Hypotheses: Melatonin/steroid combination contraceptives will prevent breast cancer

Summary The use of the conventional combination oral contraceptives (containing ethinyl-estradiol and a progestin) is associated with reduced risk of ovarian and endometrial cancer. However, prolonged use of these pills before first term pregnancy apparently increases the risk of pre menopausal breast cancer. We propose that the pineal gland hormone melatonin, combined with a progestin, as a new and novel oral contraceptive combination might prevent breast cancer in long term users. This hypothesis is based on the assumption that women have a propensity to develop breast cancer which correlates with number of ovulatory cycles over their lifetime. In evolution, the phylogenetic point at which women became sensitive to breast cancer evolved at a transfer point of the mechanism of ovulation from seasonal ovulation, which is still common in many mammalian species, to the current human pattern of continuous ovulatory cycles. We suggest that melatonin/ovariansteroid contraceptive will restore the lost mechanism of endogenous anovulation, and thus, by preventing continuous epithelial breast cell proliferation, will reduce the risk of breast cancer in long-term users.     

HPLC法同时测定复方雌二醇控释贴片中雌／孕激素的含量

目的：建立同时测定复方雌二醇透皮控释巾片中雌二醇（Ｅ２）和炔诺酮醋酸酯（ＮＥＴＡ）含量的反相ＨＰＬＣ法。方法：色谱柱为岛津柱（５μｍ,６．０ｍｍ＊１５０ｍｍ）检测波长为２８０ｍｍ（０－－８．５ｍｉｎ）,２４０ｎｍ（８．５１－－１５ｍｉｎ）;流动相为甲醇－水（７５：２５）。结果：Ｅ２、ＮＥＴＡ线性范围分别为２．０～２０、６．０～６０ｍｇ．Ｌ^-1。平均回收率分别为１０１．０％（ＲＳＤ＝１．６％）、９９     

Effects of levonorgestrel, medroxyprogesterone acetate, norethindrone, and 17beta-estradiol on vascular endothelial growth factor isomers 121 and 165 in Ishikawa cells

OBJECTIVE: To determine the effect of 17beta-E(2), levonorgestrel, medroxyprogesterone acetate, and norethindrone on the expression of vascular endothelial growth factor (VEGF) isoforms 121 and 165 in Ishikawa cells in vitro. DESIGN: Prospective basic research study. SETTING: Basic research laboratory. PATIENT(S): None. INTERVENTION(S): Ishikawa cells were cultured in vitro. After 24 hours' incubation in serum-free media, 1.0, 0.1, and 0.01 microM concentrations of E(2), levonorgestrel, medroxyprogesterone acetate, and norethindrone were added for a further 24 hours of incubation. MAIN OUTCOME MEASURE(S): Isolation and identification of VEGF isoforms 121 and 165 using semiquantitative polymerase chain reaction, gel electrophoresis, with beta-actin as an internal control. RESULT(S): Estradiol stimulated VEGF isoforms 121 and 165. The progestins studied increased mRNA for VEGF isoforms 121 and 165 at all doses. Medroxyprogesterone acetate resulted in the greatest increase in both VEGF 121 and 165 compared with norethindrone and levonorgestrel. CONCLUSION(S): Estradiol and progestins increased VEGF 121 and 165 isoform mRNA in Ishikawa cells in vitro. We hypothesize that differences in VEGF expression may be associated with the irregular bleeding during progestin use in clinical situations.     

Tissue Response to Bioerodible,Subcutaneous Drug Implants: A Possible Determinant of Drug Absorption Kinetics

The fibrous tissue compartments that develop in response to the subcutaneous implantation of bioerodible heat-fused rods of norethindrone and cholesterol (85 and 15%, respectively) were studied by light and electron microscopy at various intervals after implantation to determine whether the biological inflammatory response may play a role in drug absorption. Thirty-five regularly menstruating, sterilized (tubal ligation), healthy females each received four Annuelle rods. The microanatomy of seven of the largest implants (135 mg norethindrone) was studied. A dense fibrous biological compartment was found to surround each rod. By light microscopy no abnormal tissue response was revealed. Scanning and transmission electron microscopy showed that the surfaces of the rods were covered by a cellular matrix of mononuclear cells. The fibrous compartment was composed of a loose cellular bed immediately surrounding the norethindrone rod, a dense fibrous connective tissue envelope containing blood and lymphatic vessels, and an outer fatty connective tissue layer. Transmission electron microscopy confirmed that the cellular tissue immediately surrounding the rods was composed mainly of lipid laden macrophages. Norethindrone levels in tissue capsules at 3 and 10.5 months were 0.05 and 8.4% by weight, respectively. These observations suggest that the local imflammatory response plays a role in the active processing of this delivery system. This picture is qualitatively different from the general view of the fibrous capsule as a simple rate limiting membrane. The effects observed in this study suggest that a more complex, functional biological system develops in response to the subcutaneous introduction of a drug delivery device.     

A randomized study of metabolic effects of four low-estrogen oral contraceptives: I. Results after 6 cycles

Healthy, non-smoking, normotensive, well-motivated young women were assigned at random to one of four different, commercial, low-estrogen, oral contraceptive products. Measurements of biochemical parameters were made on blood specimens collected from fasting subjects twice during the late pretreatment cycle, then again during each late treatment cycle for six months. All women assigned to one product (0.5mg NET + 35 microgram EE) dropped out of the study before the end of the fifth cycle, but discontinuations with the other three products were few. While numbers of subjects are small, the groups are closely matched and most metabolic differences are statistically significant. Products containing EDA and NET were associated with increases in serum total cholesterol and triglycerides, but decreases in HDL-cholesterol. In contrast, the LNG-containing preparation produced significantly less effect on these tests. A similar pattern was seen with a range of blood coagulation and fibrinolytic factors, Minimal alterations were seen with the LNG preparation, while those containing NET or EDA showed marked increases in factors I. VII, VIII, X and plasminogen, associated with a decrease in antithrombin III. It is suggested that differences in the metabolic impact of the various commercially available low-estrogen preparations, combined with effects on intermenstrual bleeding, allow a choice of the progestogen component most suitable for general use.     

Aromatase inhibitors: the next generation of therapeutics for endometriosis?

OBJECTIVE AND DESIGN: To review the role of aromatase inhibitors (AIs) in the treatment of endometriosis. CONCLUSION(S): Endometriosis is a common estrogen-dependent disorder that can result in substantial morbidity, including pelvic pain, multiple operations, and infertility. Approximately only half of women with endometriosis get pain relief from existing medical or surgical treatments. Medical treatments usually are directed at inhibiting estrogen action or its production from the ovaries and do not address local estrogen biosynthesis by the aromatase enzyme in endometriotic lesions. A single gene encodes aromatase, which is the final enzyme in the estrogen biosynthesis pathway, and its inhibition effectively eliminates estrogen production. The recently introduced highly specific AIs have successfully treated pelvic pain and significantly reduced the lesion size. In premenopausal women, an AI alone may induce ovarian folliculogenesis, and thus AIs are combined with a progestin, a combination oral contraceptive, or a GnRH analogue. The side-effect profile of AIs administered in combination with an oral contraceptive or a progestin is remarkably benign. We review herein the published clinical evidence for the use of AIs in the treatment of endometriosis.     

炔诺酮、米非司酮治疗绝经过渡期功能性子宫出血的对比性研究

目的：探讨炔诺酮、米非司酮治疗绝经过渡期功能性子宫出血（功血）的疗效及其对性激素的影响。方法：选择绝经过渡期功血患者６０例，随机分为两组，各３０例，其中一组为炔诺酮组，另一组为米非司酮组。用药前后测定血ＦＳＨ、ＬＨ、Ｐ、Ｅ２，停药后观察３个月的月经情况。结果：使用两种药物治疗绝经过渡期功血均有效，性激素改变：米非司酮组显示用药后ＦＳＨ、Ｐ较用药前降低，ＬＨＬ略有升高，均有统计学意义，Ｅ２略降低，但无统计学意义；炔诺酮组均无明显变化。结论：使用炔诺酮治疗绝经过渡期功血更符合绝经过渡期妇女的生理过程．而且其副作用小、价廉，使用方便。     

Novel progesterone receptor modulators with gene selective and context-dependent partial agonism

Progesterone receptor (PR) modulators are used in contraception and post-menopausal hormone therapy, and are under clinical development for reproductive disorders such as uterine fibroids and endometriosis. Development of tissue selective PR modulators (SPRMs) with reduced side effects and improved pharmacology represents a large unmet medical need in the area of women’s health. One approach to addressing this need is to focus on the two PR isoforms PR-A and PR-B. In vitro and in vivo studies have revealed both distinct as well as overlapping gene regulation and functional responses of the two PR isoforms that suggests that PR-A selective modulators may retain a desired biological profile. We have identified a chemical series of 4-(4-chlorophenyl)-substituted piperazine carbimidothioic acid esters (PCEs) that have partial PR agonist activity and selectively activate some PR-A isoform regulated genes in T47D cells. However, full microarray analysis in these cells does not predict a global isoform selective profile for these compounds, but rather a unique gene-selective profile is observed relative to steroidal progestins. Using multiplexed peptide interaction profiling and co-activator recruitment assays we find that the mechanism of partial agonism is only partly defined by the ability to recruit known co-activators or peptides but also depends on the cell and promoter context of the gene under investigation. The data demonstrate global consequences of mechanistic and functional differences that can lead to selective biological responses of novel steroid receptor modulators.     

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 Å; frictional ratio 1.29; isoelectric pH 4.6; molecular radius 2.7 nm; and molecualr 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 KC1. The progestin binding was saturable and stereospecific. The sequential variation in receptor concentration (early proliferative, 3800–4300 sites/cell; late proliferative, 9500–11200 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 progestin receptor by forming a slowly dissociating complex with a $\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}\text{～ 110?130}\text{min}$ as compared with the progesteronereceptor complex dissociating with $\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}\text{～41}\text{min}$. 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.