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PubMed1992

Estrogenic potential of progestins in oral contraceptives to stimulate human breast cancer cell proliferation.

Most oral contraceptives (OC) contain a progestin in combination with an estrogen, and the progestin component in OC includes one of the following 19-nortestosterone derivatives: norethynodrel; norethindrone; or norgestrel (levonorgestrel). It is well known that estrogens promote the growth of breast cancer. However, progestins have recently also been implicated in the development of breast cancer. We have compared and contrasted the ability of synthetic progestins to stimulate the proliferation of cultured human breast cancer cells and examined their possible mechanism of action. We found that some progestins used in OC were able to stimulate the growth of estrogen receptor-positive (ER+) MCF-7 and T47DA18 human breast cancer cells but not ER- MDA-MB-231, BT-20, and T47DC4 human breast cancer cells. However, two other progestins, MPA and R5020, which are not used in OC, were either not able to stimulate or only slightly stimulated growth. The potency of norethynodrel [median effective dose (EC50) = 4 x 10(-8) M] and norethindrone (EC50 = 3 x 10(-8) M) was greater than norgestrel (EC50 = 2 x 10(-7) M) in MCF-7 cells. E2 (EC50 = 8 x 10(-13) M) was an even more potent stimulator of growth. More importantly, the progestin-induced growth stimulation was blocked by the antiestrogens 4-hydroxytamoxifen and ICI 164,384 but not the antiprogestin 17 beta-hydroxy-11 beta-(4-dimethylaminophenyl)-17 alpha-(1-propynyl)-estra-4, 9-dien-3-one (RU486). To determine whether the proliferative action of progestins was mediated through the ER, cells were transfected with a chloramphenicol acetyltransferase reporter gene containing an estrogen response element derived from vitellogenin 2A gene. The progestins which stimulated the growth of breast cancer cells also increased chloramphenicol acetyltransferase activity. The induction of chloramphenicol acetyltransferase activity was blocked by the addition of the antiestrogens 4-hydroxytamoxifen and ICI 164,384 but not the antiprogestin RU486. This study provides direct evidence that the 19-nortestosterone derivatives in OC have estrogenic properties and suggests that activation of ER, but not progesterone receptor, is the growth-stimulatory mechanism for these synthetic progestins. Our results may help to explain the conflicting evidence linking OC and breast cancer risk. A rigorous evaluation of the "total" estrogenic potential of OC might produce a better correlation with breast cancer risk.

Amino Acid Sequence↗

PubMed2005

The estrogenic activity of synthetic progestins used in oral contraceptives enhances fatty acid synthase-dependent breast cancer cell proliferation and survival.

Overexpression of the lipogenic enzyme fatty acid synthase (FAS) is a common molecular feature in subsets of sex-steroid-related tumors including breast carcinomas that is associated with poor prognosis. In this study, we explored whether breast-cancer associated FAS (oncogenic antigen-519) is regulated by the progestin component in oral contraceptives. In addition, we examined the role of FAS hyperactivity on progestin-regulated breast cancer cell proliferation, survival and metastatic properties. We found that in estrogen receptor (ER)- and progesterone receptor (PR)-positive MCF-7 human breast cancer cells, synthetic progestins used in oral contraceptives including norethynodrel (NOR) and norethindrone, induced a dose-dependent increase of FAS enzymatic activity, with a maximum response (> or = 4-fold) occurring at a concentration of 10(-8) M. FAS activity was only slightly stimulated after exposure to two other progestins, medroxy-progesterone acetate (MPA) and megestrol acetate (MGA), which are used in postmenopausal hormone replacement therapy and high-dose progestin treatment therapy. Western blot analyses showed that NOR-induced stimulation of FAS activity correlated closely with NOR-induced up-regulation of FAS protein expression. To determine the role of FAS accumulation following NOR exposure, we pharmacologically examined the requirement for FAS activity in NOR-stimulated breast cancer cell proliferation and survival. The novel small compound C75 (a slow-binding FAS inhibitor) blocked NOR-induced breast cancer cell proliferation in anchorage-dependent assays. More importantly, pharmacological inhibition of FAS activity completely abolished NOR-stimulated soft-agar colony formation of MCF-7 cells. To evaluate the involvement of PR and ER signalings in NOR-induced up-regulation of FAS expression and activity, NOR was used in combination with either the anti-progestin RU486 (mifepristone) or the pure antiestrogen ICI 182,780 (Faslodex). RU486 and ICI 182,780 similarly abolished NOR-induced FAS activation, supporting the notion that PR- and ER-mediated FAS up-regulation might play different roles in NOR-stimulated breast cancer cells. Interestingly, when we evaluated the involvement of PR and ER signalings on NOR-induced breast cancer cell proliferation, the anti-estrogen ICI 182,780, but not the anti-progestin RU486, was found to inhibit NOR-stimulated proliferation and survival of MCF-7 cells in anchorage-dependent and -independent assays. To further determine whether NOR produced their effects via the ER, we evaluated its effects on endogenous ER transcriptional activity by using transient transfection assays with an estrogen-response element reporter construct (ERE-Luciferase). In the absence of E2 stimulation, treatment with NOR dramatically increased the levels of ERE-dependent transcriptional activity. This estrogenic like-effect of NOR was blocked by the addition of ICI 182,780, whereas RU486 failed to inhibit NOR-induced ERE activity. In summary, this study provides direct evidence that: a) a number of synthetic progestins used in oral contraceptives significantly activates breast cancer-associated FAS (OA-519) activity and expression in hormone-dependent breast cancer cells; b) FAS activity is necessary for progestin-induced anchorage-independent growth and survival of human breast cancer cells, and c) activation of ER, but not PR signaling, is the stimulatory mechanism through which synthetic progestins enhance a FAS-dependent proliferative and pro-survival signaling. These findings should be helpful to explain the conflicting evidence linking oral contraceptives and breast cancer risk through the estrogenic activation of tumor-associated FAS (OA-519), a molecular marker associated with poor clinical outcome of breast cancer disease.

Breast Neoplasms↗

PubMed1992

Suppression of ovarian function with the transdermally given synthetic progestin ST 1435.

OBJECTIVE: To study transdermal administration of the synthetic progestin ST 1435 and effectiveness of the steroid in suppression of ovarian function. DESIGN, PATIENTS: The effect of transdermal administration of the synthetic progestin ST 1435 in suppression of ovarian function was studied in a short term (17 to 93 days) study in healthy regularly menstruating women. SETTING: The outpatient clinic of the City Maternity Hospital, Helsinki, Finland. INTERVENTION: Nine women used the progestin ST 1435 transdermally during a total of 21 menstrual cycles. Treatment was started on the 5th day of the menstrual cycle and continued for 17 to 93 days. Three different daily doses (0.5, 0.8, and 1.0 mg) were tested. The steroid was applied to the periumbical area once a day in a gel. MAIN OUTCOME MEASURES: Serum concentrations of ST 1435, progesterone, and estradiol (E2) were determined during the luteal phase of control cycles and in a total of 16 treatment cycles. Bleeding records were kept and side effects registered. RESULTS: Transdermal absorption of the progestin ST 1435 resulted in relatively constant serum concentrations in each subject, depending on the dose used. All doses caused changes in ovarian function. With the 0.5-mg/d dose, inhibition of ovulation was observed in three of five treatment periods. The 0.8-mg/d dose was high enough to inhibit ovulation in 7 of 10 cycles analyzed. With the 1.0-mg/d dose, the serum concentrations of the progestin were high, and anovulation was seen. Serum E2 concentrations were variable in all cases; occasional high peak values were seen, typical of progestin treatment. Bleeding control was variable; irregular bleeding was seen, especially in anovulatory cases. CONCLUSIONS: A 0.8-mg dose of the progestin ST 1435 administered transdermally once a day appeared to suppress ovulation, if properly applied, and excessive suppression of ovarian function was not seen. The steroid was well accepted. The synthetic progestin ST 1435 given transdermally represents an effective alternative for inhibition of ovulation and for progestin therapy.

Administration, Cutaneous↗

PubMed1980

Progestin receptors in human uterine cytosol.

Progestin(norethindrone and norethindrone acetate)-binding protein, exhibiting characteristics similar to uterine progesterone receptor, has been identified in human uterine cytosol. The progestin receptor was characterized by sedimentation coefficient, 4.2 S; Stokes radius, 39 A; frictional ratio, 1.29; isoelectric pH, 4.6; molecular radius, 2.7 nm; and molecular weight in the range 67 000--74 000. The ammonium-sulfate-precipitated progestin-receptor complex was eluted from a DEAE-cellulose column at 0.18 M KCl. The progestin binding was saturable and stereospecific. The sequential variation in receptor concentration (early proliferative, 3800--4300 sites/cell; late proliferative, 9500--11 200 sites/cell; early secretory, 4900--6200 sites/cell; late secretory, 1800--2300 sites/cell) was in conformity for progesterone and the progestins, when concurrently measured. Oral administration of norethindrone significantly reduced the cytoplasmic and nuclear receptor concentration for estradiol and progesterone. A significant observation was that the progestins stabilized the receptor by forming a slowly dissociating complex with a t 1/2 approximately 110--130 min as compared with the progesterone-receptor complex dissociating with t 1/2 approximately 41 min. Thus, the uterine progestin receptor recognizes progestins in general, although with a varying degree of affinity, and the altered rate constants could be of putative importance in determining the biological potency of the progestins.

Cytosol↗

PubMed2000

Estrogen with interrupted progestin HRT: a review of experimental and clinical studies.

This review outlines the basic principles of a novel interrupted progestin HRT regimen in which estrogen is administered continuously, and progestin is given in a 3-days on, 3-days off pulsed fashion. The rationale for this regimen is to prevent receptor down-regulation and allow increased estrogen and progestin sensitivity during the progestin-free periods. Background information is provided including the reasons for poor patient acceptance of HRT, and the concerns of the potential association of HRT with breast and endometrial cancer. Experimental studies in the rat are described which provide evidence in support of the rationale for the interrupted progestin regimen. Clinically, two pilot studies examining symptom control, bleeding rates and safety of the interrupted progestin regimen, as well as preliminary results of a third study examining the usefulness of this regimen for addback therapy in GnRH agonist treated patients, are outlined. The preliminary results of phase III trials are presented. These clinical studies all demonstrated good symptom control, low bleeding rates, endometrial protection, and excellent patient acceptance. The combination of continuous estrogen with interrupted progestin appears to result in increased sensitivity to estrogen and progestin in estrogen responsive tissues. As a result, lower doses of estrogen and progestin may be used for HRT with good biological effects. Further clinical studies, preferably in prospective randomized trials, are required to demonstrate an advantage of this new regimen compared to continuous combined HRT.

Animals↗

PubMed1997

A sequence in the 5' flanking region confers progestin responsiveness on the human c-myc gene.

Previous reports have shown that progestins stimulate the proliferation of the human breast cancer cell line T47D in culture. Under different conditions other reports have shown progestin stimulation, inhibition or no effect on growth. It has also been shown that c-myc expression is stimulated at early times by progestins. We are currently testing the hypothesis that the mechanism of growth enhancement by progestins involves the stimulation of expression of c-myc. This hypothesis predicts a progesterone regulatory region in or near the c-myc gene. We have identified a region, from -2327 to -1833, which serves this function. This region includes a 15 bp sequence with homology to the PRE (progesterone response element) consensus sequence. Human progesterone receptor (PR) binds to this sequence in a specific, ligand-enhanced manner in electrophoretic mobility shift assays (EMSA). A 3507 bp HindIII-XbaI fragment of the 5' flanking region of the c-myc gene, -2327 to +1180, containing the progestin regulatory region and the c-myc promoter, confers progestin responsiveness to the CAT (chloramphenicol acetyl transferase) reporter gene in progesterone receptor (PR)-rich T47D human breast cancer cells, but not in PR-negative MDA-MB-231 cells. Removal of the progestin regulatory region abrogates progestin responsiveness. These data demonstrate that the sequence from -2327 to -1833 of the human c-myc gene includes a positive progestin regulatory region.

Animals↗

PubMed1997

Regulation of progesterone receptor messenger ribonucleic acid by progestin in human endometrial stromal cells.

Down-regulation of the progesterone receptor (PR) by its ligand has been demonstrated in breast cancer cell lines and in the rat uterus. However, in the stromal cells of endometrium, reduction of the PR level is not apparent in the luteal phase of the menstrual cycle. The purpose of this study was to determine the effect of progestin on PR and PR mRNA in isolated human endometrial stromal cells. Western blot analysis showed that progesterone or medroxyprogesterone acetate increased the two isoforms, PR-A and PR-B, in stromal cells but reduced them in glandular epithelial cells. Progestin increased the PR-A and PR-B mRNA by 2- to > 10-fold in the stromal cells of 12 specimens measured by solution hybridization-ribonuclease protection assay. A time study showed that the increase in PR mRNA required at least a 2- to 3-day incubation with progestin and that the high mRNA levels were maintained or increased slightly beyond 10 days of progestin incubation. The stimulatory effect of progestin was inhibited by RU-486 and by cycloheximide, suggesting that the up-regulation requires ligand binding to PR and de novo protein synthesis. Progestin also increased the stability of PR mRNA in endometrial stromal cells. These results demonstrated for the first time that progestin exerts an up-regulation of PR by increasing the steady-state level of PR mRNA specifically in human endometrial stromal cells. The up-regulation of PR by progestin may be mediated in part by progestin-induced endometrial stromal cell factors such as estrogen and insulin-like growth factor-I, both of which stimulated the PR-A and PR-B mRNA in stromal cells.

Cycloheximide↗

PubMed2005

Endometrial carcinoma risks among menopausal estrogen plus progestin and unopposed estrogen users in a cohort of postmenopausal women.

BACKGROUND: Because unopposed estrogen substantially increases endometrial carcinoma risk, estrogen plus progestin is one menopausal hormone therapy formulation for women who have not had a hysterectomy. However, endometrial carcinoma risks among estrogen plus progestin users and among former unopposed estrogen users are not firmly established. METHODS: We evaluated endometrial carcinoma risks associated with estrogen plus progestin and unopposed estrogen therapies in 30,379 postmenopausal Breast Cancer Detection Demonstration Project follow-up study participants. We ascertained hormone therapy use and other risk factors during telephone interviews and mailed questionnaires between 1979 and 1998. We identified 541 endometrial carcinomas via self-report, medical records, the National Death Index, and state cancer registries. Poisson regression generated time-dependent rate ratios (RR) and 95% confidence intervals (95% CI). RESULTS: Endometrial carcinoma was significantly associated with estrogen plus progestin only use (n = 68 cancers; RR, 2.6; 95% CI, 1.9-3.5), including both sequential (progestin <15 days per cycle; n = 32 cancers; RR, 3.0; 95% CI, 2.0-4.6) and continuous (progestin at least 15 days per cycle; n = 15 cancers; RR, 2.3; 95% CI, 1.3-4.0) regimens. The RR increased by 0.38 (95% CI, 0.20-0.64) per year of estrogen plus progestin use, and RRs increased with increasing duration of use for both regimens. The strong association with unopposed estrogen use declined after cessation but remained significantly elevated > or =10 years after last use (RR, 1.5; 95% CI, 1.0-2.1). CONCLUSIONS: Both estrogen plus progestin regimens significantly increased endometrial carcinoma risk in this study. Risks among unopposed estrogen users remained elevated long after last use. The prospect that all estrogen plus progestin regimens increase endometrial carcinoma risk deserves continued research.

Aged↗

PubMed1980

A sex difference in the progestin receptor system of guinea pig brain.

Female guinea pigs are more sensitive than males to the lordosis-promoting effects of sequential estradiol-progesterone treatment. This study explored a possible cellular basis for this reduced sensitivity. Cytoplasmic progestin receptor concentrations were determined using a [3H]R5020 binding assay for a dissection of brain tissue which included the hypothalamus, preoptic area and septum (HPS) from male and female guinea pigs 40 h after administration of estradiol benzoate (EB). Male guinea pigs injected with 10 micrograms EB have a progestin binder in cytosol from HPS and cerebral cortex that is similar to that in females on the basis of apparent dissociation constant and steroid specificity. Injection of either 1.6 or 10 micrograms EB caused a larger increase in the concentration of cytoplasmic progestin binding in female HPS compared to the same dose in males. A 10 microgram EB injection induced a concentration of progestin binding in male hypothalamus not significantly different from that induced in female hypothalamus by a 1.6 microgram EB injection (a dose that consistently facilitates sexual recepivity in females when followed 40 h later by 0.5 mg progesterone). Despite the induction by EB of a behaviorally-sufficient concentration of cytoplasmic progestin receptors, fewer males (3/10) than females (8/10) responded to EB (10 micrograms)-progesterone treatment with the expression of lordosis. Finally, using a nuclear progestin receptor [3H]R5020 exchange assay, we found that male guinea pigs injected with 10 micrograms EB accumulated a slightly lower concentration of progestin receptors in HPS cell nuclei 4 h after a 0.5 mg progesterone injection than similarly-treated females. Therefore, male guinea pigs show decreased induction of cytoplasmic progestin receptors in HPS after estradiol injection, and a decreased cell nuclear accumulation of these receptors after progesterone injection compared to females. We conclude that this sex difference in the progestin receptor system is insufficient to account, in itself, for the sex difference in behavioral sensitivity to estradiol and progesterone.

Animals↗

PubMed2002

G protein-coupled receptor 30 is critical for a progestin-induced growth inhibition in MCF-7 breast cancer cells.

The issue of how progesterone affects mammary gland growth is controversial, and the mechanism governing the effects of the hormone remains mostly unknown. We have previously shown that G protein-coupled receptor 30 (GPR30) is a progestin target gene whose expression correlates with progestin-induced growth inhibition in breast cancer cells. In this study, we investigate the role of GPR30 in regulating cell proliferation and mediating progestin-induced growth inhibition. When progestin failed to inhibit the growth of MCF-7 cells and instead stimulated growth, GPR30 was down-regulated. In this way, the inhibitory or stimulatory affects that progestin has on proliferation correlated with the level of expression of GPR30. Transient expression of GPR30 resulted in a marked inhibition of cell proliferation independent of estrogen treatment. GPR30 antisense was used to evaluate the role of GPR30 expression in progestin-induced growth inhibition. A diminished GPR30 mRNA expression by the antisense stimulated growth. Interestingly, GPR30 antisense abrogated the growth inhibitory effect of progestin and progesterone. Indeed, progestin induced 1) a reduction in cell proliferation, 2) G1-phase arrest, and 3) down-regulation of cyclin D1 was diminished. These data suggest that the orphan receptor, GPR30, is important for the inhibitory effect of progestin on growth.

Breast Neoplasms↗

PubMed2003

Effect of estrogen plus progestin on global cognitive function in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial.

CONTEXT: Observational studies have suggested that postmenopausal hormone treatment may improve cognitive function, but data from randomized clinical trials have been sparse and inconclusive. The Women's Health Initiative Memory Study (WHIMS) is an ancillary study of the Women's Health Initiative (WHI) hormone therapy trials. On July 8, 2002, the estrogen plus progestin therapy in the WHI trial was discontinued because of certain increased health risks for women. OBJECTIVE: To determine whether estrogen plus progestin therapy protects global cognitive function in older postmenopausal women. DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled clinical trial, WHIMS is an ancillary study of geographically diverse, community-dwelling women aged 65 years or older from 39 of 40 clinical centers within the WHI estrogen plus progestin trial that started in June 1995. Of 4894 eligible postmenopausal women aged 65 years or older and free of probable dementia at baseline, 4532 (92.6%) were enrolled in the estrogen plus progestin component of WHIMS. A total of 4381 participants (96.7%) provided at least 1 valid cognitive function score between June 1995 and July 8, 2002. INTERVENTIONS: Participants received either 1 daily tablet containing 0.625 mg of conjugated equine estrogen with 2.5 mg of medroxyprogesterone acetate (n = 2145) or matching placebo (n = 2236). MAIN OUTCOME MEASURE: Global cognitive function measured annually with the Modified Mini-Mental State Examination. RESULTS: The Modified Mini-Mental State Examination mean total scores in both groups increased slightly over time (mean follow-up of 4.2 years). Women in the estrogen plus progestin group had smaller average increases in total scores compared with women receiving placebo (P =.03), but these differences were not clinically important. Removing women by censoring them after adjudicated dementia, mild cognitive impairment, or stroke, and nonadherence to study protocol, did not alter the findings. Prior hormone therapy use and duration of prior use did not affect the interpretation of the results, nor did timing of prior hormone therapy initiation with respect to the final menstrual period. More women in the estrogen plus progestin group had a substantial and clinically important decline (> or =2 SDs) in Modified Mini-Mental State Examination total score (6.7%) compared with the placebo group (4.8%) (P =.008). CONCLUSIONS: Among postmenopausal women aged 65 years or older, estrogen plus progestin did not improve cognitive function when compared with placebo. While most women receiving estrogen plus progestin did not experience clinically relevant adverse effects on cognition compared with placebo, a small increased risk of clinically meaningful cognitive decline occurred in the estrogen plus progestin group.

Aged↗

PubMed2003

Effect of estrogen plus progestin on stroke in postmenopausal women: the Women's Health Initiative: a randomized trial.

CONTEXT: The Women's Health Initiative (WHI) trial of estrogen plus progestin was stopped early because of adverse effects, including an increased risk of stroke in the estrogen plus progestin group. OBJECTIVE: To assess the effect of estrogen plus progestin on ischemic and hemorrhagic stroke and in subgroups, and to determine whether the effect of estrogen plus progestin was modified by baseline levels of blood biomarkers. DESIGN: Multicenter double-blind, placebo-controlled, randomized clinical trial involving 16 608 women aged 50 through 79 years with an average follow-up of 5.6 years. Baseline levels of blood-based markers of inflammation, thrombosis, and lipid levels were measured in the first 140 centrally confirmed stroke cases and 513 controls. INTERVENTIONS: Participants received 0.625 mg/d of conjugated equine estrogen plus 2.5 mg/d of medroxyprogesterone acetate (n = 8506) or placebo (n = 8102). MAIN OUTCOME MEASURES: Overall strokes and stroke subtype and severity were centrally adjudicated by stroke neurologists. RESULTS: One hundred fifty-one patients (1.8%) in the estrogen plus progestin and 107 (1.3%) in the placebo groups had strokes. Overall 79.8% of strokes were ischemic. For combined ischemic and hemorrhagic strokes, the intention-to-treat hazard ratio (HR) for estrogen plus progestin vs placebo was 1.31 (95% confidence interval [CI], 1.02-1.68); with adjustment for adherence, the HR was 1.50 (95% CI, 1.08-2.08). The HR for ischemic stroke was 1.44 (95% CI, 1.09-1.90) and for hemorrhagic stroke, 0.82 (95% CI, 0.43-1.56). Point estimates of the HRs indicate that excess risk of all stroke was apparent in all age groups, in all categories of baseline stroke risk, and in women with and without hypertension, prior history of cardiovascular disease, use of hormones, statins, or aspirin. Other risk factors for stroke, including smoking, blood pressure, diabetes, lower use of vitamin C supplements, blood-based biomarkers of inflammation, higher white blood cell count, and higher hematocrit levels did not modify the effect of estrogen plus progestin on stroke risk. CONCLUSIONS: Estrogen plus progestin increases the risk of ischemic stroke in generally healthy postmenopausal women. Excess risk for all strokes attributed to estrogen plus progestin appeared to be present in all subgroups of women examined.

Aged↗

PubMed2005

Estrogen-plus-progestin use and mammographic density in postmenopausal women: Women's Health Initiative randomized trial.

BACKGROUND: Increased mammographic density reduces the sensitivity of screening mammography, is associated with increased breast cancer risk, and may be hormone related. We assessed the effect of estrogen-plus-progestin therapy on mammographic density. METHODS: In a racially and ethnically diverse ancillary study of the Women's Health Initiative, we examined data from 413 postmenopausal women who had been randomly assigned to receive daily combined conjugated equine estrogens (0.625 mg) plus medroxyprogesterone acetate (i.e., progestin; 2.5 mg) (n = 202) or daily placebo (n = 211). We assessed the effect of estrogen plus progestin on measured mammographic percent density and abnormal findings over a 1-year and 2-year period. All tests of statistical significance were two-sided and were based on F tests or t tests from mixed-effects models. RESULTS: Mean mammographic percent density increased by 6.0% at year 1, compared with baseline, in the estrogen-plus-progestin group but decreased by 0.9% in the placebo group (difference = 6.9%, 95% confidence interval [CI] = 5.3% to 8.5%; P < .001). The mean changes in mammographic density persisted but were attenuated slightly after 2 years, with an absolute increase of 4.9% in the estrogen-plus-progestin group and a decrease of 0.8% in the placebo group (difference = 5.7%, 95% CI = 4.3% to 7.3%; P < .001). These effects were consistent across racial/ethnic groups but were higher among women aged 70-79 years in the estrogen-plus-progestin group (mean increase at year 1 = 11.6%) than in the placebo group (mean decrease at year 1 = 0.1%) (difference of the means = 11.7%, 95% CI = 8.2% to 15.4%; P < .001, comparing across age groups). At year 1, women who were adherent to treatment in the estrogen-plus-progestin group had a mean increase in density of 7.7% (95% CI = 5.9% to 9.5%), and women in the placebo group had a mean decrease in density of 1.1% (95% CI = 0.3% to 1.9%). Use of estrogen plus progestin was associated with an increased risk of having an abnormal mammogram at year 1 (relative risk = 3.9, 95% CI = 1.5 to 10.2; P = .003), compared with placebo, that was not explained by an increase in density. CONCLUSIONS: Use of up to 2 years of estrogen plus progestin was associated with increases in mammographic density.

Age Factors↗

PubMed1990

Nuclear progestin receptors in rat thymic tissue.

The thymus and its associated endothelial cells and lymphocytes act as an important immunological tissue. The endothelial cells of the thymus have been reported to synthesize cytoplasmic progestin receptor in response to estrogen priming. To measure nuclear progestin receptor, female rats were castrated and primed for 3 days with estradiol benzoate (30 micrograms/0.1 ml/d) and immediately before sacrifice injected subcutaneously with 0.2 mg of progesterone. By Scatchard plot analysis we found that specific progestin receptor (KA = 0.89 +/- 0.10 x 10(9) M-1) was present in the KCl-nuclear extract. The concentration of nuclear progestin receptor was found to be in the range of 312.6 +/- 49 fmole/g tissue (n = 9, 1 hour after progesterone injection) while the nuclear receptor was significantly reduced (approximately 44 fmol/g tissue) in the oil treated controls. This level verges on the limits of sensitivity for this assay. For cytoplasmic progestin receptor the concentration was 3.46 +/- 0.20 pmole/g tissue in oil treated controls (n = 14) and 3.36 +/- 0.20 pmole/g tissue in progesterone treated animals (n = 24). The KA of this thymic cytoplasmic progestin receptor was 1.35 +/- 0.06 x 10(9) M-1. By competition assay, the relative binding affinity of nuclear progestin receptor was: R5020 (a potent synthetic progestin) (100%), progesterone (9%), testosterone (0.56%), corticosterone (0.53%), estradiol-17 beta (0%). It is concluded that thymic reticuloepitheleal cells contain nuclear progestin receptor and this finding supports the hypothesis that progesterone, like other sex steroids may play a regulatory role in thymic cell function.

Animals↗

PubMedDate not supplied

Desogestrel, norgestimate, and gestodene: the newer progestins.

OBJECTIVE: To review and compare the newer progestins desogestrel, norgestimate, and gestodene with regard to chemistry, pharmacokinetics, efficacy, and tolerability. DATA SOURCES: Primary literature on desogestrel, norgestimate, and gestodene was identified from a comprehensive MEDLINE English-literature search from 1984 through 1994, with additional studies selected by review of the references. Indexing terms included progestins, desogestrel, gestodene, norgestimate, levonorgestrel, and norgestrel. STUDY SELECTION: Only human clinical and pharmacokinetic trials performed in Europe, Canada, and the US were included. DATA EXTRACTION: All available data from human studies were reviewed; both comparative and noncomparative studies were included because of the paucity of direct comparative information available. DATA SYNTHESIS: The newer progestins were designed to minimize the adverse effects (e.g., acne, hirsuitism, nausea, carbohydrate and lipid metabolism changes) observed with older oral contraceptives (OCs) while maintaining efficacy and good menstrual cycle control. Desogestrel, norgestimate, and gestodene have minimal amounts of androgenicity and antiestrogenic potential. All of these agents are pharmacokinetically similar to older agents: they are highly bioavailable when administered orally, hepatically metabolized, and obtain steady-state concentrations after 8-10 days of continuous administration. The newer agents have similar Pearl Indexes and slightly better cycle control. Furthermore, the new progestins appear to cause fewer adverse effects, such as acne and hirsuitism, and similar rates of weight gain, blood pressure changes, and lipid and carbohydrate metabolism changes. CONCLUSIONS: Desogestrel, norgestimate, and gestodene appear to offer clinical advantages because of their decreased androgenicity. Women whose cycles are currently well controlled with other OCs should not be switched to a newer progestin. However, any of the combination OC products that contain these progestins may be prescribed for women intolerant of older agents or to first-time users of OCs. The newer progestins appear to be efficacious and offer similar cycle control, improved safety and tolerability profiles, and comparable price with the older agents.

Clinical Trials as Topic↗

PubMed2001

Pharmacological and endogenous progestins induce vascular endothelial growth factor expression in human breast cancer cells.

Tumor expansion is dependent on angiogenesis, which is regulated by peptide growth factors of which vascular endothelial growth factor (VEGF) is one of the most selective and potent. VEGF expression is regulated by steroid hormones in a number of systems, including T47-D human breast cancer cells in which VEGF protein levels are elevated by progestins. In the present study, we investigated the effect of progestins on VEGF mRNA levels in human breast cancer cells. For these experiments, T47-D cells were exposed to progestins, RNA was prepared for measurement of VEGF transcript levels by Northern blot analysis and VEGF protein in the cell culture media was measured by enzyme-linked immunosorbent assay. Basal expression of VEGF mRNA is low in these cells, and is rapidly induced following exposure to progestins, reaching a maximum induction of 2- to 5-fold between 3 and 6 hr after hormone addition. This induction was inhibited by the antiprogestin RU-486 indicating that it is progesterone receptor (PR) dependent. Transcripts for VEGF165 and VEGF121 were the two major spliced forms of VEGF mRNA that were detected by reverse transcription-polymerase chain reaction in basal and progestin-stimulated T47-D cells. Maximum induction of VEGF mRNA was achieved with 10(-8) M progesterone, and induction was hormone specific, as estrogens, glucocorticoids, and androgens were without effect. Actinomycin D completely abolished the induction of VEGF transcript levels by progestins, suggesting that this response involves de novo mRNA synthesis, but puromycin did not inhibit induction, suggesting that this effect does not require protein synthesis. This report demonstrates that progestins stimulate VEGF mRNA levels and raises the possibility that anti-progestins may be useful to inhibit proliferation and metastasis in some human breast cancers by blocking VEGF production.

Alternative Splicing↗

PubMed1997

Binding activity of 5alpha-reduced gestagens to the progestin receptor from African elephant (Loxodonta africana).

Recent findings in the African elephant (Loxodonta africana) indicate that the major progestins contained within and biosynthesized by corpora lutea are 5alpha-reduced metabolites and that progesterone is quantitatively of minor importance. The specific gestagenic action within the reproductive tract of elephants was determined by measurement of relative binding affinity of the respective progestins to the gestagen receptor extracted from elephant endometrium. The cytosol was incubated with 40 nmol/liter [3H]ORG-2058 and increasing concentrations of the tested progestin. Progesterone (P4), 5alpha-pregnane-3,20-dione (DHP), and 5alpha-pregnane-3alpha-ol-20-one (5alpha-P-3OH) were used. The competition for binding sites on the progestin receptor was shown by decreasing counts measured after extraction with scintillation fluid. The progestin concentration which induced a 50% reduction of measured counts was estimated (C50) and relative binding affinity of progesterone to other progestins was calculated (RBA = C50progestin/C50p4). The relative binding affinity of DHP to P4 at the gestagen receptor of elephant endometrium was equivalent. The other 5alpha-reduced progestin (5alpha-P-3OH) showed no competition to the [3H]ORG-2058 receptor binding. We conclude that the biological significance of P4 and DHP at the receptor level is very similar. The higher quantitative levels of DHP in corpus luteum and serum support the hypothesis that this progestin is the major gestagen in the elephants, whereas 5alpha-P-3OH is an inactive metabolite.

5-alpha-Dihydroprogesterone↗

PubMed1992

The role of progestins in hormone replacement therapy.

Long-term estrogen replacement therapy prevents osteoporosis and reduces the risk of cardiovascular disease in postmenopausal women. Progestins are used to prevent endometrial hyperplasia and carcinoma but should not be prescribed for women who have had hysterectomies. Doses that decrease mitotic activity are sufficient. Recent data suggest that a continuous combined regimen of estrogen and progestin may increase bone mass in women who have established osteoporosis. Some progestins may oppose the beneficial effects of estrogen on the cardiovascular system in some women. Critical cardiovascular effects of progestins include a reduction in the serum level of high-density lipoprotein cholesterol and a direct effect on arterial tone, which may be mediated by an attenuation of prostacyclin production and other factors. Therefore it is prudent to prescribe the lowest effective dose of a progestin that demonstrates the least metabolic impact. The dose and type of progestin should be balanced with the estrogen component so that the estrogen-dominant metabolic effects prevail. With this approach the difference in mortality rates between women who use unopposed estrogen and women who use estrogen-progestin therapy will be minimized and will make the appropriate sequential addition of progestin an option in postmenopausal hormone replacement therapy.

Estrogen Replacement Therapy↗