Efficacy of oral or intrauterine device-delivered progestin in patients with complex endometrial hyperplasia with atypia or early endometrial adenocarcinoma: a meta-analysis and systematic review of the literature

Objectives

To investigate the efficacy of progestin treatment to achieve pathological complete response (pCR) in patients with complex atypical endometrial hyperplasia (CAH) or early endometrial adenocarcinoma (EC).

Methods

A systematic search identified 3245 potentially relevant citations. Studies containing less than ten eligible CAH or EC patients in either oral or intrauterine treatment arm were excluded. Only information from patients receiving six or more months of treatment and not receiving other treatments was included. Weighted proportions of patients achieving pCR were calculated using R software.

Results

Twelve studies met the selection criteria. Eleven studies reported treatment of patients with oral (219 patients, 117 with CAH, 102 with grade 1 Stage I EC) and one reported treatment of patients with intrauterine progestin (11 patients with grade 1 Stage IEC). Overall, 74% (95% confidence interval [CI] 65-81%) of patients with CAH and 72% (95% CI 62-80%) of patients with grade 1 Stage I EC achieved a pCR to oral progestin. Disease progression whilst on oral treatment was reported for 6/219 (2.7%), and relapse after initial complete response for 32/159 (20.1%) patients. The weighted mean pCR rate of patients with grade 1 Stage I EC treated with intrauterine progestin from one prospective pilot study and an unpublished retrospective case series from the Queensland Centre of Gynaecologic Oncology (QCGC) was 68% (95% CI 45-86%).

Conclusions

There is a lack of high quality evidence for the efficacy of progestin in CAH or EC. The available evidence however suggests that treatment with oral or intrauterine progestin is similarly effective. The risk of progression during treatment is small but longer follow-up is required. Evidence from prospective controlled clinical trials is warranted to establish how the efficacy of progestin for the treatment of CAH and EC can be improved further.     

Predictors of resolution of complex atypical hyperplasia or grade 1 endometrial adenocarcinoma in premenopausal women treated with progestin therapy

Objective

To identify clinical and pathologic predictors of response to progestin treatment in premenopausal women with complex atypical hyperplasia (CAH) and Grade 1 endometrial adenocarcinoma (Grade 1 EA).

Methods

Forty premenopausal patients with Grade 1 EA or CAH who underwent progestin therapy for a minimum of 8 weeks were retrospectively identified. Patient characteristics and histopathologic features of pretreatment and first follow-up endometrial specimens were evaluated as predictors of resolution, defined as absence of hyperplasia or carcinoma.

Results

Kaplan-Meier analysis indicated 63% resolution at 18 months of follow-up. Multivariate classification analysis showed that resolution rates were higher in individuals with a low pre-treatment qualitative abnormal architecture score and a BMI < 35 (Standardized Resolution Ratio (SRR) = 1.48, p = 0.03). The diagnosis of benign endometrium or simple hyperplasia on the first follow-up specimen was highly predictive of resolution (SRR = 2.25, p = 0.002). Resolution rates were lower among subjects with a high pre-treatment qualitative abnormal architecture score (SRR = 0.37, p < 0.03) and lowest in subjects whose first follow-up specimen showed persistent complexity, atypia, or carcinoma with adjacent stromal decidualization (SRR = 0.24, p = 0.002).

Conclusions

Clinical and pathologic parameters can predict response to progestin therapy in premenopausal women with CAH and Grade 1 EA. A low likelihood of resolution is predicted by an unfavorable pre-treatment architectural score and lack of pathological response in the first specimen, despite adjacent stromal decidualization.     

Oncologic and reproductive outcomes with progestin therapy in women with endometrial hyperplasia and grade 1 adenocarcinoma: a systematic review

Objective

The objective of this review was to analyze published contemporary oncologic and reproductive outcomes in women with endometrial hyperplasia or cancer undergoing medical management with progestin therapy.

Methods

A systematic review of oncologic and pregnancy outcomes in women with complex atypical hyperplasia or grade 1 adenocarcinoma was performed using a comprehensive search of the MEDLINE literature. English language studies published from 2004 to 2011 which utilized hormonal therapy were identified using key words endometrial hyperplasia, endometrial cancer, fertility preservation, hormone and progestin therapy. Fisher's exact test was used to calculate statistical differences.

Results

Forty-five studies with 391 study subjects were identified. The median age was 31.7 years. Therapies included medroxyprogesterone (49%), megestrol acetate (25%), levonorgestrel intrauterine device (19%), hydroxyprogesterone caproate (0.8%), and unspecified/miscellaneous progestins (13.5%). Overall, 344 women (77.7%) demonstrated a response to hormonal therapy. After a median follow up period of 39 months, a durable complete response was noted in 53.2%. The complete response rate was significantly higher for those with hyperplasia than for women with carcinoma (65.8% vs. 48.2%, p = .002). The median time to complete response was 6 months (range, 1-18 months). Recurrence after an initial response was noted in 23.2% with hyperplasia and 35.4% with carcinoma during the study periods (p = .03). Persistent disease was observed in 14.4% of women with hyperplasia and 25.4% of women with carcinoma (p = .02). During the respective study periods, 41.2% of those with hyperplasia and 34.8% with a history of carcinoma became pregnant (p = .39), with 117 live births reported.

Conclusion

Based on this systematic review of the contemporary literature, endometrial hyperplasia has a significantly higher likelihood of response (66%) to hormonal therapy than grade 1 endometrial carcinoma (48%). Disease persistence is more common in women with carcinoma (25%) compared to hyperplasia (14%). Reproductive outcomes do not seem to differ between the cohorts.     

Fertility sparing treatment of complex atypical hyperplasia and low grade endometrial cancer using oral progestin

Objective

Oral progestin is an alternative to hysterectomy for women with complex atypical hyperplasia (CAH) or grade one endometrial cancer (G1EC) who wish fertility preservation. We evaluated treatment efficacy and fertility outcomes in this population.

Methods

Women < 45 y treated with oral progestin for CAH or G1EC were identified from two cancer centers. Data were obtained from medical records and telephone questionnaires. Time until complete response (CR), and from CR until recurrence was censored for patients without events and analyzed for associations with patient and treatment characteristics; cumulative incidence functions were used to estimate event probability over time.

Results

44 patients were identified, 19 (43%) with CAH and 25 (57%) with G1EC. Median age was 36.5 y (26–44). 24 (55%) achieved CR (median time: 5.7 months). Older age was associated with a lower likelihood of CR (HR 0.84, p = 0.0003, 95% CI, 0.8–0.9). CR probability appeared to plateau after 12 months of therapy. Among those with CR, 13 (54%) recurred (median time 3.5 y). 24 patients (55%) underwent hysterectomy; 3 (13%) were upstaged. 11 (25%) underwent fertility treatment with the following outcomes: 6 (55%) no pregnancy, 2 (18%) at least one live infant, and 3 (27%) spontaneous abortion. One achieved a live birth without intervention.

Conclusion

Oral progestin is an effective temporizing fertility-sparing treatment for women with CAH/G1EC. Fertility specialist involvement is recommended due to the low live birth rate without intervention. Progestin therapy should be re-evaluated at 1 year in non-responders due to a low probability of success. Hysterectomy is recommended after childbearing due to a high recurrence rate.     

不孕症合并子宫内膜非典型增生患者助孕治疗的临床分析

目的探讨不孕症合并子宫内膜非典型增生患者经保守治疗后助孕治疗的疗效和安全性。方法回顾性分析8例不孕症合并子宫内膜非典型增生患者，经孕激素或促性腺激素释放激素激动剂（GnRHa）治疗子宫内膜非典型增生缓解后，采用助孕治疗，观察助孕治疗的疗效及其对子宫内膜的影响。结果经孕激素或GnRHa治疗后，8例患者子宫内膜非典型增生全部缓解。共进行单纯促排卵治疗7个周期，促排卵联合人工授精2个周期，体外受精-胚胎移植（IVF—ET）7个周期，冻融胚胎移植2个周期。单纯促排卵周期均未妊娠，人工授精1个周期双胎妊娠；7个IVF—ET周期中，胚胎移植6个周期，3个周期获得临床妊娠；冻融胚胎移植1个周期获得临床妊娠。现足月分娩6活婴。1例未妊娠患者在促排卵后4个月发现子宫内膜癌变。结论不孕症合并子宫内膜非典型增生的患者经孕激素或GnRHa治疗缓解后，及时助孕治疗能提高妊娠率，但需严密观察，注意子宫内膜癌发生的可能。     

The outcome of infertility treatment in patients undergoing assisted reproductive technology after conservative therapy for endometrial cancer

Purpose

To elucidate the problems in infertility treatment for women after conservative therapy for endometrial cancer (EC) or atypical complex endometrial hyperplasia (ACEH).

Methods

The clinical outcomes of 21 patients who underwent assisted reproductive technology after conservative therapy (group A) and 42 control women (group B) were retrospectively analyzed.

Results

There was no significant difference in the number of retrieved oocytes, fertilization rate or the number of transferred embryos between the two groups. Women in group A had a significantly thinner endometrium and a reduced implantation rate compared to those for women in group B. There was no significant difference in the cumulative clinical pregnancy and delivery rates between group A and B. The patients in group A required significantly more embryos for achieving a live-birth.

Conclusions

Our results indicate that a thin endometrium after repeated curettage may have a negative effect on endometrial receptivity of patients after conservative treatment for EC/ACEH. Clinicians should reconsider their present protocols and make efforts to minimize the damage to normal endometrium.     

Fertility sparing management of endometrial complex hyperplasia and endometrial carcinoma

The standard treatment of endometrial cancer or atypical hyperplasia is surgical removal of the uterus and ovaries. In early stage disease this has an excellent chance of cure but results in infertility. Although the majority of patients are postmenopausal an increasing number of patients with atypical hyperplasia or endometrial cancer are presenting with a desire to retain their fertile potential. In the last 8 years a number of studies have been published involving 403 patients with endometrial cancer and 151 patients with Atypical hyperplasia treated with high dose progestagens. The response rate is 76.2% and 85.6% respectively with endometrial cancer having a recurrence rate of 40.6%. There is a 26% recurrence rate in atypical hyperplasia. Overall 26.3% of those wishing to conceive had a live baby. Although concerns exist about the risks of medical treatment, those that fail this treatment do not appear to have a significantly poorer prognosis although 20 patients (3.6%) had either ovarian cancer or metastatic disease discovered during treatment or follow up.     

Pathologic features associated with resolution of complex atypical hyperplasia and grade 1 endometrial adenocarcinoma after progestin therapy

Objective

To determine the response of complex atypical hyperplasia (CAH) and well differentiated endometrioid adenocarcinoma of the uterus (WDC) to progestin therapy and whether pre-treatment estrogen and progesterone receptor status predicts outcome.

Methods

We performed a retrospective review encompassing women treated with progestin therapy for CAH or WDC at two institutions. Clinicopathologic, treatment, and recurrence data were recorded. Pre/post-treatment pathologic evaluation was performed. SAS 9.2 was used for statistical analyses.

Results

Forty-six patients were included. The median age was 35, and median BMI was 36.9. Thirty-seven percent were diagnosed with CAH and 63% had WDC. Megestrol acetate was the most commonly used agent (89%); 24% received multiple progestin therapies. Median treatment length was 6 months (range, 1–84); 36% of the patients underwent eventual hysterectomy, and 17.4% had carcinoma in their uterine specimens (8 primary endometrial, 1 primary ovarian). After a median follow-up of 35 months (range, 2–162), 65% experienced a complete response (CR), 28% had persistent or progressive disease, and 23% had a CR followed by recurrence. On univariate analysis, decreased post-treatment glandular cellularity (p = 0.0006), absence of post-treatment mitotic figures (p = 0.0008), and use of multiple progestin agents (p = 0.025) were associated with CR; however, only decreased glandular cellularity was significant on multivariate analysis (p = 0.007). Estrogen and progesterone receptor expression was not associated with treatment response.

Conclusion

In women with CAH or WDC, the overall response rate to progestin therapy was 65%; pre-treatment estrogen/progesterone receptor status did not predict response to treatment.     

高分化子宫内膜样癌及子宫内膜重度不典型增生患者孕激素治疗的临床分析

目的探讨35岁以下高分化子宫内膜样癌及子宫内膜重度不典型增生患者采用孕激素治疗以保留患者子宫的疗效,并随访其治疗后的生育情况.方法采用回顾性分析的方法对1991年至2005年北京协和医院收治的35岁以下、接受孕激素治疗（以醋酸甲羟孕酮为主）的25例高分化子宫内膜样癌及子宫内膜重度不典型增生患者的临床病理资料进行研究.其中,子宫内膜样癌8例（内膜癌组）,子宫内膜重度不典型增生17例（不典型增生组）.孕激素治疗前对患者进行全面的分期评估,治疗后每1～6个月诊刮以评价疗效,对有生育要求者随访其生育情况.结果内膜癌组患者孕激素治疗前经全面的分期评估,证实为早期、高分化子宫内膜样癌.除1例子宫内膜样癌患者尚未评估疗效外,内膜癌组其他7例及不典型增生组17例患者治疗后有效者分别为6例（6/7）、17例（100%）;缓解者分别为5例（5/7）、14例（82%）;缓解后复发者分别为1例（1/5）、3例（21%）,复发时间为缓解后6～30个月;随访缓解后要求生育的14例患者中,内膜癌组4例患者尚未生育,不典型增生组10例患者中4例妊娠共7次.1例自然受孕后失访;3例经促排卵治疗后受孕并足月分娩,其中1例产后人工流产3次.结论对于要求保留子宫的高分化子宫内膜样癌及子宫内膜重度不典型增生的年轻患者,孕激素治疗是一种治疗选择.孕激素治疗前应对子宫内膜样癌患者进行详细全面的分期评估,辅助生殖措施的介入有望提高治疗后的妊娠率.     

Impact of obesity on the results of fertility-sparing management for atypical hyperplasia and grade 1 endometrial cancer

Objectives

The aim of the present study was to evaluate the impact of obesity on reproductive and oncologic outcomes on the success of fertility-sparing management.

Methods

This retrospective multicenter cohort study included women treated conservatively for atypical hyperplasia (AH) and endometrial cancer (EC) to preserve fertility. Five inclusion criteria were defined: (i) the presence of AH or grade 1 EC confirmed by two pathologists; (ii) adequate radiological examination before conservative management; (iii) available body mass index (BMI) at the beginning of treatment; and (iv) a minimum follow-up time of six months.

Results

Forty patients fulfilled the inclusion criteria (17 had EC, and 23 had AH), mean age and BMI were 33 years and 29 kg/m² respectively. Among the 15 obese patients, after medical treatment, 10 patients responded (67%) and three relapsed, whereas in the 25 non-obese patients, 19 responded (76%) and three relapsed (p = 0.72). The overall pregnancy rate and follow-up time were 35% and 35 months respectively. Among the 15 obese patients, after medical treatment, two patients became pregnant, whereas in the 25 non-obese patients, 12 became pregnant (p = 0.04).

Conclusion

Despite similar response and recurrence rates, our results suggest that fertility-sparing management for AH and EC is associated with a lower probability of pregnancy in obese patients.     

Efficacy of IVF following conservative management of endometrial cancer

Five cases of conservative management of early stage uterine carcinoma were reported. All patients successfully underwent in vitro fertilization (IVF). Role of conservative treatment, IVF and prophylactic surgery followed competition of parity was discussed.     

PTEN、bcl-2/Bax表达预测子宫内膜增生孕激素治疗反应的研究

目的:研究孕激素治疗前后子宫内膜增生组织中PTEN基因、bcl-2/Bax的表达,结合临床治疗效果探讨其在预测孕激素治疗反应中的作用。方法:回顾分析子宫内膜增生患者56例(复杂性增生31例,非典型性增生25例),孕激素治疗3个月,留取治疗前后子宫内膜组织,取石蜡切片进行免疫组化染色,应用H-score评价孕激素治疗前后子宫内膜腺体中PTEN、bcl-2/Bax的表达。结果:(1)56例患者治疗3个月后,44例(78.57%)缓解,7例(12.50%)有效,1例(1.79%)治疗后复发,4例(7.14%)治疗无效,平均随访(33.49±9.62)个月。复杂性增生、轻度非典型性增生和中重度非典型性增生3组缓解+有效率的差异无统计学意义(P=0.245)。(2)子宫内膜增生组织中PTEN基因表达缺失率为16.07%(9/56),PTEN表达阳性组缓解+有效率为97.87%(46/47),PTEN表达阴性组缓解+有效率为55.56%(5/9),两组间比较差异有统计学意义(P<0.05)。(3)56例患者孕激素治疗前后子宫内膜腺体中bcl-2及Bax表达均阳性。缓解和有效组与复发和无效组治疗前bcl-2/Bax的H-score值无明显差异(P=0.486),两组治疗前后H-score差值亦无明显差异(P=0.368)。结论:子宫内膜增生组织中PTEN基因表达阳性组对孕激素治疗反应较好,PTEN基因表达缺失可能提示病变对孕激素抵抗,因此治疗前检测子宫内膜腺体细胞中PTEN基因的表达可以预测疗效;bcl-2/Bax不能作为预测孕激素治疗反应的指标。     

Uses of dietary supplements and herbal medicines during pregnancy in women undergoing assisted reproductive technologies– A study of taiwan birth cohort

Objective

This study aimed to assess the efficacy of dietary supplements and herbal medicines for the care of pregnant women undergoing assisted reproductive technologies (ART).

Assessing the reproductive performance of men co-infected with HIV-1 and hepatitis C undergoing assisted reproduction

Objective: To assess the reproductive performance of men co-infected with hepatitis C virus (HCV) and human immunodeficiency virus (HIV-1) undergoing assisted reproduction. Design: A retrospective analysis. Setting: University-based assisted reproductive technology (ART) center. Patients: We reviewed 217 consecutive ART cycles performed on 106 HIV-1 serodiscordant couples between August 1997 and March 2004, in which 28 men (26%) were seropositive for HCV and HIV-1 (group 1). Main outcome measures: Patient demographics and laboratory testing were compared to reproductive outcomes of men undergoing similar treatment but infected only with HIV-1 (group 2). Results: Co-infected men and their partners were of similar age as men infected only with HIV-1. Comparing group 1 to group 2, like values were noted for HIV-1 viral loads [1,993 ± 1,140 copies/ml (mean ± SE) vs. 1,659 ± 487 copies/ml]; CD4 counts (520 ± 98 vs. 604 ± 38 mm⁻³); and semen parameters. IVF performance and outcomes were similar, with fertilization rate (0.68 ± 0.03 vs. 0.71 ± 0.02); number of normally cleaving embryos (6.0 ± 0.5 vs. 5.3 ± 0.3); embryo implantation rate (0.27 ± 0.04 vs. 0.2 ± 0.02); and clinical pregnancy rate (40 vs. 29%). Although the male mortality rate was low in both groups, morbidity among co-infected men was significantly higher. Seven of 28 men (25%) had detectable HCV viral loads, and 14 (50%) had elevated liver function tests. Conclusion: Men co-infected with HCV and HIV-1 do reasonably well undergoing ART to prevent transmission of viruses to their partners and children.