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Problems in evaluating chronic toxicity of contraceptive steroids in dogs.

The long-term effects of oral contraceptive steroids including a combination of norethindrone and ethynylestradiol, a sequential regimen of dimethisterone and ethynylestradiol, and daily administration of megestrol acetate were studied in female beagle dogs at dose levels of 1, 10, or 25 times the projected human dose levels. The major findings included cystic endometrial hyperplasia and pyometra requiring hysterectomies and alopecia for the norethindrone-ethynylestradiol and dimethisterone-ethynylestradiol treated dogs. These groups did not have accentuated mammary development or treatment-related hyperplastic or neoplastic changes. For dogs given dimethisterone-ethynylestradiol, numerous acne-like lesions occurred in the skin of the mammary areas. Dogs given the higher dose levels of megestrol acetate had marked mammary stimulation, hyperplastic and neoplastic changes in the mammary glands, and clinical and pathologic changes typical of diabetes mellitus. Mammary changes of nodular hyperplasia, benign mixed tumor, and adenocarcinoma appeared as distinct entities although constant and intense mammary stimulation may be a common denominator. Such mammary changes have not been found in long-term studies in monkeys or rats with megestrol acetate, and the relevance of the canine mammary changes to projecting potential tumorigenesis in women is questioned.

Alopecia↗

Oral contraceptives and ascorbic acid.

Plasma, leukocyte, and platelet ascorbic acid levels are decreased in women ingesting oral contraceptive steroids. Studies have shown that it is the estrogenic component of the oral contraceptive agents that is associated with the decresased ascorbic acid concentrations. Urinary excretion of ascorbic acid does not appear to be increased by the steroids. Although serum levels of copper are increased by estrogens and oral contraceptives, ascorbic acid catabolism does not appear to be increased (unpublished). Our preliminary data on tissue uptake of ascorbic acid suggest that changes in tissue distribution are one possible answer for the observed effects of the steroids on blood levels of ascorbic acid.

Adrenal Glands↗

Acceptability of injectable contraceptives in Assiut, Egypt.

The present work was a randomized comparative study of two injectable progestogen-only contraceptives. The first group (200 subjects) received 150 mg of depotmedroxyprogesterone acetate (Depoprovera) every 84 +/- 7 days and the second (200 subjects) received 200 mg of norethisterone enanthate (Noristerat) every 56 +/- 7 days. Acceptors of injectable contraceptives in Assiut, Egypt, were mainly women looking for fertility termination. Menstrual disruption was the main side effect among both treatment groups. Amenorrhoea was the commonest menstrual complaint and was the main reason for discontinuation in both groups. Only one pregnancy occurred during NET-EN use; two more pregnancies occurred, one in each of the two groups but there were indications that conception preceded the first injection. Menstrual irregularities were generally more frequent with DMPA users. However, DMPA had better one-year continuation rates than NET-EN (68.8 +/- 3.5 and 57.1 +/- 3.6 per 100 women, respectively).

Adolescent↗

[Effect of oral contraceptives on the psyche and on sexuality].

The problem of whether or not oral contraceptives affect the psychic function of the female is still controversal. The purpose of the present investigation was to study the occurrence of psychic and sexual effects in women taking either Ovosiston (mestranol 0,08 mg + chlormadinone acetate 2, 0 mg) or Non-Ovlon (ethinylestradiol 0,05 mg + norethisterone acetate 1,0 mg). 186 somatically healthy women were subject to two interviews, immediately before the start of therapy and six months after it. Most of the patients recorded distinctly alterations of their mood, their initiative, their elemental desires such as appetite, sleep, need of warmth, and their sexual behaviour. 73 of them noted a change in their emotional pattern, which was positive in 34 and negative in 39 cases. 99 women reported changes in their elemental desires. 136 patients exhibited alterations of their sexual behaviour, which were assessed as an improvement or impairment in 108 and 28 cases, respectively. There is a statistically significant correlation between the impairment of sexual function and the incidence of other untoward side effects. On the other hand, negative suggestion by poor experience of other women on by the influence of mass media seems to play a minor role in producing changes of sexual behaviour. There is, however, a clearcut relationship between negative suggestion and the incidence of unfavourable emotional alterations. The findings are discussed with reference to their clinical significance.

Adult↗

Clinical aspects of the relationship between oral contraceptives, abnormalities in carbohydrate metabolism, and the development of cardiovascular disease.

Although large epidemiologic studies indicated no difference in the frequency of diabetes mellitus in nonusers and everusers of high-dose combination oral contraceptives, other studies had shown an increased risk of impaired glucose tolerance in current users, which is estimated to be roughly twice as frequent as that in nonusers. Women at risk of developing impaired glucose tolerance while receiving high-dose oral contraceptives either had previous gestational diabetes mellitus or were older, obese, or had a positive family history of diabetes mellitus. The tendency to decreased glucose tolerance seems essentially related to the dosage and chemical structure of the progestogen used in oral contraceptives, namely, estrane and particularly gonane progestins. However, increased frequency of impaired glucose tolerance and potentially diabetes mellitus are obviously not linked to the use of the more potent gonane progestins. The use of low-dose oral contraceptives, particularly with reduced progestogen content (such as in the triphasic formulations and last-generation monophasic preparations), is accompanied by a low risk of impaired glucose tolerance, even in previous gestational diabetes mellitus. The mechanism of decreased glucose tolerance in oral contraceptive users is unknown but seems related partially to increased peripheral resistance that is potentially caused by a postreceptor defect in insulin action. Changes in insulin production or metabolic clearance rate are not excluded by recent, sophisticated investigations of carbohydrate metabolism in oral contraceptive users. Impaired glucose tolerance and diabetes mellitus, chronic hyperglycemia, and hyperinsulinemia are believed to increase atherogenic risk either by their direct action or their effects on lipid metabolism. Newer epidemiologic studies now indicate that the incidence of cardiovascular disease in low-dose, low-risk, current oral contraceptive users has been substantially decreased. The use of low-dose oral contraceptives with reduced dosages of better adapted progestogens seems effective in decreasing alterations in carbohydrate metabolism and may thereby contribute to decrease further atherogenic risk in oral contraceptive users.

Carbohydrate Metabolism↗

Effect of long-term hormonal contraception on plasma lipids.

Serum lipid and apoprotein levels were determined in fasting women after long-term use (5-12 years) of Depo Provera, Orgametril, Ortho Novum SQ, Binordiol, Microgynon-50, and Ministat. Compared with matched controls, pure progestogens (Depo Provera and Orgametril) caused a moderate decrease of TG, HDL chol, and Apo A1, whereas estrogen-dominant oral contraceptives (Ortho Novum SQ) increased the same parameters. The effects of long-term use of hormonal contraception on lipids did not differ from those predicted from short-term (6 months) studies.

Adult↗

Response to medroxyprogesterone acetate (NSC-26386) as secondary hormone therapy for metastatic breast cancer in postmenopausal women.

We have treated 40 postmenopausal women with documented metastatic breast cancer with medroxyprogesterone acetate. The average age was 63 years and the patients were, on the average, 14 years' postmenopausal. Only two patients had received no prior additive hormone therapy. The remainder had previously received estrogen, androgens, or both. Only two patients had objective evidence of tumor regression. In one patient a metastatic node disappeared for 7+ months, and the other patient had well-documented clinical improvement and control of brain mestastases for 22 months. Two other patients had mixed responses of chest wall metastases (regression of some but not all lesions), lasting 3 and 4 months respectively. Five other patients had obvious subjective benefit. There were four objective responses (10%) and five subjective responses (12%). There was no correlation between route of administration and response. All patients receiving benefit had previously responded to other hormones. Side effects were usually absent or consisted of mild fluid retention; however, four patients had disease stimulation from therapy.

Administration, Oral↗

[Multiple nodular hyperplasia of liver associated with oral contraceptives (author's transl)].

Two cases of multiple nodular hyperplasia of liver in patients with intake or oral contraceptives for several years are described. In one case the tumours appeared simultaneously, in the other case succesively. Macroscopically the nodular hyperplasia was misdiagnosed as metastasis. Microscopially the nodes presented an intense inflammatory infiltration of the septa, in one case with tuberculoid granulomas. The lesions showed a marked vascularity. Extremely dilated sinusoids could be seen in the needle biopsy of the macroscopically unchanged liver, a phenomenon occasionally seen in cases treated with oral contraceptives.

Adult↗

[Liver function tests under the influence of sequential treatment using ethinyl estradiol-norethisterone acetate and ethinyl estradiol-chlormadinone acetate].

30 young healthy women were investigated during the first therapy cycle with ethinyl-estradiol-norethisterone acetate and ethinyl-estradiol-chlormadinone acetate as a sequential regime. The following laboratory data were achieved by each of the investigated group of young women: serum aminotransferase (GOT and GPT), serum alkaline phosphatase and alpha-amylase-activity in serum, serum proteins, serum cholesterol, serum bilirubin, serum ZST, serum TTT and the indocyaningreen-clearance of the liver. The serum protein pattern was determined by the paper electrophoretic method. A significant decrease of the aminotransferase GPT was viable during the sequential therapy with ethinyl-estradiol and norethisterone acetate. This viable decrease of the GPT was induced through the application of norethisterone acetate to estrogen. The alkaline phosphatase was significant lightly lower and the beta-globuline lightly elevated at the end of the therapy cycle. The sequential therapy with ethinyl-estradiol and chlormadinone acetate induced only a significant increase of the ZST in serum.

Adolescent↗