Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0338671 (Steroids)
 9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The molecular conformation of 17-hydroxy-6 alpha-methylprogesterone has been determined crystallographically and is compared with 17-hydroxy-progesterone, 17-acetoxyprogesterone and 17-acetoxy-6 alpha-methylprogesterone (MPA). The analysis demonstrates that the 6 alpha-methyl substituent is not sufficient by itself to induce inversion of the A-ring. Consequently, the inverted form observed in MPA and proposed to be responsible for high affinity binding to the progesterone receptor appears to be induced by the combined long range influence of 17 alpha-acetoxy substituent and the direct interaction of the 6 alpha-methyl group with the flexible A-ring.
Steroids 1979 Nov
PMID:Steroid structure and function V. A-ring conformation in 17-hydroxy-6 alpha-methylprogesterone. 51 15

In vivo research has shown that the gestagenic potency of MPA (medroxyprogesterone acetate) is greater than that of progesterone in virtually all species tested. It was hypothesized that this was due to a slower rate of metabolism of MPA relative to progesterone. In women, the clearance rate of the 2 substances was found to be similar, suggesting that the functional groups at the 6alpha- and 17alpha-positions might not influence the rate of progestin metabolism in humans as had been suspected. To test this hypothesis, independent effects of the 6alpha-methyl and the 17alpha-acetoxy substitutions on the metabolism of progesterone were examined. For this purpose, 6alpha-methylprogesterone was synthesized for metabolic studies. The clearance rate of this substance, tested by plasma concentrations, was found to be higher than that of either MPA or progesterone. This rate was not attributable to binding or metabolism by red cells. The differences in clearance rates do not seem to be related to steroid-protein interactions in plasma.
Steroids 1977 May
PMID:The in vivo metabolism of progestins. IV. The metabolic clearance rate and plasma binding of 6alpha-methylpregn-4-ene-3, 20-dione in women. 89 33

Radioimmunoassay of serum medroxyprogesterone (MPA, Provera) in 7 wo men following oral and intravaginal administration is presented. The assay utilizes benzene: isooctane extraction, tritiated-MPA to assess procedural losses, goat-MPA-(O-carboxymethyl) oxime-bovine serum albumin serum, and dextran coated charcoal separation. Buffer and control serum blanks were indistinguishable from 0. 200 pg/ml of MPA was measurable with high reliability, and intra- and interassy coefficients of variation were 6 and 13%, respectively. Various amounts of MPA added to control serum were measured with accuracy. MPA levels in the 3 women who injested 10 mg of MPA rose to 3.4-4.4 ng/ml within 1-4 hours after oral intake and fell rapidly thereafter to .3-.6 ng/ml within 24 hours. MPA levels in the 4 women with Silastic intravaginal rings (IVRs) containing 100 or 200 mg of MPA rose rapidly after insertion, were rather stable (.9-1.6 ng/ml) while the IVRs were in place, and declined rapidly following IVR removal. Estradiol-17 beta and progesterone levels indicated that ovulation was consistently inhibited. The MPA levels in this study were approximately 5 times lower than those reported by others using a double-antibody radioimmunoassay of MPA in unextracted serum.
Steroids 1975 Sep
PMID:Radioimmunoassay of serum medroxyprogesterone acetate (Provera) in women following oral and intravaginal administration. 119 24

Uteri and cervices were obtained from estrous rabbits (controls) and from rabbits 24 h or 7 days after a single intramuscular injection of medroxyprogesterone acetate (MPA; 2.14 mg/kg). Estrogen and progesterone receptor concentrations were measured by Scatchard analysis, cell-free DNA synthesis was measured by (3H)-TTP incorporation, and tissue sections were examined histologically. The uterine endometrium underwent marked changes in histology, including extensive infoldings of the mucosal surface, glands were continuous into crypts and secretory epithelial cells were noted. In addition, total estrogen receptor content and DNA synthesis were decreased. In contrast, there was no significant change in the histology of the endocervical epithelial-stromal complex, and total estrogen receptor remained constant. However, DNA synthesis in the endocervix was decreased. Thus we conclude that: DNA synthesis is not linked to changes in estrogen receptor in the endocervix; and differential effects of progestogen on the estrogen receptor system occur coincident with different morphological responses within two target tissues from the same animal.
Steroids
PMID:Differential responses of rabbit endocervix and uterus to medroxyprogesterone acetate. 294 53

Estrogen replacement therapy (ERT) increases a woman's risk of developing endometrial cancer approximately 120% for each 5 years of use. ERT increases a woman's risk of developing breast cancer approximately 10% for each 5 years of use. To reduce the greatly increased endometrial cancer risk, progestins have been added to ERT (estrogen-progestin replacement therapy; EPRT) for between 5 and 15 days (usually 7 or 10 days) per month in a sequential fashion (sequential EPRT; SEPRT) or with each dose of ERT (continuous-combined EPRT; CEPRT). We conducted two large case-control studies in postmenopausal women in Los Angeles to evaluate the effects of these changes on endometrial and breast cancer risks. As expected CEPRT was not associated with any increased risk of endometrial cancer. SEPRT with the progestin being given for 10 days per month also did not increase endometrial cancer risk. SEPRT with the progestin being given for 7 days per month did increase endometrial cancer risk with only a relatively slight reduction in risk compared to ERT effectively proportional to the reduction in the number of days of unopposed estrogen. The sharp contrast between the effects of 7 days and 10 days of progestin in SEPRT suggests that the extent of endometrial sloughing or of 'terminal' differentiation at the completion of the progestin phase may play a critical role in determining endometrial cancer risk. This may provide an explanation of why endometrial cancer risk increases so sharply with age in young women even in countries where obesity-associated anovulation is very uncommon; extended periods of unopposed estrogen is not an explanation but less than 10 days of an 'adequate' progesterone level may be. EPRT significantly increased the risk of breast cancer. EPRT was associated with an approximately 24% increase in risk for each 5 years of use; the effect was some 212-fold greater than the effect of ERT, which we had previously predicted on theoretical grounds. This effect could also be predicted from the results on mammographic densities seen in the PEPI randomized trial of different forms of hormone replacement therapy (HRT). In the PEPI trial EPRT increased mammographic densities to a much greater extent than ERT. Progestins need to be given to protect the endometrium. They need to be delivered to the endometrium in a manner that will have the least effect on the breast. This can be carried out by using a vaginal or direct endometrial route of administration. The vaginal route will provide adequate endometrial progestin levels with low blood levels so that the effects of the progestin on the breast should be small; with the direct endometrial route the blood progestin levels are even lower, and the effects of the progestin on the breast will be effectively zero. If this is unacceptable to a woman, then giving progestins by mouth (or transdermally) for 10 days every 3 to 4 months should provide satisfactory protection of the endometrium when used with standard-dose conjugated estrogen (CE). This regimen has much less effect on the breast than monthly SEPRT or CEPRT. Two clinical trials of 10 mg per day of MPA for 14 days every 3 months and 0.625 mg/day of CE have been published. Both studies suggest that this approach may be satisfactory in that the extent of hyperplasia was minimal. More studies of this approach are urgently needed.
Steroids
PMID:Progestins and menopause: epidemiological studies of risks of endometrial and breast cancer. 1110 73

Whether progestins protect against the risk of breast cancer or enhance that risk has been a major area of controversy over the past several years. Observational studies have reported conflicting results and experimental studies examining whether progestins exert mitogenic or anti-mitogenic actions on breast tissue report divergent results. Based upon a wide range of animal, epidemiologic and clinical data, most investigators agree that estrogens contribute to the development of breast neoplasms. However, the additional effect of progestins on this risk has been the subject of substantial discussion and controversy. A variety of experiments have been carried out using human breast cancer cells grown in vitro and as xenografts in nude mice. These studies demonstrated both mitogenic and anti-mitogenic effects depending upon the precise experimental conditions. Two potential reasons for these differences include differential metabolism of progestins into inhibitory pregnenes or stimulatory 5-alpha-reduced pregnanes or the presence of a protein (GPR 30) which allows the anti-mitogenic effects of progestins to be manifest. Based upon the conflicting nature of the results in experimental studies, we believe that only data in patients provide substantial insight into the actions of progestins on the intact human breast. Studies have now demonstrated that cell proliferation and breast density is higher during the luteal than during the follicular phase of the menstrual cycle. In postmenopausal women, long-term exposure to estrogen plus a progestin results in a marked enhancement of proliferation of the terminal duct lobular units as well as in breast density. These data, taken together, provide substantial evidence that progestins are mitogenic on the human breast when given long term to postmenopausal women. To critically evaluate the observational studies regarding breast cancer risk from progestins, we developed a set of stringent criteria for acceptance of individual studies. Four of the five studies meeting these criteria reported a greater risk of breast cancer with combination estrogen/progestin regimens than with estrogen alone. More importantly, the first randomized, prospective, controlled trial of the risk of breast cancer with an estrogen/progestin combination (the Women's Health Initiative Study) has now been published. This study reported a 26% increased relative risk of breast cancer with the estrogen/progestin combination. Based upon these data, we believe that progestins do add to the risk of breast cancer over and above that imparted by estrogen alone. The attributable risk during use for 5 years or less is small but increases logarithmically during long-term use. The majority of data regarding progestins are derived from regimens using MPA. However, we conclude from our analysis that the burden of proof regarding progestins has now shifted. One must now prove that an estrogen/progestin combination is safe with respect to breast cancer rather than having to prove it harmful.
Steroids 2003 Nov
PMID:Risk of breast cancer with progestins: critical assessment of current data. 1466 88

The chemical study of the Antarctic octocoral Dasystenella acanthina has led to the isolation of the new polyoxygenated steroids (24R,22E)-24-hydroxycholest-4,22-dien-3-one (1), 23-acetoxy-24,25-epoxycholest-4-en-3-one (2), 12beta-acetoxycholest-4-en-3,24-dione (3), 12beta-acetoxy-24,25-epoxycholest-4-en-3-one (4), (22E)-25-hydroxy-24-norcholest-4,22-dien-3-one (5), 3alpha-acetoxy-25-hydroxycholest-4-en-6-one (6), and 3alpha,11alpha-diacetoxy-25-hydroxycholest-4-en-6-one (7), whose structures have been established by spectroscopic analysis. The absolute stereochemistry at C-24 in compound 1 has been determined through the 1H NMR study of the corresponding (R)- and (S)-MPA esters. All the new compounds showed significant activities as growth inhibitors of several human tumor cell lines. In addition, cytostatic and cytotoxic effects were also observed on selected tumor cell lines.
Steroids 2004 Apr
PMID:New polyoxygenated steroids from the Antarctic octocoral Dasystenella acanthina. 1518 95

Dienogest was introduced as an oral progestin. Yet its strong oral potency on endometrial activity is not clearly explained. To circumvent this situation, steroid hormone receptor profiling using transactivation assay and endometrial activity test in rabbits were carried out with determination of plasma drug concentration. Agonistic/antagonistic activity on human progesterone receptor (PR), androgen receptor (AR), glucocorticoid receptor (GR), mineralocorticoid receptor (MR), estrogen receptor alpha (ERalpha), or estrogen receptor beta (ERbeta) were determined. Dienogest activate PR (EC50=3.4 or 10.5 nmol/l) with antagonistic activity on AR (EC50=420.6 or 775.0 nmol/l) but not agonistic nor antagonistic action on GR, MR (3000 nmol/l). Dienogest activate neither ERalpha nor ERbeta (3000 nmol/l). Progesterone activated PR with antagonistic activity on AR and on MR. Dydrogesterone showed a similar profile to progesterone. Norethisterone activated PR, AR, and ERalpha. Medroxyprogesterone acetate activated PR, AR, and GR. Danazol activated PR and AR. Collectively, dienogest has a good specificity to PR compared with the other drugs. By oral treatment, dienogest showed the strongest endometrial activity (ED50=0.0042 mg/kg) in McPhail test among other progestins (ED50 values for MPA, DYG, NES were 0.074, 1.9, >0.05 mg/kg, respectively). Dienogest showed higher plasma concentrations than those of the other progestins with higher doses. The estimated plasma concentration of dienogest at ED50 (3.66 nmol/l) was close to its EC50 value to activate PR. Thus, the stronger oral activity of dienogest could be explained simply by its in vitro potency on PR and its oral pharmacokinetic profile.
Steroids 2008 Feb
PMID:Dienogest is a selective progesterone receptor agonist in transactivation analysis with potent oral endometrial activity due to its efficient pharmacokinetic profile. 1806 38