Progesterone and endometrial cancer

It is well established that unopposed estrogen, either endogenous or therapeutic, can induce endometrial hyperplasia and potentially endometrial cancer (EC). Anovulatory cycles, obesity, and insulin resistance are major risk factors for EC. Progestogen (progesterone and progestin), including levonorgestrel intrauterine device, are able to prevent or to treat hyperplasia, atypical hyperplasia, and even well-differentiated EC, as presented in this review. During menopausal hormone therapy, progestogens protect the endometrium against the proliferative effects of estrogens in women with a uterus. Whereas, recent epidemiologic data suggest that micronized progesterone (MP) is apparently safer for the breast, it could be less efficient than synthetic progestin on the endometrium. However, several studies from biopsies during treatment with MP do not show any increased risk of hyperplasia. Lack of compliance could explain the results on EC.     

Progesterone,progesterone/estradiol and ART outcomes in day-5 transfer cycles

The objective of this study was to assess the effects of elevated luteal-phase progesterone levels (PE) and high progesterone/estradiol ratio (‘P/E2’ ratio) on IVF outcomes, exclusively in GnRH-antagonist cycles with day-5 embryo transfer. PE was not found to have a significant effect on implantation or clinical pregnancy rate (CPR) (OR 0.56, 95% CI 0.25–1.25, p?=?.16). Elevated ‘P/E2’ ratio (≥0.55) on trigger day was associated with a poorer response to stimulation and lower clinical pregnancy rates (OR 0.58, 95% CI 0.34–1.00, p?=?.05). Patients with PE and low ‘P/E2’ ratio yielded significantly more oocytes than patients with PE and high ‘P/E2’ ratio. The mean implantation rate per patient decreased by 60% in the group with PE and high ‘P/E2’ ratio in comparison to the group with PE and low ‘P/E2’ ratio (17.9%±36.6 vs. 45.5%±47.2, p?=?.06), although no statistical significance was observed. The detrimental effect of PE may be mitigated by culturing embryos to day-5 before embryo transfer. Combined assessment of serum progesterone and ‘P/E2’ ratio may predict pregnancy outcome better than progesterone levels alone.     

白介素-6调节颗粒细胞雌孕激素分泌的作用

目的 :探讨白介素 -6 (IL -6 )对颗粒细胞分泌雌孕激素的影响。方法 :收集行 IVF-ET穿卵时的颗粒细胞作体外培养 ,在有或无 FSH条件下 ,以不同浓度的 rh IL-6作用于颗粒细胞 ,2 4、48、72和 96 h后收集培养液作雌二醇、孕酮测定 ,观察基因重组人白介素 -6 (rh IL-6 )对体外培养中的颗粒细胞分泌雌二醇、孕酮的影响 ;通过 m RNA狭缝杂交 (m RNA slotblot)检测颗粒细胞是否存在 IL-6 R m RNA。结果 :在无 FSH条件下 ,rh IL-6对颗粒细胞分泌雌二醇有抑制作用 ,对孕酮分泌的影响不明显 ;而加入 FSH后 ,发现 rh IL-6对 FSH刺激颗粒细胞所分泌的雌二醇、孕酮均有明显抑制作用。这些作用呈现一定的时间和剂量依赖性。结论 :rh IL-6可抑制 FSH刺激颗粒细胞所致的甾体激素分泌 ,从而参与调节卵巢功能。     

Influence of thyroxine on human granulosa cell steroidogenesis in vitro

Purpose The objective of this study was to investigate the influence of thyroid hormone on estradiol and progesterone secretion of human granulosa cells maintained in vitro.Methods Granulosa cells were obtained by aspiration of preovulatory follicles of woman undergoing assisted reproductive technology. Ovulation induction was performed with GnRH agonist, hMG, and hCG.Results Granulosa cells were maintained in vitro in a defined medium with added insulin. Twenty-four-hour estradiol and progesterone secretion into the medium were determined for granulosa cells growing in serum-free medium and in serum-free medium with added T₄ in a concentration range of 10^–7 to 10^–11 M.Conclusions All concentrations of T₄ used produced a statistically significant increase in progesterone secretion (range, 1.39 to 1.60 times the baseline amount). The increase in estradiol secretion reached statistical significance only at a T₄ concentration of 10^–8 M (1.24 times the baseline amount).     

非注射黄体酮在冻融胚胎移植激素替代周期中的应用

目的:比较口服地屈孕酮联合阴道用微粒化黄体酮黄体支持与肌肉注射黄体酮应用于冻融胚胎移植(FET)激素替代黄体支持的临床效果。方法:月经第3日起口服17β雌二醇片8 mg;第14日超声监测,同时测定血清E2,内膜≥8 mm、E2≥150 pg/ml时,加用口服地屈孕酮40 mg联合阴道用微粒化黄体酮软胶囊400 mg(A组)转化内膜,或肌注油剂黄体酮60 mg(B组),3～5 d后解冻第3～5日胚胎。结果:共完成1 805个FET激素替代周期,A、B组临床妊娠率分别为41.4%(389/940)、38.4%(332/865),种植率分别为26.2%(485/1 851)、23.8%(438/1 837),继续妊娠率分别为34.1%(321/940)、33.4%(289/865),组间均无统计学差异;A组流产率为19.8%(77/389),高于B组的13%(43/332)(P<0.05)。结论:FET激素替代周期中口服地屈孕酮与阴道塞安琪坦联合用药,简单方便,临床结果理想,可逐步替代肌肉注射油剂黄体酮。     

Activin a stimulates meiotic maturation of human oocytes and modulates granulosa cell steroidogenesis in vitro

Objective: To test the hypothesis that activin A promotes in vitro human oocyte meiotic maturation while inhibiting steroid secretion by nonluteinized antral granulosa cells.

Design: Prospective randomized controlled study.

Setting: A university medical center.

Patient(s): Nine women ranging in age from 31–44 years who were undergoing oophorectomy for nonovarian pathology.

Intervention(s): Analysis of meiotic maturation of oocytes and steroid secretion by granulosa cells cultured in the presence or absence of activin A.

Main Outcome Measure(s): Germinal vesicle breakdown (GVBD) and attainment of metaphase II (MII) in oocytes, and progesterone and E₂ secretion by granulosa cells.

Result(s): Activin A significantly enhanced GVBD (91% vs. 65%) for control and maturation to MII (56% vs. 35% for control) of immature oocytes. Activin A significantly suppressed basal, and inhibin A–and FSH-stimulated progesterone and E₂ secretion by nonluteinized granulosa cells.

Conclusion(s): Activin A is a promoter of oocyte maturation in vitro and a modulator of granulosa cell steroidogenesis in culture.     

Effects of the route of estrogen administration and exercise on hormonal levels in postmenopausal women

Objective: To examine the effects of exercise on serum estrogens, growth hormone, insulin, cortisol, lactate, and glucose levels in postmenopausal women receiving two routes of administration of estrogen replacement therapy (ERT).

Design: Prospective, randomized, crossover study.

Setting: The general clinical research center of an academic medical center.

Patient(s): Eleven active, postmenopausal women.

Intervention(s): The patients were screened with exercise stress testing, then oral micronized estradiol or transdermal estradiol was administered, followed by two 45-minute submaximal exercise tests. Dietary intake before the tests was standardized.

Main Outcome Measure(s): The study measured maximal heart rate and aerobic power ( ₂max), and serum levels of estradiol (E₂), estrone (E₁), cortisol, growth hormone (GH), insulin, glucose, and lactate.

Result(s): Growth hormone, cortisol, and insulin all changed significantly in response to the 45-minute exercise bouts, but no differences were observed between the oral micronized estradiol and transdermal estradiol responses. E₂ levels increased significantly during the transdermal estradiol 45-minute exercise bout; this change did not occur during the oral estradiol exercise bout. In the transdermal estradiol treatment group, the E₂ levels at +30 and +45 minutes of exercise were elevated compared to the post-exercise levels at −15, 0, and 30 minutes. E₁ was not significantly changed during the 45-minute exercise bouts in either group.

Conclusion(s): During exercise, serum E₂ levels rise significantly higher with transdermal but not oral routes of E₂ administration. However, the elevated levels are not prolonged and normalize by 30 minutes after exercise.     

种植窗期血清孕激素水平及子宫内膜整合素α_vβ_3表达对IVF-ET结局的预测价值

目的：探讨种植窗期血清雌(E_2)、孕激素(P)水平及子宫内膜整合素α_vβ_3表达与IVF-ET结局的关系。方法：对40例拟行IVF-ET妇女在IVF-ET前1周期采用磁分离酶联免疫法测定种植窗期血清E_2、P水平；采用免疫组化SP法和组织学积分H-score法对整合素α_vβ_3在种植窗期子宫内膜中的表达进行定位和半定量分析。按IVF-ET后是否妊娠将40例不孕患者分为2组：妊娠组和未妊娠组。结果：种植窗期血清P和整合素α_vβ_3水平妊娠组较未妊娠组高,差异有统计学意义(P：17．80±6．08 ng/ml vs 14．12±4．74 ng/ml,P＜0．05。整合素α_vβ_3：腺体1．73±0．18 vs 1．50±0．23,P＜0．01；腔上皮1．53±0．28 vs 1．12±0．24,P＜0．01)。结论：种植窗期血清P水平下降及子宫内膜整合素α_vβ_3的表达减弱,可导致IVF-ET妊娠失败。种植窗期血清P水平和子宫内膜整合素α_vβ_3的表达可作为预测妊娠是否成功的指标。     

Vaginal rings delivering progesterone and estradiol may be a new method of hormone replacement therapy

OBJECTIVE: To determine whether a low dose of P delivered together with E(2) from a vaginal ring on a continuous schedule can prevent endometrial proliferation and yield a bleeding pattern dominated by amenorrhea. DESIGN: Longitudinal clinical study. SETTING: Three university hospitals. PATIENT(S): Fifty-five women 45 to 75 years of age, not hysterectomized, with E(2) levels of <20 pg/mL and hot-flash incidence of two or more per day in the past week. INTERVENTION(S): A vaginal ring delivering approximately 150 microg/d of 17beta-E(2) and approximately 5 mg/d or approximately 9 mg/d of P used continuously for 4 and 6 months. MAIN OUTCOME MEASURE(S): Endometrial thickness, bleeding pattern, and hot flash incidence. RESULT(S): Endometrial proliferation was prevented by both P doses. Bleeding incidence decreased. In months 4, 5, and 6, 8 of 12 women had no bleeding. Incidence of hot flashes and night sweats decreased quickly and significantly.CONCLUSION(S): A vaginal ring delivering E(2) and a low dose of P merits further study as a method for long-term hormone replacement therapy.     

低剂量与标准剂量结合雌激素联合天然孕酮或地屈孕酮治疗围绝经期综合征的疗效观察

目的:研究低剂量结合雌激素(CEE)与标准剂量CEE联合天然孕酮或地屈孕酮治疗围绝经期综合征的疗效比较。方法:本试验为单中心、前瞻性随机对照试验,2014年2月至2015年12月招募绝经早期有子宫、有绝经相关症状的妇女(共107例完成试验),随机分为3组:A组35例(低剂量CEE+天然孕酮)、B组37例(标准剂量CEE+天然孕酮)、C组35例(标准剂量CEE+地屈孕酮),采用连续序贯方案治疗12个周期,在第3、6、9、12周期结束后记录改良Kupperman评分,计算有效率,用药前与用药后抽血测定卵泡刺激素(FSH)、雌二醇(E2)。结果:在治疗3个周期后,改良Kupperman评分值均显著性下降(P均0.01),3组间的完全缓解率、显效率差异均无统计学意义,但B组有效率(89.2%)显著高于A组(60%,P=0.024)和C组(61.9%,P=0.035)。治疗结束后,3组的完全缓解率、显效率、有效率差异均无统计学意义(P0.05)。治疗结束后与治疗前比,3组的FSH值均有显著性降低(P0.001),E2值均显著性升高(P0.001)。治疗结束后,3组FSH值比较差异无统计学意义(P=0.26);E2值A组显著低于B组(P=0.002)及C组(P=0.004),B组与C组比较差异无统计学意义(P=0.832)。不良反应主要为阴道不规则流血和乳房胀痛,A、B、C组阴道不规则流血的发生率分别为20.91%、39.51%、19.99%,B组显著高于A与C组(PAB=0.034,PBC=0.015),A组与C组比较差异无统计学意义;乳房胀痛的发生率A、B、C组分别为30.22%、37.46%、68.06%,A、B两组差异无统计学意义,C组显著高于A、B组(PAC=0.008,PBC=0.002)。结论:低剂量雌激素补充已可满足大部分患者缓解围绝经期综合征的需求,加用天然孕酮比加用地屈孕酮对围绝经期症状的缓解作用更显著。     

Incomplete Androgen and Progesterone Suppression Following Midluteal GnRHa Prior to Controlled Ovarian Hyperstimulation for IVF-ET

Purpose: We aimed to determine if midluteal GnRH agonist (GnRHa) use prior to controlled ovarian hyperstimulation (COH) results in uniform progesterone and androgen suppression and whether elevations of these hormones occurring early in follicular development may adversely effect the outcome of IVF-ET. Methods: Forty-four COH cycles using midluteal GnRHa were evaluated. Serum gonadotropins (LH and FSH) and gonadal steroids (E ₂ , A, P ₄ , and T) were measured after 10 days of GnRHa administration [cycle day 31 (CD 31)] and again on the day of hCG administration, following COH. Cycle outcomes evaluated were the number of oocytes retrieved, morphologic grade, fertilization, implantation, pregnancy, and spontaneous abortion rates. Results: Endogenous serum FSH was uniformly suppressed (6.32 ± 0.47 IU/L) on CD 31, however, LH was not (23.76 ± 0.76 IU/L). Five and four tenths percent of cycles demonstrated low-level P4 elevations (0.9 ng/ml), 24.4% demonstrated serum androstenedione levels 600 pg/ml, and 39% of cycles were characterized by serum T levels 200 pg/ml despite evidence of E ₂ suppression (30 pg/ml) and the absence of follicular growth by sonography. LH levels were not predictive of incomplete P ₄ or androgen suppression. Elevations of either P ₄ , A, or T occurring early in the follicular phase were not found to correlate with an impairment in clinical cycle outcome. Conclusions: Midluteal GnRHa use prior to COH may result in incomplete suppression of circulating progesterone and androgens. However, these relative elevations, occurring early in the development of the follicular cohort, did not appear to affect IVF cycle outcome adversely.     

Effectiveness,tolerability and acceptance of a low-dosed estradiol/dienogest formulation (Lafamme 1 mg/2 mg) for the treatment of menopausal complaints: a non-interventional observational study over 6 cycles of 28 days

Abstract

Background: Concern and controversy characterize nowadays the use of hormone therapy for management of patients with menopausal complaints. This observational non-interventional study examined the use of a marketed oral formulation containing 1?mg estradiol valerate and 2?mg dienogest for treatment of menopausal symptoms in 1292 women visiting 243 gynecological practices in Germany.

Methods: Score changes in the Menopausal Rating Scale (MRS) after three and six 28-day cycles were primary endpoints. Subjective reports on skin- and hair-related complaints and satisfaction with treatment effects were assessed. The incidence of adverse drug reactions (ADRs), adverse events (AEs) and vaginal bleeding was evaluated.

Results: MRS total score decreased substantially and stronger than the clinically relevant change of 5 points (p?<?0.0001) as compared with baseline. Subjective skin- and hair-related complaints declined. No unexpected ADRs were reported. AEs (including ADRs) were registered in 8.8% of the participants; most frequent AEs/ADRs were postmenopausal hemorrhage (2.9%) and drug ineffective (1.4%). Nearly 76% of the subjects remained amenorrheic. Approximately 90% of the patients rated the medication’s effectiveness/tolerability as good/very good; 84% intended to continue the treatment.

Conclusion: This low-dose estradiol/dienogest formulation proved efficient and well-tolerated option for the alleviation of menopausal symptoms associated with estrogen deficiency.     

激素替代治疗预防绝经后女性心血管疾病的作用机制

停经后女性由于卵巢功能的衰退,自身分泌的性激素开始减少,血清中雌激素浓度明显降低,将面临多种神经系统与生理功能的变化,尤其是心血管疾病的发生。激素替代治疗（hormone replacement therapy,HRT)具有改善脂质代谢的作用,降低体内血脂浓度,减少心脑血管疾病的发病率和病死率。但激素替代治疗在预防心血管疾病中的作用机制研究较少,医务工作者对其在临床中的应用还存在疑虑。本文将激素替代治疗在预防心血管疾病中的作用机制进行综述。     

Estradiol therapy and breast cancer risk in perimenopausal and postmenopausal women: a systematic review and meta-analysis

Objective: To investigate the association between estradiol therapy and incidence of breast cancer, taking into consideration of different types of combined progestogen, the duration of exposure and the type of regimen.

Method: A systematic review and meta-analysis.

Result: A total of 14 studies were included in our study. In estradiol-only therapy analysis, meta-analysis resulted a pooled OR?=0.90, 95% CI (0.40, 2.02) from the RCTs and pooled OR?=?1.11, 95% CI (0.98, 1.27) from observational studies. However, in the analysis of estradiol-progestogen therapy, the risk of breast cancer varies according to the type of progestogen and the duration with more than five years (OR?=?2.43, 95% CI (1.79, 3.29)) presented a higher risk than using less than five years (OR = 1.49, 95% CI (1.03, 2.15)).

Conclusions: Estradiol-only therapy carries no risk for breast cancer, while the breast cancer risk varies according to the type of progestogen. Estradiol therapy combined with medroxyprogesterone, norethisterone and levonorgestrel related to an increased risk of breast cancer, estradiol therapy combined with dydrogesterone and progesterone carries no risk. The breast cancer risk rise progressively by prolonged use, furthermore, comparing to sequential therapy, continuous therapy carries a higher risk.     

Ovarian function in relation to the outcome of in vitro fertilization (IVF) treatment in regularly menstruating women with tubal infertility

Study Design Ovarian endocrine function was evaluated in 53 regularly menstruating women, 27 to 38 years of age, who failed to conceive at least 2 years following reconstructive surgery for tubal infertility. Thirty apparently healthy women, 24 to 40 years of age with proven fertility, served as controls. Blood samples were obtained daily on cycle days 2–4 and 22–26 to assess FSH, E2, and P4 levels.Results There was a tendency for women with more advanced tubal damage to be subjected to more extensive surgery. Based on extent of reconstructive surgery, the patients were divided into three groups. Group A (n=29) had less extensive surgery, limited to the fallopian tubes, group B (n=14) included patients with extended adhesiolysis, and group C (n=10) comprised patients that had the most extensive reconstructive procedures involving ovarian surgery. Significantly higher FSH levels were found in group C (P<0.001) compared to groups A and B in the early follicular phase. During the luteal phase, E2 levels were lower in groups B (P<0.01) and C (P< 0.001) compared to group A. P4 levels were lower in group C compared to groups A and B.Conclusion When the patients underwent IVF treatment higher grades of tubal damage, more extensive surgery and hormonal signs of ovarian insufficiency were highly related to treatment failure.