Molecular characterization of sarcomatous change in a granulosa cell tumor.

Sarcomatous transformation of a granulosa cell tumor (GCT) is a rare event. We describe the development of a rapidly progressive sarcomatous change in a woman who had initially presented with a classical GCT. A first recurrence occurred 23 months after the initial diagnosis when she was treated with external beam radiotherapy to her pelvis. A second recurrence 76 months following her initial surgery was consistent with a GCT. At 92 months, she presented with a further recurrence, outside of the radiotherapy field. This last recurrence had a different histologic appearance with features of sarcomatous change. Molecular analysis, using both reverse transcription-polymerase chain reaction and complementary DNA microarrays, has been used to analyze tissue obtained before and after the observed change in the tumor. The data show that GCT-specific genes, such as inhibin alpha, estrogen receptor, and follicle-stimulating hormone receptor, have been downregulated in the sarcomatous change. Significant upregulation of genes associated with an inflammatory response was also noted in the sarcoma, and this was consistent with the presence of a marked inflammatory infiltrate seen on histopathology. This study represents the novel application of microarray technology and demonstrates the unexpected finding of expression of the fibroblast activation protein gene in normal ovary. Although tumors such as this may be targets for the novel fibroblast activating protein-directed chemotherapeutic monoclonal antibody sibrotuzumab, the finding of expression in the normal ovary suggests the need for caution.

Insulin-like growth factor, insulin-like growth factor-binding protein-4, and pregnancy-associated plasma protein-A gene expression in human granulosa cell tumors.

The insulin-like growth factor (IGF) system plays an important role in folliculogenesis. It is also thought to contribute to the pathogenesis of many cancers, including those of the ovarian epithelium. In the human follicle, the predominant IGF is IGF-II and its actions are modulated by insulin-like growth factor-binding protein-4 (IGFBP-4), the IGFBP-4 protease, and the pregnancy-associated plasma protein-A (PAPP-A). These peptide components are synthesized by the granulosa cells of the developing follicle. The aim of this study was to characterize the expression of these components of the IGF system in granulosa cell tumors (GCT) of the ovary. IGF-I, IGF-II, IGFBP-4, and PAPP-A gene expression was determined in a panel of GCT and compared to the levels in normal ovary and in epithelial ovarian tumors. Although both the IGF-I and IGF-II genes were expressed in the GCT, the levels were lower than in the other tissue groups. IGFBP-4 expression was also low in the GCT, whereas PAPP-A gene expression was highest in the GCT. These findings were unexpected given the prominent role this signaling system plays in normal granulosa cells. In conclusion, these observations suggest that the IGF system may have a limited role in the pathogenesis of GCT with PAPP-A subserving a function other than IGFBP-4 proteolysis.

Inhibins/activins as diagnostic markers for ovarian cancer.

It is widely recognised that the early detection and subsequent assessment of recurrence of ovarian cancers are key steps for successful treatment. Available serum markers (e.g. CA125) are sensitive for some epithelial carcinomas (e.g. serous, endometrioid, clear cell), however, these markers are less sensitive for granulosa cell tumours and mucinous carcinomas. Serum inhibin is an ovarian product which decreases to non detectable levels after menopause, however, certain ovarian cancers (mucinous carcinomas and sex cord stromal tumours such as granulosa cell tumours) continue to produce inhibin which provides a basis for a serum diagnostic test. Studies from this and other laboratories have investigated the suitability of inhibin as a diagnostic marker by identifying which inhibin (inhibin A (alphabetaA), inhibin B (alphabetaB), free alpha subunit) or activin (betaAbetaA) form is associated with these cancers. Available data show that inhibin assays which detect all inhibin forms, i.e. assays which detect the alpha subunit both as the free form and as an alphabeta subunit dimer provide the highest sensitivity/specificity characteristics as an ovarian cancer diagnostic test. This review will discuss the data supporting these observations and show recent studies in which a new alpha subunit monoclonal antibody-based ELISA is used as a potential diagnostic test. Furthermore, based on the high sensitivity/specificity characteristics of the respective assays for the various types of ovarian cancer, the combination of the inhibin assay with CA125 detects the majority of all ovarian cancers.

FSH-regulated gene expression profiles in ovarian tumours and normal ovaries.

Development, growth and function of the ovary are controlled by endocrine and paracrine signals. These may also influence the development of ovarian cancer. The aim of this study was to identify the key molecular markers of the unregulated growth and hormone synthesis seen in ovarian tumours, particularly in granulosa cell tumours (GCT). Genes used in this study were chosen on the basis of our understanding of growth and differentiation in the normal ovary. We sought to define the patterns of gene expression in a panel of epithelial and stromal ovarian tumours. Expression was determined by RT-PCR using gene-specific primers for the FSH receptor (FSHR); the FSH early response genes: regulatory subunit of protein kinase A (RII-beta), cyclin D2 (cycD2) and sgk; and late response markers: cyclooxygenase-2 (COX-2) and the LH receptor (LHR). The GCT had high expression of FSHR compared with normal ovaries and the other tumours. cycD2 and RII-beta and COX-2 genes were also highly expressed in the GCT. sgk and LHR expression was lower in all of the tumours than in normal ovaries. Serous cystadenocarcinomas also had an unexpectedly high expression of COX-2. Comparison of the gene expression profiles between each tumour group suggests a molecular phenotype for GCT that is similar to that reported for FSH stimulated pre-ovulatory granulosa cells.

Characterization of inhibin forms and their measurement by an inhibin alpha-subunit ELISA in serum from postmenopausal women with ovarian cancer.

The aim of this study was to characterize the molecular wt forms of inhibins A and B and its free alpha-subunit present in serum from women with ovarian cancer as a basis for developing improved monoclonal antibody-based inhibin assays for monitoring ovarian cancer. Three new inhibin alpha-subunit (alphaC) ELISAs were developed using monoclonal antibodies directed to three nonoverlapping peptide regions of the alphaC region of the inhibin alpha-subunit. To characterize serum inhibin molecular wt forms present in women with ovarian cancer, existing inhibin immunoassays (inhibin A, inhibin B, and pro-alphaC) and the new alphaC ELISAs were applied to sera from women with granulosa cell tumors and mucinous carcinomas previously fractionated using a combined immunoaffinity chromatography, preparative SDS-PAGE, and electroelution procedure. The distribution and molecular size of dimeric inhibins and alpha-subunit detected were consistent with known mol wt forms of inhibins A and B and inhibin alpha-subunit and their precursor forms present in serum and follicular fluid from healthy women. The alphaC ELISAs recognized all known forms of inhibin and the free inhibin alpha-subunit, although differences between alphaC ELISAs were observed in their ability to detect high mol wt forms. To assess which of the alphaC ELISAs was preferred in application to ovarian cancer, the alphaC ELISAs were applied to serum from a range of normal postmenopausal women (n = 61) and postmenopausal women (n = 152) with ovarian (serous, mucinous, endometrioid, clear cell carcinomas, and granulosa cell tumors) and nonovarian (breast and colon) cancers. Despite differences in their ability to detect high mol wt forms of inhibin, the alphaC ELISAs showed similar sensitivity (i.e. proportion of cancer patients correctly detected) and specificity (proportion of controls correctly detected) indexes in the detection of mucinous carcinomas (84% and 95%) and granulosa cell tumors (100% and 95%) compared with earlier inhibin RIA or polyclonal antibody-based immunofluorometric assays. A combination of the alphaC ELISAs with the CA125 assay, an ovarian tumor marker that has a high sensitivity and specificity for other ovarian cancers (serous, clear cell, and endometrioid), resulted in an increase in sensitivity/specificity indexes (95% and 95%) for the all ovarian cancer group. These new monoclonal antibody-based inhibin alphaC ELISAs now provide practical and sensitive assays suitable for evaluation as diagnostic tests for monitoring ovarian cancers.

The inhibins and ovarian cancer.

Interest in inhibin as a marker of ovarian malignancy was stimulated by the description of elevated immunoreactive inhibin levels in the sera of patients with granulosa cell tumours. Several groups have confirmed the value of serum inhibin in the diagnosis and follow-up of patients with this uncommon malignancy. Immunoreactive inhibin levels are also frequently elevated in patients with mucinous cystadenocarcinoma and less frequently in other forms of ovarian tumour. Assay of sera using the specific dimeric inhibin assays has shown that ovarian tumours are able to secrete dimeric inhibin particularly inhibin B. The less specific alpha-subunit directed assays, however, most frequently show elevated concentrations. Used in combination with CA125 as a dual tumour marker, it appears in principle that inhibin can be a useful diagnostic agent. Immunohistochemistry for the inhibin subunits has been reported with increasing frequency as a helpful method to assess suspected ovarian stromal cell tumours. Its diagnostic accuracy for other types of ovarian adenocarcinoma appears less reliable. Expression of the inhibin subunit mRNAs has been demonstrated in a variety of ovarian malignancies. The observation that inhibin levels are elevated in ovarian cancer has stimulated studies of their relevance to the molecular pathogenesis of these malignancies. Findings to date have been largely negative with no evidence for activating mutations of the FSH receptor or of the post-receptor signalling pathway proteins.

Inhibins A and B are regulated differentially in the early post-partum period.

BACKGROUND: The early postpartum period is characterized endocrinologically by a rapid fall in the levels of oestradiol (E2) and immunoreactive inhibin, and a delayed rise in serum follicle stimulating hormone (FSH). No description is currently available of changes in serum inhibins A and B. OBJECTIVES: The present study aimed to examine the levels of inhibin A and B during the early weeks of postpartum lactational amenorrhoea, to determine whether there was evidence for differential regulation of the two hormones at a time when no dominant follicle was developing in the ovary. SUBJECTS AND METHODS: Serum samples were available from 12 subjects aged 29-38 in whom postpartum levels of FSH, immunoreactive inhibin, E2 and prolactin had been examined previously. Samples for hormone assays had been obtained prior to delivery, daily for the 3-5 days postpartum, and weekly thereafter. Inhibins A and B were measured by specific ELISA assays, and results were calculated as 10 day averages for samples obtained on days 1-10, 11-20, 21-30, etc. postpartum. Normal hormone concentrations for reference were obtained from volunteers, also aged 29-38, sampled on days 3-5 of a normal menstrual cycle. RESULTS: Inhibin A in the predelivery sample ranged from 62 to 1243 ng/l, geometric mean 592. Concentrations fell rapidly postpartum and reached a nadir in the low follicular phase range between days 5 and 37 postdelivery, mean 13.6 days. The concentrations of both inhibin B and FSH rose 14-27 days postpartum from their initially low postdelivery levels, to reach the normal follicular phase range. These increases in concentration were significantly correlated in all individual subjects. CONCLUSIONS: The secretion of inhibin A and B is regulated differentially during the early stages of lactational amenorrhoea, just as it is in the late luteal phase of the normal menstrual cycle. Whilst inhibin A falls postpartum, reflecting cessation of placental function, and remains low until ovulatory cycles are resumed, FSH and inhibin B rise after a delay of two weeks or more. It is postulated that the rise of inhibin B is the result of secretion from a cohort of small follicles stimulated by rising FSH levels.

Estrogen receptor isoform gene expression in ovarian stromal and epithelial tumors.

The factors involved in the pathogenesis of ovarian cancers remain unclear, and the response of these tumors to hormonal therapy is limited. The identification of a second estrogen receptor gene (ERbeta), expressed predominantly in ovarian granulosa cells, led us to explore its possible role in ovarian cancer, particularly in granulosa cell tumors (GCT). Several isoforms of ERbeta have been identified. We sought to define the patterns of both ERalpha and ERbeta gene expression in a panel of ovarian tumors consisting of GCT and serous and mucinous cystadenocarcinomas as well as in normal ovary. Expression was determined by RT-PCR using gene- and isoform-specific primers and probes combined with Southern blot analysis of the PCR products. Widespread expression of ERalpha was observed in all tumor types, but at relatively low levels. ERbeta is expressed predominantly in GCT, with lower levels in mucinous tumors and very low levels in serous tumors. The ERbeta2 splice variant previously reported in rodents was not observed. Only very low levels of the exon 5, exon 6, and exon 5/6 deletion variants were detected. The C-terminal truncation variant ERbeta(cx), however, exhibited widespread expression across all the tumor types. As ERbeta(cx) has been shown to be a ligand-independent antagonist of ERalpha action, the relative ratios of ERbeta(cx), ERalpha, and ERbeta may influence the response of a tumor to antiestrogen therapy.

Early follicular phase serum FSH as a function of age: the roles of inhibin B, inhibin A and estradiol.

OBJECTIVE: Reproductive aging in regularly cycling normal women is characterized by a gradual decline in ovarian follicle number and a progressive increase in serum follicle stimulating hormone (FSH), particularly over the age of 40 years. The lack of any consistent decrease in circulating estradiol and progesterone has led to the hypothesis that the FSH increase results from decreasing ovarian inhibin production. The aim of this study was to investigate the relationship between serum inhibins A and B, FSH and estradiol in normal women between the ages of 20 and 50 years. DESIGN AND PATIENTS: Serum from 66 regularly cycling subjects, aged 20-50 years, was collected on days 3-5 of the menstrual cycle for this cross-sectional study. MEASUREMENTS: Serum inhibin A and inhibin B levels were measured by specific enzyme-linked immunosorbent assays (ELISAs). Alpha subunit forms were determined by an immunofluorometric assay which detects all known monomeric and dimeric forms of inhibin A and inhibin B and free alpha subunit. FSH and estradiol levels were measured by immunoassay. Data were log transformed before analysis. RESULTS: Serum FSH, inhibin A and estradiol, but not inhibin B, were positively correlated (p < 0.05-p < 0.001) with age between years 20 and 50. Between 40 and 50 years, serum FSH was negatively correlated with inhibin B (r = -0.61, p < 0.001) and alpha subunit forms (r = -0.47, p < 0.05) and with estradiol (r = -0.39, p < 0.05), but not with inhibin A (r = -0.21, not significant). When log(FSH) was modelled as a function of log(inhibin B) and log(estradiol) with age fitted as a covariate, inhibin B only was a significant independent predictor of FSH (beta = -0.30, p < 0.01). Using purified inhibin A and B standards for the three assays, which were calibrated in terms of their alpha subunit content, serum inhibin A levels were 10-15% of those of inhibin B, with inhibin A + B levels being 22% of total alpha subunit levels. No significant correlation was observed between total inhibin alpha subunit and its dimers. The free alpha subunit, as determined from the difference in levels of total alpha subunit and inhibin A + B, remained relatively unchanged with age, suggesting that it is not differentially regulated. CONCLUSIONS: This study shows that, during the early follicular phase, FSH, inhibin A and estradiol but not inhibin B increase with age. Some of the increase in inhibin A and estradiol may be the result of accelerated follicular development with increasing age. Serum inhibin B and estradiol but not inhibin A are inversely correlated with FSH between ages 40 and 50, but only inhibin B is a significant independent predictor of FSH. This supports the postulate that inhibin B is the main form of inhibin regulating FSH at this stage of the menstrual cycle. During the early follicular phase, serum levels of inhibin A are presumably too low to play a significant physiological role or are less active.

[Inhibin and ovarian cancer]. / Ingibin i rak iaichnikov.

Previous observations from our laboratory have demonstrated that the levels of immunoreactive inhibin (ir-inh) are elevated in almost all patients with granulosa cell tumors and in the majority of postmenopausal women with mucinous ovarian cancers. The present report confirms these findings in a larger group of post-menopausal women. Immunohistochemistry for the inhibin alpha. beta A and beta B sununits shows predominantly epithelial staining in granulosa cell tumors and in the majority of mucinous cancers. Serous cystadenocarcinomas also frequently show positive staining. Studies seeking to identify G alpha i-2 or FSH receptor mutations have provided negative results in contrast to other reports. Further studies of the roles of the inhibin-related family of peptides in ovarian cancer diagnosis and monitoring are clearly indicated.

Inhibin forms in serum from postmenopausal women with ovarian cancers.

BACKGROUND AND OBJECTIVE: Previous studies have shown that serum inhibin as measured by alpha subunit-directed radioimmunoassay (RIA) and inhibin A ELISA was elevated in postmenopausal women with mucinous and granulosa cell cancers, with the RIA showing a more frequent elevation than the inhibin A ELISA. It was thus hypothesised that these cancers may also produce inhibin B or the free alpha subunit. The aim of the study was to identify the forms of inhibin found in a range of ovarian cancers using a range of inhibin assays with varying specificities. DESIGN: Serum samples obtained from women with ovarian cancer were assayed by inhibin B ELISA and Pro-alpha C subunit ELISA and compared with inhibin RIA and inhibin A ELISA. PATIENTS: Blood samples were obtained from 34 postmenopausal women (> 55 years) with no history of endocrine disease and from women with ovarian serous cystadenocarcinomas (n = 66), mucinous cystadenocarcinomas (n = 20), granulosa cell tumours (n = 9-11), miscellaneous ovarian cancers (n = 46) and non ovarian cancers (n = 23). MEASUREMENTS: Inhibin B and inhibin Pro-alpha C subunit levels were determined by ELISA and compared to values obtained by RIA and inhibin A ELISA. Cancers were discriminated from controls based on values obtained 2SD above the geometric mean of the control values. RESULTS: Granulosa cell tumours were detected by RIA and inhibin B ELISA (100%), Pro-alpha C ELISA (90%) and inhibin A ELISA (77%). Mucinous tumours were detected by RIA (70%), inhibin B ELISA (60%), Pro-alpha C ELISA (55%) and inhibin A (20%). Serous tumours were detected by RIA (35%) and the other assays (< 15%). Miscellaneous tumours were detected by RIA (41%) and other assays < 30%. CONCLUSIONS: Ovarian neoplasms may produce a variety of peptides related to the inhibins, including dimeric inhibin A and B. Inhibin B is detected in more ovarian cancers than inhibin A but does not discriminate as well as the alpha subunit directed assays. The higher discrimination index obtained with the RIA compared to the Pro-alpha C ELISA suggests that assays detecting all inhibin forms containing the alpha subunit and not just those detecting the Pro-alpha C subunit will provide the most useful detection method.

Combined inhibin and CA125 assays in the detection of ovarian cancer.

BACKGROUND: The reproductive hormone inhibin has been used as a diagnostic marker of ovarian mucinous and granulosa cell cancers. The aims of this study were to develop a new inhibin immunofluorometric assay (alphaC IFMA) to replace an inhibin RIA as a diagnostic marker of these ovarian cancers and to assess whether the alphaC IFMA in combination with CA125, which detects serous cancers, leads to an improved biochemical diagnosis of all ovarian cancers. METHODS: Serum inhibin concentrations were determined in healthy postmenopausal women (n = 165) and women with ovarian cancers (n = 154), using an inhibin RIA and an alphaC IFMA, which detects inhibin forms containing the alphaC subunit as well as the free alphaC subunit. RESULTS: The alphaC IFMA gave a similar or better discrimination of mucinous (90% vs 71%) and granulosa cell (100% vs 100%) cancers compared with the inhibin RIA. Combination of CA125 and alphaC IFMA values by canonical variate analysis or by multiROC analysis showed that the percentage of all ovarian cancers detected was significantly increased compared with either CA125 or alphaC IFMA alone. CONCLUSIONS: The alphaC IFMA shows a similar or better specificity compared with the RIA, but with increased sensitivity. In combination with CA125, the alphaC IFMA provides an effective dual test for the detection of the majority (90%) of ovarian cancers.

Inhibin subunit gene expression in ovarian cancer.

OBJECTIVE(S): Granulosa cell tumors (GCT) and mucinous cystadenocarcinoma of the ovary are associated with elevated circulating levels of immunoreactive inhibin. Measurement of serum inhibin levels provides a useful tumor marker in the management of ovarian tumors. Inhibin is a dimeric ovarian glycoprotein hormone consisting of one alpha and one of two beta subunits. The beta subunits can dimerize to form activin. Activin is bound and its action modulated by another gonadal peptide, follistatin. In this study the patterns of expression of the three inhibin subunit genes, the follistatin gene, and the activin receptor type II gene have been determined. METHODS: Gene expression was analyzed in RNA prepared from 16 primary ovarian tumors using reverse transcriptase-polymerase chain reaction (RT-PCR). Gene-specific primes were used for RT-PCR; the products were analyzed by Southern blot analysis with gene-specific 32P-labeled probes. RESULTS: Widespread expression of these genes was found in all of the tumor types examined. Abundant expression of the inhibin alpha subunit gene was observed in the GCT and to a lesser extent in the mucinous and serous tumors. beta subunit expression was also present in the GCT and to a lesser extent in the other tumors. Widespread expression of both the activin receptor type II and the follistatin genes was also observed. CONCLUSIONS: Expression of the inhibin subunit genes in GCT and some epithelial tumors confirms that these tumors are the source of the increased immunoreactive inhibin seen in the circulation of patients with ovarian tumors. Expression of the activin receptor type II and follistatin genes suggests a paracrine role for activin in these tumors which may be modulated by follistatin, particularly in the GCT.

A casemix cost comparison of 2 treatments for ectopic pregnancy.

In this paper a retrospective cost comparison between laparoscopic treatment of ectopic pregnancy and conventional laparotomy under casemix funding has been performed. The total mean cost of laparoscopic treatment was $2,930 while the total mean cost of laparotomy was $4,259 per patient.

Evaluation of serum inhibin A as a surveillance marker after conservative management of tubal pregnancy.

Tubal pregnancy is now commonly managed by laparoscopic salpingostomy or systemic methotrexate. A disadvantage of such conservative management is the need for appropriate follow-up, with serial measurement of serum concentrations of human chorionic gonadotrophin (HCG), to exclude persistent ectopic pregnancy (PEP). Concentrations of inhibin A, also a placental product, are significantly increased during pregnancy and the half-life of inhibin A is significantly shorter than that of HCG. To assess the suitability of inhibin A as a marker of PEP, we studied 16 women who had undergone surgery for a tubal pregnancy, measuring HCG and inhibin during follow-up. The mean +/- SEM time taken to achieve non-pregnant concentrations of inhibin A was significantly shorter than for HCG (4.2 +/- 0.8 days versus 21.6 +/- 4.4 days respectively; P < 0.001 Wilcoxon signed rank test). However, in all women the inhibin A concentration increased rapidly after reaching a nadir, reflecting the return of ovarian function, complicating the interpretation of results. In four women inhibin A was almost undetectable preoperatively, while the corresponding HCG concentration was high. These data suggest that inhibin A will not be a useful marker for PEP but that it may provide a more accurate preoperative assessment of trophoblast viability than HCG, thereby improving management.

Inhibin and ovarian cancer.

Previous observations from our laboratory have demonstrated that the levels of immunoreactive inhibin (ir-inh) are elevated in almost all patients with granulosa cell tumours and in the majority of postmenopausal women with mucinous ovarian cancers. The present manuscript confirms these findings in a larger group of postmenopausal women. Immunohistochemistry for the inhibin alpha, betaA and betaB subunits shows predominantly epithelial staining in granulosa cell tumours and in the majority of mucinous cancers. Serous cystadenocarcinomas also frequently show positive staining. Studies seeking to identify G alpha(i-2) or FSH receptor mutations have provided negative results in contrast to other reports. Further studies of the roles of the inhibin-related family of peptides in ovarian cancer diagnosis and monitoring are clearly indicated.

Increased microvessel density in mucinous compared with malignant serous and benign tumours of the ovary.

Microvessel density of benign, borderline and malignant ovarian tumours was studied immunohistochemically using antibodies to the endothelial cell markers CD31, CD34 and factor VIII-related antigen. Microvessel density was compared in tumours of different histological subtype, stage and patient outcome. CD31-immunostained sections were examined and regions of high and average microvessel density were selected. Identical regions were located on CD34- and factor VIII-related antigen-immunostained serial sections and microvessel counts obtained and converted to vessels mm(-2). CD31 and CD34 immunostaining revealed increased microvessel density in both the high and average vessel density regions of mucinous (222.4 +/- 24.8; 79.9 +/- 8.5) compared with serous (105.4 +/- 20.7; 33.3 +/- 6.8) and benign (84.4 +/- 19.4; 20.4 +/- 4.4) tumours (P < 0.001). CD31 and CD34 immunostaining also revealed increased microvessel density in early-stage mucinous tumours (234.6 +/- 28.2; 87.8 +/- 9.2) compared with that observed in both early- (72.8 +/- 15; 12.9 +/- 2.4) and late- (115.6 +/- 26.5; 29.8 +/- 8.5) stage serous tumours (P < 0.001). No differences in microvessel density in samples from patients with differing outcomes were observed (P > 0.05). Reduced factor VIII-related antigen compared with CD31 and CD34 immunostaining was observed in both borderline and malignant mucinous and serous tumours (P < 0.02) but not in benign tumours (P > 0.05). Our results contradict the putative association between increased microvessel density and poor prognosis and suggest that the level and control of angiogenesis may differ between ovarian tumour types.

No evidence of a role for mutations or polymorphisms of the follicle-stimulating hormone receptor in ovarian granulosa cell tumors.

The molecular pathogenesis of granulosa cell tumors of the ovary is not understood, although recent studies have shown that immunoreactive inhibin secretion by these tumors may be used as a tumor marker. Granulosa cell tumors exhibit many features of normal granulosa cells, including a response to FSH and inhibin secretion. FSH levels are suppressed in patients with inhibin-secreting granulosa cell tumors, suggesting FSH-independent growth of these tumors. Activating mutations of the FSH receptor might, therefore, be involved in tumorigenesis. We sought to identify mutations in the FSH receptor genes of these tumors using PCR to amplify the exon encoding the transmembrane and cytoplasmic domains from the tumor DNA. Analysis of the amplicons for single strand conformational polymorphisms and direct sequencing confirmed a previously reported polymorphism in the C-terminal region of the receptor, but did not identify tumor-specific missense mutations and/or polymorphisms. In addition, ribonucleic acid from 3 granulosa cell tumors was used to confirm expression of the FSH receptor; expression was unexpectedly also observed in several ovarian mucinous cystadenocarcinomas used as controls. In conclusion, our failure to identify activating mutations of the FSH receptor in 15 granulosa cell tumors argues against a role for the FSH receptor in tumorigenesis and suggests that some subsequent component of this signal transduction pathway may be activated.

Women's satisfaction with medical abortion with RU486.

The combination of RU486 (mifepristone) and prostaglandin analogues has been used for medical abortion in several European centres. We surveyed 41 Australian women who successfully used this method of abortion in a World Health Organization-sponsored trial. Overall, the women were satisfied with the method and found the associated pain level acceptable.

PIP: A World Health Organization-sponsored study evaluated the efficacy and side effects of 2 doses of mifepristone (600 or 200 mg) followed by 400 mcg of misoprostol 48 hours later for the termination of early pregnancy in an international multicenter, randomized controlled trial. Reported are the partial results for 38 women from Monash University and Family Planning Victoria (Australia) enrolled in the trial's experimental group. Women were asked to rate their degree of satisfaction with the medical abortion on a scale of 1 (completely dissatisfied) to 5 (completely satisfied); the mean score was 4.5 (range, 1-5). The 15 women who had previously had a surgical abortion found the medical approach more acceptable (mean score, 4.5; range, 3-5). 34 participants (89.5%) rated the level of pain and discomfort associated with their medical abortion as acceptable. The main perceived advantages of medical abortion were its naturalness and non-invasiveness and the avoidance of anesthesia.

Laparoscopic and abdominal hysterectomy: a cost comparison.

OBJECTIVE: To compare the cost of laparoscopically assisted vaginal hysterectomy (LAVH) with that of total abdominal hysterectomy (TAH) under casemix. DESIGN: Retrospective comparison of the costs, operating time and length of hospital stay. PATIENTS: The 16 women undergoing consecutive LAVH and 16 age-matched women undergoing TAH between 1 February 1994 and 31 July 1995; all women were public patients undergoing hysterectomy for benign disease. SETTING: Monash Medical Centre, a large tertiary teaching hospital in Melbourne, Australia, where casemix is used to determine funding and budget allocation. RESULTS: The difference between the costs of the two procedures was not statistically significant (P = 0.5), despite the cost of laparoscopic hysterectomy including that of disposables. The mean operating time for TAH was 86 minutes (95% CI, 65.5-106.5), compared with 120 minutes (95% CI, 100.8-140.5) for LAVH (P < 0.01). The mean length of stay in the TAH group was 5.75 days, compared with 3.25 days in the LAVH group (P < 0.001). CONCLUSION: In hysterectomy for benign gynaecological disease, the laparoscopic procedure costs the same as the total abdominal procedure. Audit such as this is important in patient management and in guiding hospitals in funding and bed allocation.