Leslie Kimberly K, Walter Sarah A, Torkko Kathleen, Stephens Janet K, Thompson Chesney, Singh Meenakshi
Department of Obstetrics and Gynecology, University of New Mexico, Albuquerque, NM, USA.
Appl Immunohistochem Mol Morphol. 2007 Sep;15(3):284-93. doi: 10.1097/01.pai.0000213147.54901.12.
Our major hypothesis for these studies was that tamoxifen's varied effects on the endometrium might be due in part to differences in effect on estrogen and progesterone receptors [ER, progesterone receptor isoform A (PRA), and progesterone receptor isoform B (PRB)]. We aimed to evaluate the changes in histology in serial endometrial biopsies (Em bx), Papanicolaou smears (Pap smears), and endometrial ultrasounds as well as changes in the expression of ER, PRA, and PRB in response to tamoxifen. We propose that understanding and correlating the dynamics of receptor expression with histologic and cytologic changes will help us better understand the effect of tamoxifen on the endometrium and its role in the development of endometrial carcinoma in some patients.
Forty-two patients to be started on tamoxifen underwent a pretreatment Em bx and Pap smear. Follow-up serial Em bxs and Pap smears were obtained at sixth month and then at yearly intervals for up to 6 biopsies per case. Maturation indices (MIs) were determined on the Pap smears, and ER, PRA, and PRB immunostains were performed on the biopsies. Follow-up data is for a maximum of 10 years. Trends in changes in endometrial histology were analyzed and when atrophic or inactive endometrium changed to proliferative endometrium on treatment it was considered to be an increase in estrogen effect and the vice versa changes as a decrease in estrogen effect.
None of the subjects developed hyperplasia or malignancy. Two patients' Em bx demonstrated atypical cells associated with eosinophilic metaplasia, but subsequent biopsies had no atypia. Of the 42 patients, 37 had serial Em bxs in which evaluation for trends could be performed. Twelve of 37 (32.4%) had an overall decrease in estrogen effect on endometrial histology with another 12/37 (32.4%) showing no estrogenic effect on endometrial histology. Six of 37 patients (16.2%) showed an increased estrogen effect on endometrial histology. Seven of 37 (18.9%) had variable endometrial histology with no definable pattern. There was a statistically significant increase in PRA expression compared with baseline as time progressed (P<0.05). The PRB showed a contrasting significant decrease in expression at 2.5 and 3.5 years (P<0.05). There was no significant change in ER expression over the course of the study (P>0.05). Seven of 12 (58.3%) with a decreased estrogenic effect on endometrial histology had a concordant decrease in PRB expression. Seven of 12 (58.3%) with no change in endometrial histology also had a concordant decrease in PRB expression. Comparing the MI of Pap smears with histologic activity of the endometrium revealed minimal correlation between the two. However, in the patients with an increased estrogen effect on endometrial histologic activity, there was no correlation with the MI. Additionally, 57% of patients showed no correlation between endometrial histologic activity and ultrasound findings.
Tamoxifen had an antiestrogenic or neutral effect on endometrial histology and Pap smears of most subjects, but estrogenic, or variable effects were also observed in a minority of patients. Tamoxifen treatment was accompanied by an uncoupling of the regulation of PRA and PRB expression without effect on ER expression. Overall, expression of PRB decreased whereas that of PRA increased.
我们对这些研究的主要假设是，他莫昔芬对子宫内膜的多种作用可能部分归因于其对雌激素和孕激素受体[雌激素受体（ER）、孕激素受体异构体A（PRA）和孕激素受体异构体B（PRB）]作用的差异。我们旨在评估系列子宫内膜活检（Em bx）、巴氏涂片（Pap涂片）和子宫内膜超声检查中的组织学变化，以及ER、PRA和PRB表达对他莫昔芬的反应变化。我们认为，了解受体表达动态并将其与组织学和细胞学变化相关联，将有助于我们更好地理解他莫昔芬对子宫内膜的作用及其在某些患者子宫内膜癌发生中的作用。
42例即将开始服用他莫昔芬的患者在治疗前进行了Em bx和Pap涂片检查。在第6个月进行随访系列Em bx和Pap涂片检查，之后每年进行一次，每个病例最多进行6次活检。在Pap涂片上测定成熟指数（MI），并对活检组织进行ER、PRA和PRB免疫染色。随访数据最长为10年。分析子宫内膜组织学变化趋势，当萎缩或静止的子宫内膜在治疗后转变为增殖性子宫内膜时，认为是雌激素作用增强，反之则认为是雌激素作用减弱。
所有受试者均未发生增生或恶性病变。2例患者的Em bx显示与嗜酸性化生相关的非典型细胞，但随后的活检未发现非典型性。42例患者中，37例有系列Em bx，可对其趋势进行评估。37例中的12例（32.4%）子宫内膜组织学的雌激素作用总体下降，另外12/37例（32.4%）对子宫内膜组织学无雌激素作用。37例患者中的6例（16.2%）子宫内膜组织学的雌激素作用增强。37例中的7例（18.9%）子宫内膜组织学变化不定，无明确模式。随着时间推移，PRA表达与基线相比有统计学意义的增加（P<0.05）。PRB在2.5年和3.5年时表达有显著的相反下降（P<0.05）。在研究过程中ER表达无显著变化（P>0.05）。12例子宫内膜组织学雌激素作用下降的患者中有7例（58.3%）PRB表达一致下降。12例子宫内膜组织学无变化的患者中有7例（58.3%）PRB表达也一致下降。比较Pap涂片的MI与子宫内膜的组织学活性，发现两者之间相关性极小。然而，在子宫内膜组织学活性雌激素作用增强的患者中，与MI无相关性。此外，57%的患者子宫内膜组织学活性与超声检查结果无相关性。
他莫昔芬对大多数受试者的子宫内膜组织学和Pap涂片有抗雌激素或中性作用，但在少数患者中也观察到雌激素或可变作用。他莫昔芬治疗伴随着PRA和PRB表达调节的解偶联，而对ER表达无影响。总体而言，PRB表达下降而PRA表达增加。
