed in 357 (92%) of the bitches. Additionally, 119 bitches in anestrus were given the drug at the rate of 0.55 mg/kg (0.25 mg/lb) per day for 32 days. Estrus was suppressed in 115 (98%) of these bitches. Adverse effects were minimal. Pyometra developed in 3 (0.8%) of the 389 bitches treated in early proestrus. The drug also was given to 19 bitches at the rate of 0.55 mg/kg/day for 32 days, regardless of the stage ofting at the 1st posttreatment estrus and 4 after mating at the 2nd posttreatment estrus. Litter size, success in rearing pups, and sex ratios were not significantly different from these factors in 53 litters from untreated bitches.

PIP: The postponement of estrus by megestrol acetate (MA) was evaluated in 389 female dogs. MA was administered for 8 days in a daily dose of 2.2 mg/kg body weight, beginning in early proestrus. Estrus was suppressed in 357 of these animals (92%). An additional 119 bitches in anestrus received MA in a daily dose of .55 mg/kg body weight for 32 days. Estrus was suppressed in 115 of these animals (97%). Pyometra was observed in 3 of 389 animals (.8%); other adverse affects were minimal. 19 animals received MA in a daily dose of .55 mg/kg body weight for 32 days, regardless of the stage of the estrous cycle. 15 of these bitches whelped normal litters after the 1st posttreatment estrus, and 4 after mating at the 2nd posttreatment estrus. Litter characteristics were similar to those observed in controls.

The use of conjugated oestrogen in oral contraception.

PIP: To find a suitable contraceptive combination 11 dosage combinations of estrogen and megestrol acetate were studied clinically. An additional combination for treatment of menopausal symptoms was used in 603 treatments, each with 21 pills. A dose of 3.75 mg and even 4.0 mg of conjugated estrogen was not sufficient to inhibit ovulation. Pregnancies occurred also when 21 daily doses of 3 mg conjugated estrogen were combined with 2 or 3 mg megestrol acetate daily. Consequently, not even 3 mg megestrol acetate can be considered a sufficient dose to prevent the pentration of spermatozoa through the cervical mucus when used in combination with estrogens. Clinically best results were obtained with following 2 combinations (2 and 7): conjugated estrogen 3.75 mg/day for 21 days + 5 mg megestrol acetate for the last 5 days and conjugated estrogen 4 mg/day for 21 days + 5 mg megestrol acetate for the last 7 days. The tolerance to conjugated estrogen was good in the whole series. No embolism was observed, nor were any changes in the ASAT; GOT or ALAT; GPT values recorded.^ieng

Low dose of gestagen as a contraceptive method. A clinical trial.

PIP: The effectiveness of megestrol acatate (350 mcg/day) was studied in 194 women over a total of 2048 woman-months of use. There were 23 pregn ancies, 7 of which could be attributed to patient error, for an adjusted pregnancy rate of 9.4/100 woman-years of use. Abnormal bleeding was the most dominant side effect (22.2%). 11.8% of the women discontinued the regimen because of unwanted pregnancy, and 8.2% did so because of abnormal bleeding. The acceptability rate was 73.3%. Similar results were reported in another trial.^ieng

Direct effects of medroxyprogesterone acetate (MPA) and megestrol acetate (MGA) on rat testicular steroidogenesis.

The effects of MPA and MGA on rat testicular steroidogenesis were examined by studying: 1) serum testosterone in hCG primed animals treated with MPA or MGA, 2) testosterone synthesis in rat Leydig cells cultured with MPA or MGA, 3) MPA and MGA binding to rat testis microsomal cytochrome P-450 and 4) MPA and MGA inhibition of enzymes of rat testicular steroidogenesis. In immature rats receiving 1.0 IU of hCG per day 20 mg/kg of MPA or MGA reduced serum testosterone by 57 and 56%, respectively. In mature male rats receiving 50.0 IU of hCG per day 20 mg/kg of MPA or MGA reduced serum testosterone by 40 and 29%, respectively. In rat interstitial cells cultured with 10 ng of rat LH, 1 microM MPA or MGA inhibited testosterone production by 32 and 23%, respectively. Addition of MPA or MGA to microsomal preparations resulted in a type I cytochrome P-450 difference spectrum. MPA and MGA inhibited rat testicular 17 alpha-hydroxylase, 17,20-lyase, and the 3 beta- and 17 beta-hydroxysteroid dehydrogenases. These findings suggest that MPA and MGA inhibit rat testicular steroidogenesis in vivo and in vitro.

PIP: The effects of (MPA) medroxyprogesterone acetate and (MGA) megestrol acetate on rat testicular steroidogenesis were examined by studying: 1) serum testosterone in hCG primed animals treated with MPA or MGA; 2) testosterone synthesis in rat Leydig cells cultured with MPA or MGA; 3) MPA and MGA binding to rat testis microsomal cytochrome P-450; and 4) MPA and MGA inhibition of enzymes of rat testicular steroidogenesis. In immature rats receiving 1.0 IU of hCG/day 20 mg/kg of MPA or MGA reduced serum testosterone by 57 and 56%, respectively. In mature male rats receiving 50.0 IU of hCG/day 20 mg/kg of MPA or MGA reduced serum testosterone by 40 and 29%, respectively. In rat interstitial cells cultured with 10 ng of rat LH, 1 mcM MPA or MGA inhibited testosterone production by 32 and 23%, respectively. Addition of MPA or MGA to microsomal preparations resulted in a type I cytochrome P-450 difference spectrum. MPA and MGA inhibited rat testicular 17alpha-hydroxylase, 17,20-lyase, and the 3beta-and 17beta-hydroxysteroid dehydrogenases. These findings suggest that MPA and MGA inhibit rat testicular steroidogenesis in vivo and in vitro.

Oral contraceptives and plasma lipids.

PIP: The effects of 2 types of oral contraceptives (OCs) on plasma lipids in 45 healthy women were studied. The women received 1 mg lynestrenol plus .1 mg mestranol (Days 5-27), 4 mg megesterol acetate plus .05 mg ethinyl estradiol (Days 5-26), or .05 mg megesterol acetate daily for 3 months. Blood samples were collected prior to medication and subsequently in each of 3 consecutive cycles during medication between Days 23 and 26. The only change observed was a significant rise (p .05) in beta lipoproteins with a corresponding decline in alpha lipoproteins in the group receiving lynestrenol plus mestranol. It is concluded that if the desired efficacy and minimum clinical side effects can be obtained, either progestogens alone or progestogens with a small dose of estrogen should be the choice of medication.^ieng

[Personal experiences with Minitrol]. / Nase zkusenosti s Minitrolem.

PIP: Minitrol (.5 mg megestrol acetate) is an oral contraceptive preparation whose effect is directed toward a lower level than hypothalamic-hypophysial-ovarian preparations, and it does not affect the neurohormonal regulation of the cycle. 28 women participated in the experiment, taking Minitrol for 1-8 months. 122 cycles were examined. Acne and increased hair loss were experienced, believed to be due to relatively strong antiestrogen effects of the preparation. Of the 122 cycles, 68% fluctuated between 26-32 days, 6% were longer and 26% shorter. In 10% of the cases, intermenstrual bleeding occurred. In 1 woman whose cycle was irregular, an endometrial polyp was found. For a certain number of women, the .5 mg dosage is too strong, and its effect exceeds the desired contraceptive level as well as disturbs ovarian activity. For the group of women for which the preparation is too strong, a capsule with lesser content is recommended, as this contraceptive substance is highly suitable to young women.^ieng

Microdose intrauterine progestagen associated with intrauterine contraceptive devices.

PIP: This study investigated the response of the human female to a potent progestagen implanted in a Silastic capsule attached to an IUCD and inserted into the uterine cavity. Megestrol acetate's permeability was laboratory tested using tritiated material since the daily amount of progestagen eluted was too small to be determined by other methods. Polyethylene capsules with Silastic plugs allowed a daily elution into the surrounding bath of about 1% of the daily dose needed for satisfactory systemic contraceptive effect. Such capsules, loaded with 2.7 mcg of megestrol acetate, were attached to Maizlin Springs and used through 3 cycles of 3 months each for 5 patients. After removal the capsules were tested for residual progestagen by paper chromatography. All capsules still had residual medication after 3 month's use. Control tests were also done for preinsertion and postremoval cycles. Other contraceptive measures were used only during these control cycles. Continuous basal temperature records were obtained. During the 28 recorded cycles, 43 plasma progesterone tests, 42 urinary pregnanediol excretions, and 38 endometrila biopsies were obtained. No evidence of cyclic derangement was evidenced. All temperature records were biphasic. Ovulation was consistently confirmed. 1 patient developed acute endometritis during the second treatment cycle. This required premature removal of the IUCD. Studies are in progress to determine the highest intrauterine dosage which will cause no systemic effect but should make nidation impossible and thus protect completely against intrauterine pregnancy without the risks of other routes of aadministration.^ieng

Metabolic effects of contraceptive steroids. III. Intravenous glucose tolerance--short term observations.

Intravenous glucose tolerance tests were carried out in women taking 2 types of estrogen/progestogen combination oral contraceptives. Each subject had the test done on days 18-21 in a control cycle before the medication was begun and 3 consecutive cycles during administration of the drug. Fasting blood glucose levels and K values showed no significant changes with a combination of megestrol acetate (4 mg) with 0.05 mg of ethinyl estradiol. A significant decline in glucose tolerance was observed by the change in K values during all 3 cycles of medication with a combination of 2.5 mg lynestrenol and 0.075 mg mestranol. Tests repeated 2 months after stoppage of the medication in 5 subjects showed that blood sugar levels and K values had returned to pretreatment levels.

Carbohydrate and lipid studies during six months' treatment with megestrol acetate. Measurements of blood glucose, insulin, growth hormone, and triglycerides.

PIP: This paper reports a study of lipid and carbohydrate metabolism in 42 women who took megestrol acetate (MA) .5 mg daily for 6 months. Blood glucose, plasma insulin, fasting plasma growth hormone and fasting plasma triglycerides were measured both before and after 6 months of MA treatment. Before each test the women were instructed to eat a high carbohydrate diet for 3 days; they then reported in the morning after fasting overnight. After a blood sample was drawn, they were given a solution of 100 gm glucose to drink and blood samples were drawn at .5, 1,2, and 3 hours. Although the group mean weight increased 3.6 pounds, there were minimal changes in the glucose or insulin curves, with only the slight elevations at the 2 hour drug test being significant. There were no significant changes in the growth hormone or triglyceride values. The data suggest that the substituted-progesterone progestins in oral contraceptives exert little metabolic effect as compared to the 19-norprogesterone progestins. Thus MA might be used for contraceptive purposes without producing carbohydrate or lipid metabolic changes.^ieng

Studies on sustained contraceptive effects with subcutaneous polydimethylsiloxane implants. 2. Maintenance of ovarian function in patients with megestrol acetate implants.

PIP: Ovarian function was assessed in 10 healthy young women before and after the insertion of 3 or 4 polydimethylsiloxane capsules filled with 20 mg of megestrol acetate. Each capsule released in vitro approximately 20 mcg/24h of the hormone. During treatment no changes were observed in the FSH excretion pattern. The mid-cycle LH peak was present in all ovulatory cycles, although it was usually much less evident under the action of megestrol acetate. The excretion of estradiol was significantly increased in all subjects (p less than .05) during the first cycle following implantation. The menstrual bleeding did not change in the majority of the cases. It is concluded that megestrol acetate sustained-release preparations do not inhibit ovulation under the experimental conditions used.^ieng