Ovarian preservation in stage I low-grade endometrial stromal sarcomas

OBJECTIVE: To examine the impact of ovarian preservation in a case-control study of women with stage I low-grade endometrial stromal sarcomas. METHODS: Patients with low-grade endometrial stromal sarcomas were identified at 5 institutions from 1976 to 2002. Cases were defined as patients who retained ovarian function; each case was matched to 2 control patients who underwent bilateral salpingo-oophorectomy (BSO). Immunostaining for estrogen and progesterone receptors was performed. Data were examined with Student t, chi(2), Cox regression, and Kaplan-Meier analyses. RESULTS: Twelve premenopausal patients with low-grade endometrial stromal sarcomas who did not undergo BSO were matched to 24 controls. Of the 36 patients in the entire cohort, disease recurred in 14 (39%). Recurrences were identified in the pelvis, abdomen, lung, or lymphatics in both cases and controls. Disease recurred in 4/12 (33%) case patients, compared with 10/24 (42%) control patients (P = .63). When case patients were compared with controls, no differences in progression-free (91.3 months versus 68.6 months, P = .44) or overall survival (median survival not yet reached versus 406 months, P = .82) were identified. This study had 13% power to detect the observed difference in median disease-free survival. After controlling for use of adjuvant therapy and BSO, older age remained the only independent poor prognostic factor for progression-free survival (P = .008). Twenty-two available tumors demonstrated positivity for both estrogen and progesterone receptors. CONCLUSION: Bilateral salpingo-oophorectomy did not appear to affect time to recurrence or overall survival. Retention of ovarian function may be an option for premenopausal women with low-grade endometrial stromal sarcomas.     

Harm or benefit of hormonal treatment in metastatic low-grade endometrial stromal sarcoma: single center experience with 10 cases and review of the literature

Endometrial stromal sarcoma (ESS) is a rare disease with probably less than 700 new cases in the US or EU per year. ESS usually expresses steroidal receptors and is regarded to be hormone-sensitive. A higher risk in women receiving estrogen replacement therapy (ERT) or tamoxifen has been suspected, and remissions following treatment with progestins have been reported in case studies. Aromatase inhibitors represent an interesting new treatment option. Due to the rarity of the tumor, only few case series and no prospective studies are published. We therefore conducted a retrospective study to evaluate the influence of hormonal treatment to ESS. METHODS: Our institutional sarcoma data bank was screened for cases of ESS since 1999. All corresponding files and radiographs were reviewed retrospectively. RESULTS: Ten patients with low-grade ESS were identified. Diagnosis was established before or by hysterectomy in 6 patients, by local recurrence after previous hysterectomy for nonmalignant disease in 3 patients or by pulmonary metastases with no primary tumor found so far in 1 patient. 5/10 patients were on ERT and 3/10 on tamoxifen at the time of diagnosis of metastatic disease. Treatment strategies consisted of stopping ERT and tamoxifen, respectively, or initiation of the progestin MPA or letrozole. Three patients achieved stable disease after stopping ERT. 2/3 patients responded to MPA as first-line treatment (1 CR; 50+ months, 1 PR; 9 months). 4/5 patients responded to letrozole as first-line therapy (3 PR;3+, 9+ and 10+ months) or second-line treatment after MPA (1 PR; 37+ months). 9/10 patients are alive 33 to 255 months after hysterectomy. Survival since diagnosis of metastatic disease is 4 to 164 months. CONCLUSIONS: Patients with a previous history of low-grade ESS should not be treated with estrogens or tamoxifen. If nevertheless present, withdrawal of ERT or tamoxifen is strongly advised, resulting in disease stabilization in some cases. MPA and letrozole, in particular, are highly effective and lead to sustained disease control in most cases.     

Estrogen and progesterone receptors in uterine sarcomas

Estrogen and progesterone receptors were measured in tissues from 43 patients with various uterine sarcomas using the dextran-coated charcoal assay. Estrogen receptor was present in 55.5% and progesterone receptor in 55.8% of samples, at median estrogen and progesterone receptor concentrations of 10.7 and 15.8 fmol/mg cytosol protein, respectively. These median values are much lower than those in 30 consecutive endometrial adenocarcinomas and 50 breast carcinomas assayed in our laboratory. Progesterone receptor status correlated strongly with estrogen receptor status in uterine sarcomas (P = .001). Estrogen and progesterone receptor levels were not influenced by stage, grade, or mitotic count. Patients 50 years of age or less had significantly higher progesterone receptor than those over 50. No such age effect was seen for estrogen receptor. Endometrial stromal sarcoma had higher estrogen and progesterone receptor levels than other histologic types. Low-grade endometrial stromal sarcomas had higher median estrogen receptors (238.9 fmol/mg) and better survival (all patients alive at 6-12 months) than did high grade (N = 7) endometrial stromal sarcomas (median ER = 6.6 fmol/mg, all dead of disease at 8-27 months). For all histologic types, evaluable patients with stage I or II disease (N = 16) were more likely to survive longer than one year than those with stage III or IV disease (N = 13, P = .003). Evaluable patients with estrogen receptor-positive sarcomas were more likely to survive longer than one year than those with estrogen receptor-negative tumors (P = .006). With one exception, an endometrial stromal sarcoma, hormonal therapy exerted no beneficial effect.(ABSTRACT TRUNCATED AT 250 WORDS)     

Estrogen receptor expression in an endometrial stromal sarcoma after tamoxifen therapy

INTRODUCTION: Several cases of low-grade endometrial stromal sarcomas in women with breast cancer have been reported to be associated with tamoxifen therapy. Estrogen receptor expression has been used to characterize the partial estrogenic action of tamoxifen on the endometrium and has been found in tamoxifen-associated endometrial pathologies. CASE: A low-grade endometrial stromal sarcoma in a woman with a history of breast cancer treated with adjuvant tamoxifen is presented. Steroid receptor studies performed on the tumor were negative for estrogen and positive for progesterone. CONCLUSION: The absence of estrogen receptor expression suggests that endometrial stromal sarcomas are not necessarily caused by the estrogenic properties of tamoxifen.     

Expression of estrogen receptors alpha and beta in two uterine mesenchymal tumors after prolonged tamoxifen therapy. Report of two cases

INTRODUCTION: Tamoxifen therapy is associated with an increased risk of endometrial carcinoma, and possibly uterine sarcomas. Little is known about hormone receptor expression in mesenchymal tumors of the uterus after tamoxifen therapy. CASES: The cases of two patients with uterine mesenchymal tumors after prolonged tamoxifen therapy due to breast cancer are presented. The expression of estrogen receptors alpha (ERalpha) and beta (ERbeta) and progesterone receptors (PR) was studied immunohistochemically in both cases. Both tumors were negative for ERalpha and positive for ERbeta. In the first case the tumor was negative for PR, while in the second only 20% of nuclei were PR-positive. CONCLUSIONS: Consistent with previous studies, uterine mesenchymal tumors after tamoxifen therapy do not express ERalpha. The results of the present report provide for the first time evidence that tamoxifen might exert a stimulatory effect on the uterus, at least during tumor progression, through ERbeta but not through ERalpha.     

Cytoplasmic progesterone and estradiol receptors in normal, hyperplastic, and carcinomatous endometria: therapeutic implications

This study was designed to determine whether the presence of progesterone receptors (PR) and/or estradiol receptors (ER) could be used to predict progestin responsiveness of recurrent or advanced endometrial cancers. We have demonstrated the presence of physicochemically similar cytoplasmic progesterone and estradiol receptors in normal, hyperplastic, and carcinomatous endometria. All normal endometria contained both PR and ER. Seventy-three percent of endometrial hyperplasias were PR(+) and 93% were ER(+). A decreasing concentration of progesterone receptor activity was observed with increasing tumor anaplasia [grade 1, 84% PR(+); grade 2, 55% PR(+); grade 3, 22% PR(+)] and in irradiated tumors. A statistically significant (p less than 0.001) relationship has been demonstrated between the presence of specific cytoplasmic PR and response to progestin therapy in recurrent or advanced endometrial adenocarcinomas. Thus, we conclude that a PR assay may be used to help select the most appropriate therapy for patients with recurrent or advanced endometrial adenocarcinoma.     

Heterogeneity in hormone receptor status in primary and metastatic endometrial cancer

The rationale for endocrine therapy in patients with advanced endometrial carcinoma may be based on the presence of estrogen or progesterone receptors in the primary tumor. A study was designed to evaluate tumor cell heterogeneity of steroid hormone receptors in the primary and metastatic sites in endometrial cancer. Primary endometrial cancer tissue samples from 10 patients and 16 metastatic tumor sites were simultaneously analyzed for estrogen and progesterone receptors, using a radioligand biochemical assay. The primary tumor was estrogen receptor (ER) and progesterone receptor (PR) positive in 70 and 60% of the patients, respectively. The metastatic sites were ER positive in 63% and PR positive in 25%. The primary tumor tissue and the metastatic disease showed an identical ER and PR status in only 25 and 19%, respectively. Four patients had multiple metastatic sites analyzed. In two of four patients the PR values, and in three of four patients the ER values, in these metastatic sites were discordant. These data support the concept of tumor cell heterogeneity for steroid hormone receptors in endometrial cancer. To optimize treatment planning, it may be important to biopsy primary, metastatic, and recurrent tumor sites for individual analysis of receptor activity.     

Endometrial stromal sarcoma: a clinicopathologic study of 11 cases with determination of estrogen and progestin receptor levels in three tumors

Eleven cases of endometrial stromal sarcoma were obtained from the files of Yale New Haven Hospital from 1969 to 1981 for clinicopathologic correlation and determination of the outcome after hormonal therapy with progestational agents. Histologically, nine of the tumors were classified as low grade stromal sarcomas, and two were of a high grade. All of the patients underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy as the main modality of treatment. Two patients received radiation, three adjuvant chemotherapy, two hormonal therapy (Megace 160 mg qd), three received no therapy at all, and the treatment is not known in one case. Two of the patients who received no therapy had recurrences and were placed on hormonal therapy. The remaining patient was a stage IV and died of disease 3 months after diagnosis. All four of the patients who were treated with hormonal therapy are alive, free of disease, or with stable tumor from 2 to 6 years after diagnosis. The presence of estrogen receptors (ER) and progestin receptors (PR) was demonstrated in the tumor in some of the cases; this may explain the sensitivity of this neoplasm to hormonal therapy.     

Estrogen and progesterone receptors in endometrial cancer and their prognostic relevance

Three hundred and nine malignant endometrial tumors were biochemically analyzed with respect to estrogen (ER) and progesterone (PR) receptors. Fifty-seven percent of endometrial carcinomas were ER and PR positive (greater than or equal to 50 fmole/mg of cytosol protein); 24% were negative for both receptors. Five sarcomas and 16 of 21 mixed müllerian tumors were receptor negative. Receptor status correlated with clinical stage and grade of histological differentiation, but not with myometrial invasion. Anamnestic data on patients showed no differences between those with receptor-negative and receptor-positive tumors. Five-year survival rate (stage I) and median survival time (stages II-IV, recurrences) for patients with ER+/PR+ and ER-/PR+ endometrial cancer were significantly better than for ER-/PR- and ER+/PR- patients. A multivariate analysis demonstrated progesterone receptor as a significant prognostic factor next to clinical stage. Estrogen receptor had no significant prognostic relevance. A retrospective analysis of gestagen treatment and progesterone receptor status confirms the importance of PR, possibly independent of hormonal treatment.     

Effects of subdermal implants of estradiol and testosterone on the endometrium of postmenopausal women.

A retrospective review of the medical records of 258 postmenopausal patients using estradiol and testosterone implants as combined hormone therapy was carried out to evaluate the effects of testosterone on the endometrium after two years of continuous use. Endometrial thickness was measured by ultrasonography. Histology was performed on samples of thickened endometria obtained during hysteroscopy with biopsy. In the 44 patients in whom endometrial thickening was >5 mm at the end of the second year of implant use, the most frequent finding at hysteroscopy was polypoid lesion in 61.3% of cases, followed by normal uterine cavity in 31.8% of cases and submucous myoma in 6.8%. Histology of the endometrial samples confirmed endometrial polyp in 38.6% of cases, a histologically normal endometrium in 31.8% of cases, simple endometrial hyperplasia in 20.4% of cases, and myoma and atrophic endometrium in 4.5%. It is possible that testosterone may exert its antiproliferative effects on the endometrium but not on polyps in an action similar to that exerted by combined estrogen/progestin therapies. A greater incidence of simple, low-grade endometrial hyperplasia was found in our study compared with studies using continuous estrogen/progestin regimens. The use of progestins as the ideal endometrial protection should therefore be reconsidered.     

Effects of subdermal implants of estradiol and testosterone on the endometrium of postmenopausal women

A retrospective review of the medical records of 258 postmenopausal patients using estradiol and testosterone implants as combined hormone therapy was carried out to evaluate the effects of testosterone on the endometrium after two years of continuous use. Endometrial thickness was measured by ultrasonography. Histology was performed on samples of thickened endometria obtained during hysteroscopy with biopsy. In the 44 patients in whom endometrial thickening was >5 mm at the end of the second year of implant use, the most frequent finding at hysteroscopy was polypoid lesion in 61.3% of cases, followed by normal uterine cavity in 31.8% of cases and submucous myoma in 6.8%. Histology of the endometrial samples confirmed endometrial polyp in 38.6% of cases, a histologically normal endometrium in 31.8% of cases, simple endometrial hyperplasia in 20.4% of cases, and myoma and atrophic endometrium in 4.5%. It is possible that testosterone may exert its antiproliferative effects on the endometrium but not on polyps in an action similar to that exerted by combined estrogen/progestin therapies. A greater incidence of simple, low-grade endometrial hyperplasia was found in our study compared with studies using continuous estrogen/progestin regimens. The use of progestins as the ideal endometrial protection should therefore be reconsidered.     

The role of hormones for the treatment of endometrial hyperplasia and endometrial cancer

PURPOSE OF REVIEW: Hormone therapy has been palliative for advanced/ recurrent endometrial cancer. High remission rates are seen in well-selected stage I, grade 1 endometrial cancer of young women using hormone therapy (usually progestins) as fertility-preserving treatment. Many other hormones, such as gonadotropin-releasing hormone analogs (GnRHa), selective estrogen receptor modulators, aromatase inhibitors, intrauterine progestins, and others are potential modalities. This review updates the recent publications in this area. RECENT FINDINGS: Two reports investigating different scheduling of tamoxifen and progestins indicated that tamoxifen may be a valuable adjunct to progestin therapy. GnRHa has been used adjunctively to tamoxifen as second-line hormone therapy for fertility sparing after progestin failed. Aromatase inhibitors have shown their potential in treating endometrial cancer and endometrial hyperplasia as single agent or in combination with progestins. Intrauterine progestins seem efficacious in treating endometrial hyperplasia; its applications on endometrial cancer patients, however, have been limited to postmenopausal women with poor surgical risk. SUMMARY: Translational research based on molecular mechanisms is mandatory to a more appropriate utilization of hormone therapy. The role of dose, scheduling, route of administration of progestins as well as the addition of other hormonal agents should be further explored by well designed randomized controlled trials.     

Endometrial "sarcomas" complicating ovarian thecoma, polycystic ovarian disease and estrogen therapy

Unopposed endogenous and exogenous estrogenic stimulation has been considered by most investigators to have a role in the pathogenesis of carcinoma of the endometrium. Although a few cases of "sarcomas" of the endometrium that had developed in an estrogenic setting have been reported, a clear-cut association between estrogenic stimulation and these forms of endometrial cancer has not been established. We report six cases of endometrial sarcomas complicating ovarian thecomas, polycystic ovarian disease, or prolonged estrogen therapy. Three ovarian thecomas, which are considered to be estrogenic tumors, were associated with endometrial malignant mullerian mixed tumor, mullerian adenosarcoma, and low-grade stromal sarcoma in postmenopausal women. Polycystic ovarian disease, a condition characterized by unopposed estrinism due to the peripheral conversion of excessive androstenedione to estrone, was found in a 27-year-old infertile woman with an endometrial malignant mullerian mixed tumor. A pure osteogenic sarcoma of endometrial stromal origin developed in a 28-year-old woman with gonadal dysgenesis (Turner's syndrome) who had received estrogens for 18 years. The sixth woman, with an empty sella turcica after radiation therapy of a pituitary adenoma, had an endometrial mullerian adenosarcoma at the age of 40 years after 16 years of estrogen therapy. None of these patients had had pelvic radiation therapy. The evidence from this series of cases and from six additional cases identified in the literature suggests that the risk of endometrial sarcomas may be increased by estrogen therapy or endogenous disorders that lead to unopposed estrogenic stimulation of the uterus.     

Serum hormone and steroid hormone receptor levels during luteal-phase and long-term treatment with danazol

This study was designed to clarify the effects of danazol on levels of serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin, progesterone (P), and 17 beta-estradiol and endometrial steroid receptors (for estrogen [ER], progestin [PR], and androgen [AR] ) during luteal-phase and long-term treatment. These levels were compared with midluteal-phase levels for a histologically in-phase endometrium. Danazol given during the luteal phase to patients with in-phase endometrium decreased endometrial steroid receptor levels (total ER and total PR), and decreased serum P, LH, and FSH levels. Ten of the 17 patients treated (59%) still had in-phase endometrium. Danazol (400 mg/day) given for 1 month or more to patients with pelvic endometriosis increased serum LH and FSH levels within the normal range and endometrial total ER and PR levels. It appears that the effects of short-term and long-term treatment with danazol on serum hormone and endometrial steroid receptor levels differ.     

子宫内膜癌组织中雌激素及孕激素受体亚型的表达研究

目的探讨子宫内膜癌组织中雌激素受体(ER)亚型mRNA及孕激素受体(PR)亚型mRNA和蛋白表达水平的变化及其意义。方法采用RT-PCR法检测66例子宫内膜癌和30例正常子宫内膜组织ER、PR亚型mRNA的表达,采用蛋白印迹法检测PR亚型蛋白的表达。结果(1)ERαmRNA在子宫内膜癌和正常子宫内膜组织中的表达水平分别是8.00±7.77、3.84±2.57,而ERβmRNA的表达水平分别是4.15±3.55、0.41±0.29,子宫内膜癌组织中ERα、ERβmRNA表达水平均高于正常子宫内膜,两种组织间分别比较,差异均有统计学意义(P<0.05)。(2)PR、PRA和PRB蛋白表达及PR mRNA表达的降低与子宫内膜癌的发生有关(P<0.05),而PRA与PRB蛋白表达的比值和PRB mRNA的表达与子宫内膜癌的发生无明显相关性(P值分别为0.550、0.901)。(3)子宫内膜癌组织中PRB mRNA与ERβmRNA的表达水平呈正相关关系(r=0.43,P<0.01)。结论子宫内膜癌组织中ER亚型mRNA表达上调、PR蛋白和mRNA表达的下调可能参与了子宫内膜癌的发生;PRB mRNA与ERβmRNA表达呈正相关关系。     

子宫内膜间质肿瘤19例病理形态分析

目的 加深对子宫内膜间质肿瘤病理形态的认识。方法 对1例间质结节、15例低度恶性及3例高度恶性间质肉瘤进行临床病理分析。结果 肉瘤组中4例以粘膜下肿物为主要表现，4例手术后复发。病理检查4例有宫外病灶，6例伴有性索样分化，7例有明显的平滑肌分化。结论 低度恶性间质肉瘤是子宫内膜间质肿瘤的主要表现形式，性索样分化与平滑肌分化在间质肿瘤中不少见。     

Cyproterone,norethindrone, medroxyprogesterone and levonorgestrel are less potent local human growth hormone and insulin-like growth factor I secretion stimulators than progesterone in human breast cancer explants expressing the estrogen receptor

The aim of the present study was to compare the ability of natural progesterone and synthetic progestins to stimulate local growth hormone (GH) and insulin-like growth factor I (IGF-I) secretion by breast cancer explants. Explants obtained during surgery were divided according to their estrogen/progesterone receptor phenotype – ER(+)PR(–); ER(+)PR(+); ER(–)PR(+) – as determined by immunocytochemistry. Natural progesterone (10^-5 mol/l) and synthetic progestins (cyproterone acetate (5 × 10^-7 mol/l), norethindrone (10^-5 mol/l), medroxyprogesterone acetate (10^-7 mol/l), and levonorgestrel (10^-7 mol/l) were tested in vitro for their ability to induce secretion of proliferation-promoting agents such as human GH (hGH) and IGF-I. All hormone-dependent breast cancer cell types responded to progesterone stimulation with increased local hGH secretion, while in the non-malignant tissue this effect was observed only in PR(+) cells. Moreover, progesterone in only PR(+) cells in vitro stimulated local IGF-I secretion by both malignant and non-malignant tissue. Medroxyprogesterone and levonorgestrel increased GH secretion by both malignant and non-malignant ER(–)PR(+) breast cancer explants, while cyproterone stimulated it only in non-malignant tissue. None of the synthetic progestins tested in this experiment exerted an effect on GH secretion by both malignant and non-malignant tissue of ER(+) breast cancer explants. The present data additionally showed that, apart from cyproterone, which increased IGF-I secretion in the same manner as progesterone by both malignant and non-malignant ER(–)PR(+) breast explants, other progestins tested had either no effect on IGF-I local secretion or decreased it. Medroxyprogesterone and levonorgestrel induced a decrease in IGF-I secretion noted in ER(+) explants of non-malignant tissue and in malignant ER(–)PR(+) breast tissue. All progestins tested decreased IGF-I secretion by malignant ER(+)PR(+) explants. Taken together, the tested synthetic progestins widely used as oral contraceptives and in hormone replacement therapy were less potent than progesterone in inducing secretion of proliferation-promoting agents such as hGH and IGF-I in ER-containing breast tissue. Despite the lack of confirmation of the link between the use of progestins and breast cancer risk, patients should be informed that the use of certain estrogen/progestin preparations is of no influence on breast cancer risk while others may increase it.     

Low-grade stromal sarcoma: DNA flow cytometric analysis and estrogen progesterone receptor data

DNA flow cytometry (FCM) data and estrogen receptor (ER) and progesterone receptor (PR) status were studied in three cases of low-grade stromal sarcoma (LGSS). One case was a primary presentation and the remaining two were recurrent tumors. DNA FCM showed a DNA index (DI) equal to 1.00, consistent with a diploid cell population, for four of the six specimens studied. The other two showed near-diploid populations. Proliferation indices (PI) were low in two of the patients' tumors (8.0 and 12.7%). These findings are consistent with the clinical history of LGSS and its propensity for indolent growth, long intervals between recurrences, and generally favorable prognosis. In case 2, a patient with several recurrences, the PI was increased to 20.3% in a specimen from the first recurrence. She subsequently recurred within 1 year with a more aggressive tumor, characterized by a mitotic index of greater than 10 mitoses/10 high-power fields (HPF), absence of ER and PR, and an aneuploid population (DI = 1.19). Receptor data, obtained by dextran-coated charcoal assay, showed that all tumors except the aggressive recurrence in case 2 had high ER (average 316 fmole/mg protein) and high PR (average 753 fmole/mg protein) levels. These ER and PR data are similar to the two other reports in the literature and the usual clinical response to progestational therapy was demonstrated. Further studies will help define the possible role of FCM and ER and PR determinations in patients with LGSS. These preliminary data suggest that they may be of prognostic significance.     

Survey of adjuvant hormone therapy in patients after endometrial stromal sarcoma

INTRODUCTION: We surveyed the use of adjuvant hormonal therapy in patients with endometrial stromal sarcomas. MATERIAL AND METHODS: A questionnaire was circulated among the 130 members of an Internet-based endometrial stromal sarcoma support group. The questions pertained to age at diagnosis, organs involved at diagnosis, recurrences, metastases, current disease status, and treatment protocols, with special focus on hormonal therapy. RESULTS: The questionnaire was returned by 64 of 120 women (49%). At the time of the study 48 patients (mean follow-up 2.4 (range, 1-9) years) had no evidence of disease (NED) and 16 (mean follow-up 6.2 (range, 1-22) years) were alive with disease (AWD). Of the 16 women AWD, 15 (95%) were being treated with hormones as opposed to ten of 48 (21%) women with NED. Hormone treatment consisted of progestins (15 patients), aromatase inhibitors, aromatase inhibitor plus GnRH analog], or tamoxifen. DISCUSSION: Adjuvant hormonal therapy presently appears to be used predominantly in women with advanced or recurrent endometrial stromal sarcomas but is also a potential option for patients after surgery without residual tumor.     

Endometrial steroid receptor during normal menstrual cycle and physiopathology of nidation

Human uterine endometrial steroid receptor [estrogen (ER), progestin (PR) and androgen (AR) receptors] in the normal menstrual cycle were determined at the cellular level. Endometria with pathological out-of-phase findings or with hypoplastic uterus were evaluated for the concentration of steroid receptors, for a better understanding of their pathophysiology. ER and PR levels gradually rose toward the early secretory phase, remained at the maximum level during the mid-secretory phase and dropped to the lowest level during the late secretory phase. Especially nuclear PR reached the maximum level during the mid-secretory phase. These results indicate that the endometrial ER and PR, especially the endometrial nuclear PR, is kept in the maximum level at implantation. AR showed only a slight change in a very low level throughout the menstrual cycle. This indicates that androgen may not play so important a role in endometrial physiology. Endometria with out-of-phase or with hypoplastic uterus contained significantly low levels of endometrial ER and PR, while serum hormones levels were normal. This indicates indigenous reduction of ER and PR synthesis in such endometria.