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PubMed1985

Relative potency of progestins used in oral contraceptives.

Epidemiologic studies indicate that the risk of complications with oral contraceptive use is related to the steroid content and potency of the various formulations. This paper summarizes human data in which potencies of progestins in oral contraceptives can be compared. Data on delay of menses and endometrial subnuclear vacuolization, an indirect assessment of glycogen deposition, are presented. The relative effects of various progestins on serum lipids and lipoproteins are also summarized. The object of this review is to examine the available scientific evidence which generally supports the conclusion that there is a marked similarity of potency of the dose of various progestins used in many of the formulations currently available in the U.S. The progestins norethindrone, norethindrone acetate and ethynodiol diacetate are roughly equivalent in potency while norgestrel is roughly five to ten times and levonorgestrel ten to 20 times as potent.

Contraceptives, Oral, Combined↗

PubMed1990

Metabolism of levonorgestrel, norethindrone, and structurally related contraceptive steroids.

There is limited information on the metabolism of levonorgestrel, norethindrone and structurally related contraceptive steroids. Both levonorgestrel and norethindrone undergo extensive reduction of the alpha, beta-unsaturated ketone in ring A. Levonorgestrel also undergoes hydroxylation at carbons 2 and 16. The metabolites of both compounds circulate predominantly as sulfates. In urine, levonorgestrel metabolites are found primarily in the glucuronide form, whereas norethindrone metabolites are present in approximately equal amounts as sulfates and glucuronides. Of the progestogens structurally related to norethindrone, norethindrone acetate, ethynodiol diacetate, norethindrone enanthate, and perhaps lynestrenol, undergo rapid hydrolysis and are converted to the parent compound and its metabolites. There is no convincing evidence that norethynodrel is converted to norethindrone. Of the progestogens structurally related to levonorgestrel, it appears that neither desogestrel nor gestodene are transformed to the parent compound. However, there is evidence that norgestimate can be, at least partly, converted to levonorgestrel. Further studies on the metabolism of these progestogens are required before we can understand their mechanism of action.

Animals↗

PubMed1981

Mutagenicity of some contraceptive drugs in Drosophila melanogaster.

Combinations of 3 progestins, ethynodiol diacetate, norethynodrel and norgestrel, and 2 oestrogens, ethinyloestradiol and mestranol, were fed to larval Oregon-R fruit flies. None of the steroids studied induced X-linked recessive lethal mutations above the control level in Drosophila melanogaster.

Animals↗

PubMed1983

Analytical methods based on transformations with hydrochloric acid.

Ultraviolet spectrophotometric methods are described for alpha-ethyl benzhydrol derivatives, 3-trifluoromethyl-alpha-ethyl benzhydrol (flumecinol), 2,5-dimethyl-alpha-ethyl benzhydrol (RGH-3395) an impurity of the latter, (1,4-di-(2,5-dimethyl-phenyl)-1,4-diphenyl-butan-1,4-diol). The methods are based on dehydrations catalysed by hydrochloric acid yielding unsaturated aromatic chromophores. The determination of 2-acetyl-3-phenyl-tetrahydro-1,2,4-oxadiazin-5-one (RGH-4615) is also based on treatment with hydrochloric acid; the chromophoric compound is a benzaldoxime derivative. The hydrochloric acid-catalysed transformation of ethynodiol diacetate to its 3,5-diene derivative enables the parent compound to be determined by gas chromatography.

Journal Article↗

PubMedDate not supplied

Estimation of impurity profiles in drugs and related materials. Part 11--The role of chromatographic and spectroscopic methods in the estimation of side-reactions in drug syntheses.

Impurities in drugs are classified on the basis of the types of side-reactions in drug syntheses resulting in their formation. This is shown by summarizing the authors' earlier results in the field of impurity profiling of 19-nor-steroids, ethynodiol diacetate, mazipredone, pipecuronium bromide, flumecinol, enalapril, pyridinol carbamate, phenylbutazone, thymotrinan and some new results related to danazol and famotidine.

Chemistry, Pharmaceutical↗

PubMed1987

Effects of female sex steroids on concanavalin A-mediated agglutination of hepatocytes from nonregenerating and regenerating rat liver and hepatic tumor marker enzymes.

Effect of treatment of female rats with an oral contraceptive agent (OCA), Ovulen-50, for 7 weeks on agglutination of hepatocytes with concanavalin A (con A) and activities of certain tumor marker enzymes were examined to find out if OCA treatment is related to preneoplastic or neoplastic processes. Hepatocytes from regenerating and nonregenerating livers of control female rats showed negligible agglutination with Con A, whereas hepatocytes from non regenerating but not from the regenerating livers of female rats treated with a combination of 5 micrograms ethinyl estradiol and 100 micrograms ethynodiol diacetate showed agglutination. Of the tumor marker enzymes such as hepatic glucose 6-phosphatase, gamma-glutamyl transpeptidase (gamma-GT), and arginase examined in the liver, only gamma-glutamyl transpeptidase showed a significant increase in activity in the steroid-treated rats. Plasma alkaline phosphatase activity was also higher in the treated animals. However, the magnitude of the changes observed was relatively small and perhaps unrelated to the neoplastic process.

Animals↗

PubMed1995

The androgenicity of progestins.

All steroid hormones are structurally similar, but relatively minor differences cause profound alterations in biochemical activity. The 21-carbon series (pregnane nucleus) includes the corticoids and the true progestins (e.g., medroxyprogesterone acetate). The 19-carbon series (androstane nucleus) includes all the androgens, among them the progestins used in most oral and parenteral contraceptives. The removal of carbon 19 from testosterone changes the major hormonal effect from androgenic to progestogenic, but these "19-nor" steroids retain varying degrees of androgenic activity. (They can also have limited estrogenic activity, but this is insignificant at the low doses used for contraception.) Some of the 19-nortestosterone progestins are metabolized to other compounds (e.g., norethynodrel, ethynodiol diacetate, and lynestrenol to norethindrone), and some (levonorgestrel, desogestrel) are active unchanged. The lingering androgenic effects of 19-nor progestins are dose-related, opposed by estrogen, and are manifested metabolically (e.g., glucose tolerance, lipoprotein synthesis) and symptomatically (e.g., acne, weight gain). The effect of 19-nortestosterones on lipoproteins prompted the development of less androgenic compounds, but the obvious benefit of the new progestins (desogestrel, gestodene, norgestimate) is a reduction in the symptoms associated with the androgenicity of the older compounds. Mitigation of androgenic effects on lipoprotein and carbohydrate metabolism could have long-term benefits, especially for women who are at risk of arteriosclerotic vascular disease; however, these effects remain to be epidemiologically demonstrated.

Androgens↗

PubMed1982

Carbohydrate metabolism during treatment with estrogen, progestogen, and low-dose oral contraceptives.

The combination oral contraceptives have generally been shown to have an adverse effect on carbohydrate metabolism with resultant elevations of both blood glucose and insulin in users. Studies of the individual steroid components suggest that the estrogen is not at fault. The 19-norprogestins can produce these carbohydrate changes and seen to act at the insulin receptor level. Norgestrel, ethynodiol diacetate, and norethindrone alter carbohydrate metabolism, but norgestrel produces the most marked changes. Use of oral contraceptives containing less than 50 microgram of estrogen resulted in fewer metabolic changes than were seen with the drugs containing higher doses of estrogen.

Blood Glucose↗

PubMed2000

Determination of steroid sex hormones and related synthetic compounds considered as endocrine disrupters in water by liquid chromatography-diode array detection-mass spectrometry.

In this study, a procedure for the determination of various naturally occurring hormones and of some related synthetic chemicals, commonly used for birth control and treatment of certain hormonal disorders and cancers, in water is described. The procedure includes solid-phase extraction of 0.5 l of water and subsequent analysis of the extract by liquid chromatography with diode array detection and mass spectrometric detection in series (LC-DAD-MS). DAD has been performed at 197, 225, and 242 nm for quantification and confirmatory identification purposes. For MS detection two interfaces--electrospray and atmospheric pressure chemical ionization--in both the positive and the negative ion mode have been tested and the MS parameters influencing the MS signal optimized. DAD and MS have been intercompared for selectivity, sensitivity, precision, and linearity of response. Selected conditions have been applied to the determination of six estrogens (17beta-estradiol, estriol, estrone, ethynylestradiol, mestranol, and diethylstilbestrol) and four progestogens (progesterone, levonorgestrel, norethindrone and ethynodiol diacetate) in several types of water bodies, including sewage influents and effluents, surface water and drinking water. Recoveries greater than 83% and detection limits in the ng/l range have been achieved for most compounds.

Chromatography, Liquid↗

PubMed2000

Cleaning validation procedure eased by using overpressured layer chromatography.

In the manufacturing plants of many pharmaceutical companies the reaction apparatus is suitable to produce different active pharmaceutical ingredients. After completing the production of a compound the equipment should be cleaned in order to avoid the cross contamination in the next lot of the other products. In the authors' laboratory several chromatographic methods were introduced to measure the amount of the residual substances remaining on the surface of the apparatus after the cleaning procedure. A sensitive and fairly rapid overpressured layer chromatographic (OPLC) procedure--suitable to separate and control five steroid hormone compounds (allylestrenol, estradiol, ethynodiol diacetate, levonorgestel, norethisterone) produced in the same equipment at different times--was developed and validated.

Chromatography, Liquid↗

PubMed1975

Contraceptive steroid binding to the human uterine progesterone-receptor.

Using an equilibrium dialysis method, the competition was investigated between tritated-progesterone and a range of synthetic steroids for binding to 20,000 g. supernatants of human uterine endometrium and myometrium. Both types of uterine tissue showed similar patterns of progestogen binding and probably contain similar, or even identical, progesterone receptors. The gonane progestogen norgestrel binds strongly to the uterine receptors, but only the d-isomer is active. All three pregnane progestogens used in this study (chlormadinone acetate, medroxprogesterone acetate, megestrol acetate) also showed significant binding to receptors, but for the estrane progestogens, norethisterone was the only compound to show a high binding capacity. Other estranes (ethynodiol diacetate, lynestrenol, norethisterone acetate, norethynodrel) showed insignificant binding to the receptors and probably require prior metabolic activation to norethisterone before they can induce progestogenic effects.

Binding, Competitive↗

PubMed1995

Leuprolide and estrogen versus oral contraceptive pills for the treatment of hirsutism: a prospective randomized study.

The administration of long-acting GnRH analogs (GnRH-a) results in gonadotropin and androgen suppression in hyperandrogenic women. Nonetheless, no randomized studies are available comparing GnRH-a with currently used treatments for hirsutism. We have hypothesized that the greater degrees of androgen suppression achieved with GnRH-a therapy could result in a more rapid improvement in hirsutism compared to oral contraceptive (OCP) administration. To test this hypothesis, we studied 17 hirsute women before and during 6 months of randomized treatment with 1) leuprolide depot (3.75 mg/month) plus conjugated estrogen (0.625 mg/day) and medroxyprogesterone acetate (10 mg; days 1-12; n = 9; leuprolide+ERT), or 2) an OCP containing ethynodiol diacetate (1 mg) and ethinyl estradiol (35 micrograms; n = 8). LH, FSH, estradiol, dehydroepiandrosterone sulfate, androstenedione (A4), sex steroid-binding globulin, and total and free testosterone (T) were measured at weeks 0, 2, 4, 8, 12, and 28. At 0 and 28 weeks of treatment, hirsutism was evaluated subjectively by patient self-evaluation and by the Ferriman-Gallwey score, and objectively by determination of facial hair density, outer hair shaft diameter, and growth rate, determined both photographically and in plucked hairs. In the leuprolide+ERT, but not OCP, groups, there was a significant decrease in the circulating LH and FSH levels. In both groups, T and A4 decreased with treatment, although the decrease in A4 levels did not reach significance in OCP-treated women. The circulating sex steroid-binding globulin level increased in both treatment groups, but the changes in the OCP-treated women was greater. Consequently, although the calculated percent free T decreased significantly in both treatment groups, the decrease was greater in the OCP-treated women. The dehydroepiandrosterone sulfate level did not change with either therapy. A significant percent decrease in the Ferriman-Gallwey score was noted in the leuprolide+ERT, but not OCP, patients, and by self-evaluation, seven (78%) and five (55%) of leuprolide+ERT patients, compared to two (25%) and two (25%) OCP-treated women, noted an improvement in hair growth and texture, respectively. No significant difference in mean facial hair density or outer hair diameter was noted with either therapy. Patients treated with leuprolide+ERT demonstrated a decrease in the actual hair growth rate, using the photographic method, or percent decrease in growth rate, using plucked hair. In conclusion, treatment with leuprolide plus cyclic estrogen/progestin appears to provide a more rapid, and possibly greater, improvement in hirsutism, compared to a standard OCP regimen.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1979

Interaction of synthetic progestagens with renal mineralocorticoid receptors.

Progesterone increases urinary sodium excretion at least in part by competition for renal mineralocorticoid receptors. In contrast, synthetic progestagens do not increase sodium excretion or even cause a slight sodium retention. We therefore compared the ability of progesterone and 12 progesterone like compounds to displace [3H]aldosterone from binding at cytoplasmic mineralocorticoid receptors in rat kidney. All synthetic progesteronelike steroids were less active than progesterone in competing with [3H]aldosterone for the receptor binding: progesterone 100%, 11 beta-OH progesterone 50%, 17 alpha OH-progesterone 24% and 16 alpha-methyl-progesterone 3%. Derivates of 17 alpha OH-progesterone (medrogestone 5%, dydrogestone 4%, medroxy progesterone-acetate 2% and chlormadinone-acetate 0.5%) were more potent than 19-nor-testosterone derivates: ethisterone 1%, norethisterone less than 1%, norethindrone less than 1%, norethyl-nodrel less than 1%, and ethynodiol-diacetate less than 1%. The decreased affinity of synthetic progestins for mineralocorticoid receptors explains in part the lack of natriuretic activity of these compounds.

Aldosterone↗

PubMed1976

Steroid effects on human endometrial glycoprotein biosynthesis.

Human endometrium from the secretory phase of the menstrual cycle was incubated with 3H- and 14C-labelled glucosamine and [3H]leucine. Incorporation into secreted extracellular glycoprotein and accumulation of the label into the microsomal fraction were measured. When oestradiol or progesterone were added to the medium, medroxyprogesterone acetate (MPA), ethynodiol diacetate and chlormadinone acetate reduced incorporation of glucosamine and MPA reduced incorporation of leucine into glycoprotein. MPA reduced the amount of glucosamine in the microsomal fraction and also had an effect on amino acid transport within the endometrial cells, as indicated by intracellular alpha-aminoisobutyric acid space measurements. These results and the ratios of 3H and 14C in the microsomal fraction and secreted protein suggest that MPA has a primary effect in decreasing amino sugar incorporation and a secondary effect in reducing amino acid incorporation into glycoprotein.

Amino Acids↗

PubMed1986

Progestins and carbohydrate metabolism.

The effect of hormonal oral contraceptives (OCs) on carbohydrate metabolism depends on the amount of estrogen (ethinyl estradiol or mestranol), type and amount of progestin, formulation of the pill (monophasic, sequential, or triphasic), duration of use, mode of administration (oral v parenteral), and race and genetic predisposition of the user. The progestin megestrol has minimal effect on carbohydrate metabolism but is no longer available due to its carcinogenic effects in beagle dogs. Combination pills with norethindrone and its derivatives (norethindrone acetate, norethynodrel, and ethynodiol diacetate) show moderate impairment of glucose tolerance with definite hyperinsulinemia. The lowest metabolic effect was observed with triphasic formulations. The effect of levonorgestrel depends on the formulation; the highest impairment of glucose and insulin response after oral glucose loading is found in sequential and combined formulations with doses of 50 micrograms ethinyl estradiol, whereas with doses of 30 micrograms ethinyl estradiol only minor effects on glucose tolerance are seen. Few effects were observed while using triphasic preparations. Therefore, to minimize disturbances of carbohydrate metabolism, low-dose formulations and triphasic preparations should be used.

Carbohydrate Metabolism↗

PubMed1987

[Progestagens in contraception].

The different spectrum of biological actions of the various synthetic progestogens is compared on the basis of their chemical structure, pharmacokinetics and interaction with the multiple receptors. In detail, the mechanism of action of the progesterone derivatives (medroxyprogesterone acetate, chlormadinone acetate and cyproterone acetate), the norethisterone-related (norethisterone, ethynodiol diacetate, lynestrenol and norethynodrel) and the norgestrel-related progestogens (levonorgestrel, desogestrel, gestodene and norgestimate), and a possible influence of some metabolites upon the biological profile are discussed. With regard to the progestogenic activity, the time-course of the serum concentrations of the steroids after the application (pharmacokinetics) which is dependent upon absorption, metabolization in the gastro-intestinal tract and liver (first-pass effect), distribution and storage in fat and other tissues, binding to serum proteins, inactivation, and conjugation, is of particular importance. The various side-effects of the progestogens are mainly based on their influence upon hepatic metabolism (lipids, lipoproteins, serum proteins) and upon other organs which is dependent on their different estrogenic, antiestrogenic, androgenic, antiandrogenic, glucocorticoid and antimineralocorticoid actions.

Contraceptives, Oral, Synthetic↗

PubMed1978

Plasminogen activator levels in plasma and urine during exercise and oral contraceptive use.

The effect of Demulen (ethinyl estradiol 0.05 mg and ethynodiol diacetate 1 mg) and exercise on the level of plasminogen activators was studied in 25 women (12 controls and 13 contraceptive users). Plasma plasminogen activator level was increased by the use of the oral contraceptive and further increased by exercise. Urine plasminogen activator level was unchanged by the use of Demulen but, in both groups of subjects, was decreased by exercise.

Blood Coagulation↗

PubMed1978

The effect of ovarian sex steroids on bone mineral status in the oöphorectomized rat and in the human.

The effect of oöphorectomy and hormone replacement therapy after oöphorectomy on bone mineral in the femur and vertebra of the rat has been studied. Oöphorectomy resulted in osteoporosis of the femur but not of the seventh caudal vertebra. The administration of a progestogen (ethynodiol diacetate 9 microgram/day) apparently prevented loss of bone mineral content of the femur. This was due to increased periosteal bone formation and widening of the femur. An oestrogen (mestranol 0.9 microgram/day) had no significant effect on the femoral osteoporosis but increased bone mineral content of the vertebra. Combined therapy with oestrogen and progestogen had no effect on any parameter of bone mineral content. The preliminary human study indicated that a progestogen may also be as effective as an oestrogen in prevention of post-menopausal bone loss. There was no evidence of reduction of bone resorption (as indicated by urinary hydroxyproline output) by the progestogen and therefore it is postulated that a progestogen might retard bone loss in the post-menopausal era by stimulating bone formation.

Animals↗