Manuel Maqueo

Induction of degenerative changes in uterine myomas by high-dosage progestin therapy

Abstract 1. 1. Continuous administration of 2 mg. estrogen-free norethindrone daily for periods of 1 to 3 months had no effect on uterine myomas in 14 women. 2. 2. Forty-six patients with uterine myomas were treated with a large dose (25 mg. daily) of a highly potent “pure” oral progestin, medrogestone, for periods of 14 or 21 days. Hysterectomies were scheduled at intervals up to 120 days following treatment. Myomas from 40 women at various stages of pregnancy served as a comparison group. Medrogestone therapy for 21 days evoked intense degenerative changes in both small and large myomas exceeding those seen at the end of pregnancy. There was no evidence of cellular proliferation. These changes progressed to fibrosis and hyalinization. Treatment for 14 days produced similar but less consistent changes. It is suggested that brief, intense exposure to appropriate progestational agents has potentialities in the therapy of the myomatous uterus.

Comparative studies of the ethynyl estrogens used in oral contraceptives

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.

Morphology of the cervix in women treated with synthetic progestins.

Abstract A study of cervical morphology was carried out in 5 groups of subjects: (1) 104 women using oral contraceptives for 9 months or longer; (2) 43 women receiving continuous, usually high-level oral progestational therapy with little or no estrogen; (3) 20 women dying of accidental deaths; (4) 30 women dying in the third trimester of pregnancy; and (5) 24 women with endometrial hyperplasia. The patients on oral contraceptives were studied by multiple biopsies, while in the others the entire cervix was examined. Cervical glandular hypersecretion and stromal edema increased with the exposure to progestational influences. With continuous progestin dosage or in pregnancy, an increase of pronounced squamous metaplasia was noted. There was no evidence of an increase of epithelial changes in the cervix of women receiving contraceptive therapy, as compared to the other groups.

Comparison of the long-term endometrial effects of synthetic progestins used in fertility control

With the widespread use of progestational hormones as oral contraceptives the impact of these agents on the endometrium led to an evaluation of 2 representative preparations norethindrone (a 19-nor steroid) and chlormadinone (a 17-acetoxyprogesterone derivative) in order to study the changes resulting from the long-term cyclic use of these compounds. One group of women received a combination of 60 mcg mestranol and 10 mg norethindrone and the other group received a combination of 80 mcg mestranol and 2 mg chlormadinone. Almost 1100 endometrial biopsies were made. The endometria of the norethindrone subjects were completely different from those of the normal cycle the postmenopausal period and those produced during the first cycle of oral progestin treatment. The morphological picture was one of inhibition of endometrial growth and especially of glandular development reaching a stable degree of involution soon after the third cycle of treatment. Stromal edema and minor degrees of predecidual change continued to develop to about the same extent even after 36 months of cyclic treatment. The endometria of the chlormadinone subjects were markedly underdeveloped with transitory minimal and irregular secretory changes. By Day 19 or later the tissue was similar to an atrophic postmenopausal endometrium except that the stroma instead of having a fibrous appearance showed edema and cells with pyknotic nuclei. These endometria showed the same general differences in comparison to norethindrone as were observed during the initial cycle of treatment i.e. earlier and more marked glandular involution less secretion slightly more intense edema and less frequent predecidual reaction.

Ovarian morphology after prolonged use of steroid contraceptive agents

To assess the effect of oral contraceptives on ovarian morphology, 125 users (average age 30) and 42 controls (average age 24) were studied histologically. The duration of the steroid treatment in the 125 subjects varied from 2 to 91 months. 60 used combination oral contraceptives, 28 used sequential, 21 received depot progestins, and 16 used continuous low dose progestin. Investigation was directed to the presence or absence of the various ovarian structures. In all specimens primary follicles were seen. Women using combined and depot progestins showed disturbance in the secondary follicles development. Tertiary follicles were common in the low dose progestin, occurring occasionally with sequential and combination treatment, and never with depot progestin. Ovaries from steroid treated patients appeared to have a large number of atretic follicles with cystic dilatations. An increase in ovarian connective tissue occurred in half of the cases using combined preparations, one third of those using sequential, and almost all of those using depot progestin.

Histology of the baboon endometrium during the menstrual cycle and pregnancy

The histologic characteristics of baboon endometrium during the menstrual cycle and pregnancy were studied and compared with those of human endometrium. Eight phases of endometrial change during the menstrual cycle are described. The samples were dated on the basis of sex skin changes. The basic histology of the baboon endometrium is similar to that of human endometrium, but some differences were observed. The growth of baboon endometrium is more sluggish, secretion is less intense, and many of the changes, especially in the stroma, are localized, less diffuse than they are in human endometrium. During pregnancy, decidual transformation in the baboon is much less intense than that in the human. No differences were observed between endometrium in association with preimplantation embryos and that from nonpregnant animals at comparable times following ovulation.

The evaluation of quingestanol acetate as a low dose oral contraceptive

Abstract Four hundred patients completed 4,370 cycles of treatment using quingestanol acetate, 300 mcg daily. Twelve pregnancies occurred resulting in a failure rate of 3.3 per 100 woman years. Seven of these pregnancies were considered drug failures giving a rate of 1.9 per 100 woman years. Cycle length, amount and duration of flow were not significantly different from pretreatment. Intermenstrual bleeding occurred in 51% of the patients and in 12% of cycles; amenorrhea occurred in 20% of the patients and in 5% of cycles. Endometrial biopsies showed normal patterns in 92% of specimens taken during the follioular phase of the menstrual cycle and in 67% of those taken during the luteal phase. An anovulatory pattern was shown in 14% taken during the luteal phase. Numerous laboratory tests demonstrated no abnormalities which could be associated with therapy. The discontinuance rate of 15% for drug-related reasons during the three years of this program indicated favorable patient acceptance. This study indicated that quingestanol acetate used at a daily dose of 300 mcg is a safe and effective oral contraceptive.

Clinical evaluation of norethindrone acetate in fertility control

A clinical evaluation of 300 Mexican women accumulating 5902 treatment cycles representing 454 woman-years with 4 mg norethindrone acetate and .05 mg ethinyl estradiol (Anovlar) is presented. Each woman was instructed to take 1 tablet daily for 20 consecutive days beginning on Cycle Day 5. Anovlar was virtually 100% effective. Unpleasant side effects were minimal and transient occurring principally in the first 3 cycles and disappearing rapidly thereafter. Acceptability was high in women of all social classes. Fertility was rapidly restored after discontinuing medication. Extensive laboratory tests confirm the harmlessness of this compound. Consistent negative Papanicolaou tests during long-term treatment with this compound as with other progestagen-estrogen compounds warrent further study to determine a possible anticarcinogenic effect.(AUTHORS MODIFIED)

The effect of contraceptive steroids on endometrial sinusoids and the failure of these changes to correlate with breakthrough bleeding or systemic vascular effects

The occurrence of dilated sinusoids in human endometrium is associated with prolonged exposure to progestational agents, orally or parenterally. No clearcut dose-related response could be demonstrated, and the changes were apparently unaffected by various levels of concomitant estrogenic stimulation. There was no correlation between this histological feature and the frequency of clinically observed breakthrough bleeding. There was no association with any subjective symptoms which could be classified as of peripheral vascular origin.