The predictive role of estrogen, FSH, and LH in combination with biomarkers for early ovarian cancer detection

Ovarian cancer is a highly lethal gynecological malignancy with poor prognosis. Early diagnosis of ovarian cancer is crucial for improving patient survival rates. Ultrasound is currently the most used imaging modality for the detection of ovarian cancer. However, its diagnostic accuracy is limited, particularly in the early stages of the disease. Circulating tumor DNA (ctDNA) has emerged as a promising noninvasive biomarker for cancer diagnosis. In this study, we aimed to investigate the clinical value of ultrasound combined with ctDNA (mutations in: TP53, KRAS, and PIK3CA) in the early diagnosis of ovarian cancer. A total of 686 participants were enrolled, comprising 186 advanced symptomatic ovarian cancer patients, 16 histologically confirmed asymptomatic ovarian cancer patients, and 484 patients with benign ovarian lesions. Of the 202 ovarian cancer cases, 57.4% were high-grade serous carcinomas, followed by endometrioid (15.8%), clear cell (9.9%), mucinous (7.9%), and low-grade serous carcinomas (6.9%). All participants underwent standardized ultrasound examination and ctDNA analysis. Ultrasound characteristics were evaluated for morphological features including mass composition, border definition, and presence of ascites. Circulating tumor DNA was analyzed for mutations in TP53, KRAS, and PIK3CA genes. Diagnostic performance was assessed through sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) calculations for individual and combined detection methods. In asymptomatic ovarian cancer patients, ultrasonography revealed complex solid-cystic masses in 50.0% of cases and ascites in 43.75%, with 87.50% sensitivity and 94.33% specificity. Molecular analysis detected ctDNA mutations in 81.25% of asymptomatic cases, predominantly in TP53 (31.25%), KRAS (25.00%), and PIK3CA (25.00%). This analysis, which focused exclusively on these three genes, demonstrated 81.25% sensitivity and 97.46% specificity. The combined diagnostic approach significantly improved detection parameters (p < 0.001), with sensitivity increasing to 93.75%, specificity to 99.25%, PPV to 75.00%, and NPV to 99.85%. False-positive results decreased from 38 (ultrasound alone) and 17 (ctDNA alone) to 5 cases with the combined approach. Distinct mutation profiles were observed between cancer and benign groups, with only 15.91% of benign cases showing detectable ctDNA mutations. Our results suggest that ctDNA is a promising biomarker for the early detection of ovarian cancer, with higher sensitivity and specificity than ultrasound. The combination of ultrasound and ctDNA may provide a more accurate diagnostic strategy for the early detection of ovarian cancer. These findings may contribute to the development of novel noninvasive biomarkers for the early diagnosis of ovarian cancer.

Differential Methylation Profile of Ovarian Cancer in Tissues and Plasma

Ovarian cancer is the second most common type of female reproductive cancer, and more women die from ovarian cancer than from cervical cancer and uterine cancer combined. Currently, there is no strategy for early detection of ovarian cancer that reduces ovarian cancer mortality. Taking a detailed personal and family history for breast, gynecologic, and colon cancer facilitates categorizing women based on their risk (average risk or high risk) of developing epithelial ovarian cancer. Women with a strong family history of ovarian, breast, or colon cancer may have hereditary breast and ovarian cancer syndrome (BRCA mutation) or hereditary nonpolyposis colorectal cancer (Lynch syndrome), and these women are at increased risk of developing ovarian cancer. Women with these conditions should be referred for formal genetic counseling to better assess their cancer risk, including their risk of ovarian cancer. If appropriate, these women may be offered additional testing for early detection of ovarian cancer. The use of transvaginal ultrasonography and tumor markers (such as cancer antigen 125), alone or in combination, for the early detection of ovarian cancer in average-risk women have not been proved to reduce mortality, and harms exist from invasive diagnostic testing (eg, surgery) resulting from false-positive test results. The patient and her obstetrician-gynecologist should maintain an appropriate level of suspicion when potentially relevant signs and symptoms of ovarian cancer are present.

Ovarian cancer is the second most common type of female reproductive cancer, and more women die from ovarian cancer than from cervical cancer and uterine cancer combined. Currently, there is no strategy for early detection of ovarian cancer that reduces ovarian cancer mortality. Taking a detailed personal and family history for breast, gynecologic, and colon cancer facilitates categorizing women based on their risk (average risk or high risk) of developing epithelial ovarian cancer. Women with a strong family history of ovarian, breast, or colon cancer may have hereditary breast and ovarian cancer syndrome (BRCA mutation) or hereditary nonpolyposis colorectal cancer (Lynch syndrome), and these women are at increased risk of developing ovarian cancer. Women with these conditions should be referred for formal genetic counseling to better assess their cancer risk, including their risk of ovarian cancer. If appropriate, these women may be offered additional testing for early detection of ovarian cancer. The use of transvaginal ultrasonography and tumor markers (such as cancer antigen 125), alone or in combination, for the early detection of ovarian cancer in average-risk women have not been proved to reduce mortality, and harms exist from invasive diagnostic testing (eg, surgery) resulting from false-positive test results. The patient and her obstetrician-gynecologist should maintain an appropriate level of suspicion when potentially relevant signs and symptoms of ovarian cancer are present.

Paraneoplastic antigens as biomarkers for early diagnosis of ovarian cancer

There is a monotypic change in basal serum gonadotropin levels following retinol treatment of chronically vitamin A-deficient (VAD) male rats. The present study was undertaken to investigate the hypothesis that the specific increase in serum follicle-stimulating hormone (FSH) represents a change in gonadotrope responsiveness to gonadotropin-releasing hormone (GnRH). To this end, a test dose of GnRH was given to VAD rats pre-, 5 days post-, and 10 days postreplacement of vitamin A (PVA). In VAD rats, basal serum FSH and luteinizing hormone (LH) levels were higher than those of controls. Increased LH/testosterone ratios, both in basal levels and in the secretory response to GnRH, suggested Leydig cell hyporesponsiveness in VAD animals. Both the FSH and LH responses to GnRH were maximal at 1 h, declining thereafter. Although the absolute increments in FSH and LH 1 h after GnRH in VAD rats were greater than in controls, the percent increase in FSH tended to be lower in VAD rats and to increase after vitamin A replacement. The specific enhancement of FSH release PVA became evident only when assessing total secretion of FSH and LH after GnRH. Luteinizing hormone response to GnRH increased PVA, but not significantly, while FSH secretion after GnRH increased both 5 and 10 days PVA, times during which basal FSH levels were also increasing. These changes in FSH secretion could not be attributed either to increases in endogenous GnRH or to changes in testosterone or estradiol levels. Basal serum androgen binding protein levels, elevated in VAD animals, did not respond to the acute increases in FSH after GnRH and remained high PVA, suggesting no acute change in Sertoli cell function. Thus, the PVA increase in FSH secretion unmasks a partial inhibition of the gonadotrope present in the retinol-deficient, retinoic acid-fed male rat.

Luteinizing hormone (LH) and follicle stimulating hormone (FSH) patterns were studied in 16 patients with psychogenic estrogen-deficient amenorrhea of at least 1 year duration to determine whether or not these patterns illuminate the mechanism of estrogen deficiency. Each subject had a history of profound emotional stress. Gonadotropin levels by radioimmunoassay were (in milliinternational units per milliliter): 1) high LH (41-76) and low-normal FSH (7-10) in 4 subjects; 2) high LH (40-70) and high FSH (83-102) in 2 patients; 3) high-normal LH (31-33) and FSH (24-25) in 2 subjects; and 4) normal to low LH (3-18) and FSH (5-15) in 8 subjects. These various gonadotropin patterns may be mistaken for 1) polycystic ovarian disease or 2) premature menopause so diagnostic care is emphasized. Findings reveal no correlation between estrogen levels as determined by vaginal cytology and gonadotropin levels in psychogenic amenorrhea and psychogenic stress can induce a variety of gonadotropin patterns without the modulating effect of estrogen.

Background. Surfaced-enhanced laser desorption-ionization-time of flight mass spectrometry (SELDI-TOF-MS) technology plays an important role in the early diagnosis of ovarian cancer. However, the raw MS data is highly dimensional and redundant. Therefore, it is necessary to study rapid and accurate detection methods from the massive MS data. Methods. The clinical data set used in the experiments for early cancer detection consisted of 216 SELDI-TOF-MS samples. An MS analysis method based on probabilistic principal components analysis (PPCA) and support vector machine (SVM) was proposed and applied to the ovarian cancer early classification in the data set. Additionally, by the same data set, we also established a traditional PCA-SVM model. Finally we compared the two models in detection accuracy, specificity, and sensitivity. Results. Using independent training and testing experiments 10 times to evaluate the ovarian cancer detection models, the average prediction accuracy, sensitivity, and specificity of the PCA-SVM model were 83.34%, 82.70%, and 83.88%, respectively. In contrast, those of the PPCA-SVM model were 90.80%, 92.98%, and 88.97%, respectively. Conclusions. The PPCA-SVM model had better detection performance. And the model combined with the SELDI-TOF-MS technology had a prospect in early clinical detection and diagnosis of ovarian cancer.

Ovarian cancer is a leading cause of death in women. Early detection of ovarian cancer is essential to decrease mortality. However, the early diagnosis of ovarian cancer is difficult due to a lack of clinical symptoms and suitable molecular diagnostic markers. Thus, identification of meaningful tumor biomarkers with potential clinical application is clearly needed. To search for a biomarker for the early detection of ovarian cancer, we identified human anterior gradient 2 (AGR2) from our systematic analysis of paired normal and ovarian tumor tissue cDNA microarray. We noted a marked overexpression of AGR2 mRNA and protein in early stage mucinous ovarian tumors compared to normal ovarian tissues and serous type ovarian tumors by Western blot analysis and immunohistochemistry. To further elucidate the role of AGR2 in ovarian tumorigenesis, stable 2774 human ovarian cancer cell lines overexpressing AGR2 were established. Forced expression of AGR2 in 2774 cells enhanced the growth and migration of ovarian cancer cells. AGR2 protein was detected in the serum of mucinous ovarian cancer patients by Western blot and ELISA analysis. Thus, AGR2 is a potential biomarker for the diagnosis of mucinous ovarian cancer and an ELISA assay may facilitate the early detection of mucinous ovarian cancer using patient serum.

Early detection and treatment of ovarian cancer: shifting from early stage to minimal volume of disease based on a new model of carcinogenesis

Mechanisms of FSH synthesis: what we know, what we don't, and why you should care

Early detection of ovarian cancer has been a challenge to manage the high mortality rate caused by this deadly disease. The trends in mortality have been reduced by the scientific contributions from the corners across the globe, however accounting for the fifth leading cause of gynecological mortality. The complexities in the clinical presentation, origin of tumor, and gene expression profiles had added to much difficulty in understanding and diagnosis of the disease. Stage 1 diagnosis of ovarian cancer improves the 5-year survival rate to around 92%. Cancer antigen-125 (CA-125) is the gold standard tumor marker found at abnormally high levels in the blood of many women in ovarian cancer. However, many non-cancerous conditions exhibit high levels of CA-125 and several women have normal CA-125 level in the early stage of ovarian cancer, suggesting CA-125 biomarker is not specific enough for the screening of early stage ovarian cancer. In addition, several other biomarkers, including HE4 have been added in the diagnostic field for higher sensitivity and specificity in the diagnosis and progression of ovarian cancer. HE4 is a prospective single serum biomarker which has been approved by the FDA to monitor the disease progression in epithelial ovarian cancer. However, owing to low sensitivity and specificity, combination of a panel of biomarkers has been proposed in the diagnosis of the disease. Based on extensive biomarkers research findings, here we discuss current trends in diagnostic approaches and updated potential several panels of cancer biomarkers for early detection of ovarian cancer. It has been recently reported that CA125 in combinations with two or more biomarkers have outperformed single biomarker assays for early detection of the disease. Moreover, CA-125 with CA 19–9, EGFR, G-CSF, Eotaxin, IL-2R, cVCAM, MIF improved the sensitivity with 98.2 % and specificity of 98.7% in early stage detection of ovarian cancer. Overall, this review demonstrates a panel of biomarkers signature as the potential tool for prototype development in future and other advanced approaches for early diagnosis of ovarian cancer to avoid false-diagnosis and excessive cost.

Use of luteinizing hormone in the treatment of infertility: time for reassessment?

Ovarian cancer is the sixth most common cancer in women. The overall 5-year survival rate for ovarian cancer is approximately 40% due to the fact that most cases are diagnosed at late stages. Detection of ovarian cancer at the earliest possible stages is a public health priority. The article provides a review of existing scientific data regarding the early detection and screening of ovarian cancer, based on an analysis of publications in international electronic databases. Screening strategies are most effective for detecting diseases in their early stages, but at the moment there is no standard instrumental method that could be recommended as a screening examination for detecting ovarian cancer at an early stage. In this regard, most researchers have switched to the field of biomarkers and their combinations. Currently, more than 200 tumor markers, which are produced with varying intensity in ovarian cancer, have been proposed, but only two of them, CA-125 and HE4, have been tested in clinical experience. The article highlights the role of new tumor markers, multimarker panels, longitudinal algorithms in the early diagnosis of ovarian cancer. Most of the studies on the early diagnosis of ovarian cancer is aimed at searching for new biomarkers or developing multimodal algorithms that include both tumor markers, free deoxyribonucleic acid, and ultrasound of the pelvic organs. However, there are still no convincing data on mortality reduction based on randomized controlled trials, which stops doctors from including one or another strategy for the early diagnosis of ovarian cancer in national protocols and/or recommendations as a screening examination.

To examine the impact of low basal cycle day 3 serum LH levels or a high FSH:LH ratio on IVF results. A homogeneous group of patients was analyzed as identified by normal basal cycle of follicle stimulating hormone (FSH), Luteinizing hormone (LH), and estradiol (E2) levels. High responders (high LH:FSH ratio) and low responders (high FSH or E2 levels, and women > or = 42 years of age) were excluded from analysis. Only cycles stimulated with a combination of a GnRHa (luteal suppression) and pure FSH were studied. Patients with low basal LH levels (< 3 mIU/mL) did not differ significantly from controls in terms of response to controlled ovarian hyperstimulation but there was a clear trend toward poorer implantation and clinical pregnancy rates. On the other hand, patients with a high FSH:LH ratio (> 3) had significantly fewer mature oocytes aspirated, and lower implantation and clinical pregnancy rates than patients with gonadotropin ratio < or = 3. These negative effects were evident in the presence of normal basal FSH levels and after adequate matching of female's age and number of embryos transferred. These studies highlight a negative impact of a basal cycle high FSH:LH ratio (and possibly low LH levels) on follicular development and oocyte quality in these patients subjected to pituitary down-regulation followed by pure FSH administration. A high FSH:LH ratio may be therefore used as an early biomarker of poor ovarian response.