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PubMed1991

Cell surface-binding sites for progesterone mediate calcium uptake in human sperm.

Recent studies (e.g. Blackmore, P. F., Beebe, S. J., Danforth, D. R., and Alexander, N.) (1990) J. Biol. Chem. 265, 1376-1380) have shown that in human sperm, progesterone produces a rapid increase in intracellular free calcium ([Ca2+]i) and an induction of the acrosome reaction (e.g. Osman, R. A., Andria, M. L., Jones, A. D., and Meizel, S. (1989) Biochem, Biophys. Res. Commun. 160, 828-833). In this study, the location of progesterone receptors on the cell surface of human sperm was identified using progesterone immobilized on bovine serum albumin (BSA) (progesterone 3-(O-carboxymethyl)oxime:BSA) as well as progesterone and its 3-O-carboxymethyloxime derivative. Using fluorescence microscopy, BSA-fluorescein isothiocyanate was shown to be excluded from intact sperm, thus validating the use of progesterone 3-(O-carboxymethyl)oxime:BSA to identify cell surface-binding sites for progesterone. The immobilized progesterone and the 3-O-carboxymethyloxime derivative rapidly increased [Ca2+]i and were full agonists, although they were approximately 1.5 orders of magnitude less potent than progesterone. They also displayed an identical time course to increase [Ca2+]i as free progesterone, and the entire increase in [Ca2+]i was due to the influx of Ca2+. This progesterone-mediated response displayed different steroid receptor characteristics since the very potent inhibitors of genomic progesterone responses, RU38486 and ZK98.299, were very ineffective at inhibiting the progesterone-mediated increase in [Ca2+]i. Also the synthetic progestins megestrol, medroxyprogesterone acetate, norgestrel, norethynodrel, norethindrone, R5020, and cyproterone acetate did not mimic the effects of progesterone to increase [Ca2+]i. It is proposed that a distinct nongenomic cell surface receptor for progesterone exists in human sperm.

Calcium↗

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↗

PubMedDate not supplied

Hormone prevention of mammary carcinogenesis: a new approach in anticancer research.

The observation that chemically induced breast cancer is prevented when the mammary gland is completely differentiated by a full term pregnancy prior to exposure to a carcinogen, led us to test the hypothesis that synthetic ovarian hormones commonly used for the purpose of contraception might drive mammary gland differentiation enough to be protective from carcinogen--induced neoplastic transformation. This hypothesis was only partially proven, due to the unexpected finding that a high dose of the progestagenic agent medroxyprogesterone acetate (MPA), increased tumor incidence, whereas a similar dose of the mostly estrogenic norethynodrel--mestranol (NM) was protective. An additional finding was the fact that these two agents exerted a different action on thoracic than on abdominal mammary glands. MPA inhibited differentiation of TEBs in the former, but stimulated lobule development in the latter. This difference in response seemed to be associated to the asynchronous development of the mammary glands located in different topographic regions. These observations indicated that the response of the mammary gland epithelium with either differentiation or cell proliferation is in great part modulated by the condition of the target organ. Although the concept of hormone prevention of breast cancer promises to be an achievable goal, there are still basic fundamental questions that need to be answered. First, how do estrogens and progesterone act on the mammary epithelium, second, what is the sequence in which they act on the mammary gland in order to induce differentiation of the organ, third, why the same homonal milieu in a single animal results in asynchronous development of glands located in thoracic versus those in the abdominal region.

9,10-Dimethyl-1,2-benzanthracene↗

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↗

PubMed1988

Quantitative structure-activity studies on effects of sixteen different steroids on growth and monooxygenases of rat liver.

Sixteen steroids with different endocrine activities were administered to female rats for 6 or 7 days, in a broad range of doses. Liver growth was recorded by measuring weight and DNA contents and monooxygenase activity by assaying the turnover of five different substrates. According to their effects on these parameters steroids were assigned into one of the following three groups: (a) Estrogens estradiol and ethinylestradiol, as well as the progestins norethynodrel and norethisterone (norethindrone) which have estrogenic activity in rats. These agents induced pronounced liver growth and excessive DNA increase which was not associated with major monooxygenase induction. (b) A different type of response consisted of liver growth and DNA increase associated with a pronounced induction of monooxygenase(s) in a characteristic pattern. This response was elicited by pregnenolone-16 alpha-carbonitril, by progestins progesterone, cyproterone acetate, and medroxyprogesterone (but not gestoden and levonorgestrel), by the antimineralocorticoid spironolactone and by the glucocorticoids cortisol and dexamethasone. Apparently, this response pattern was not related to any specific endocrine action but to certain structural features, in particular to the presence of a saturated, at least two-membered alkyl substituent at C17 of the steroid ring system. (c) No or small effects were observed after gestoden, levonorgestrel and the androgens testosterone and methyltestosterone. Dose-response stuides revealed that estrogens estradiol and EE2 induced hepatic effects more potently by four orders of magnitude than progestins. The response patterns observed may be relevant to the tumor-promoting activity of some of the steroids tested.

Animals↗

PubMed1995

[Positive and negative effects of progestins on platelet-activating factor acetylhydrolase activity in rat plasma].

Platelet-activating factor acetylhydrolase (PAF-AH), the enzyme that inactivates PAF, is regulated by steroid hormones including progestin. It has been reported that 17 alpha-ethynylestradiol decreases plasma PAF-AH activity and medroxyprogesterone increases the enzyme activity. In this study, we elucidated the effects of various progestins on plasma PAF-AH activity and lipoprotein cholesterol levels. Plasma PAF-AH activity in female adult rats treated with either progesterone or 17 alpha-hydroxyprogesterone (50mg/kg, 3 days) did not change significantly. Both medroxyprogesterone and megestrol acetate (50mg/kg, 3 days) significantly increased plasma PAF-AH activity, but both norethindrone acetate and norethynodrel (50mg/kg, 3 days) significantly decreased the enzyme activity. In addition, not only did medroxyprogesterone increase plasma PAF-AH activity but plasma lipoprotein cholesterol and norethindrone acetate decreased both of them. A significant correlation between plasma PAF-AH activity and the lipoprotein level was found (r = 0.974, p < 0.01). When PAF (10nmol/kg) was administered to female adult rats pretreated with progestins, the mortality of the rats that had low plasma PAF-AH activity due to norethindrone acetate was increased in the same manner as observed in the 17 alpha-ethynylestradiol-pretreated group. These findings indicate that progestins have various effects on plasma PAF-AH activity and the lipoprotein level. In addition, some progestins, which have an estrogenic effect on enzyme activity, may be related to the thrombotic episodes observed in oral contraceptive users.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗

PubMed1996

Unusual steroid specificity of the cell surface progesterone receptor on human sperm.

The steroid specificity of the cell surface progesterone receptor in human sperm was examined with the use of progesterone, testosterone, and androstane analogues. Many compounds were shown to be more effective than progesterone at increasing intracellular free calcium concentration, e.g., 2 alpha-methyl-17beta-methoxy-5 alpha-androstan-3-one. Several testosterone analogues were demonstrated to be antagonists of progesterone, e.g., 9(11)-dehydro-2 alpha,17alpha-dimethyltestosterone. The synthetic potent progestigens, norethynodrel, cyproterone acetate, norethindrone, and megestrol acetate, were found to be only weak stimulators of the sperm cell surface receptor. Furthermore, these compounds were shown to antagonize the effect of progesterone to elevate intracellular free calcium concentration in sperm. It is known that progesterone and some of its analogues bind to the intracellular progesterone nuclear receptor via the alpha-face of the steroid molecule. In stark contrast, it was concluded from the analysis of the steroid analogues examined on human sperm in this study that intimate contact exists between the effective progesterone analogues and the sperm cell surface progesterone receptor across the beta-face of the steroid C/D-ring "upper" edge (C11, C12, and C17). Positioning of the C21 methyl group is also critical for efficacy, and recognition of the steroid A-ring seems not to be involved.

Dose-Response Relationship, Drug↗

PubMed1976

The effect of steroid contraceptives on the concentrations of brain monoamines in rats and mice.

The effect of three estrogen-progestin combinations on biogenic amines in discrete brain areas of rats and mice has been investigated. With the exception of a significant decrease of brain 5-hydroxyindolacetic acid in the rats treated for 30 days with the combination norethynodrel + mestranol, no significant changes in the levels of serotonin, noradrenaline or dopamine in the rat brain were found following the administration of the compounds under study. On the other hand, in mice moderate but significant changes in the levels of serotonin, dopamine, noradrenaline and 5-hydroxyindolacetic acid were found in various brain areas depending on the estrogen-progestin combination used. The potential importance of these effects for the contraceptive as well as for some central actions of these compounds is discussed.

Amines↗

PubMed1972