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Biomedical subjects

Andrew Berchuck

Publications and source records attributed to Andrew Berchuck.

At least 55 records · Page 3Linked to original sources
PubMed2004

Progesterone receptor promoter +331A polymorphism is associated with a reduced risk of endometrioid and clear cell ovarian cancers.

OBJECTIVE: The progestagenic milieu of pregnancy and oral contraceptive use is protective against epithelial ovarian cancer. A functional single nucleotide polymorphism in the promoter of the progesterone receptor (+331A) alters the relative abundance of the A and B isoforms and has been associated with an increased risk of endometrial and breast cancer. In this study, we sought to determine whether this polymorphism affects ovarian cancer risk. METHODS: The +331G/A polymorphism was genotyped in a population-based, case-control study from North Carolina that included 942 Caucasian subjects (438 cases, 504 controls) and in a confirmatory group from Australia (535 cases, 298 controls). Logistic regression analysis was used to calculate age-adjusted odds ratios (OR). RESULTS: There was a suggestion of a protective effect of the +331A allele (AA or GA) against ovarian cancer in the North Carolina study [OR, 0.72; 95% confidence interval (95% CI), 0.47-1.10]. Examination of genotype frequencies by histologic type revealed that this was due to a decreased risk of endometrioid and clear cell cancers (OR, 0.30; 95% CI, 0.09-0.97). Similarly, in the Australian study, there was a nonsignificant decrease in the risk of ovarian cancer among those with the +331A allele (OR, 0.83; 95% CI, 0.51-1.35) that was strongest in the endometrioid/clear cell group (OR, 0.60; 95% CI, 0.24-1.44). In the combined U.S.-Australian data that included 174 endometrioid/clear cell cases (166 invasive, 8 borderline), the +331A allele was significantly associated with protection against this subset of ovarian cancers (OR, 0.46; 95% CI, 0.23-0.92). Preliminary evidence of a protective effect of the +331A allele against endometriosis was also noted in control subjects (OR, 0.19; 95% CI, 0.03-1.38). CONCLUSIONS: These findings suggest that the +331G/A progesterone receptor promoter polymorphism may modify the molecular epidemiologic pathway that encompasses both the development of endometriosis and its subsequent transformation into endometrioid/clear cell ovarian cancer.

Adenocarcinoma, Clear Cell↗
PubMed2003

Prognostic significance of p53 mutation and p53 overexpression in advanced epithelial ovarian cancer: a Gynecologic Oncology Group Study.

PURPOSE: The prognostic significance of p53 mutations and overexpression in advanced epithelial ovarian cancers was examined in primary tumors from 125 patients participating in a Gynecologic Oncology Group randomized phase III treatment protocol. PATIENTS AND METHODS: Mutational analysis of p53 was performed in RNA or genomic DNA extracted from frozen tumor. An immunohistochemistry assay was used to detect p53 overexpression in fixed tumor. RESULTS: There were 81 patients (74%) with a single mutation, three patients (3%) with two mutations, and 25 patients (23%) lacking a mutation in exons 2 to 11 of p53. Although most mutations occurred within exons 5 to 8, mutations outside this region were observed in 11% of patients. A mutation in exons 2 to 11 of p53 was associated with a short-term improvement in overall survival and progression-free survival. Adjusted Cox modeling demonstrated a 70% reduction in risk of death (P =.014) and a 60% reduction in risk of disease progression (P =.014) for women with such mutations. However, these striking risk reductions increased over time (P <.02) and eventually disappeared with longer follow-up. Overexpression of p53 was observed in 55 patients (100%) with only missense mutation(s), seven patients (32%) with truncation mutations, and eight patients (40%) lacking a mutation in exons 2 to 11. Overexpression of p53 was associated with tumor grade but not with patient outcome. CONCLUSION: Alterations in p53 are a common event in advanced epithelial ovarian cancer. A mutation in p53, but not overexpression of p53, is associated with a short-term survival benefit. Additional studies are required to define the roles that p53 plays in regulating therapeutic responsiveness and patient outcome.

DNA Mutational Analysis↗
PubMed2003

Polymorphisms in BRCA1 and BRCA2 and risk of epithelial ovarian cancer.

PURPOSE: Because inherited BRCA1 or BRCA2 mutations strikingly increase ovarian cancer risk, polymorphisms in these genes could represent low penetrance susceptibility alleles. Previous studies of the BRCA2 N372H polymorphism suggested that HH homozygotes have a modestly increased risk of both breast and ovarian cancer. We have examined whether BRCA2 N372H or common amino acid-changing polymorphisms in BRCA1 predispose to ovarian cancer. EXPERIMENTAL DESIGN: A population-based, case control study of ovarian cancer was performed in North Carolina. Cases included 312 women with ovarian cancer (76% invasive and 24% borderline) and 401 age- and race-matched controls. Blood DNA from subjects was genotyped for BRCA2 N372H and BRCA1 Q356R and P871L. RESULTS: There was no association between BRCA2 N372H and risk of borderline or invasive epithelial ovarian cancer. The overall odds ratio (OR) for HH homozygotes was 0.8 [95% confidence interval (CI) = 0.4-1.5] and was similar in all subsets, including invasive serous cases. In addition, neither the BRCA1 Q356R (OR = 0.9, 95% CI 0.5-1.4) nor P871L (OR = 0.9, 95% CI 0.6-1.9) polymorphisms were associated with ovarian cancer risk. There was a significant racial difference in allele frequencies of the P871L polymorphism (P = 0.64 in Caucasians, L = 0.76 in African-Americans, P < 0.0001). CONCLUSIONS: In this population-based, case control study, common amino acid changing BRCA1 and 2 polymorphisms were not found to affect the risk of developing ovarian cancer.

Adenocarcinoma, Clear Cell↗
PubMed2003

Role of decreased levels of lipid phosphate phosphatase-1 in accumulation of lysophosphatidic acid in ovarian cancer.

The levels of lysophosphatidic acid (LPA) are consistently elevated in the ascites of ovarian cancer patients, suggesting that ovarian cancer cells are exposed to an LPA replete environment. LPA stimulates cell proliferation, cell survival, resistance to cisplatin, production and activation of proteases, invasiveness and production of the neovascularizing factors, vascular endothelial growth factor, and interleukin 8. Although ovarian cancer cells can produce LPA, this may not be the major reason for altered LPA levels in ascites. We have demonstrated that the major mechanism of degradation of LPA by ovarian cancer cells is through a lipid phosphate phosphatase (LPP)-like activity. We demonstrate herein that LPP-1 mRNA is decreased in the majority of ovarian cancers. This is recapitulated in ovarian cancer cell lines, where LPP-1 RNA levels are lower than those in normal ovarian epithelium and immortalized ovarian epithelial cells. Introduction of LPP-1 into ovarian cancer cell lines results in increased LPA hydrolysis, which is associated with a marked inhibition of cell proliferation and colony-forming activity and a marked increase in apoptosis. Thus, the LPA-rich environment of the ovarian cancer cell in vivo and the subsequent effects of cellular pathophysiology may be a consequence of both increased LPA production and decreased LPA metabolism by ovarian cancer cells.

Cell Division↗
PubMed2003

A pilot Phase II trial of concurrent radiotherapy, chemotherapy, and hyperthermia for locally advanced cervical carcinoma.

BACKGROUND: Five randomized studies have demonstrated a benefit derived from adding cisplatin (CDDP)-based chemotherapy to radiotherapy (RT) for treatment of cervical carcinoma. The Dutch Phase III pelvic tumor trial demonstrated a survival and local control benefit due to the addition of hyperthermia (HT) to RT. The authors evaluated response and toxicity in patients with locally advanced cervical carcinoma (LACC) who were treated with concurrent weekly CDDP, HT, and RT (whole pelvis [n=7] and whole pelvis and paraaortic nodes [n=5]). METHODS: From August 1998 through December 2000, 12 patients with LACC or locally recurrent cervical carcinoma (LRCC) following hysterectomy were enrolled on a pilot study combining weekly CDDP, HT, and RT. RESULTS: Ten patients were treated at initial diagnosis. All achieved clinical complete response and durable local control. Two of the 10 experienced recurrence outside the pelvis; 1 of these patients had pulmonary metastasis, and the other had isolated paraaortic nodal involvement. Two patients treated for LRCC experienced local and systemic progression and died of disease within 6 months. CONCLUSIONS: In this small series, trimodality therapy resulted in an excellent clinical response and was well tolerated. The addition of HT to chemoradiotherapy represents a promising new strategy that warrants multiinstitutional collaborative efforts to confirm its efficacy.

Adenocarcinoma↗
PubMed2003

Microarray analysis reveals distinct gene expression profiles among different histologic types of endometrial cancer.

Previous studies of oncogene and tumor suppressor gene alterations have suggested that differences exist in the molecular pathogenesis of the various histological types of endometrial cancer. To elucidate further the molecular events involved in endometrial carcinogenesis, we examined global expression patterns of 16 nonendometrioid cancers (13 serous papillary and 3 clear cell), 19 endometrioid cancers, and 7 age-matched normal endometria using cDNA microarrays. Unsupervised analysis of gene expression identified 191 genes that exhibited >2-fold differences (P < 0.001) between the histological groups. Many genes were similarly dysregulated in both nonendometrioid and endometrioid cancers relative to normal endometria. Gene expression differences in only 24 transcripts could distinguish serous from endometrioid cancers, the two most common subgroups. These data provide the basis for investigation of previously unrecognized novel pathways involved in the development of endometrial cancers.

Endometrial Neoplasms↗
PubMed2003

Weekly low-dose carboplatin and paclitaxel in the treatment of recurrent ovarian and peritoneal cancer.

OBJECTIVES: Weekly paclitaxel alone has moderate activity in the salvage treatment of recurrent ovarian cancer and is associated with a favorable toxicity profile. Combination paclitaxel and carboplatin is a well-established first-line regimen for ovarian cancer. The purpose of this study was to evaluate weekly low-dose paclitaxel and carboplatin in recurrent ovarian or peritoneal cancer. METHODS: Patients with recurrent ovarian or peritoneal cancer previously treated with between one and four chemotherapeutic regimens were eligible. Patients had measurable or assessable disease defined by clinical exam, radiographic studies, or serum CA-125 greater than 75 U/ml. One cycle of treatment consisted of carboplatin at an area under the curve of 2 and paclitaxel at 80 mg/m(2) on days 1, 8, and 15 on a 28-day cycle. Clinical responses were defined by established criteria. RESULTS: Twenty-nine patients were included in this intent-to-treat study. The median number of prior treatment regimens was 2 (range 1 to 4). The overall response rate was 82.8% (16 complete clinical responses, 8 partial responses). Among 8 platinum-refractory patients, the response rate was 37.5%, while 21 platinum-sensitive patients had a 100% response rate. Median time to progression was 13.7 months among platinum-sensitive patients and 3.2 months among platinum-refractory patients. Overall median time to progression was 11.5 months and median-duration of response was 9.9 months. Hematologic toxicity was common (32% grade 3 neutropenia, no grade 4 neutropenia, 14.2% grade 3 or 4 thrombocytopenia) and managed by treatment delay, dose reduction of paclitaxel, or discontinuation of carboplatin. CONCLUSION: Weekly low-dose carboplatin and paclitaxel has significant activity in both platinum-sensitive and platinum-resistant recurrent ovarian cancer with acceptable toxicity that is easily managed by dose adjustment.

Adult↗
PubMed2003

Predictors of clinical outcomes in the laparoscopic management of adnexal masses.

OBJECTIVE: Laparoscopy has become an accepted approach in the management of adnexal masses. We evaluated clinical outcomes of laparoscopic management of adnexal masses thought to be benign preoperatively. METHODS: We performed a retrospective study of patients undergoing laparoscopic evaluation of adnexal masses over a 7-year period. Regression models evaluated predictors of blood loss, length of stay, complications, mass rupture, conversion to laparotomy, and operating time. Preoperative predictors of malignant and borderline disease were evaluated using a separate model. RESULTS: Complications occurred in 8% of 396 patients undergoing laparoscopic evaluation of adnexal masses and were associated with concurrent hysterectomy (P =.01) and smaller mass (P =.01). Conversion to laparotomy occurred in 25% and was associated with larger mass (P =.001), prior hysterectomy (P =.002), and younger age (P =.002). Mass rupture occurred in 25% and was associated with prior (P <.001) or concurrent (P =.003) hysterectomy and younger age (P =.001). Blood loss greater than 500 mL was associated with concurrent hysterectomy (P <.001). Length of stay was associated with concurrent (P <.001) and prior (P <.001) hysterectomy, larger mass (P =.01), prior abdominal surgery (P =.009), and medical comorbidities (P =.007). Malignancy occurred in 2%, and laparoscopic management was not associated with adverse outcomes. CONCLUSION: Adnexal masses thought to be benign preoperatively were successfully managed laparoscopically in three fourths of cases and clinical outcomes were acceptable. To a great extent, adverse events were attributable to concurrent hysterectomy rather than removal of the adnexal mass.

Adnexal Diseases↗
PubMed2003

Characterization of prediagnostic symptoms among primary epithelial ovarian cancer cases and controls.

OBJECTIVE: The goal of this study was to characterize types, frequency, combinations, and relative onset of symptoms among ovarian cancer cases and controls. METHODS: Participants were from an ongoing, population-based, case-control study of primary epithelial ovarian cancer in a 48-country region of North Carolina. Incident cases (N = 267), aged 20-74, were identified by area hospitals on a rapid case ascertainment basis between April 1999 and March 2001. Population-based controls, with at least one intact ovary, frequency matched on age and race, were identified using random-digit dialing (N = 287) and Health Care Financing Administration (HCFA) phone lists (N = 30). Trained nurse-interviewers, using a standardized questionnaire, asked participants about specific symptoms experienced for at least 2 weeks in the year prior to diagnosis (cases)/interview (controls). RESULTS: More than 90% of cases reported at least one symptom and symptoms were most often the reason for the doctor visit leading to diagnosis (74%), followed by routine examination (12%). Among invasive cases, symptoms with onsets longer before diagnosis (median 5-7 months) included gas/nausea/indigestion; urinary frequency/urgency; bowel irregularity; abnormal menstrual/vaginal bleeding or discharge; pain during intercourse; and ongoing fatigue. Symptoms with onsets closer to diagnosis (median of 2-4 months) included distended/hard abdomen; bloating/feeling of fullness; unexplained weight gain/loss; pelvic/abdominal discomfort; chest pain/respiratory difficulties; and "other" symptoms. Controls reported fewer symptoms than cases (median 1 vs 5 or 6). Control symptoms were of longer duration and much less likely to occur in combination. CONCLUSION: Earlier diagnosis of ovarian cancer may be possible if women and physicians recognize the importance of combinations of seemingly unrelated symptoms, especially those identified as occurring longer before diagnosis.

Adult↗
PubMed2003

The role of PET scanning in the detection of recurrent cervical cancer.

OBJECTIVES: [(18)F] Fluoro-2-deoxyglucose positron emission tomography (FDG PET) has recently been established as a sensitive and specific method of detecting lymph node metastases in newly diagnosed cervical cancer. Little is known about the efficacy of PET for detecting recurrent disease. We evaluated the potential role of FDG PET in the context of suspected recurrent cervical cancer. METHODS: The records of patients undergoing PET scan to evaluate for cervical cancer recurrence between July 1998 and February 2002 were reviewed. Radiographic findings were classified as negative, suspicious, or equivocal. PET scan findings were compared to available clinical data to classify each PET result as a true positive, true negative, false positive, or false negative. Clinical proof of recurrence consisted of a tissue biopsy revealing recurrent cancer within 3 months of the PET scan. Clinical proof of no evidence of disease consisted of a negative tissue biopsy within 3 months or no clinical evidence of recurrence within 6 months after the PET scan. RESULTS: Twenty-eight patients underwent 37 PET scans. Twenty-nine cases among 22 patients were clinically evaluable for recurrence status. Median age was 42, and stage distribution was IB 1 (n = 3), IB2 (n = 4), IIA (n = 1), IIB (n = 10), IIIB (n = 9), IVB (n = 1). Histologic types included squamous (n = 23) adenocarcinoma (n = 4) and unknown (n = 1). There were 12 true positive PET scans, 13 true negatives, 2 false positives, and 2 false negatives. The sensitivity and specificity of FDG PET for detecting recurrent cervical cancer were 85.7 and 86.7%, respectively. The positive and negative predictive values were 85.7 and 86.7%, respectively. CONCLUSIONS: Whole-body FDG PET is a sensitive and specific tool for the detection of recurrent cervical cancer in patients who have clinical findings suspicious for recurrence. A larger prospective trial will determine whether this modality should be used routinely in conjunction with, or in lieu of, other imaging studies to detect recurrent disease in a broader population of cervical cancer patients.

Adult↗
PubMed2003

Matrix metalloproteinase-1 gene promoter polymorphism and risk of ovarian cancer.

OBJECTIVE: It has been suggested that the 2G allele of a guanine insertion-deletion promoter polymorphism in the promoter of the matrix metalloproteinase-1 (MMP1) gene may increase susceptibility to ovarian cancer. The 2G allele also has been associated with increased MMP1 expression. We investigated the relationship between the MMP1 polymorphism and ovarian cancer risk in a large population-based, case-control study. METHODS: The MMP1 promoter polymorphism was examined in white blood cell DNA from 311 cases and 387 age- and race-matched controls using a radiolabeled polymerase chain reaction assay. In addition, genotyping of the MMP1 polymorphism performed in 42 advanced-stage invasive serous ovarian cancers was compared to their mean relative MMP1 expression from Affymetrix microarrays. RESULTS: The 2G allele frequency did not differ significantly between cases (0.49) and controls (0.48), and the distribution of genotypes was in Hardy-Weinberg equilibrium. Using 1G homozygotes as the reference group, neither 2G homozygotes (odds ratio 1.1, 95% confidence interval 0.7-1.7) nor heterozygotes plus 2G homozygotes (odds ratio 0.9, 95% confidence interval 0.7-1.3) had an increased risk of ovarian cancer. There was also no relationship between MMP1 genotype and histologic grade, histologic type, stage, or tumor behavior (borderline versus invasive). The mean MMP1 expression was twice as high in 2G homozygotes relative to 1G homozygotes, but this difference was not statistically significant. CONCLUSION: The reported association between the MMP1 promoter polymorphism and ovarian cancer risk was not supported by our data. There was a suggestion that the 2G allele may be associated with higher MMP1 expression, and this finding is worthy of further investigation.

Adult↗
PubMed2003

Galectin-1 accumulation in the ovary carcinoma peritumoral stroma is induced by ovary carcinoma cells and affects both cancer cell proliferation and adhesion to laminin-1 and fibronectin.

Galectin-1 (gal-1) is a 14-kDa laminin-binding galectin involved in several biologic events including regulation of cancer cell proliferation and adhesion to the matrix. In this study, we examined gal-1 expression in 30 human epithelial ovary carcinoma samples by Western and Northern blotting and by immunohistochemistry. Gal-1 mRNA levels were increased in more than 95% of the examined ovary carcinoma samples, compared with a wedge resection of a normal ovary. Immunohistochemical analysis of the samples demonstrated gal-1 expression in cancer epithelial cells from 17 of 30 samples, with a cytoplasmic pattern. Gal-1 immunostaining was significantly increased in the stroma associated with carcinoma cells compared with the normal, noninvaded stroma (p = 0.003). This pattern of expression was confirmed by examination of 12 other frozen epithelial ovary carcinomas, using in situ hybridization. Immunohistochemical staining of the specimens demonstrated colocalization of gal-1, laminin-1, and fibronectin. In vitro experiments were conducted to elucidate the potential biologic role of gal-1 in ovarian cancer progression. Gal-1 protein expression and release was detected in AZ364, SK-OV-3, and AZ224, but not in OVCAR-3, AZ419, and AZ382, human ovary carcinoma cell lines. Incubation of 84BR fibroblasts with conditioned media harvested from the ovary carcinoma cell lines induced an increased expression of gal-1 in the cultured fibroblasts in all cases except AZ419 and SK-OV-3. High concentrations of gal-1 (100 micro g/ml) induced significantly decreased cell proliferation in all cell lines, as defined by bromodeoxyuridine incorporation. Additionally, recombinant gal-1 induced a dose-dependent increase in in vitro adhesion of AZ224, SK-OV-3, and AZ382 cells to laminin-1; adhesion to fibronectin was increased by gal-1 in OVCAR-3, AZ224, and SK-OV-3. No effect was observed in the other cases. Our data contribute to define a role for gal-1 during the interactions between human ovary carcinoma cells and host fibroblasts.

Adenocarcinoma↗
PubMed2003

Promoter hypermethylation as an epigenetic component in Type I and Type II endometrial cancers.

Epigenetic mechanisms that result in aberrant gene expression are a prominent feature of many cancer types. One main epigenetic mechanism for gene silencing involves promoter hypermethylation. Type I and type II endometrial cancers exhibit differing clinical, histologic, and molecular genetic characteristics. We hypothesize that these differences also extend to epigenetic phenomena. Promoter methylation analysis of 11 genes in a panel of endometrial cancers supports this hypothesis. These initial data indicate that promoter hypermethylation events occur frequently in type 1 cancer and were not detected in type II cancers using this panel of loci. These data tend to support the hypothesis that type I and type II endometrial cancers will exhibit distinct patterns of gene silencing based on promoter hypermethylation events.

Cell Transformation, Neoplastic↗
PubMed2003

High expression of tumor necrosis factor-related apoptosis-inducing ligand is associated with favorable ovarian cancer survival.

PURPOSE: The molecular determinants of survival in ovarian cancer are poorly understood. Using expression microarrays, we recently found that high expression of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene is associated with prolonged survival in advanced ovarian cancer. TRAIL has also been shown to synergize with chemotherapeutic agents to induce apoptosis in ovarian cancer cell lines. We therefore sought to confirm the association between TRAIL expression and survival in a larger group of women with ovarian cancer. EXPERIMENTAL DESIGN: TRAIL expression was measured using quantitative real-time PCR in 120 epithelial ovarian cancers (11 stage I/II, 109 stage III/IV) and 8 normal ovarian surface epithelial samples. RESULTS: Ovarian cancers demonstrated 10-fold higher mean TRAIL expression than normal ovarian epithelial samples (P < 0.001). Among ovarian cancers, high TRAIL expression was associated with prolonged survival and was 2.2-fold higher in cancers from patients who lived more than 5 years compared with patients who died within 1 year (P = 0.03). CONCLUSIONS: TRAIL expression is higher in ovarian cancers relative to normal ovarian epithelium. High TRAIL expression is associated with favorable ovarian cancer survival, which may be attributable to increased chemosensitivity of cancers that express the most TRAIL. The use of TRAIL to enhance sensitivity of ovarian cancers to therapy represents an appealing molecular therapeutic strategy worthy of further investigation.

Apoptosis Regulatory Proteins↗
PubMed2002

Cell proliferation and apoptosis in human uterine leiomyomas and myometria.

To determine the role of cell proliferation and apoptosis in uterine leiomyoma growth, we studied protein expression of two major regulatory proteins of apoptosis -- Bcl-2 (anti-apoptotic) and Bax (pro-apoptotic) -- and two endogenous markers of cell replication - proliferating cell nuclear antigen (PCNA) and Ki-67 - in tumors and matched myometrium from premenopausal women. Conventional mitotic indices also were determined, and all proliferation data were correlated to tumor size. In situ end-labeling of fragmented DNA and routine histology were used to assess apoptosis. Our results showed that the apoptosis-regulating proteins (Bcl-2 and Bax) were expressed in the cytoplasm of the leiomyoma and myometrial smooth muscle cells throughout the menstrual cycle. Bax expression differed from Bcl-2 in that it also was found in the cytoplasm of vascular smooth muscle cells of the myometria and tumors. Both tumors and myometrial samples expressed 26-kDa and 21-kDa proteins that reacted with antibodies directed towards Bcl-2 and Bax, respectively. Apoptosis was not a prominent feature of uterine leiomyomas or myometrium. PCNA- and Ki-67-labeling and mitotic counts were significantly ( P<0.05) higher in leiomyomas than in matched myometrial samples. Proliferative activity was variable for individual tumors of the same patient and independent of tumor size. Our results suggest that altered apoptosis by overexpression of Bcl-2 or by decreased expression of Bax does not appear to be a major factor in uterine leiomyoma growth. We conclude that increased cell proliferation is the most significant contributor to growth and that the proliferative state is autonomous for each tumor in a given patient and is independent of tumor size.

Apoptosis↗
PubMed2002

Progestin-induced apoptosis in the Macaque ovarian epithelium: differential regulation of transforming growth factor-beta.

BACKGROUND: Oral contraceptive (OC) use is associated with a reduced risk of ovarian cancer. An OC component, progestin, induces apoptosis in the primate ovarian epithelium. One regulator of apoptosis is transforming growth factor-beta (TGF-beta). We determined the effect of progestin on TGF-beta expression in the primate ovarian epithelium and examined the relationship between TGF-beta expression and apoptosis. METHODS: Female cynomolgus macaques were randomly assigned to receive a diet for 35 months containing no hormones (n = 20); the OC Triphasil (n = 17); or each of its constituents, ethinyl estradiol (estrogen, n = 20) or levonorgestrel (progestin, n = 18 ), alone. Ovarian sections were immunostained with monoclonal antibodies against TGF-beta1 or TGF-beta2 plus TGF-beta3 (TGF-beta2/3) isoforms. The expression of TGF-beta isoforms in four ovarian compartments (epithelium, oocytes, granulosa cells, and hilar vascular endothelium) was compared among treatment groups. The association between TGF-beta expression and apoptosis, as determined by morphology and histochemistry, was examined in ovarian epithelium. All statistical tests were two-sided. RESULTS: Compared with ovaries from the control and estrogen-only-treated monkeys, the ovaries of progestin-treated monkeys showed 1) a marked decrease in the expression of TGF-beta1 and a concomitant increase in the expression of the TGF-beta2/3 isoforms in the ovarian epithelium (P<.001), 2) an increase in the expression of TGF-beta2/3 in the hilar vascular endothelium (P<.001), and 3) a marked decrease in TGF-beta2/3 expression in granulosa cells (P<.001). The apoptotic index of the ovarian epithelium was highly associated with the change in expression from TGF-beta1 (P<.001) to TGF-beta2/3 (P</=.002) induced by progestin treatment. CONCLUSIONS: Progestin induces differential regulation in the ovarian epithelium of TGF-beta, a change in the expression of which is highly associated with apoptosis. These data suggest a possible biologic mechanism for the protective association between OC use and reduced ovarian cancer risk.

Animals↗