The prevention of endometrial cancer in postmenopausal women with progestogens

Due to adverse publicity alleging an increased risk of endometrial cancer with estrogen therapy, a prospective study was begun in 1976 to determine the incidence of this disease in postmenopausal women. During 5,025 patient-years of observation in 1976–1977, 6 adenocarcinomas of the endometrium were diagnosed for an incidence of 1.2: 1,000 postmenopausal women per year. No endometrial malignancies were detected in 2,552 patient-years of therapy with estrogens and progestogens. In 1,028 patient-years of observation where estrogens only was the therapy, there were 3 endometrial cancers for an incidence of 2.9: 1,000. Adenocarcinoma of the endometrium was found in 2 of the untreated group, which gave an incidence of 3.0: 1,000. The sixth endometrial cancer occurred in a patient using estrogen vaginal cream. During this same period, 139 perimenopausal and postmenopausal women were treated with progestogens for endometrial hyperplasia. The hyperplasia was reversed to normal endometrium in 133 patients (95.7%). Hyperplasia is a precancerous lesion and should be treated with either progestogens or hysterectomy. All postmenopausal women with a uterus should be given the Progestogen Challenge Test and the progestogen continued each month as long as bleeding follows. These methods will prevent most endometrial cancers.     

Impact of high levels of progesterone on alpha(1)-integrin distribution in the endometrium of patients with unexplained infertility

Irregular or low expression of integrins, which are cell adhesion molecules, may be associated with infertility. We conducted a prospective controlled study evaluating the effects of supraphysiological levels of estrogen and progesterone created by human menopausal gonadotropins (HMG) and progesterone support on alpha(1)-integrin immunolocalisation in the endometrium. Three groups were enrolled in the study. The first group of patients (group 1) had unexplained infertility and had been treated with HMG and progesterone (n=27). The second group of patients (group 2) was an untreated fertile group (n=24). The third group (group 3) consisted of patients who had unexplained infertility and had received no treatment (n=11). Endometrial biopsy specimens were taken from individuals from each group during the ovulation induction period. alpha(1)-integrin immunohistochemistry was performed. Serum estradiol and progesterone levels were also measured in parallel with histological dating of endometrial biopsies. Group 1 showed no statistical difference from group 2 in alpha(1)-integrin or histological dating. Group 3 showed less alpha(1)-integrin in the glandular epithelium in the secretory phase. We observed that alpha(1)-integrin was specific to the secretory phase. Its localization was denser in group 2 when compared with group 3, which supports the conclusion that alpha(1)-integrin may be a useful marker for luteal phase quality. Moreover, the supraphysiological estrogen and progesterone levels created by HMG and progesterone support may affect the alpha(1)-integrin in the endometrium in the secretory phase in the case of unexplained infertile patients.     

Effect of progesterone injection on progesterone receptor levels and distribution in untreated and short-term Premarin-primed pre-menopausal and post-menopausal endometrium

Cytosolic and nuclear progesterone receptors (RP_C, RP_N) were measured in post-menopausal endometria, using [³H]R5020 as the radioligand, and the findings compared with those in pre-menopausal endometria. Total RP levels (RP_C + RP_N) in post-menopausal endometria were low, i.e. < 2000 fmol/mg DNA. A 7–11 day course of Premarin (conjugated equine oestrogen) treatment in post-menopausal subjects resulted in RP levels in 11818 ± 3008 fmol/mg DNA, which were higher than those in proliferative, mid-cycle and Premarin-primed pre-menopausal endometria. Progesterone injection 1–3 h before tissue collection resulted in a change in the distribution of the RP in both premenopausal and post-menopausal Premarin-primed endometria and pre-menopausal proliferative and mid-cycle endometria. Following the progesterone injection RP_N levels increased to 57±9% of the total as compared with 23±8% in endometrial samples from women who received no progesterone.     

Management of patients with non-atypical and atypical endometrial hyperplasia with a levonorgestrel-releasing intrauterine system: long-term follow-up

OBJECTIVES: Levonorgestrel (LNG), delivered locally into the uterine cavity has a profound effect on the endometrium. The aim of the study was to use a LNG intrauterine system to treat non-atypical and atypical endometrial hyperplasia in women and to evaluate the long-term cure (remission) rate. METHODS: Each of the 20 women in the study, of whom eight were diagnosed with atypical hyperplasia, received a LNG-IUS, releasing 20 microg LNG/day. The study is a non-comparative study with long-term follow-up (range 14-90 months). RESULTS: All women developed a normal endometrium, except one asymptomatic woman with atypical hyperplasia who still had focal residual non-atypical hyperplasia at 3 years follow-up in the presence of a thin (< 4 mm) endometrium. CONCLUSION: Continuous intrauterine delivery of LNG appears to be a promising alternative to hysterectomy for the treatment of endometrial hyperplasia and could enhance the success rate when compared with other routes of progestagen administration as well as intrauterine progesterone delivery. The significant reduction of the PR expression observed during treatment with the LNG-IUS appears to be a marker for the strong antiproliferative effect of the hormone at a cellular level resulting in an inhibition of estrogen bioactivity and endometrial suppression.     

Inhibin/activin subunits beta-A (-betaA) and beta-B (-betaB) are differentially localised in normal, hyperplastic and malignant human endometrial tissue

Inhibins (INHs) are dimeric glycoproteins composed of an alpha (-alpha) subunit and one of two possible beta (beta-) subunits (betaA or betaB). The aims of this study were to determine the frequency and distribution of INH beta (betaA and betaB) subunits in normal, hyperplastic and malignant human endometrium. Endometrial tissue was obtained from normal, hyperplastic (simple, complex and atypical) and endometrioid adenocarcinoma (EC) and INH-alpha, -betaA and -betaB were labelled using immunohistochemistry and immunofluorescence. INH-betaA and -betaB labelling was increased significantly between the proliferative and secretory phase (p<0.05). The lowest labelling was demonstrated in EC, being significantly lower than in secretory phase (p<0.01) and in simple, complex and atypical hyperplastic tissue (p<0.05). For inhibin-betaB, the most intense labelling was noted in atypical hyperplasia compared to EC (p<0.05). A strong colocalisation of inhibin-alpha and -betaA could be demonstrated in malignant endometrial tissue, suggesting the production of inhibin A within the tumour. Additionally, only limited colocalisation of inhibin-betaB with -alpha subunit could be observed, suggesting the synthesis of activin B rather than inhibin B in malignant endometrium. In conclusion, INH-betaA and -betaB were labelled in normal, hyperplastic and malignant endometrium. Hyperplastic tissue labelled more intensely than EC for the presence of INH-betaA and -betaB, suggesting a substantial function in endometrial pathogenesis and an important role in endometrial carcinogenesis.     

不明原因复发性流产患者分泌中期子宫内膜血管内皮生长因子和孕激素受体的表达

目的 检测不明原因复发性流产(URSA)患者分泌中期子宫内膜的血管内皮生长因子(VEGF)和孕激素受体(PR) mRNA及蛋白的表达及探讨其意义.方法 选取2010年6月至2011年10月在广州医学院第三附属医院生殖医学中心和广东省妇幼保健院生殖医学中心及产前诊断科的22例URSA患者为研究组;20例正常妇女为对照组.采用实时荧光定量PCR和免疫组化法检测2组人群分泌中期子宫内膜VEGF和PR的mRNA及蛋白的相对表达水平.结果 VEGF和PR的mRNA和蛋白在两组表达率均为100％;VEGF蛋白表达于腔上皮和间质;PR蛋白表达于腺上皮和间质.研究组VEGF的mRNA和蛋白表达水平均低于对照组(0.16±0.10比0.34±0.22,0.014±0.004比0.018±0.005,均P＜0.05);研究组PR的mRNA和蛋白表达水平均低于对照组(2.52±0.99比4.38± 1.44,0.25±0.02比0.32±0.02,均P＜0.05).结论 URSA患者分泌中期VEGF、PR的相对低表达可能是导致URSA的分子机制之一.     

Correlation between the DNA global methylation status and progesterone receptor expression in normal endometrium,endometrioid adenocarcinoma and precursors

Endometrial carcinomas are the most common malignancy of the female genital tract and the third most common cancer in women. Progesterone and oestrogen receptors (PRs, ERs) are the most widely documented prognostic and predictive factors in endometrioid adenocarcinoma. Besides the hormonal pathway involved in the progression of preneoplastic and neoplastic lesions, alterations of the DNA methylation status have been shown to be an early signal of tumorigenesis. In this study, we show that in normal endometrium, during the proliferative phase, DNA methylation and PR expression are high, with a significant decline towards the end of the secretory phase and a gradual increase in non-atypical and atypical endometrial hyperplasia; they reach their highest level in grade I, then decrease significantly in grade-II and grade-III endometrioid adenocarcinomas. During each stage, a significant positive correlation is observed between DNA methylation and PR (P<0.0001). The strong parallelism between DNA methylation and PR expression precludes establishing a precise determination regarding the timing of these events, clearly involved in the genesis of endometrioid adenocarcinoma.     

妊娠早期绒毛膜促性腺激素和孕酮的临床意义分析

目的研究妊娠早期绒毛膜促性腺激素和孕酮变化情况,从而得到妊娠早期的血清HCG、P的参考值范围及变化曲线。方法对306例正常妊娠早期的妇女进行血清HCG、P动态监测,每周测定一次。结果正常妊娠早期孕妇血清HCG、P变化有一定规律性,在5-10w,HCG值的变化呈直线上升趋势,到达10w左右后逐渐缓慢下降;在孕12w前, P维持在一定水平,各个孕周的P平均值波动在46-15μg／L之间,各孕周间孕酮无显著差异。结论掌握了妊娠早期的血清HCG、P的参考值范围及变化曲线,对早期判断胚胎发育情况,为及早诊断异常妊娠提供客观依据。     

宫腔内人工授精HCG注射日血清雌孕激素比值、子宫内膜类型及厚度对妊娠的影响

目的探讨宫腔内人工授精HCG注射日血清雌孕激素比值、子宫内膜类型及厚度对妊娠的影响。方法分析了338例经促排卵后行人工授精治疗的患者注射HCG日雌孕激素的比值和子宫内膜的厚度、超声类型及妊娠结局。结果 338倒患者中,P／E2比值为0．5-2．0组临床妊娠率为30．05％,与<0．5组及>2．0组比较,均有显著性差异(P< 0．005);子宫内膜厚度为8-12mm组临床妊娠率为25．93％,分剐与<8mm组及>12mm组比较,均有显著性差异(P< 0．005和P<0．05);子宫内膜类型为A型组临床妊娠率为21．45％,分别与B型组及C型组比较,A、B两组无显著性差异(P>0．05),A、C两组有显著性差异(P<0．05)。结论在IUI治疗当中,特别是应用促排卵的IUI治疗中,围排卵期适宜的雌孕激素协同作用和子宫内膜厚度及类型对妊娠率的提高有重要意义。     

The significance of Wilms Tumor Gene (WT1) and p53 expression in curettage specimens of patients with endometrial carcinomas

In this retrospective experimental study, we assessed the immunohistochemical expression of Wilms Tumor Gene (WT1) and p53 in endometrial biopsies of patients with endometrial cancer, and correlated their expression with the final pathological findings.     

The antiovulatory potential of progesterone antagonists correlates with a down-regulation of progesterone receptors in the hypothalamus, pituitary and ovaries

These studies analyze the regulation of progesterone receptors (PRs) in central and peripheral tissues with the aim of further understanding mechanistically the inhibition of ovulation by progesterone antagonists (PA). Therefore, it was of interest to investigate the influence of the progesterone receptor antagonist, Onapristone (ON), on PRs in the ovary, pituitary (PT), and hypothalamus (HYP), since ON effectively inhibits ovulation in rats. For this study PMSG/hCG-primed immature and adult female rats were treated with ON. Immunohistochemistry was used for the detection of PRs. Progesterone (P4) and estradiol (E2) levels were determined by RIA. PR expression in the ovaries of immature rats was not detectable until after hCG administration. In these animals, ON caused a reduction in the staining intensity of PR in the tertiary follicles at the time when the preovulatory P4-surge was inhibited (6 h post hCG). Adult rats treated for 15 days with ON showed a decreased PR expression in PT and HYP. At this time (proestrus, 7 p.m.) the P4 and E2 levels are significantly lowered. These results suggest that after treatment with ON the expression of PR is reduced in the ovary, PT and HYP. The regulation of PR in the ovary seems to be less dependent on estrogens than on LH. Thus, it is conceivable that the reduced PR expression after ON treatment may be a result of decreased LH sensitivity in the ovary. In the pituitary and hypothalamus, PR expression is stimulated by estrogens and progesterone, and therefore the fall in the P4 and E2 levels in ON-treated animals may be responsible for the reduced PR expression in PT and HYP, and may contribute to the antiovulatory effect of ON. We therefore conclude that the mechanism of the antiovulatory potency of progesterone antagonists is based on a reduced preovulatory P4-production and PR expression in the ovary and also on the down-regulation of PR in the anterior pituitary and hypothalamus.     

Serum levels of oestrogens, progesterone, follicle-stimulating hormone and sex-hormone-binding globulin during simultaneous vaginal administration of 17β-oestradiol and progesterone in the pre- and post-menopause

Serum concentrations of 17β-oestradiol (E₂), unconjugated oestrone (E₁), total oestrone (tE₁), progesterone (P), follicle-stimulating hormone (FSH) and sex-hormone-binding globulin (SHBG) were measured before and after daily intravaginal administration of 250 μg micronized E₂ and 10 mg micronized P for 14 days to 12 post-menopausal and for 1 day only (during cycle days 5–8) to 11 pre-menopausal women. In the post-menopausal women the levels of all steroids increased to maximum values on day 1, 8–10 h after administration and fell thereafter. In the pre-menopausal women the steroid concentrations rose slowly to a plateau level 10–15 h after administration. Significantly higher absorption of E₂ and E₁ (area under the curve increments) was noted in the post-menopausal than in the pre-menopausal women.

In the post-menopausal women the steroid levels measured on days 7 and 14 corresponded to those observed in the very early or late luteal phase. Area under the curve increments were usually smaller on days 7 and 14 than on day 1 and the absorption kinetics altered to a ‘pre-menopausal’ pattern. FSH levels were significantly reduced as from 12 h after administration on day 1 and onwards. A slight (10%) but significant increase in SHBG levels was noted on day 14. It was concluded that the combined E₂ and P treatment used in this investigation brings about a physiological response with only minimal side effects on the liver as judged from changes in SHBG concentrations.     

Endometrial safety of continuous combined hormone replacement therapy with 17beta-oestradiol (1 or 2 mg) and dydrogesterone

Objectives: To determine the endometrial safety of oral 17β-oestradiol combined continuously with dydrogesterone in preventing endometrial proliferation. Methods: The low dose group comprised three 52-week (13 cycles of 28 days) studies (two of which were double blind) using a 17β-oestradiol dose of 1 mg daily combined with dydrogesterone 2.5, 5, 10 or 20 mg daily. The high dose group comprised two 24-week double-blind studies using a 17β-oestradiol dose of 2 mg daily combined with dydrogesterone 2.5, 5, 10 or 15 mg daily. Endometrial safety was verified by aspiration endometrial biopsies. Inadequate progestational response was defined as proliferative endometrium, endometrial polyp, hyperplasia and carcinoma. Results: Data was evaluable from 650 healthy postmenopausal women in the low dose group and 310 in the high dose group. Endometrial protection was achieved with dydrogesterone at doses of 5 mg or higher combined with 1 or 2 mg 17β-oestradiol. The success rate was 97%, 97% and 98% in women receiving 1/5, 1/10 and 1/20 mg, respectively, and 95%, 98% and 91% in women receiving 2/5, 2/10 and 2/15 mg, respectively. A lower success rate was achieved with the 2.5 mg dydrogesterone dosage (93% in the 1/2.5 mg group and 85% in the 2/2.5 mg group) due to more cases of proliferative endometrium. None of the women in the low dose group developed hyperplasia or carcinoma; five (0.7%) had endometrial polyps. In the high dose group, one woman given 2.5 mg dydrogesterone developed hyperplasia; there were no cases of carcinoma. Conclusion: 5 mg daily dydrogesterone appears to be the lowest effective dose to ensure endometrial safety in a continuous combined regimen with 1 or 2 mg 17β-oestradiol.     

Pituitary adenoma,primary parathyroid hyperplasia and papillary (non-medullary) thyroid carcinoma

Summary An acidophilic pituitary adenoma associated with primary nodular parathyroid hyperplasia and a small papillary thyroid carcinoma was discovered at the autopsy of a 44 year old female acromegalic. The thyroid carcinoma showed evidence of lymphatic spread. Several etiopathogenetic mechanisms for the non-medullary thyroid carcinomata associated with Multiple Endocrine Neoplasia (MEN) have been postulated, since the follicular epithelium of the thyroid does not belong to the neural ectoderm derivates unlike the C-cells of the thyroid, the adenohypophysis and probably the parathyroid glands. Apart from genetic influence, or coincidence, one has to rule out carcinogenic exposure or hormonal influence. Clinically speaking, one should always consider whether malignant thyroid disease coexists with hyperplastic or neoplastic parathyroid tissue.     

Role of angiogenesis in endometrial repair of patients with severe intrauterine adhesion

Objective: To detect vascular endothelial growth factor (VEGF) expression and micro-vessel density (MVD) in patients with severe intrauterine adhesion before and after therapy, and to preliminarily explore the role of angiogenesis in the therapy of severe intrauterine adhesion. Methods: A total of 36 patients with severe intrauterine adhesion were prospectively recruited into the treatment group. In the control group, 20 patients with normal uterine were recruited. Patients with severe intrauterine adhesion received transcervical resection of adhesions under hysteroscope and then received artificial hormone therapy for 3 months. Methods: The changes in the organelles of endometrial cells were evaluated under an electric microscope; Immunohistochemistry was done to detect the VEGF expression and MVD in patients with severe intrauterine adhesion, which was compared with that in the control group; VEGF expression and MVD were compared among patients with different prognoses. Results: Electric microscopy showed vascular closure and hypoxic changes in the endometrial tissues of patients with intrauterine adhesion. After treatment, angiogenesis was observed, and the hypoxic changes in the endometrial glands and interstitium were also improved. Moreover, the VEGF expression and score of MVD also increased significantly when compared with those before treatment and in the control group. The VEGF expression and MVD score in intrauterine adhesion patients recovering from treatment were significantly higher than those in patients non-responding to treatment. Conclusion: In patients with intrauterine adhesion, the endometrial tissues present with vascular closure, and angiogenesis will be present in the endometrial tissues after treatment. The angiogenesis in the endometrial tissues may affect the endometrial repair.     

Investigations of the estrogen (ER-ICA-test) and the progesterone receptor in the prostate and prostatic carcinoma on immunohistochemical basis

Summary Estrogen (ER) and Progesterone receptors (PR) were demonstrated immunohistochemically on frozen sections from 11 prostatectomy and 7 cystoprostatectomy specimens in the nuclei of various cell types. The periglandular fibrocytes and smooth muscle cells were extensively positive, the interglandular stromal cells were only partly so. Normal basal cells stained focally positive, hyperplastic basal cells stained extensively. The glandular secretory epithelium and atrophic glands were negative. The same findings were obtained in hyperplastic nodules. Both ER and PR also occurred in the urothelium of central prostatic ducts and of the prostatic urethra. The fibrous stroma around the ejaculatory ducts and seminal vesicles was extensively positive while the epithelium was negative. The smooth musculature of the seminal vesicles was only partly positive. On large field sections, the ER as well as the PR were numerically equally distributed throughout the inner zone of the prostate and the prostate proper. 12 prostatic carcinomas (G I–G III) were ER- and PR-negative. Estrogens may contribute to nodular hyperplasia by triggering a stromal proliferation with a secondary inductive epithelial growth. Obviously they do not act directly on prostatic carcinoma but inhibit growth via the hypophyseal-testicualr axis. The biological significance of the PR in the prostate is unknown.     

Continuous combined hormone replacement therapy with 1 mg 17beta-oestradiol and 5 mg dydrogesterone (Femoston-conti): endometrial safety and bleeding profile

OBJECTIVES: The aim of the study was to confirm the endometrial safety and describe the bleeding profile of continuous combined 1 mg 17beta-oestradiol and 5 mg dydrogesterone in post-menopausal women. METHODS: An open, multicentre study was carried out in 290 healthy, non-hysterectomised post-menopausal women receiving oral continuous combined 1 mg 17beta-oestradiol and 5 mg dydrogesterone (Femoston-conti) for 1 year. Aspiration endometrial biopsies were performed at baseline and at the end of the study; those classified as hyperplasia or malignancy were considered treatment failures. RESULTS: Only one woman developed simple hyperplasia without atypia at the end of the study; the treatment failure rate was therefore 0.4%. Cross-sectional analysis showed that the percentage of women without bleeding increased from 71% during the first cycle to around 80% by the end of the study. Approximately 50% of the bleeding episodes occurred in the form of spotting; severe bleeding was rare and only seven women withdrew prematurely from the study due to uterine bleeding. Overall, 41% of the women were amenorrhoeic throughout the study. CONCLUSIONS: Continuous combined 1 mg 17beta-oestradiol and 5 mg dydrogesterone provides excellent endometrial safety and is associated with an acceptable bleeding profile.     

Immunohistochemical localization of androgen and progesterone receptors in the uterus of the camel (Camelus dromedarius)

Ten adult, cyclic female camels (Camelus dromedarius) were used to describe the distribution of androgen (AR) and progesterone (PR) receptors in the uterus using immunohistochemistry. Both AR and PR were distributed throughout the different compartments of the uterus with nuclear staining for AR and PR seen in the cells of epithelia (luminal and glandular), stroma and myometrial smooth muscles. AR immunostaining was not uniform in distribution and intensity; the surface epithelium and the glandular epithelium in the adluminal region of the endometrium showed lower AR immunoreactivity than other compartments of the uterus. PR immunostaining showed uniformity in both distribution and intensity strong PR immunostaining intensity in almost all cells of the different uterine compartments. The intensity and distribution of PR immunostaining in epithelia of lumen and glands in the adluminal regions of endometrium was higher (P < 0.05) than that of AR. In conclusion, immunohistochemical localization of AR and PR in the uterus of the cyclic dromedary camel indicates the important roles of androgen and progesterone in controlling the uterine activity during the follicular phase.