Ultrastructure of human uterine epithelium at the time of implantation after postovulatory administration of norethindrone.
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OBJECTIVE: To provide a worldwide review of all studies that have examined the relationship between progestins, as contained in both contraceptive and postmenopausal replacement therapies, and breast cancer risk. An overview of utilization patterns for progestins, as well as a review of possible biological mechanisms for progestins' action on breast tissue, are also presented. DATA IDENTIFICATION: All major epidemiologic studies conducted since 1980 have been identified through MEDLINE searches through the published literature and personal communications with prominent researchers in the area. STUDY SELECTION: Only studies that specifically examined the effects of progestin use are discussed here; these include investigations of progestins, in combination or singularly, as the main hypothesis or a subgroup analysis. RESULTS: The majority of studies have examined combination estrogen and progestin products (oral contraceptives), and subgroup analyses of progestins have been impeded by low statistical power and the fact that each progestin possesses different types of pharmacological activity. Only a few studies of long-acting injectable progestins exist, confirming a general lack of specific information on the progesterone-breast cancer relationship. Investigations of the effect on breast cancer of the addition of progestins to postmenopausal replacement therapy have also produced inconsistent results. CONCLUSIONS: To date, there is no consistent evidence of an association between progestins and breast cancer. There is need for further study, particularly of patients in potentially high-risk groups, including those with (1) extended hormone exposure before age 25 and/or first full term pregnancy and (2) exposure in the postmenopausal period.
The subcutaneous implantation of estradiol pellets was found to be a simple and effective contraceptive method with good patient acceptance and minimal untoward effects. The pellets (25 mg each) were implanted through a Kearn's trocar into the abdominal wall, 2.5 to 5 cm above and parallel to Poupart's ligament. The regimen began with four pellets, and the dose was maintained or decreased by one pellet every 6 months (four, three, two, one). A potent progestogen was utilized monthly for induction of withdrawal bleeding. Altogether, 236 patients were followed for a total of 1,060 courses in 6,360 cycles (489,02 woman-years). Two pregnancies occurred during therapy. Pearl's index was 0.37. No significant alterations occurred in body weight and blood pressure. Glucose tolerance test, standard blood profiles, and Papanicolaou smears were normal during therapy. No cases of thrombophlebitis, blurred vision, headaches, gastric symptoms, or amenorrhea-galactorrhea were observed. The suppression of ovulation was confirmed by endometrial biopsies, basal body temperature, and serum follicle-stimulating hormone, luteinizing hormone, estradiol, and progesterone in a selected group of patients.
The author reports the results of a prospective study of 10 women during six months use of an oral contraceptive combination with gestodene. Inhibition of ovarian function is showed by rapidly decreasing serum levels of estradiol and progesterone. Clinical and metabolic tolerance is excellent.
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1. Adenosine 3',5'-(cyclic)-monophosphate (3',5'-AMP) stimulates the synthesis of progestational steroids by rabbit ovarian tissue in vitro. 2. Other adenosine phosphates fail to increase steroidogenesis. 3. The ratio of 20alpha-hydroxypregn-4-en-3-one to progesterone, the maximal response of the tissue, and the responses of separated corpora lutea and interstitial tissue produced by luteinizing hormone are closely paralleled by 3',5'-AMP. 4. In tissues maximally stimulated by luteinizing hormone, 3',5'-AMP fails to produce an additional response. 5. The addition of theophylline, an inhibitor of phosphodiesterase, potentiates the effects of 3',5'-AMP and also luteinizing hormone. 6. The results obtained suggest that 3',5'-AMP is a mediator of the action of luteinizing hormone on progestational steroid synthesis by rabbit ovarian tissue.
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The time to resumption of ovulation following the discontinuation of levonorgestrel subdermal implants (Norplant) was assessed in 10 women. A blood sample (2 ml) was taken at the time of Norplant removal and then twice weekly until the first evidence of ovulation (serum progesterone concentration greater than or equal to 5 ng/ml) was documented. Ovulation was resumed in 80% of the cases by 3 weeks and in all the cases by 7 weeks. Prompt return of ovulation following Norplant removal is an additional advantage of this mode of long-acting contraception.
Vaginal rings of Dow Corning 382 Silastic polymer, having identical outside dimensions, were fabricated to contain cores of different diameters loaded with 25% w/w progesterone. Elution of rings was carried out in continuously flowing baths of isotonic saline at 37 degrees C and quantities of progesterone released in 24 h periods measured for up to 128 days. Release of the steroid was shown to be a membrane diffusion-controlled process, modified by the development of a gradually increasing zone of depletion at the core surface. Rings of a suitable core diameter were selected to give initial release of 5 mg/24 h progesterone and sterile batches of these rings, prepared for WHO-sponsored clinical studies in post-partum, lactating women, were shown to give highly consistent and reproducible rates of in vitro drug delivery. A comparison was made with the in vitro release rates of rings containing a homogeneous dispersion of progesterone.