Ovulation inhibition doses of progestins: a systematic review of the available literature and of marketed preparations worldwide.

BACKGROUND: The objective of this analysis was to provide a comprehensive review of ovulation inhibition data of progestins currently available worldwide. This analysis may serve as a reference tool for research on new progestin molecules. STUDY DESIGN: We used literature search engines to detect data of progestin monotherapies on ovulation inhibition in humans. Only treatments with stable dosing during a cycle were accepted. In a second step, we tried to estimate the 99% ovulation inhibiting doses and their fiducial confidence limits using the probit dose-response model. Finally, we analyzed the progestin doses of combined oral contraceptives currently on the market. RESULTS: We found original data on 29 marketed and nonmarketed progestins in a total of 60 publications, published between 1956 and May 2010. Details on methods used for determining ovulation, number of doses and daily dose of each tested progestin, number of subjects, cycles and ovulations are summarized in a table. We designed one example of a dose-response curve using the statistical model. For most progestins, literature data were insufficient for this purpose. A total of 13 progestins are components of oral contraceptives currently on the market worldwide, five of them in combination with 20 mcg ethinyl estradiol (EE). CONCLUSION: This review provides a comprehensive overview of all progestins ever tested for their ovulation inhibition potency and a summary of all preparations currently on the world market, including their regimens and their combinations with EE.

Digitized assessment of mammographic breast density--effects of continuous combined hormone therapy, tibolone and black cohosh compared to placebo.

OBJECTIVES: To determine the effects of continuous combined hormone therapy, tibolone, black cohosh, and placebo on digitized mammographic breast density in postmenopausal women. STUDY DESIGN: A prospective, double-blind, placebo-controlled study of 154 postmenopausal women randomized to estradiol 2 mg/norethisterone acetate 1 mg (E2/NETA), tibolone 2.5 mg or placebo and a prospective, open, uncontrolled drug safety study, of which 65 postmenopausal women were treated with black cohosh. Mammograms, at baseline and after six months of treatment, were previously classified according to visual quantification scales. MAIN OUTCOME MEASURES: Reanalysis of assessable mammograms by digitized quantification of breast density. RESULTS: Treatment groups were comparable at baseline. During treatment, both E2/NETA and tibolone significantly increased breast density (mean increase 14.3%, p<0.001 and 2.3%, p<0.001, respectively), while black cohosh and placebo did not. Twenty-four out of the 43 women on E2/NETA had an increase in density exceeding 10% and 6 women had an increase of 30% or more. In the tibolone group, only one woman had an increase in density of more than 10%. The difference in increase in breast density between E2/NETA on the one hand and tibolone, black cohosh and placebo on the other was highly significant (p<0.0001). CONCLUSIONS: Digitized mammographic breast density is a highly sensitive method confirming significant increase in density by standard E2/NETA treatment and to a lesser extent by tibolone, whereas black cohosh does not influence mammographic breast density during six months treatment. Digitized assessment also yields data on individual variation and small increases left undetectable by visual classification.

Avaliaçao audiológica em mulheres que fazem uso de anticoncepcionais hormonais orais / Audiological assessment in womwn taking oral hormonal contraceptive

Tema: avaliaçao audiológica am mulheres que fazem uso de anticoncepcionais hormonais orais. Objetivo: verificar a açao de anticoncepcionais hormonais orais sobre o sistema auditivo periférico. Método: investigaçao da capacidade auditiva e da auto-percepçao auditiva em mulheres (18 a 25 anos), distribuídos em dois grupos: I (Controle) - 19 que nunca fizeram uso da droga; II(Estudo) - 19 estavam fazendo uso da droga (período médio=67 meses). Resultados: Gráficos e Tabelas mostraram os achados das avaliaçoes e das análises estatísticas nos dois grupos. Conclusao: o uso de anticoncepcionais orais nao determina alteraçao da capacidade auditiva, mas favorece a ocorrência de zumbido.

A quantitative biometrological assessment of acne and hormonal evaluation in young women using a triphasic low-dose oral contraceptive containing gestodene.

OBJECTIVE: To investigate the effect of a triphasic low-dose oral contraceptive pill containing gestodene on acne severity and hormone levels in young women over 13 menstrual cycles. METHODS: A total of 33 subjects aged 16-25 years with moderate facial acne were enrolled in the study. The primary efficacy end-points used in the clinical assessment of acne were the overall severity and number of lesions, sebum secretion and superficial follicular biopsy. Both physicians and patients evaluated acne status. Blood levels of sex hormone binding globulin (SHBG), estradiol, progesterone and androgens were monitored. RESULTS: By cycle 13, the total lesion count had been reduced by 80%. Physicians and patients assessed acne status in 90% and 95% of cases, respectively, as better or much better (p < 0.001). At the end of the study, SHBG levels had increased by 229% and total and free testosterone levels had decreased by 41% and 70%, respectively. CONCLUSION: An oral contraceptive containing triphasic gestodene has a beneficial effect on the severity ofacne, decreases major circulating androgen levels and is well tolerated.

In vitro molecular assessment of the mechanisms of action of 19-nor progestins used as contragestational agents.

Norethisterone (NET) and levonorgestrel (LNG) are synthetic progestins used as contragestational agents. Both compounds are biotransformed at target tissues into A-ring reduced metabolites which possess different pharmacological properties. The aim of this study was to determine the molecular mechanisms of the progestational and antiprogestational effects of NET, LNG and their metabolites by using a highly efficient, sensitive in vitro molecular assay based on the detection of a reporter gene expression (the bacterial chloramphenicol acetyltransferase (CAT) inserted downstream of a minimal promoter containing two progesterone responsive elements (PRE2) and the TATA box. For this purpose we used CV-1 monkey kidney cells, which do not possess steroid receptors. These cells were cotransfected with a progesterone receptor expression vector and the reporter vector PRE2-TATA-CAT. Data obtained using this model showed that NET and LNG induced CAT activity in a manner similar to that of the potent progestin R5020. NET and LNG metabolites exhibited a weak progestational activity; however, when 5 alpha-NET metabolite was simultaneously administered with R5020, a clear antiprogestational effect similar to that of the antiprogestin RU486 was observed. Therefore, the results clearly demonstrate that the use of the reporter CAT vector containing hormone responsive elements is a suitable assay for the screening and evaluation of new synthetic steroids with agonist or antagonist progestational activities in transfected CV-1 cell line.

Comparative assessment of two low-dose oral contraceptives, Lo-Femenal and Lo-Estrin, in Mexican women.

This trial was designed to determine the differences in effectiveness, clinical acceptability, and one-year discontinuation rates of two low-dose oral contraceptives: Lo-Estrin (norethindrone acetate 1.5 mg plus ethinyl estradiol 0.030 mg) and Lo-Femenal (norgestrel 0.30 mg plus ethinyl estradiol 0.030 mg) in 148 Mexican women. In addition, the effects of both oral contraceptive preparations on blood lipids were prospectively evaluated in a subgroup of 41 women. The results indicated that there were no differences in pregnancy rates, discontinuation or clinical acceptability between the two groups. The lipid changes observed were minimal for the Lo-Femenal subgroup and somewhat greater for the Lo-Estrin group, mainly an increase in serum triglycerides. These changes were interpreted as estrogen induced effects of norethindrone-containing oral contraceptives. Overall, the data indicate that both Lo-Femenal and Lo-Estrin are effective and safe combined oral contraceptives.

The vitamin B6 requirement in oral contraceptive users. I. Assessment by pyridoxal level and transferase activity in erythrocytes.

Eight college-age women using estrogen-containing oral contraceptives (OC) were fed a low vitamin B6 diet (0.36 mg/day) for 42 days. During the first 10 days (adjustment period) the diet was supplemented with 1.7 mg pyridoxine hydrochloride bringing the total intake to 2.06 mg/day. Following depletion, repletion was done in three consecutive steps: intakes of 0.96, 1.56, and 5.06 mg were consumed for 8, 9, and 7 days, respectively. Continuous 24-hr urine collections were made throughout the study and fasting blood samples were drawn periodically. Vitamin B6 nutriture was assessed by erythrocyte pyridoxal level, erythrocyte alanine aminotransferase and erythrocyte aspartic aminotransferase activity; and stimulation of these enzyme systems with pyridoxal phosphate. Results were compared with data obtained from non-OC users who consumed a similar diet. The data obtained suggest that 0.96 mg vitamin B6 was not adequate to meet the needs of OC users. Predepletion levels had been reached in almost all subjects at an intake of 1.5 mg/day. Assessed by the parameters studied, an intake between 1.5 and 5.0 mg/day of vitamin B6 was adequate to meet the needs of OC users; this compares with 1.5 mg/day previously suggested for the nonuser.

PIP: A 3-phase study was conducted to evaluate the Vitamin B6 nutritional requirement of oral contraceptive users. 8 young women (mean age, 20 years; mean body weight, 63.2 kg.) on oral contraceptives (OCs) served as the study group and another 8 (mean age, 21 years; mean body weight, 61.4 kg.) not on OCs served as controls. The 1st 10 days of the study were designated as the predepletion phase: all subjects were given a basal diet with supplement of 1.7 mg/day pyridoxine hydrochloride (PN-HCL). The depletion phase consisted of withdrawing Vitamin B6 supplement of 1.7 mg/day for 32 days; the repletion phase consisted of supplementing the basal diet with specific amounts of PN-HCL (intakes of 0.96, 1.56, and 5.06 mg were taken for 8,9, and 7 days, respectively). Only the study group went through the depletion and repletion phases. Fasting blood samples and continous 24-hour urine samples were obtained for analysis. The Vitamin B6 nutriture was measured by erythrocyte pyridoxal level, erythrocyte alanine aminotransferease and erythrocyte aspartic aminotransferase activity. The results indicated that 0.96 mg Vitamin B6 was insufficient to meet nutritional requirements of OC users. Almost all subjects reached a predepletion level at an intake of 1.5 mg/day. An intake of between 1.5 and 5.0 mg/day of Vitamin B6 was deemed sufficient for OC users, and compares favorably with nonusers' measurement of 1.5 mg/day.

The vitamin B6 requirement in oral contraceptive users. II. Assessment by tryptophan metabolites, vitamin B6, and pyridoxic acid levels in urine.

PIP: The requirement for vitamin B6 in oral contraceptive users was studied in 8 college-age women who used combined (7) or sequential (1) oral contraceptives. The subjects and 8 controls consumed a basal diet supplemented to result in daily intake of 2.06 mg pyridoxine hydrochloride for 10 days (predepletion) and then containing only .36 mg of vitamin B6 for 32 days. After the depletion period, the diet was supplemented with pyridoxine hydrochloride to increase the intake of B6 to .96, 1.56, and 5.06 mg for 8, 9, and 7 days respectively. Complete 14-hour urine collections were analyzed for xanthurenic acid, kynurenic acids, kynurenine, and 3-hydroxykynurenine after administration of a l load-dose of 2 gm L-trytophan on days 2, 11, 18, 25, 32, 39, 43, 50 , 59, and 66 for the subjects and days 2 and 10 for the controls. Pretryptophan urine was analyzed for vitamin B6. Posttryptophan urine was analyzed for 4-pyridoxic acid. It was found that during the depletion phase the excretion of tryptophan metabolites increased significantly. Excretion dropped significantly upon supplementation with 1.56 or 5.06 mg of vitamin B6, returning values to normal. Levels of vitamin B6 and 4-pyridoxic acid in the urine decreased during depletion to be restored to normal upon supplementation with 1.56 mg/day. Since an intake of 5.0 mg vitamin B6 caused a loss of the vitamin in the urine and all levels were returned to normal with an intake of 1.56 mg, it is suggested that 1.5 mg of vitamin B6 is sufficient to meet the needs of most oral contraceptive users and that there is no significant difference in the vitamin B6 requirement of oral contraceptive users and nonusers.^ieng

Effect of oral contraceptives on folate economy--a study in female rats.

Daily administration of one tenth of a tablet of Ovulen-50 (ethinodiol diacetate, 1 mg, ethinylestradiol, 50 microgram) to adult female rats resulted in an increase in the liver and kidney folate levels, increased urinary excretion of folate and a fall in serum folate while red blood cell folate levels remained unaffected. The tissue folate levels did not indicate adverse effect of OCA on folate economy of the body.

Effect of oral contraceptives on nutrients. III. Vitamins B6, B12, and folic acid.

The interactions of oral contraceptive agents (OCA's) with vitamins were studied in a large population of women. In the upper socioeconomic groups, higher incidences of abnormal clinical signs related to vitamin deficiencies were seen in OCA users than in the control subjects. Plasma pyridoxal phosphate and red cell and serum folate were lower in subjects using OCA's in the upper socioeconomic group as compared to levels in the control subjects. Reduction in erythrocyte glutamic oxalacetic transaminase (EGOT) activity and elevation in the EGOT-stimulation test were observed in subjects using OCA's in both upper and lower socioeconomic groups. These observations suggest a relatively deficient state with respect to vitamins B6 and folic acid in OCA users. No significant effect on serum vitamin B12 was observed as a result of OCA administration.

PIP: The effect of oral contraceptives (OCs) on Vitamins-B6, -B12, and folic acid metabolism was studied in a large population of women. The OCs Norinyl (1 mg norethindrone plus 50 mcg mestranol) and Ovral (.5 mg norgestrel and 50 mcg ethinyl estradiol) were administered for 3 or more months. Higher incidences of abnormal clinical signs related to vitamin deficiency were seen in the upper socioeconomic OC users then in the control subjects. Plasma pyridoxal phosphate and red cell and serum folate were lower in OC users in the upper socioeconomic group as compared with levels in control subjects. A reduction in erythrocyte gl utamic oxalacetic transaminase (EGOT) activity and an elevation in the EGOT-stimulation test were observed in OC users in both upper and lower socioeconomic groups. These results suggest a relatively deficient state with respect to Vitamin-B6 and folic acid in OC users. No marked effects were seen with respect to Vitamin-B12 levels. These data are consistent with the hypothesis that the subjects in lower socioeconomic groups were already marginally deficient in Vitamin-B6 and folic acid and further reduction due to OCs could not be detected.

Effect of oral contraceptive agents on vitamin nutrition status.

Effects of low estrogen combination type oral contraceptives on some of the biochemical parameters used for assessing vitamin nutritional status were investigated in a group of women who had used the pill for 6 to 12 months. Another group of women was examined initially and then at one or more points of time within the first 6 months of treatment. Following changes were observed in women treated with oral contraceptives: 1) increased excretion of kynurenic acid and xanthurenic acid following tryptophan load; 2) increased EGOT activity and also an increase in vitro stimulation of EGOT with added PALP; 3) increased plasma vitamin A levels; 4) fall in erythrocyte folate levels; 5) fall in erythrocyte transketolase activity with no change in vitro stimulation with TPP; and 6) fall in erythrocyte riboflavin concentration associated with a decrease in erythrocyte glutathione reductase activity and increase in vitro stimulation with FAD. Most of these changes were observed during the first few cycles of oral contraceptive treatment.

Effect of oral contraceptive agents on nutrients: II. Vitamins.

Clinical, biochemical and nutritional data were collected from a large population of women using oral contraceptive agents. Higher incidence of abnormal clinical signs related to malnutrition were observed in the lower (B) as compared to the higher (A) socioeconomic groups, and also in the nonsupplemented groups as compared to the supplemented groups in the B subjects. As a rule the intake of oral contraceptive agent subjects of vitamin A, C, B6 and folic acid did not differ from that of the controls As expected, subjects from the supplemented groups had higher intake of vitamin A, C, B6, thiamin, riboflavin and folic acid, and A groups had higher intake of vitamin C, B6, riboflavin and folic acid. Increased plasma vitamin A and decreased carotene levels were observed in oral contraceptive agent users. In general oral contraceptive agents had little or no effect on plasma ascorbic acid. Urinary excretion of both thiamin and riboflavin in subjects using oral contraceptive agents were lower in A groups. Erythrocyte folate and plasma pyridoxal phosphate was decreased in A groups due to oral contraceptive agents. Subjects who took supplements had higher levels of plasma vitamin A, ascorbic acid and folate. But urinary thiamin and riboflavin were higher only in group A subjects who took supplements.

PIP: 18-45 year old women were tested to determine if the use of oral contraceptive agents (OCAs) affects the metabolism of vitamins. 4 different hormonal conditions and 2 socioeconomic levels in 8 groups were considered. Some of each socioeconomic level had taken Norinyl (1 mg norethisterone and 50 mcg mestranol) for 3 months or more. Others had used Ovral (.5 mg norgestrel and 5 mcg ethinyl estradiol) for equal periods. There were some in each group who had resumed use of OCAs during lactation within 5 weeks after pregnancy. Vitamins and mineral supplements were given to groups in each socioeconomic classification. They had a higher intake of Vitamins-A, C, thiamin, riboflavin, and folic acid. Incidence of clinical sings of malnutrition, such as dry skin, easily pluckable hair, angular lesions of the mouth, dental caries, bleeding gums, glossitis, and scaling of the skin, were significantly more frequently observed in the lower socioeconomic groups, and especially in nonsupplemented groups of women taking OCAs than in others. OCA administration increased plasma Vitamin-A levels but no socioeconomic effect was found. Plasma carotene levels were decreased by OCA therapy, but less so in the higher socioeconomic subjects. Plasma ascorbate was not affected by OCA use. Urinary excretion of thiamin annd riboflavin was decreased in subjects using OCAs. Erythrocyte folate and plasma pyridoxal phosphate (PLP) were also decreased. Results show a definite lowering effect of OCAs on red cell folate in subjects in the upper socioeconomic levels. There may also be a depletion of body stores of folic acid. It has been suggested that women who become pregnant soon after discontinuing OCA therapy have a high chance of developing folic acid deficiency during pregnancy. The lower socioeconomic group may be marginally deficient in folic acid. Similar results were obtained with thiamin and riboflavin. Changes due to OCA use with respect to thiamin, riboflavin, folate, and PLP were seen mainly in subjects in the upper lower socioeconomic groups may have prevented detection of smaller similar alterations due to OCA use.

Effect of oral contraceptive agents on nutrients: I. Minerals.

The epidemiological aspects of oral contraceptive agents on nutrient metabolism were studied in a large population of women. Incidence of clinical abnormalities, related to malnutrition, were more frequently observed in the lower (B) as compared to the higher (A) socioeconomic groups. In the A groups some clinical signs were more common in the nonsupplemented groups of subjects. In general, the intake of oral contraceptive agent subjects for calories, protein, calcium, magnesium, iron, copper and zinc did not differ from the controls. The intake of the above nutrients in group A subjects were higher than those of group B except for calories. The subjects who took supplements had higher intakes of calcium, iron, magnesium and copper. No effect of oral contraceptive agents was seen on hemoglobin, hematocrit and erythrocyte count. Serum iron was increased due to "Norinyl." Total iron binding capacity was increased as a result of oral contraceptive agent administration. Total iron binding capacity values were higher in group B as compared to group A and in the nonsupplemented as compared to the supplemented groups. Plasma copper was increased and plasma zinc was decreased as a result of oral contraceptive agent administration. An increase in erythrocyte zinc was observed due to "Norinyl." No effect of oral contraceptive agents on plasma calcium, magnesium and erythrocyte magnesium was observed. Although no effect of oral contraceptive agents on plasma total protein was found, serum albumin was decreased.