Oral contraceptives and riboflavin nutriture.
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48 fertile women took in three weeks 1 mg ethinylestradiolsulfonate weekly and in the 4th week 10 mg norethisterone acetate, respectively d-norgestrel in different dosages (0,5 mgs, 1,0 mgs, 1,5 mgs or 3,0 mgs). On this 48 women 69 abrasiones were made between the first and 37th treatment cycles in order to estimate the endometrium. Ethinylestradiolsulfonate caused for the most part a proliferation of endometrium, which reached to a glandulare cystic hyperplastic endometrium. We did not observe a reduction of the endometrial respond to this depot-estrogen in dependence on the time of taking. Norethisterone acetate and d-norgestrel effected on a different proliferated endometrium a secretory transfer mation always.
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To assess the effect of hormonal monthly injectable contraceptives upon the serum values of immunoreactive prolactin (Prl), three groups of women of reproductive age exposed to different estrogen-progestogen injectable formulation for a minimum of one year were studied. The first group (n = 10) received dihydroxyprogesterone acetophenide 150 mg and estradiol enanthate 10 mg (DHPA/E2-EN), Group 2 (n = 21) received medroxyprogesterone acetate 25 mg and estradiol cypionate 5 mg (MPA/E2-C) and Group 3 (n = 19) was exposed to norethisterone enanthate 50 mg and estradiol valerate 5 mg (NET-EN/E2-V). A group of IUD users (n = 16) served as the control group. Serum Prl and 17 beta-estradiol (E2) concentration were determined in blood samples (0 and 15 min.) on days 0 (day of last injection), 10, 20 and 30 after last contraceptive injection. The results demonstrated a slight though not significant increase (p greater than 0.05) in serum Prl in the three experimental groups as compared with the IUD control group. This increase in Prl levels observed on day 10 post-last injection never exceeded the upper limits of the normal range (20 ng/ml). Overall, the data demonstrated that the chronic administration of these estrogen/progestogen once-a-month injectable contraceptives does not affect the Prl baseline secretion in women.
A study was performed to obtain additional information about the effects of oral contraceptives on pituitary function. A sequential pituitary stimulation test (SST) was used to study normal control women who then received either a combination pill with 50 mug of ethinyl estradiol or an injectable or oral progestin for three weeks, after which the test was repeated. The same test was also performed on five long-term oral contraceptive users. The SST consists of measurement of growth hormone (GH), thyroid-stimulating hormone (TSH), prolactin (PRL), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) at frequent intervals after stimulation by hypoglycemia, thyrotropin-releasing hormone, and gonadotropin-releasing hormone. GH and TSH release following stimulation were unaffected by the use of contraceptive steroids, while PRL release was increased by both the combination pill and the progestin alone. LH and FSH release was decreased in the three short-term and most of the long-term users of the combination pills but was not decreased in two of the long-term users as well as in those receiving the progestin alone. These results indicate that the combination oral contraceptives have a direct effect upon the pituitary gland, causing an increase in prolactin release and a decrease in gonadotropin release. This effect varies among individuals receiving the same formulation and may be related to the development of syndrome of postpill amenorrhea-galactorrhea.
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Carbohydrate metabolism, as assessed by the intravenous glucose tolerance test (i.v.-GTT), was studied in 19 healthy, non-lactating women who received injectable contraceptives containing either medroxyprogesterone acetate (DMPA) (10 subjects) or norethisterone enanthate (Net-En) (9 subjects). Tests were made prior to treatment and at intervals over a period of 15 months thereafter. Results obtained indicate that carbohydrate metabolism is not impaired by either of the two progestogens, and neither pyruvate nor cortisol concentrations changed significantly over the period of observation. However, the insulin release in response to glucose loading underwent interesting alterations during treatment. These abnormalities returned promptly to normal after withdrawal of treatment.
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.
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.
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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.
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.
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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.
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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.
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.