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PubMed1985

Localization of the synthetic progestin 3H-ORG 2058 in neurons of the primate brain: evidence for the site of action of progestins on behavior.

The location of neurons that concentrate progestin in the brains of female cynomolgus monkeys was mapped by autoradiography using the specific synthetic progestin receptor ligand 3H-ORG 2058. Three females were ovariectomized and treated with estrogen (20 micrograms estradiol benzoate daily for 7 days), and one of them was also pretreated with progesterone. Each received an i.v. injection of 1 mCi 3H-ORG 2058 and was killed 1 hour later. Thaw-mount autoradiograms revealed intense accumulation of radioactivity in the nuclei of many neurons in the mediobasal hypothalamus, particularly in the ventromedial nucleus (n.), arcuate n., and premammillary n. Neuronal labeling was also observed frequently in the medial preoptic n., and occasionally in the anterior hypothalamic area, paraventricular n., and organum vasculosum of the lamina terminalis. In the pituitary gland, about 5% of cells in the pars distalis were intensely labeled. In the female pretreated with progesterone, however, labeling was almost completely blocked. Analysis of samples by high-performance liquid chromatography demonstrated that the radioactivity extracted from brain and pituitary gland cell nuclei was almost entirely unmetabolized 3H-ORG 2058. The nuclear concentration of progestin was much greater in the pituitary gland than in the brain, and was greater in the hypothalamus than in any other brain area. These results revealed well-localized groups of progestin-concentrating neurons in the primate brain which presumably mediate the effects of progesterone on both gonadotropin secretion and female sexual behavior.

Animals↗
PubMedDate not supplied

Multiple actions of synthetic 'progestins' on the growth of ZR-75-1 human breast cancer cells: an in vitro model for the simultaneous assay of androgen, progestin, estrogen, and glucocorticoid agonistic and antagonistic activities of steroids.

This study was designed to assess the multiple steroid receptor mediated activities of a series of synthetic 'progestins' on breast cancer cell growth, using the human ZR-75-1 cell line which possesses functional estrogen (ER), androgen (AR), and glucocorticoid (GR) receptors as well as progesterone (PgR) receptors. Four 17-hydroxyprogesterone derivatives (chlormadinone acetate, CMA; cyproterone acetate, CPA; medroxyprogesterone acetate, MPA; and megestrol acetate, MGA) and two 19-nortestosterone derivatives (norethindrone, NRE, and norgestrel, NRG) were thus investigated. Based on the requirement of estrogens for PgR-mediated antiproliferative effects and the reversal of PgR-mediated action by insulin, it was found that although all 'progestins' could inhibit ZR-75-1 cell growth through the PgR at low concentrations, the relative contribution of this receptor in cell growth control is highly variable between compounds. The quantitative importance of PgR-mediated inhibition of cell proliferation was inversely related to the amplitude of the androgenic effects induced by the compounds, the AR-mediated effects increasing in the order CPA less than MGA less than CMA less than NRE less than NRG less than MPA. The specificity of these androgenic effects is further supported by their reversal upon addition of the antiandrogen hydroxyflutamide. In addition, the 17-hydroxyprogesterone derivatives, but not the 19-nortestosterone derivatives, had glucocorticoid activities at high (micromolar) concentrations, as shown by reversal of growth inhibition by the antagonist RU486 in the presence of saturating concentrations of 5 alpha-dihydro-testosterone. All 'progestins' tested, except MPA and NRE, also had some antiglucocorticoid activity, NRG being the most potent in this respect. Finally, NRE and NRG exerted a marked mitogenic effect in estrogen-free medium which was clearly mediated through the ER as shown by the competitive reversal of their action by the steroidal antiestrogen EM-139. The present results show that growth measurements of the human breast cancer cells ZR-75-1 permit, with the appropriate steroid additions, the assay of progestin, androgen, estrogen, and glucocorticoid agonistic as well as antagonistic activities of test compounds. The present study shows, somewhat surprisingly, that while the AR is almost completely responsible for the action of MPA at low concentrations, the majority of the action of NRE, NRG, and MGA is also exerted through AR, while the androgenic action of CPA plays a lower role in the growth inhibition induced by this compound.(ABSTRACT TRUNCATED AT 400 WORDS)

Binding, Competitive↗
PubMed1994

Long-term medical therapy for leiomyomata uteri: a prospective, randomized study of leuprolide acetate depot plus either oestrogen-progestin or progestin 'add-back' for 2 years.

Treatment of women with leiomyomata with gonadotrophin-releasing hormone agonists (GnRHa) for > 6 months is not recommended because of concerns regarding adverse sequelae of prolonged hypoestrogenism. It has been postulated that addition of low-dose sex steroids to GnRHa treatment, i.e. 'add-back' therapy, may avert some of these adverse effects (accelerated bone resorption, vasomotor flushes) without altering the efficacy of GnRHa therapy. To evaluate the effects of long-term GnRHa therapy on uterine size, bleeding patterns, bone mass and lipids, 51 pre-menopausal women with leiomyomata were treated with the GnRHa leuprolide acetate depot, 3.75 mg every 4 weeks for 2 years. After 3 months of leuprolide therapy, the women were randomized to receive either low-dose continuous oestropipate, 0.75 mg daily, plus cyclic norethindrone, 0.7 mg on days 1-14 each month (the oestrogen-progestin add-back group) or higher-dose norethindrone, 10 mg daily (the progestin add-back group), for the remaining 21 months. Mean uterine volume decreased by 40% in both treatment groups during the first 3 months on leuprolide treatment. There was no significant change in uterine size following oestrogen-progestin add-back. However, mean uterine volume in the progestin add-back group increased to 87% of pre-treatment size by treatment month 12 and 95% of pre-treatment size by treatment month 24. Mean bone density of the lumbar spine as measured by dual X-ray absorptiometry decreased significantly by 2.6% during the first 3 months in all patients, but did not change significantly following steroid add-back in both treatment groups during the final 21 treatment months.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1998

Comparative binding affinity study of progestins to the cytosol progestin receptor of endometrium in different mammals.

The relative binding affinity of 5 alpha-reduced progestins and a newly synthesized antiprogestin J912 (progesterone 100%) was determined in a competitive receptor binding assay using [3H]ORG-2058 as radiolabeled ligand for the progestin receptor. Uteri obtained from 12 different species of four mammalian orders were examined. The relative binding affinity of 75-100% and a blood prevalence of 5 alpha-pregnane-3,20-dione in horses and African elephants suggest a biological role of this particular 5 alpha-reduced progesterone. For pigs the binding affinity of 5 alpha-pregnane-3,20-dione was about 50% of progesterone, but blood levels are unknown. In all other cases the low binding affinity of investigated progestins precludes possible biological role. For 5 alpha-pregnane-3 alpha-ol-20-one, 5 alpha-pregnane-20 alpha-ol-3-one, and 5 alpha-pregnane-3 beta,20 alpha-diol the relative binding affinity was less than 1%. A rather low binding (< 15%) was observed in 5 alpha-pregnane-3,20-dione in all ruminant species investigated. The antiprogestin J912 was found to be highly efficient in displacing progesterone from its endometrial binding sites in carnivores and might therefore be used for pregnancy interruption during diapause in certain species, e.g., in captive bears.

Animals↗
PubMed1990

Distribution of progestin-binding cells in estrogen-treated and untreated neonatal mouse uterus and oviduct: autoradiographic study with [125I]progestin.

Progestin-binding sites in uteri and oviducts of estrogen-treated and untreated 8-day-old mice were studied by thaw-mount autoradiography with [125I]progestin. In the untreated uteri, nuclear concentration of radiolabelled progestin was observed in all tissues of the uterus, with strongest nuclear labelling in luminal and glandular epithelia and in stroma. In the estrogen-treated uteri, the degree of labelling was markedly augmented in stroma and muscle, but much reduced in the luminal and glandular epithelia, compared to untreated uteri. In untreated oviducts, nuclear labelling was observed in stroma and muscle in all regions and in epithelium in the isthmic and uterine regions. The epithelium in infundibular and ampullar regions was only scarcely labelled. The estrogen-treatment augmented the labelling in stroma and muscle of the oviduct as in the uterus, but the labelling in epithelium was not affected. These results indicate that estrogen-treatment induces progesterone receptor differentially among tissue compartments both in the uterus and oviduct.

Animals↗
PubMed1991

The anti-progestin RU486 stabilizes the progestin-induced fatty acid synthetase mRNA but does not stimulate its transcription.

Progestins induce fatty acid synthetase (FAS) in breast cancer cell lines, both increasing its gene transcription and mRNA stabilization (Joyeux, C., Rochefort, H., and Chalbos, D. (1989) Mol. Endocrinol. 4, 681-686). In vitro run-on transcription assays show that RU486, in contrast to progestin, inhibits FAS transcription by 40-50%. Moreover and surprisingly, anti-progestin RU486 also stabilizes FAS mRNA 3- to 4-fold in MCF7 cells as measured by chase experiments in the presence of actinomycin D or cordycepin or after short cell labeling with [3H]uridine. Dexamethasone is inefficient in increasing the half-life of FAS mRNA in MCF7 cells. RU486 had no effect on MDA-MB 231 cells which contain glucocorticoid but no progesterone receptors, indicating that the progesterone receptor is implicated in this regulation. RU486-induced mRNA stabilization allows delayed accumulation of FAS mRNA. These results indicate that the progesterone receptor can be activated separately to stimulate gene transcription or stabilize mRNA.

Cell Line↗
PubMed2002

Evolution of progestins. Focus on the novel progestin drospirenone.

Combination oral contraceptives have changed considerably since they were introduced, in 1960. Although ethinyl estradiol has been the primary estrogen in combination oral contraceptives for years, a number of progestogenic agents have been developed. All of the progestins currently used in combination oral contraceptives are derived from 19-nortestosterone. The exception is a new progestin derived from 17 alpha-spirolactone--drospirenone. As compared with that of other progestins used in combination oral contraceptives, drospirenone pharmacology more closely resembles the pharmacology endogenous progesterone. Its antiandrogenic and antimineralocorticoid activities result in special benefits--e.g., improvement in androgen-related disorders (such as acne and hirsutism) and avoidance of estrogen-related fluid retention.

Androgen Antagonists↗
PubMed1991

A fluorine-18 labeled progestin as an imaging agent for progestin receptor positive tumors with positron emission tomography.

The potential of the fluorine-18 labeled progestin 21-[18F]fluoro- 16 alpha-ethyl-19-norpregn-4-ene-3,20-dione [( 18F]FENP) as an imaging agent for the in vivo assessment of progestin receptor (PR) positive neoplasms with positron emission tomography has been investigated. Tissue distribution studies in immature estrogen primed female rats revealed high uptake of radioactivity, expressed as the differential absorption ratio, by uterine tissue. After simultaneous administration with unlabeled FENP, a significant decrease (83%) in uterine uptake was observed 60 min after injection. Uterine uptake was highly selective. The ratio of uptake of radioactivity by uterine tissue to that by blood was 39 at 180 min. In mice bearing transplanted Grunder strain mammary carcinomas tissue, distribution studies demonstrated a selective uptake of [18F]FENP by PR positive tumors. Pretreatment with unlabeled FENP caused a significant decrease (66%) in tumor uptake. Uptake by other tissues was not affected by the presence of unlabeled progestin. The ratio of uptake of radioactivity by tumor tissue to that by blood was 4.7 at 180 min. For FENP pretreated mice and mice bearing PR negative tumors, this ratio was 1.7 and 1.1, respectively. It is concluded that the uptake of [18F]FENP by uterine and by PR positive mammary tumor tissue in vivo is primarily receptor related, presumably to the PR. Furthermore, [18F]FENP appears to be suitable for imaging of PR positive human neoplasms with positron emission tomography.

Animals↗
PubMed1994

Progestins in preventive hormone therapy. Including pharmacology of the new progestins, desogestrel, norgestimate, and gestodene: are there advantages?

Progestins have played an important role in hormone replacement therapy (HRT). This article reviews the history, structure, and pharmacology of synthetic progestins, including the new progestins, norgestimate, gestodene, and desogestrel. The benefits and potential effect on carcinoma of the breast for each HRT are summarized. Current treatment alternatives are addressed.

Breast Neoplasms↗
PubMed1995

Specific interactions of progestins and anti-progestins with progesterone antibodies, plasma binding proteins and the human recombinant receptor.

This structure-activity study compares the affinity of a series of progestins, progesterone metabolites and anti-progestins for a panel of monoclonal antibodies to progesterone, coypu (Myocastor coypus) or guinea pig plasma progesterone-binding proteins (PPBPs) and the human recombinant progesterone receptor A form (PR-A). The compounds tested were progesterone, Promegestone (R5020), Mifepristone (RU486), ZK98,734, Onapristone (ZK98,299), 11 alpha-hydroxyprogesterone, 11 alpha-progesterone hemisuccinate, androsterone, etiocholanolone, 5 alpha- and 5 beta-pregnane-3,20-diones, and 20 alpha- and 20 beta-hydroxyprogesterones. The Ki values for these ligands were determined by competitive binding assays using radiolabelled progesterone as the binding site ligand. For anti-progesterone antibodies (e.g. DB3 and 11/32), only progesterone (3.6-8.8 nM), the 11 alpha-derivatives (1.0-5.5 nM) used to prepare the immunogen and the two 5-pregnanediones (20.9-45.1 nM) were bound with high affinity. For PR-A, high affinity binding was found with receptor agonists (Ki = 1.1-6.2 nM), both 5- and 20-reduced metabolites, and antagonists (0.6-28.0 nM), but not with the 11 alpha-derivatives (950 nM-1.0 microM). In contrast, the PPBPs displayed high affinity interactions with progesterone (3.5-4.2 nM) and both 5 alpha- and 20 alpha-reduced metabolites (2.4-3.4 nM). Binding with the beta-isomers and R5020 was less pronounced (22-170 nM) and there was no evidence of high affinity binding with PR antagonists (> 1.0 microM). Analogs with the 17-keto group did not bind to any of the binders studied. Thus, commonalities among the three types of protein binders were their comparable binding affinities for progesterone (3.5-8.8 nM) and 5-pregnanedione isomers (2.4-330 nM), and a lack of binding for two C17-keto steroids (androsterone and etiocholanolone). The results imply that the tertiary features of the binding domain of these three types of proteins are sufficiently different to result in unique binding structures.

Animals↗
PubMed1998

Aspects of progestin activity on the breast. European Progestin Club.

On 9-11 May 1997, the second Meeting of the European Progestin Club was held in Turin, Italy. Aspects of progestin use on the breast were discussed, based on the currently available scientific data. The paper covers topics addressed at the meeting and summarizes the recommendations which could be agreed on by the participants.

Breast↗
PubMed1998

Matrix metalloproteinase and matrix metalloproteinase inhibitor expression in endometrial stromal cells during progestin-initiated decidualization and menstruation-related progestin withdrawal.

Estradiol (E) primes human endometrial stromal cells (HESCs) for the decidualizing effects of progesterone in vivo and in vitro. Matrix metalloproteinase (MMP) expression was evaluated in confluent HESCs incubated in control medium, and in medium supplemented with either E, or the synthetic progestin medroxyprogesterone acetate (P), or E + P. Measurements with a specific ELISA indicated that basal pro-MMP-1 output was unaffected by E, whereas E + P, which induces the expression of several decidualization-related markers, produced a time-dependent inhibition in HESC-secreted levels of pro-MMP-1. Consistent with progestin inhibition of MMP-1 protein expression in the HESCs, P but not E, reduced steady state levels of MMP-1 messenger RNA (mRNA) as determined by Northern analysis. By contrast, mRNA levels for MMP-2 and the MMP inhibitor TIMP-1 were not altered by either P or E. Steroid withdrawal studies indicated that after MMP-1 expression was suppressed by incubation of the HESCs with E + P, 4 days of exposure to the antiprogestin RU 486 (mifepristone) significantly up-regulated MMP-1 levels in the conditioned medium by severalfold compared with cultures maintained in E + P. The change to steroid-free control medium required a more prolonged period of withdrawal to attain up regulatory effects that were comparable with those evoked by RU 486. The ELISA measurements were validated by immunoblot analysis with a specific MMP-1 antibody, which showed corresponding changes in a band at the expected mobility of about 50 kDa. Moreover, Northern analysis revealed parallel changes in MMP-1 mRNA levels, whereas neither MMP-2 nor TIMP-1 mRNA levels were modulated by adding or withdrawing steroids. The contrast between regulated MMP-1 expression and constitutive MMP-2 expression observed in the cultured HESCs is consistent with the demonstrated presence on the MMP-1 promoter of regulatory elements such as AP-1 and PEA-3 that are absent from the MMP-2 promoter. Extrapolation of these in vitro changes in HESCs to in vivo endometrial events suggests that: 1) inhibition of MMP-1 expression by E and progesterone would stabilize the perivascular endometrial ECM to prevent local hemorrhage during endovascular invasion by the implanting trophoblast; 2) enhanced expression of MMP-1 evoked by steroid withdrawal would mediate endometrial ECM degradation leading to sloughing of the functional layer during menstruation.

Blotting, Northern↗
PubMed1982

Cytosol estrogen and progestin receptors in endometrial carcinoma of patients treated with surgery, radiotherapy, and progestin. Clinical correlates.

Cytosol progestin (PR) and estrogen receptor (ER) concentrations were measured in 114 endometrial carcinoma specimens from 109 patients; these levels were correlated with clinical and histopathologic characteristics, and with clinical outcome in 44 patients followed for at least two years after the primary therapy consisting of surgery, irradiation and adjuvant administration of progestin. Eighty percent of all specimens were simultaneously PR- and ER-positive (greater than or equal to 6 fmol and greater than or equal to 3 fmol/mg protein, respectively) whereas 10% were both PR- and ER-negative. Early clinical stages (I and II) were more often receptor-positive, and the receptor concentration in these tumors was higher than in advanced or recurrent disease. The same was the case for superficial as compared with deeply invasive lesions. Both PR and ER concentrations in well or moderately differentiated tumors were higher than in anaplastic carcinomas. PR and ER concentrations did not correlate with the age of menopausal status, body weight or carbohydrate metabolism of the patients. In the patient group followed up for two years or more, the receptor-poor tumors tended to behave more aggressively than did receptor-rich malignancies in relation to patient survival. The measurement of PR and ER concentrations in advanced endometrial carcinoma has been proved useful in the selection of hormonal or cytotoxic chemotherapy. The current results advocate their use of prognostic risk factors which might be useful in selection of the most efficient treatment modalities for individual patients.

Adult↗
PubMed1990

Intermittent GnRH antagonist plus progestin contraception conserving tonic ovarian estrogen secretion and reducing progestin exposure.

The present study was designed to evaluate the effectiveness of a once-weekly regimen of GnRH antagonist followed by a progestin as a potential new contraceptive method. On menstrual cycle days 2, 9, 16, and 23 (onset of menses = Day 1) monkeys were divided into two groups: 1) those injected sc with 0.1 mg/kg Nal-Glu GnRH antagonist in saline and those given only vehicle (control). On cycle days 15 to 26, each treated female was administered 25 micrograms norgestimate/day orally. This was continued for three treatment cycles (84 days). Weekly injections of Nal-Glu GnRH antagonist effectively blocked completion of folliculogenesis, ovulation, and corpus luteum function as judged by serum LH, E2, and P levels. Serum progesterone was undetectable (less than 0.1 ng/ml) during the treatment cycles. Importantly, serum estradiol levels during GnRH antagonist plus norgestimate treatments were maintained at 35 +/- 7 pg/ml. Upon the cessation of norgestimate treatment on day 26 in each cycle, menses uniformly began within 2 or 3 days. Regarding recovery, apparently normal and presumably ovulatory menstrual cycles, as judged by timely estradiol elevations, midcycle LH surges, and luteal phase progesterone patterns, were manifest immediately following termination of the final GnRH antagonist plus norgestimate treatment cycle. Endometrial biopsies removed on day 26 of control cycles, and on day 26 of the third treatment cycle revealed appropriate late secretory phase endometrium having tortuous endometrial glands and superficial stromal edema. Histological sections of ovaries removed at the end of the GnRH antagonist plus norgestimate treatment revealed multiple small and medium-sized developing and atretic follicles, having maintained serial ablation of the potentially maturing follicles.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1999

Recommendations for estrogen and progestin replacement in the climacteric and postmenopause. European Progestin Club.

The diversity of function that sex steroids have proven to have in the female body, gives them a position of central importance in gynaecology. Scientific research demonstrates not only the well known genital functions of sexual steroids, furthermore, various extragenital organs are influenced and modulated by ovarian hormones. Therefore, the general benefit of HRT for the female organism becomes clearer and the clinical management of menopause is developing to a broad new discipline, the gender specific medicine. In clinical practise, phytosteroids are claimed by the patient and therefore, also of high interest for the scientific research. Also, tissue specificity of the endocrine treatment and the biological relevance of different steroid receptors of HRT are discussed, leading to the development of new HrT preparations. Individualisation, the tailoring of HRT, according to the patients needs, and low dose steroids management, will also become an important aspect in the recommendations for estrogen and progestin replacement therapy.

Estrogen Replacement Therapy↗
PubMed2004

Estrogen replacement therapy in combination with continuous intrauterine progestin administration reduces the amount of circulating oxidized LDL in postmenopausal women: dependence on the dose of progestin.

BACKGROUND: Oxidized low density lipoprotein (LDL) plays a key role in processes leading to atherosclerosis. Recent studies show that LDL oxidation in vitro is effectively prevented by estrogen. Yet, the effect of hormonal therapy (HT) on in vivo LDL oxidation has remained open. AIM: We used a novel methodology for the measurement of oxidized LDL in vivo in order to investigate the effects of HT. METHODS: The subjects were derived from two separate trials. In trial 1 (24 months) women (n = 32) used intra-uterine system releasing 10 micrograms/day levonorgestrel, and 2 mg oral estradiol. Trial 2 (12 months) consisted of two groups of subjects. One group (n = 30) used an intrauterine system releasing 20 micrograms/day levonorgestrel, and 2 mg estradiol; the other group (n = 32) received orally a combination of 1 mg norethisterone acetate and 2 mg estradiol. Blood samples were taken at 6 months intervals. Estimation of in vivo LDL oxidation was based on determination of baseline diene conjugation in isolated LDL. RESULTS: Hormonal therapy in trial 1 decreased markedly in vivo LDL oxidation. The effect was seen after 6 months' HT and became more pronounced towards the end of study (41% decrease; P < 0.0001). Contrary to this, in trial 2 the two different kinds of hormonal therapy schemes did not affect in vivo LDL oxidation. CONCLUSIONS: The strong effect seen in trial 1 shows that intrauterine levonorgestrel with 2 mg estradiol can lower LDL oxidation in vivo. The results show that this effect depends on dosage of the progestin.

Body Mass Index↗
PubMed1992

Immunocytochemical localization of progestin receptors in monkey hypothalamus: effect of estrogen and progestin.

The increase in PRL secretion which follows progesterone (P) administration to estradiol (E)-primed women and monkeys cannot be due to an action of P at the pituitary level because lactotropes do not contain progestin receptors (PR). To further the hypothesis that P increases PRL secretion by an action in the hypothalamus, PR-expressing neurons were studied in free-ranging and steroid-manipulated monkeys using immunocytochemistry with a monoclonal antibody to human PR. Specific PR immunoreactivity is localized in the nucleus of individual hypothalamic neurons. Male and female adult and juvenile macaque hypothalami contain significant populations of PR-positive neurons throughout the anterior and medial basal hypothalamus. Ovariectomy decreases, but does not abolish, the number of neurons expressing PR. PR expression was not altered in the supraoptic nucleus (SON) by ovariectomy. Estrogen treatment for 28 days caused a significant increase in the number of PR-positive neurons in the medial preoptic area, the ventro-medial nucleus, the arcuate nucleus, and the median eminence, but not in the SON. P treatment added to the E treatment from day 14 to day 28 did not alter the number of PR-positive neurons in any area. These data suggest that PR may be constitutively expressed in the magnocellular neurons of the SON and in certain other cells throughout the hypothalamus. E induces PR in a large proportion of neurons in the medial basal hypothalamus and this action is not blocked by subsequent P treatment. The inability of P to down-regulate PR in the hypothalamus differs from the reproductive tract and pituitary. Indeed, this observation is consistent with the fact that PRL secretion remains elevated during chronic P administration.

Aging↗