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PubMed1990

Progestational and androgenic receptor binding affinities and in vivo activities of norgestimate and other progestins.

The progestational and androgenic in vitro receptor binding affinity and the in vivo activity of norgestimate was compared with that of its metabolites and other progestins. The relative binding affinities (RBAs) of norgestimate and its 17-deacetylated metabolite for rabbit uterine progestin receptors were similar to that of progesterone (P); those of 3-keto norgestimate and levonorgestrel were about five times that of P; those of gestodene and 3-keto desogestrel were about nine times that of P. The RBAs of norgestimate, P, and 3-keto norgestimate for rat prostatic androgen receptors were from 0.003 to 0.025 times that of dihydrotestosterone (DHT); those of 3-keto desogestrel, gestodene, and levonorgestrel were from 0.118 to 0.220 times that of DHT. The order of receptor level selectivity represented by the ratio of androgen:progestin IC50 values (with a greater ratio value reflecting a better selectivity) was norgestimate greater than P = 3-keto norgestimate greater than 17-deacetylated norgestimate greater than 3-keto desogestrel greater than gestodene greater than levonorgestrel. In vivo studies demonstrated similar profiles for norgestimate and its 17-deacetylated metabolite. These latter two steroids were equally potent as progestins in stimulating rabbit endometrium, and compared with the other progestins, both steroids exhibited minimal androgenicity as measured by the stimulation of rat prostate growth. In conclusion, these studies, as well as previous preclinical and clinical studies, provide evidence of the selectivity of norgestimate based on minimal androgenicity, indicating an improvement over other progestins used in oral contraceptives.

Animals↗

PubMed1984

The relative effectiveness of progestins for facilitation and inhibition of sexual receptivity in hamsters.

In a series of experiments, we studied the biphasic actions of 4 progestins on sexual receptivity in female hamsters. Based on previous reports, we selected doses of progesterone (P), desoxycorticosterone acetate (DOCA), 5-alpha-dihydroprogesterone (DHP) and 20-alpha-hydroxyprogesterone (20-OHP) that were expected to have initial facilitative and/or subsequent inhibitory actions on sexual receptivity. Estrogen-primed ovariectomized female hamsters were given one of 4 doses of a progestin at hour 44 post EB, and were tested for facilitation (with tape over their vaginas to prevent intromissions) 4 hours later. At hour 68, all animals received 500 micrograms P and were tested for the inhibitory effects of the test progestin 4 hours later. In additional experiments, similar procedures were followed with an alternate vehicle (1% Tween-80 instead of sesame oil) and a longer initial progestin-to-facilitation test interval (8 rather than 4 hours) in attempts to improve bioavailability of the steroids. P and DOCA were clearly the most behaviorally effective progestins tested, and they were equally potent for facilitation and inhibition in an oil vehicle at the 4 hour interval. DHP given in oil caused some inhibition but no facilitation. 20-OHP had no behavioral effects at the doses tested. The results are discussed in light of previous results with these steroids in hamsters and other rodent species. Also, the differing patterns of effectiveness across conditions provide some, although qualified, support for our view that the biphasic actions of progestins may be controlled by separate mechanisms. However, an alternate explanation is also discussed.

20-alpha-Dihydroprogesterone↗

PubMed1992

External calcium dependence of the uterine contraction induced by prostaglandins E2 and F2 alpha and its antagonism with natural progestins.

Prostaglandins (PGs) E2 and F2 alpha are strong inducers of uterine contraction by promoting a Ca2+ increase into the cell through specific receptors coupled with the calcium channels. On the contrary, progesterone and 5 beta-reduced progestins promote smooth muscle relaxation by blocking the ion calcium influx. Thus, this study was designed to emphasize the importance of external calcium in the PGs-induced rat uterus contraction. Likewise, also studied was the antagonism and the interaction between PGs and progestins (progesterone and its 5 alpha and 5 beta-reduced derivatives) in the myometrium. Results showed that uterine contraction induced by PGs depends on external calcium, since verapamil or extracellular calcium depletion abolished the PGs effect. Regarding the PGs-progestins antagonism, it was observed that pregnanedione, pregnanolone and epipregnanolone were quite effective for counteracting of PGs-induced contraction. However, progesterone was effective in a middle range, whereas 5 alpha-reduced progestins (allopregnanedione and allopregnanolone) were almost ineffective. It has been concluded that the participation of PGs and progestins in the modulation of uterine contraction might be achieved through the control of calcium influx by opening (PGs) or blocking (progestins) receptor-operated calcium channels.

Animals↗

PubMed1987

Progestin stimulation of lactate dehydrogenase in the human breast cancer cell line T-47D.

We have previously reported that physiological levels of progestins alone stimulate lactate dehydrogenase in a dose-responsive manner in the progesterone-receptor-rich human breast cancer cell line T-47D. Using isozyme electrophoresis, we have not found that lactate dehydrogenase isozyme 5 is the only isozyme detectable in these cells, as has been reported for other human breast cancer cells in long-term tissue culture. Upon treatment with progestins, isozyme 5 remains the only isozyme detectable. T-47D cells were plated in charcoal-stripped serum-containing medium and grown for 2 days before treatment with progestin. Lactate dehydrogenase stimulation then plateaued after around 2-3 days of treatment with progestin and was maintained until around day 5, following which a decline in enzyme activity occurred. The effect is specific for progestins, and inhibited by the anti-progestin RU-38486 (17 beta-hydroxy-11 beta-(4-dimethyl-aminophenyl-1)-17 alpha-(prop-1-ynil)-estra-4,9-dien-3-one). Experiments using actinomycin D and cycloheximide suggests that the effect is dependent on RNA and protein synthesis, respectively. Lactate dehydrogenase stimulation occurs regardless of the presence of the estrogenic pH indicator Phenol red, and of whether it was analyzed per mg DNA or per mg protein.

Breast Neoplasms↗

PubMed1987

Differences in the association of the progesterone receptor ligated by antiprogestin RU38486 or progestin ORG 2058 to chromatin components.

We assessed the hypothesis that due to variations in the conformation of the progesterone receptor induced by the antiprogestin RU38486 compared to the progestin ORG 2058, differences may result in the association of the receptor with some of the chromatin components. The physical properties of the receptor-bound chromatin fragments released by micrococcal nuclease digestion were characterized by sucrose gradient sedimentation and by gel filtration on Agarose A-1.5m or Agarose A-5m columns. The nuclear fraction was isolated from T47D cells previously exposed to 0.1 microM [3H]RU38486 or 0.1 microM [3H]ORG 2058. Micrococcal nuclease digestion solubilized two receptor forms sedimenting at 4.4 S and 6.3 S for the antiprogestin bound receptor and only one receptor at 4.4 S for the progestin ligated receptor. High-salt buffer dissociated either the antiprogestin or the progestin-bound receptor to smaller receptor forms sedimenting at 3.5 S. Chemical cross-linking with the cross-linker 2-iminothiolane of the micrococcal nuclease solubilized receptor forms resulted in 6.7-S and 4.4-S forms sedimenting on 0.4 M KCl gradients for the antiprogestin and progestin ligated receptors, respectively. Stokes radii of 7.3 nm and 6.4 nm were determined by gel filtration in 0.4 M KCl for the 6.7-S and the 4.4-S receptor forms, respectively. Using the sedimentation coefficient and the Stokes radius, molecular weights of 202,000 and 116,000 were calculated for the antiprogestin and progestin ligated receptors. We conclude that the micrococcal nuclease solubilized antiprogestin ligated receptor is associated with additional or different chromatin components compared to the progestin bound receptor.

Cell Line↗

PubMed2005

Estrogens and progestins: background and history, trends in use, and guidelines and regimens approved by the US Food and Drug Administration.

The US Food and Drug Administration (FDA) approved marketing of diethylstilbestrol in 1941 and conjugated equine estrogens (CEE) in 1942 for treatment of menopausal symptoms. Estrogen sales doubled and tripled in the mid-1960s to mid-1970s, until 1975, when reports of increased endometrial cancer in estrogen users resulted in a dramatic decline. Estrogen use increased again, with evidence of protective effects of progestins on estrogen-induced endometrial changes, combined with a 1982 report that Premarin (conjugated estrogen tablets; Wyeth Pharmaceuticals, Philadelphia, PA) retained bone mass and a 1984 National Institutes of Health (NIH) Consensus Conference on Osteoporosis statement that estrogens were the most effective means for preventing bone loss. Despite conflicting reports in 1985 regarding the relation between estrogens and coronary heart disease (CHD), many published observations of reduced CHD risk in estrogen users--reinforced by clinical trial findings in 1995 of favorable lipoprotein changes in women assigned to CEE with or without a progestin--promoted increased use through the 1990s. By 2001, approximately 15 million US women were using estrogen therapy, with or without progestins. The 2002 Women's Health Initiative (WHI) report of greater harm than benefit of combined CEE plus a progestin resulted in a precipitous decrease in estrogen and progestin use and a serious reevaluation of menopausal hormone therapy, as well as increased interest in alternative approaches to managing menopausal symptoms, including use of "bioidentical" hormones. FDA guidelines regarding treatment indications for vasomotor symptoms, vaginal atrophy, and osteoporosis prevention have resulted in approval of several estrogen (and progestin) formulations, doses, and routes of administration, thereby providing many options for women who seek conventional therapy.

Drug Approval↗

PubMed2006

Progesterone and progestins: effects on brain, allopregnanolone and beta-endorphin.

The increased use of hormonal therapies over the last years has led to improve the knowledge of pharmacological, biochemical and metabolic properties of several progestins and their effects in target tissues, such as the central nervous system. Progesterone and synthetic progestational agents are able to modulate the synthesis and release of several neurotransmitters and neuropeptides in response to specific physiological and pathological stimuli. While these actions may relay on differential activation of progesterone receptor or recruitment of intracellular pathways, some of the differences found between synthetic progestins may depend on the specific conversion to neuroactive steroids, such as the 3-alpha, 5-alpha reduced metabolite, allopregnanolone. This is a potent endogenous steroid that rapidly affects the excitability of neurons and glia cells through direct modulation of the GABA-A receptors activity exerting hypnotic/sedative, anxiolytic, anaesthetic and anticonvulsive properties. Estrogens increase the CNS and serum levels of allopregnanolone and the addition of certain but not all synthetic progestins determines a further increase in allopregnanolone levels, suggesting that the metabolism into this reduced product is related to the chemical structure of progestin molecule used. In addition, depending on specific progestin molecule used, different interaction are found with the estradiol-induced beta-endorphin synthesis and release, showing that diverse progestins have specific and divergent actions on the opiatergic system. These results highlight the concept that natural and synthetic progesterone receptor agonists may systematically induce different biological actions in CNS. This may have far-reaching implications for the clinical effects and related indications of each compound.

Animals↗

PubMed2006

Linkage of progestin and epidermal growth factor signaling: phosphorylation of progesterone receptors mediates transcriptional hypersensitivity and increased ligand-independent breast cancer cell growth.

Progesterone receptor (PR) action is linked to epidermal growth factor (EGF) initiated signaling pathways at multiple levels; mitogen-activated protein kinases (MAPKs) are key mediators of this important cross-talk. Herein, we probed the effects of EGF on PR function and regulation of breast cancer cell growth. EGF stimulated rapid and transient phosphorylation of PR-B Ser294 relative to persistent phosphorylation of this site induced by the synthetic progestin, R5020. EGF induced nuclear translocation and DNA binding of unliganded wild-type, but not mutant PRs containing an Ala at position 294 (S294A). However, EGF alone induced little to no PR-B transcriptional activity; S294A PR-B was transcriptionally impaired. In contrast, pretreatment of cells with EGF (30min) significantly increased the potency and efficacy of wild-type, but not S294A PR transcriptional activity in response to progestin, and enhanced ligand-dependent downregulation of wild-type but not S294A PR. Replacement of Ser294 with aspartic acid (S294D) to mimic phosphorylation at this site decreased receptor stability and, as predicted, heightened progestin-induced transcription relative to wild-type PR-B. RT-PCR demonstrated the Ser294 phosphorylation-dependence of selected PR target genes (TGFalpha and HB-EGF). Surprisingly, PR-B expressing cells growing in soft agar were highly responsive to EGF or progestin, and this was further stimulated by the combination of both hormones. Cells expressing S294A PR exhibited reduced soft agar growth, and were also sensitive to R5020 alone, but failed to respond to EGF. These results suggest that PR Ser294 is an important "sensor" for growth factor inputs that affects PR function and breast cancer cell growth in the absence of progestin or in the presence of low or "sub-threshold" progestin concentrations. PR function likely contributes to breast cancer progression when EGFR family members or their ligands are overexpressed, a condition that predicts low abundance, but highly active and nuclear PR.

Animals↗

PubMed2000

Effects of progestins and relaxin on glycodelin gene expression in human endometrial cells.

OBJECTIVE: Glycodelin is an endometrial protein proposed to play an important role in embryonic implantation. We examined the effects of progestins and relaxin on glycodelin transcription, synthesis, and secretion. STUDY DESIGN: Northern blotting, metabolic labeling, and fluorography were used to assess glycodelin messenger ribonucleic acid and protein synthesis in endometrial tissue and cells. Luciferase reporter constructs transfected into endometrial adenocarcinoma cells (Ishikawa cells) were used to determine whether progestins or relaxin could activate the glycodelin gene promoter. RESULTS: Progestins but not relaxin stimulated glycodelin secretion in primary epithelial cell cultures. A 452-base pair fragment of the glycodelin gene promoter was activated 4.3 +/- 0.7 times normal by 10-nmol/L promegestone; however, addition of relaxin to the same construct repressed progestin-stimulate promoter activation by >30%. CONCLUSION: Glycodelin transcription, synthesis, and secretion by endometrial epithelial cells were stimulated by progestins. However, relaxin failed to stimulate production of this immunomodulatory protein and, in fact, repressed progestin-stimulated activation of the glycodelin gene promoter.

Endometrium↗

PubMed1994

Sex hormone receptor binding, progestin selectivity, and the new oral contraceptives.

The desired biologic effect of progestins used in OCs is progestational activity. Undesired pharmacologic properties such as androgenic activity are not necessary for contraception and increase the potential for adverse effects. A selective progestin has progestational effects at relatively low concentrations or doses and androgenic effects at only relatively high concentrations or doses. The degree to which progestational activity is maximized and androgenic activity is minimized is a measure of a progestin's selectivity. The ratio of its affinity for progesterone receptors to its affinity for androgen receptors is the selectivity index. To minimize the androgenic side effects associated with the older progestins, the doses used in OCs have been reduced over the years. These dose reductions have decreased the potential for undesired androgenic effects but also have negatively affected cycle control. Three new progestins, norgestimate, desogestrel, and gestodene, have relatively greater affinity for progesterone receptors than for androgen receptors when compared with the older agents, permitting a reduction in androgenic side effects without the need for further dose reduction. Preclinical receptor-binding studies and animal pharmacologic studies have documented the higher selectivity indexes of these new progestins. Their higher ratios of progestational to androgenic activity provide the basis for the reduction in androgenic adverse effects observed with their clinical use.

Animals↗

PubMed2000

Estradiol 17beta inhibition of LDL oxidation and endothelial cell cytotoxicity is opposed by progestins to different degrees.

UNLABELLED: Progestins oppose the effects of estrogens in many biological systems, but it is not known if progestins oppose the antioxidant effects of estrogen and to differing degrees. To test these questions, the effects of various sex steroids on LDL oxidation and cytotoxicity were studied in the absence or presence of endothelial cells. Freshly isolated LDL was incubated in the presence of Cu(++) in the absence or presence of cultured bovine aortic endothelial cells in phenol red-free medium and without or with hormones in 0.5% ethanol. The hormones included 17beta-estradiol (E(2)), progesterone (Pg), norgestimate (NGM), levonorgestrel (LNG), and medroxyprogesterone acetate (MPA). LDL oxidation was measured as formation of conjugated dienes, lipid peroxides, and TBARS, and cyotoxicity by tetrazolium salt reduction (MTT reduction). Progestins diminished conjugated diene lag phase, accelerated lipid peroxide and TBARS production in the absence and presence of cells and accelerated cytotoxicity. When E(2) and progestin were incubated with cells at a molar ratio of 1:5, lipid peroxides were reduced from baseline by E(2) alone 31%, E(2)/Pg 29%, E(2)/NGM 16%, E(2)/LNG 9% (all P<0.05 or more) and E(2)/MPA 8% (ns) (E(2) or E(2)E(2)/NGM, E(2)/LNG and E(2)/MPA [P<0.001]; E(2)E(2)/LNG or E(2)/MPA [P<0.05]). MTT reduction followed a similar gradient, greatest with E(2) alone, least with E(2)/MPA. CONCLUSIONS: Progestins promote LDL oxidation and, conjointly, endothelial cell cytotoxicity. Progestins oppose the antioxidant and cytoprotective effects of estrogen when given in combination. MPA and LNG have the strongest prooxidant and cytotoxic effects, which may limit the cardiovascular benefit of estrogen during combined administration in vivo.

Animals↗

PubMed2002

Are some progestins genotoxic liver carcinogens?

Progestins (progestogens) are classified by the International Agency for Research on Cancer (IARC) as possibly carcinogenic to humans. In the last decade evidence has shown that a synthetic drug of this family, cyproterone acetate, is activated to a reactive species by the liver, and forms DNA adducts and elicits DNA repair in hepatocytes from both rats and humans. The response is similar in humans of both genders but markedly higher in female than in male rats. The promutagenic character of DNA lesions is indicated by the increase in liver of female rats of the frequency of micronucleated cells, of mutations, and of enzyme-altered preneoplastic foci. Two other synthetic progestins, chlormadinone acetate and megestrol acetate, and an aldosterone antagonist, potassium canrenoate, share with cyproterone acetate the 17-hydroxy-3-oxopregna-4,6-diene structure. While less extensively studied, results so far obtained indicate that they are capable of inducing genotoxic effects qualitatively similar to those of cyproterone acetate. The majority of progestins have not been systematically tested for genotoxicity and the generally negative responses obtained with the standard battery of genotoxicity tests might be the consequence of the use of inappropriate target cells and/or metabolic activation systems. Cyproterone acetate, is activated by the hepatocytes to reactive species of such short half-life that they react only with the DNA of the cell in which are formed. Therefore, it cannot be excluded a priori that other progestins will not display genotoxic effects when tested adequately. This hypothesis is supported by the knowledge that estrogen-progestin combinations used as oral contraceptives are classified by the IARC as carcinogenic to humans due to the increased risk of hepatocellular carcinoma. This risk should probably be ascribed to the progestin component, since estrogens are carcinogenic to humans due to the increased risk of endometrial and possibly of breast cancer but not liver cancer.

Animals↗

PubMed2003

The effect of progesterone and synthetic progestins on serum- and estradiol-stimulated proliferation of human breast cancer cells.

The results from the Women's Health Initiative study on enhanced breast cancer risk in postmenopausal women using an estrogen/progestin combination clearly indicate the need for a comparison of different progestins with regard to cancer risk. To shed some light on this issue, we have investigated the influence of progesterone and various synthetic C19- and C21-progestins on cell proliferation of a human breast cancer cell line in vitro. Of special interested was the comparison of two different regimens commonly used in HRT, sequential and continuous combination with estradiol. We used the human breast cancer cell line MCF-7 as a model. Progesterone (P), chlormadinone acetate (CMA), dienogest (DNG), gestodene (GSD), 3-ketodesogestrel (KDG), levonorgestrel (LNG), medroxyprogesterone acetate (MPA), and norethisterone (NET) were investigated in the range of 0.01nm to 10 micro M alone and in combination with 10 nM estradiol. Cell proliferation was measured after 7 days using the ATP chemosensitivity test. Tested alone, CMA, DNG, GSD, KDG, MPA and NET significantly stimulated cell proliferation, but only at high dosages. Sequentially combined with estradiol, only CMA inhibited cell proliferation over the whole concentration range. Slight effects were found for DNG, GSD and KDG, whereas P and MPA only showed an effect at the highest concentration. NET had no significant effect on cell proliferation. Continuously combined, all progestins exhibited an inhibitory effect over the whole concentration range. The most prominent effects were found for P, CMA, GSD, and KDG. Only slight effects were found for DNG, MPA and NET. Our in vitro results indicate that the influence on breast cancer risk using HRT in postmenopausal women might depend on the type of progestin used as well as on the regimen applied. However, the net inhibitory in vitro effect of the progestins at clinically relevant dosages is rather minimal, and whether progestins in general can reduce breast cancer risk in long-term treatment remains uncertain. Further clinical trials are urgently needed to clarify this issue.

Analysis of Variance↗

PubMed1986

A simple method for determining the optimal dosage of progestin in postmenopausal women receiving estrogens.

Progestin is often added to regimens of estrogen therapy in postmenopausal women to reduce the risk of endometrial hyperstimulation, but it may cause undesirable metabolic effects. Therefore, a low dosage is recommended. At present, the only way to determine whether the dosage of progestin is causing the desired secretory transformation of the endometrium is by endometrial sampling, which is invasive. We studied 102 postmenopausal women undergoing estrogen therapy who also took a progestin for 12 days each month, and we correlated the day of onset of bleeding with the endometrial histology over a three-month period. A bleeding pattern suitable for interpretation was observed in 96 women. Regardless of the preparation and dosage of the estrogen and progestin used, wholly or predominantly proliferative endometrium was always associated with bleeding on or before day 10 after the addition of progestin; wholly or predominantly secretory endometrium, or a lack of endometrial tissue, was associated with bleeding on day 11 or later. We conclude that the bleeding pattern reflected the histologic condition of the endometrium and that adjustment of the dosage of progestin so that regular bleeding is induced on or after day 11 may obviate the need for endometrial biopsy.

Adult↗

PubMed2003

Cloning, expression, and characterization of a membrane progestin receptor and evidence it is an intermediary in meiotic maturation of fish oocytes.

The structures of membrane receptors mediating rapid, nongenomic actions of steroids have not been identified. We describe the cloning of a cDNA from spotted seatrout ovaries encoding a protein that satisfies the following seven criteria for its designation as a steroid membrane receptor: plausible structure, tissue specificity, cellular distribution, steroid binding, signal transduction, hormonal regulation, and biological relevance. For plausible structure, computer modeling predicts that the protein has seven transmembrane domains, typical of G protein-coupled receptors. The mRNA (4.0 kb) is only detected in the brain and reproductive tissues on Northern blots. Antisera only detect the protein (40 kDa) in plasma membranes of reproductive tissues. The recombinant protein produced in an Escherichia coli expression system has a high affinity (K(d) = 30 nM), saturable, displaceable, single binding site specific for progestins. Progestins alter signal transduction pathways, activating mitogen-activated protein kinase and inhibiting adenylyl cyclase, in a transfected mammalian cell line. Inhibition of adenylyl cyclase is pertussis toxin sensitive, suggesting the receptor may be coupled to an inhibitory G protein. Progestins and gonadotropin up-regulate both mRNA and protein levels in seatrout ovaries. Changes in receptor abundance in response to hormones and at various stages of oocyte development, its probable coupling to an inhibitory G protein and inhibition of progestin induction of oocyte maturation upon microinjection of antisense oligonucleotides are consistent with the identity of the receptor as an intermediary in oocyte maturation. These characteristics suggest the fish protein is a membrane progestin receptor mediating a "nonclassical" action of progestins to induce oocyte maturation in fish.

Animals↗

PubMed2006

Progestin is an essential factor for the initiation of the meiosis in spermatogenetic cells of the eel.

Meiosis is an indispensable process of sexual reproduction. However, detailed information on the regulatory mechanisms that initiate meiosis is not available. Progestins are important steroids regulating final maturation in male and female vertebrates. In male teleosts, it is known that progestin induces spermiation and sperm maturation. However, a role for progestin in early spermatogenesis or meiosis has not yet been described. In this study, we examined the functions of progestin on the initiation of meiosis in male Japanese eel. A natural progestin in teleost fish 17alpha,20beta-dihydroxy-4-pregnen-3-one (DHP) and its receptors were present in the testis at an early stage of spermatogenesis. By using an eel testicular culture system, DHP was shown to induce DNA replication in spermatogonia. Although 11-ketotestosterone, a known initiator of spermatogenesis, also stimulated DNA synthesis in spermatogonia, antibodies against DHP prevented DNA replication when added during the period in which meiosis was initiated. DHP treatment also induced the expression of meiosis-specific markers, such as DmcI and Spo11. Furthermore, Spo11 expression and synaptonemal complexes, specific features of the meiotic prophase, were detected in testicular fragments cultured with DHP in some germ cells that showed morphological characteristics of undifferentiated spermatogonia. We conclude that DHP, a progestin, is an essential factor for the initiation of meiosis.

Animals↗

PubMedDate not supplied

Effects of progestins on cardiovascular diseases: the haemostatic system.

The effect of progestin-only therapy on the haemostatic system has mainly been studied in premenopausal women. Although these studies are difficult to compare, most authors agree that there is no consistent pattern of effects on haemostasis. Oestrogen-progestin combinations have been extensively studied in pre- (combined oral contraceptives) and postmenopausal women (sequential and continuous combined hormone replacement therapy), but mostly with emphasis on the effects of oestrogens. Comparative studies into the differential effects of progestins in combined preparations are scarce. Based on these studies, there is evidence for modifying effects of progestins on oestrogen-induced changes, particularly on fibrinogen, factor VII and the fibrinolytic system. The modifying effects appear to vary among certain progestins, the variation being most likely due to differential effects on lipid metabolism. The clinical interpretation of steroid-induced effects on the haemostatic system is difficult. Retrospective analyses linking certain patterns of haemostatic regulation to the risk of venous or arterial vascular diseases are subject to bias, and no interventional studies are yet available. In the absence of such prospective studies and well-designed comparative studies, the available data do not support the notion of a superiority of certain progestins with regard to cardiovascular risks of combined preparations.

Cardiovascular Diseases↗

PubMed2002

Progestin-induced apoptosis in the Macaque ovarian epithelium: differential regulation of transforming growth factor-beta.

BACKGROUND: Oral contraceptive (OC) use is associated with a reduced risk of ovarian cancer. An OC component, progestin, induces apoptosis in the primate ovarian epithelium. One regulator of apoptosis is transforming growth factor-beta (TGF-beta). We determined the effect of progestin on TGF-beta expression in the primate ovarian epithelium and examined the relationship between TGF-beta expression and apoptosis. METHODS: Female cynomolgus macaques were randomly assigned to receive a diet for 35 months containing no hormones (n = 20); the OC Triphasil (n = 17); or each of its constituents, ethinyl estradiol (estrogen, n = 20) or levonorgestrel (progestin, n = 18 ), alone. Ovarian sections were immunostained with monoclonal antibodies against TGF-beta1 or TGF-beta2 plus TGF-beta3 (TGF-beta2/3) isoforms. The expression of TGF-beta isoforms in four ovarian compartments (epithelium, oocytes, granulosa cells, and hilar vascular endothelium) was compared among treatment groups. The association between TGF-beta expression and apoptosis, as determined by morphology and histochemistry, was examined in ovarian epithelium. All statistical tests were two-sided. RESULTS: Compared with ovaries from the control and estrogen-only-treated monkeys, the ovaries of progestin-treated monkeys showed 1) a marked decrease in the expression of TGF-beta1 and a concomitant increase in the expression of the TGF-beta2/3 isoforms in the ovarian epithelium (P<.001), 2) an increase in the expression of TGF-beta2/3 in the hilar vascular endothelium (P<.001), and 3) a marked decrease in TGF-beta2/3 expression in granulosa cells (P<.001). The apoptotic index of the ovarian epithelium was highly associated with the change in expression from TGF-beta1 (P<.001) to TGF-beta2/3 (P</=.002) induced by progestin treatment. CONCLUSIONS: Progestin induces differential regulation in the ovarian epithelium of TGF-beta, a change in the expression of which is highly associated with apoptosis. These data suggest a possible biologic mechanism for the protective association between OC use and reduced ovarian cancer risk.

Animals↗