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The effect of low-dose estroprogestinic preparations on prothrombin complex factors: no significant increase after an 8-month trial.

The behavior of the prothrombin complex factors in 16 healthy women during low-dose estroprogestinic treatment (laevonorgestrel 0.15 mg and ethynilestradiol 0.30 mg) at basal conditions and during 8 months of therapy has been investigated. We found a statistically significant decrease of the PTT (Partial Thromboplastin Time). The prothrombin time, on the other hand, became slightly decreased, but not to a statistically significant extent. Among the prothrombin time derived tests for evaluating the prothrombin complex only the PP test (Prothrombin Proconvertin test) was significantly shortened. Of the coagulation factors (factors II, VII and X) only a modest, but not statistically significant, increase in Factor VII and Factor X was noted. We conclude that, during the 8 month observation period, prothrombin complex factors are not altered substantially.

Adult↗

Hormones and breast cancer.

Patients with successfully managed breast cancer have generally been denied subsequent exposure to increased levels of estrogen (endogenous or exogenous) based on the belief that exacerbation of the cancer would occur. The advent of oral contraceptives, the trend toward childbearing later in life, and the demonstration of the protective value of menopausal estrogen replacement therapy against osteoporosis and cardiovascular disease requires that this issue be reexamined. New information bearing on this subject includes the recognition of estrogen receptors, the isolation of youth rather than pregnancy as the factor resulting in poor prognosis, epidemiologic studies showing no increased risk of breast cancer in women using oral contraceptives or taking hormonal replacement therapy, the beneficial effect of pregnancy subsequent to successfully managed breast cancer, and the absence of an adverse effect of oral contraceptives upon established breast cancer. In view of the lack of evidence relating estrogen to exacerbation of existing breast cancer, it may be in the best interest of our patients to liberalize our attitude to renewed hormonal exposure in patients with successfully managed breast cancer.

Breast Neoplasms↗

Norethisterone levels in maternal serum and milk after intramuscular injection of norethisterone oenanthate as a contraceptive.

There is concern that the breast-fed infant whose mother is receiving intra-muscular progestogens for contraception will be exposed to significant quantities of the steroid. Norethisterone levels in maternal serum and milk were studied throughout an injection interval after intramuscular administration of 200mg norethisterone oenanthate. Milk samples were taken at the beginning and at the end of the feed. Norethisterone concentrations in milk were very much lower, but declined more slowly, than serum concentrations. Post-suckling concentrations were higher than pre-suckling concentrations. Experiments in adults receiving an oral dose of norethisterone in cow's milk comparable to that ingested by an infant in a day resulted in low serum levels. It is concluded that only very low concentrations of norethisterone would be present in the infant's circulation.

Breast Feeding↗

Assessment of the potency of orally administered progestins in women.

The effects of at least three doses of each of five orally administered progestins on estrogen-primed, postmenopausal endometrial biochemistry and morphologic features were analyzed. The progestins tested were norethindrone, medroxyprogesterone acetate (MPA), norgestrel, dydrogesterone, and progesterone. The dose required to elicit responses similar to those seen in premenopausal, secretory endometria was assessed for each of the parameters measured, and the relative potencies were calculated. Potencies, relative to a value of 1 for norethindrone, are L norgestrel 8 (D/L norgestrel 4), MPA 0.1, dydrogesterone 0.02, and progesterone 0.002. The dose of norethindrone required to elicit secretory phase activity was about 0.35 mg/day. These values agree with published data obtained with the use of different methods (delay of menstruation in premenopausal women, endometrial histologic features of estrogen-primed, ovariectomized women).

Administration, Oral↗

Serum and placenta levels of ethynylestradiol in presence of ethynodiol diacetate after oral administration.

The ethynylestradiol concentration--in the presence of ethynodiol diacetate--in serum after oral administration was measured by a rapid radioimmunoassay method developed by the authors. It was found that the peak level was reached 1 h after administration, and even after 12 h a significant amount of free ethynylestradiol was present in the serum. The transfer of ethynylestradiol into the placenta was also studied in subjects who were 10-12 weeks pregnant. Placenta/serum quotients were calculated for the ethynylestradiol, and were found to increase in parallel with the dose of the drug administered, proving that an ethynylestradiol enrichment of the placenta occurred as early as 10-12 weeks of pregnancy.

Administration, Oral↗

Human liver tumors in relation to steroidal usage.

Since 1973 a number of investigators have reported an association between liver neoplasia and steroid usage. Through referral material we have examined the histology of over 250 cases of hepatic neoplasia, most in patients receiving steroid medications. The majority have been benign, predominantly focal nodular hyperplasia (55%) and hepatocellular adenoma (39%). The average age was 31.4 years; 83% had significant steroid exposure with an average duration of 71 months for focal nodular hyperplasia and 79.6 months for hepatocellular adenoma. The type of estrogenic agent was predominantly mestranol; however, during the period mestranol was the most frequently used synthetic steroid. A distinct clinical entity of life threatening hemorrhage from the lesion occurred in 31% of patients with hepatocellular adenoma and 9% of patients with focal nodular hyperplasia. Recurrence of benign tumors has occurred in some patients who continued using steroids and regression has been observed in patients who had incomplete tumor removal but discontinued steroid medication. Medial and intimal vascular changes have been present in a large number of the benign tumors. The relationship of these vascular changes to oncogenesis is unclear, but similar lesions have been described in the peripheral vasculature associated with steroid administration. A number of hepatocellular carcinomas have also been seen. Of significance is the young age of these patients and lack of abnormal histology in adjacent nonneoplastic liver. A striking number of the malignant hepatocellular tumors have been of the uncommon type described as "eosinophilic hepatocellular carcinoma with lamellar fibrosis." The epidemiology of liver lesions within this series is difficult to assess, since the material has been referred from very diverse locations.

Adenoma↗

New packaging specifications prompt OC shelf life study.

when a major donor of contraceptives changed the packaging specifications of norethindrone/mestranol oral contraceptives (OCs), the change raised some questions as to product shelf life. The new specifications called for the OCs to be packaged in bulk with 100 blister packs/aluminum/plastic overpack. These revised packaging specifications would lead to removal of the blister pack from the protective overpack at an earlier point in the supply chain, and therefore to earlier potential exposure to high temperatures and humidity. However, stability trials conducted by Kabalikat ng Pamilyang Pilipino in Manila have shown no significant deterioration in norethindrone or mestranol content, content uniformity, tablet hardness, disintegration time or blister pack integrity after blister packs without the protective overpack were exposed for 6 months to high humidity and temperatures as high as 60 degrees Celsius. Stability for longer than 6 months remains speculative and should be tested in actual field conditions. Within the limits of the study, however, these results suggest that OCs remain stable with or without the aluminum overpack.

Contraception↗

Is high dosage testosterone an effective male contraceptive agent?

In male contraceptive trials, approximately half of normal men become azoospermic on high dosages of testosterone enanthate (TE), whereas the other half of men become severely oligozoospermic. To determine whether sperm function is reduced in men with severe oligozoospermia induced by TE, we studied sperm function in six normal men whose sperm counts were reduced to less than or equal to 5 X 10(6)/ml but not to azoospermia by high-dosage TE administration for 5 to 6 months and five normal men who received placebo (sesame oil) injections for the same period of time. Seminal fluid analysis and sperm function (as assessed by zona pellucida-free hamster ova penetration test, HOPT) were performed during a pretreatment period and after at least 3 months of TE or placebo treatment. HOPT was severely reduced in all six men, whose sperm counts were suppressed to severe oligozoospermia during TE (0.8 +/- 0.8% compared to 37 +/- 14% during the pretreatment period, P less than 0.05). Five men failed to penetrate any hamster ova, while the remaining man penetrated only 5% of ova during TE treatment. There were no significant changes in other seminal fluid measurements during high-dosage TE. The five men who received placebo injections did not demonstrate any significant changes in HOPT or seminal fluid analysis during the treatment period. In summary, we found that the fertilizing capacity of sperm is markedly diminished when sperm production is severely reduced by high-dosage TE administration. These findings suggest that male contraception may be achievable by reduction of spermatogenesis to severe oligozoospermia.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Serum total and unbound testosterone and sex hormone binding globulin (SHBG) in female acne patients treated with two different oral contraceptives.

Serum total an unbound testosterone (T) and sex hormone binding globulin (SHBG) levels were studied in fifty-four female acne patients before treatment and during the treatment by two different oral contraceptives, the other containing 0.150 mg desogestrel plus 0.03 mg EE and the other 0.150 mg levonorgestrel plus 0.03 mg EE. Pretreatment values were abnormal in 57% of the patients. A borderline significant correlation between the severity of acne and SHBG was found. Ater six months' treatment a 250% increase in SHBG was seen in desogestrel/EE group and no significant change in SHBG in levonorgestrel/EE group. However, at the same time serum free testosterone fell 60% in both treatment groups. SHBG cannot be the only regulator of serum free testosterone. Acne improved significantly in both treatment groups. It is likely that the improvement was in connection with the free testosterone decrease and the improvement was better in the desogestrel/EE group where also SHBG elevation was seen.

Acne Vulgaris↗

[Measurement of serum activity in short and long-term application of various hormonal contraceptives].

The influence of several oral contraceptives on various serum enzymes was tested during a short-term and a prolonged (24 therapeutic cycles) application period. A total of 8,790 examinations was performed in 211 females, each patient being examined up to 8 times during the cycles 0, 1, 3, 6, 12, 18, 24 and the first cycle following termination of oral contraception. Since sufficiently sensitive steroid-dependent makers are lacking, it cannot be dispensed with determining the serum enzymes gamma-GT, GPT, GOT, and LAP altogether, in order to detect early damage of the liver.

Alanine Transaminase↗