Transvaginal ultrasound in evaluation and follow-up of ovarian granulosa cell tumors.

OBJECTIVE: Ultrasound features of granulosa cell tumors of the ovary are still poorly defined. The aim of this study is to widen current knowledge on the role of sonographic gray scale and pattern recognition in the characterization of these tumors and to compare the ultrasound characteristics of primary diagnosis and recurrences. METHODS: Transvaginal ultrasound images of primary diagnosis or recurrences of histologically-confirmed granulosa cell tumors of the ovary were retrospectively retrieved from a dedicated database designed for the collection of clinical and ultrasound data from January 2001 to January 2019. All patients included were treated at San Raffaele and Santa Chiara Hospitals. Women with a concomitant diagnosis of another malignancy other than endometrial carcinoma were excluded from the study. All ultrasound images were described according to International Ovarian Tumor Analysis terminology and examined by experienced ultrasound examiners. RESULTS: A total of 27 patients were included: 24 with adult and 3 with juvenile ovarian granulosa cell tumors. At primary diagnosis, mean ovarian mass size was 103.8 mm (range 30-200). On ultrasound evaluation at primary diagnosis, 12 patients presented with a multilocular solid lesion (48%), 9 with a solid lesion (36%), and 4 with a multilocular lesion(16%). The echogenicity of the cyst was low level or anechoic, mixed, or hemorrhagic in 56.3%, 31.2%, and 12.5% of cases, respectively. Most tumors (45.1%), including first diagnosis and relapses, had a moderate to high color score on doppler evaluation. CONCLUSIONS: Our study showed that sonographic features and pattern recognition of relapses were comparable to those of tumors at primary diagnosis. In order to highlight the importance of transvaginal ultrasound evaluation during follow-up, further studies based on a standardized ultrasound characterization of ovarian masses are recommended.

Gene analysis of major signaling pathways regulated by gonadotropins in human ovarian granulosa tumor cells (KGN)†.

The female reproductive function largely depends on timing and coordination between follicle-stimulating hormone (FSH) and luteinizing hormone. Even though it was suggested that these hormones act on granulosa cells via shared signaling pathways, mainly protein kinases A, B, and C (PKA, PKB, and PKC), there is still very little information available on how these signaling pathways are regulated by each hormone to provide such differences in gene expression throughout folliculogenesis. To obtain a global picture of the principal upstream factors involved in PKA, PKB, and PKC signaling in granulosa cells, human granulosa-like tumor cells (KGN) were treated with FSH or specific activators (forskolin, SC79, and phorbol 12-myristate 13-acetate) for each pathway to analyze gene expression with RNA-seq technology. Normalization and cutoffs (FC 1.5, P ≤ 0.05) revealed 3864 differentially expressed genes between treatments. Analysis of major upstream regulators showed that PKA is a master kinase of early cell differentiation as its activation resulted in the gene expression profile that accompanies granulosa cell differentiation. Our data also revealed that the activation of PKC in granulosa cells is also a strong differentiation signal that could control "advanced" differentiation in granulosa cells and the inflammatory cascade that occurs in the dominant follicle. According to our results, PKB activation provides support for PKA-stimulated gene expression and is also involved in granulosa cell survival throughout follicular development. Taken together, our results provide new information on PKA, PKB, and PKC signaling pathways and their roles in stimulating a follicle at the crossroad between maturation/ovulation and atresia.

Natural history of Ollier disease and Maffucci syndrome: Patient survey and review of clinical literature.

Ollier disease (OD) and Maffucci syndrome (MS) are characterized by multiple enchondromas. Patients with MS also have benign vascular overgrowths that become malignant in 8.5% of cases. OD is characterized by multiple enchondromas, typically unilateral in distribution with a predilection for the appendicular skeleton. MS is characterized by multiple enchondromas bilaterally distributed in most of the cases. Both disorders feature multiple swellings on the extremity, deformity around the joints, limitations in joint mobility, scoliosis, bone shortening, leg-length discrepancy, gait disturbances, pain, loss of function, and pathological fractures. About 50% of patients with OD or MS develop a malignancy, such as chondrosarcoma, glioma, and ovarian juvenile granulosa cell tumor. To better understand the natural history of OD and MS, we reviewed 287 papers describing patients with OD and MS. We also created a survey that was distributed directly to 162 patients through Facebook. Here, we compare the review of the cases described in the literature to the survey's responses. The review of the literature showed that: the patients with OD are diagnosed at a younger age; the prevalence of chondrosarcomas among patients with OD or MS was ~30%; in four patients, vascular anomalies were identified in internal organs only; and, the prevalence of cancer among patients with OD or MS was ~50%. With these data, health care providers will better understand the natural history, severity, and prognosis of these diseases and the prevalence of malignancies in these patients. Here, we recommend new guidelines for the care of patients with OD and MS.

Mitochondrial membrane depolarization enhances TRAIL-induced cell death in adult human granulosa tumor cells, KGN, through inhibition of BIRC5.

BACKGROUND: Cellular metabolic changes that accompany malignant transformation have been heralded as hallmark features of cancer. However, metabolic signatures between neoplasms can be unique, allowing for distinctions in malignancy, invasion and chemoresistance between cancer types and subtypes. Mitochondria are central metabolic mediators, as cellular bioenergetics veers from oxidative phosphorylation to glycolysis. Herein, we evaluate the role of mitochondria in maintenance of cellular metabolism, proliferation, and survival in the adult granulosa tumor cell line, KGN, as well as three epithelial ovarian cancer cell lines to determine distinctions in specific features. RESULTS: Notably, KGN cells were susceptible to TRAIL- and cisplatin-induced death following pretreatment with the metabolic inhibitor FCCP, but not oligomycin A. Collapse of mitochondrial membrane potential was found concomitant with cell death via apoptosis, independent from extrinsic canonical apoptotic routes. Rather, treatment with FCCP resulted in elevated cytochrome c release from mitochondria and decreased responsiveness to BIRC5. Following knockdown of BIRC5, mitochondrial membrane depolarization further sensitized KGN cells to induction of apoptosis via TRAIL. CONCLUSIONS: These results indicate an essential role, distinct from metabolism, for mitochondrial membrane potential in KGN cells to sense and respond to external mediators of apoptotic induction.

A rare case report of ovarian juvenile granulosa cell tumor with massive ascites as the first sign, and review of literature: Case report and review of literature.

RATIONALE: Massive ascites as the first sign of ovarian juvenile granulosa cell tumor (JGCT) in an adolescent is an extremely rare, and its clinical features and treatment methods have not been well described. PATIENT CONCERNS: The clinical characteristics, diagnosis, and treatment methods in a 19-year-old girl who presented with massive abdominal distention and ascites was retrospectively reviewed. Abdominopelvic ultrasonography showed a large amount of ascites. The nature of ascites was exudate. All tumor markers were normal, but ascites and serum tumor CA125 levels were significantly increased. Abdominal CT showed left attachment area teratoma and right attachment area capsule solid change. DIAGNOSES: Histological and immunohistochemical results were compatible with JGCT. Based on the FIGO classification, the patient with only malignant ascites was categorized into stage IC. INTERVENTIONS: The patient underwent mass resection with salpingoophorectomy. Following the operation, she received 6 courses of adjuvant chemotherapy with Nedaplatin and Paclitaxel liposome. OUTCOMES: The patient was followed up postoperatively for 6 months to date without recurrence. LESSONS: We should be highly vigilant the JGCT with massive ascites as the first clinical manifestation.

MR findings of primary ovarian granulosa cell tumor with focus on the differentiation with other ovarian sex cord-stromal tumors.

BACKGROUND: To describe magnetic resonance imaging (MRI) features of ovarian granulosa cell tumors (OGCTs) and compare with other sex cord-stromal tumors (OSCs) in ovary. METHODS: MR findings of 18 patients with surgically confirmed ovarian granulosa cell tumor were retrospectively reviewed by two radiologists with consensus reading. All MR examinations were prospectively performed within one month. Clinical and imaging characteristics of OGCTs were evaluated and compared with OSCs (control group). RESULTS: In 18 patients, 20 ovarian granulosa cell tumors were detected on MRI. Sixteen tumors appeared as solid or mostly solid mass (16/20), while 4 tumors as cystic mass. Pathological pelvic fluid was detected in 1 OGCT (1/18) and 11 OSCs (11/34) (p = 0.031).On T2 weighted imaging (T2WI), most of OGCTs displayed hyperintense signal and mixed signal (19/20); on T1 weighted imaging (T1WI), 11 OGCTs (11/20) displayed similar signal as on T2WI imaging. The lesion signal between OGCT and OSC differed significantly on both T1WI (p = 0.017) and T2WI (p = 0.002). Tumoral bleeding was detected in 6 OGCTs on MRI. On diffusion weighted imaging (DWI) images, OGCTs mostly appeared as high signal (16/20). Average apparent diffusion coefficient (ADC) value derived from DWI images in the OGCT group (0.84 ± 0.26× 10- 3 mm2/s was less than the control group (1.22 ± 0.47 × 10- 3 mm2/s) with statistical difference (p = 0.002). CONCLUSIONS: MRI could provide important information in OGCT diagnosis. ADC value might be useful in differentiating OGCT from OSC.

From Follicular Development and Ovulation to Ovarian Cancers: An Unexpected Journey.

Follicular development and ovulation are complex development processes that are regulated by multiple, interacting pathways and cell types. The oocyte, cumulus cells, granulosa cells, and theca cells communicate to impact follicular development and ovulation. Many hormones and cytokines control intracellular regulatory networks and transcription factors, some of which are cell type specific. Molecular biology approaches and mutant mouse models have contributed immensely to our knowledge of what genes and signaling cascades impact each stage of follicular development and ovulation, and how the alteration of gene expression profiles and the activation of specific signaling pathways can impact ovarian cancer development in ovarian surface epithelial cells as well as granulosa cells. This chapter explores how pathways controlling normal follicle development and ovulation can be diverted to abnormal development.

Postmenopausal mild hirsutism and hyperandrogenemia due to granulosa cell tumor of the ovary: a case report.

BACKGROUND: Among classes of ovarian tumor, granulosa cell tumors are the least common. In approximately 10% of cases of granulosa cell tumor, androgen will be secreted which will present with hirsutism and hyperandrogenemia. We describe a woman with ovarian granulosa cell tumor who presented with hirsutism. CASE PRESENTATION: A 50-year-old woman of Amhara ethnicity, para III, abortion I (induced), presented with excessive hair on her face and lower abdomen of 4 years' duration which affected her quality of life. Her menopause started 7 years ago. Her body mass index was 29.8 kg/m2. She had hair on her upper lip, chin, and lower abdomen; she had a Ferriman-Gallwey score of 10. A pelvic examination revealed that her uterus was of normal size and there was no adnexal mass. Ultrasound finding: her right ovary measured 5 × 4 cm. Her serum testosterone was 254 ng/dl; she was counseled to undergo an exploratory laparotomy but she declined. She presented to our out-patient department 10 months later with a complaint of excessive vaginal bleeding of 18 days' duration. A sonographic evaluation showed a 12 by 15 cm right adnexal cystic mass. With preoperative diagnosis of testosterone-producing sex cord-stromal tumor of the ovary, an exploratory laparotomy was performed. The laparotomy revealed a 20 by 30 cm right ovarian mass with pathology result of adult granulosa cell tumor. CONCLUSION: In postmenopausal women with new hirsutism that is severe or rapidly progressive, the possibility of an androgen-secreting tumor must be suspected and a thorough evaluation is needed before initiating treatment for idiopathic hirsutism.

Clinical presentation and outcome of adult-type granulosa cell tumors: a retrospective study of 30 patients in a single institute.

BACKGROUND: Ovarian adult-type granulosa cell tumors (GCTs) are characterized as low-malignant and late-recurrent ovarian tumors. Although some clinical and pathological prognostic factors have been reported, other factors have yet to be sufficiently investigated for necessary confirmation. The aim of this study was to test the correlation between clinical factors and outcome, based on patients seen in a single institute. METHODS: Thirty patients with pathologically confirmed adult-type GCTs between 1984 and 2010 were reviewed retrospectively. Among them, eight (26.7%) had recurrence, which subsequently contributed to two mortalities. RESULTS: In a comparison of the clinical characteristics of the premenopausal and postmenopausal women with GCT, all of the postmenopausal women had symptoms (100% vs. 63.6%, p = 0.01). With regard to disease recurrence, only abnormal preoperative serum cancer antigen 125 level (≥ 35 U/mL) was significant (50% vs. 11%, p = 0.03), and residual tumor showed a borderline trend (100% vs. 21.4%, p = 0.06). Other factors, including International Federation of Gynecology and Obstetrics stage, tumor size, tumor rupture prior to or during operation, body mass index, parity, serum estrogen level, and adjuvant therapy, were not statistically significant. CONCLUSION: Physicians should be alert to the difference in the symptom presentation of GCTs between pre- and postmenopausal women, giving particular attention to the usefulness of the preoperative serum level of cancer antigen 125 in patients with GCTs. More evidence is needed to confirm this observation.

Minireview: animal models and mechanisms of ovarian cancer development.

Ovarian cancer in women is a complex and deadly disease, where the molecular events that initiate and control tumor formation remain poorly defined. Therefore, mouse models provide one approach for determining the mechanisms by which specific oncogenic factors cause ovarian surface epithelial cell and granulosa cell transformation. This minireview summarizes the phenotypes of current mouse models that have been generated and some of the underlying mechanisms they have provided.

Anti-Müllerian hormone inhibits growth of AMH type II receptor-positive human ovarian granulosa cell tumor cells by activating apoptosis.

Ovarian granulosa cell tumors (GCTs) are sex cord stromal tumors that constitute 3-5% of all ovarian cancers. GCTs usually present with an indolent course but there is a high risk of recurrence, which associates with increased mortality, and targeted treatments would be desirable. Anti-Müllerian hormone (AMH), a key factor regulating sexual differentiation of the reproductive organs, has been implicated as a growth inhibitor in ovarian cancer. GCTs and normal granulosa cells produce AMH, but its expression in large GCTs is usually downregulated. Further, as the lack of specific AMH-signaling pathway components leads to GCT development in mice, we hypothesized that AMH inhibits growth of GCTs. Utilizing a large panel of human GCT tissue samples, we found that AMH type I receptors (ALK2, ALK3 and ALK6) and type II receptor (AMHRII), as well as their downstream effectors Smad1/5, are expressed and active in GCTs. AMHRII expression was detected in the vast majority (96%) of GCTs and correlated with AMH mRNA and protein expression. AMH mRNA level was low in large GCTs, confirming previous findings on low-AMH protein expression in large human as well as mouse GCTs. To study the functional role of AMH in this peculiar ovarian cancer, we utilized a human GCT cell line (KGN) and 10 primary GCT cell cultures. We found that the AMH-Smad1/5-signaling pathway was active in these cells, and that exogenous AMH further activated Smad1/5 in KGN cells. Furthermore, AMH treatment reduced the number of KGN cells and primary GCT cells, with increasing amounts of AMH leading to augmented activation of caspase-3 and subsequent apoptosis. All in all, these data support the premise that AMH is a growth inhibitor of GCTs.

Enhanced transplantability of a cell line from a murine ovary granulosa cell tumour in syngeneic B6C3F(1) mice continuously irradiated with low dose-rate gamma-rays.

PURPOSE: To understand the mechanisms of life-shortening due to early neoplastic death caused by chronic low dose-rate (LDR; 20 mGy/22 h/day) radiation which accumulates to a high dose (HD; 8 Gy) (LDR/HD) as reported previously. MATERIALS AND METHODS: Female B6C3F(1) mice were continuously exposed to LDR/HD gamma-rays under specific-pathogen-free (SPF) conditions for 400 days. OV3121 cells, which were derived from an ovarian granulosa cell tumour that arose in irradiated B6C3F(1) mice, were inoculated into LDR/HD irradiated and age-matched non-irradiated control mice. The transplantability of tumour cells as well as T cell subsets and the proliferative activities of T cells were compared between irradiated and non-irradiated mice. RESULTS: We found that tumour formation of subcutaneously inoculated tumour cells occurred earlier in irradiated mice than in non-irradiated mice. Proliferative activity of draining lymph node lymphocytes against transplanted tumour cells as well as allogeneic mixed lymphocyte reactions were significantly reduced in irradiated mice compared to non-irradiated mice. CONCLUSIONS: These results suggest that decreased tumour-specific immune response due to LDR/HD irradiation may enhance tumorigenesis resulting in life-shortening of mice after chronic LDR/HD irradiation.

The importance of ERbeta signalling in the ovary.

This review examines the evidence for a central role of oestrogen receptor beta (ERbeta or ESR2 as listed in the MGI Database) in folliculogenesis and hence reproductive biology. Knockout mouse models have been a valuable resource in this respect. The ERbeta-null mouse exhibits a granulosa cell phenotype associated with the partial arrest of folliculogenesis and ovulatory dysfunction. Phyto-oestrogens such as genistein, which preferentially activate ERbeta, have been shown to alleviate the ovarian phenotype of the oestrogen-depleted aromatase knockout mouse. In normal adult mice, genistein has been shown to cause reproductive defectives following neonatal administration. Studies of ovarian cancer have also informed the literature. A decline in ERbeta levels in epithelial ovarian cancers has been hypothesised to be associated with severity of disease and prognosis. Whereas the abundant expression of ERbeta in granulosa cell tumours (GCT) of the ovary and evidence that ERbeta signalling is transrepressed by the nuclear factor-kappaB pathway in GCT cell lines suggest a pathogenetic role for ERbeta in GCT. In recent years, studies into the impact of environmental oestrogens (either in the form of pesticides or plastics) on reproductive function have shown that ERbeta-selective toxins cause reproductive dysfunction and impair fertility. It remains to be established as to what genes are regulated by ERbeta in the ovary. Finally, ERbeta has been shown to be regulated by gonadotrophins, the pituitary hormones mediating ovarian function.

Expression of adrenomedullin in human ovaries, ovarian sex cord-stromal tumors and cultured granulosa-luteal cells.

The aim of the present study was to characterise the expression pattern of the multifunctional vasoactive peptide adrenomedullin (ADM) in human ovarian tumors, and to find hormonal regulators of ADM expression in human ovaries. The expression of ADM messenger RNA (mRNA) was higher in granulosa cell tumors than in fibrothecomas and normal ovaries, as analysed by Northern blots. In normal ovaries, ADM immunoreactivity was localised in both granulosa and thecal cells. Eight of the 90 granulosa cell tumors (9%) showed moderate and 53 (59%) weak ADM immunoreactivity, whereas 27% (11/41) of the fibrothecomas displayed weak ADM staining. FSH, protein kinase A activator (Bu)(2)cAMP, prostaglandin E(2) (PGE(2)), activin A and the broad protein kinase regulator staurosporine decreased ADM mRNA accumulation in cultured granulosa-luteal cells time- and dose-dependently. FSH, (Bu)(2)cAMP and PGE(2) increased progesterone secretion and the accumulation of the steroidogenic acute regulatory protein mRNA in these cells. In conclusion, ADM is expressed in normal human ovaries and sex cord-stromal tumors, particularly in those of granulosa cell origin. FSH, PGE(2,) (Bu)(2)cAMP and activin A suppress ADM gene expression in granulosa-luteal cells. Expression of ADM in human ovaries and its hormonal regulation in granulosa cells suggests a paracrine role for ADM in ovarian function.

Dysregulation of WNT/CTNNB1 and PI3K/AKT signaling in testicular stromal cells causes granulosa cell tumor of the testis.

Synergistic effects of dysregulation of the WNT/CTNNB1 and phosphatidylinositol 3-kinase (PI3K)/AKT pathways are thought to be important for the development and progression of many forms of cancer, including the granulosa cell tumor of the ovary. Sustained WNT/CTNNB1 signaling in Sertoli cells causes testicular degeneration and the formation of foci of poorly differentiated stromal cells in the seminiferous tubules in mice. To test if concomitant dysregulation of the WNT/CTNNB1 and PI3K/AKT pathways could synergize to cause testicular cancer, Pten(tm1Hwu/tm1Hwu);Ctnnb1(tm1Mmt/+);Amhr2(tm3(cre)Bhr/+) mice that express a dominant, stable CTNNB1 mutant and lack the expression of phosphatase and tensin homolog (PTEN) in their Sertoli cells were generated. These mice developed aggressive testicular cancer with 100% penetrance by 5 weeks of age, and 44% of animals developed pulmonary metastases by 4 months, whereas Pten(tm1Hwu/tm1Hwu);Amhr2(tm3(cre)Bhr/+) controls were phenotypically normal. Surprisingly, the tumors could not be classified as Sertoli cell tumors, but rather bore histologic and ultrastructural characteristics of granulosa cell tumors of the testis (GCTT). Pten(tm1Hwu/tm1Hwu);Ctnnb1(tm1Mmt/+);Amhr2(tm3(cre)Bhr/+) testicular tumors did not express CYP17, CYP19, germ cell nuclear antigen, estrogen receptor 1 or progesterone receptor, but expressed the early granulosa cell markers WNT4 and FOXL2, confirming the diagnosis of GCTT. Immunohistochemical analyses of Pten(tm1Hwu/tm1Hwu);Ctnnb1(tm1Mmt/+);Amhr2(tm3(cre)Bhr/+) GCTT demonstrated a tumor marker profile similar to that reported in human GCTT. Immunoblotting analyses revealed high levels of phosphorylation of AKT and the PI3K/AKT signaling effector FOXO1A in Pten(tm1Hwu/tm1Hwu);Ctnnb1(tm1Mmt/+);Amhr2(tm3(cre)Bhr/+) GCTT, suggesting the involvement of FOXO1A in the mechanism of GCTT development. Together, these data provide the first insights into the molecular etiology of GCTT and the first animal model for the study of GCTT biology.

[Juvenile granulosa-cell tumor: clinical and molecular expression]. / Tumeurs juvéniles de la granulosa: expression clinique et moléculaire.

Ovarian sex cord-stromal tumors are rare tumors that originate from the nongerminal cells of ovary. Two decades ago, the identification of juvenile granulosa-cell tumors (GCT), as a specific entity inside this group, allowed a better treatment of these tumors in children. However, little data have been reported on the natural course of the disease and reliable prognostic factors have not been yet defined. We here review the clinical and genetics aspects of granulosa tumors, based on a series of 40 children. This national collaborative study involved the French Society of Children Cancer and eight clinical departments of pediatric endocrinology. We found that early diagnosis of a tumor, revealed by clinical signs of hyperoestrogeny, is an important prognostic factor. The pathophysiology of these tumors is still debatable and several cellular- and molecular-abnormal signals could be implicated in their development. The role of growth factors and oncogenes through the signaling pathway of MAP kinase is still discussed. According to our data, FSH signaling-transduction pathway, such as a constitutionally activated Galphas, could also be implicated in the induction of granulosa cell proliferation and seems to modulate the invasiveness of the tumor. Last, we have described a low-expression pattern or an extinction of an ovarian-determination gene, FOXL2, which is related to a worse prognosis of this tumor.

Common variable immunodeficiency: a new look at an old disease.

Primary immunodeficiencies comprise many diseases caused by genetic defects primarily affecting the immune system. About 150 such diseases have been identified with more than 120 associated genetic defects. Although primary immunodeficiencies are quite rare in incidence, the prevalence can range from one in 500 to one in 500 000 in the general population, depending on the diagnostic skills and medical resources available in different countries. Common variable immunodeficiency (CVID) is the primary immunodeficiency most commonly encountered in clinical practice, and appropriate diagnosis and management of patients will have a significant effect on morbidity and mortality as well as financial aspects of health care. Advances in diagnostic laboratory methods, including B-cell subset analysis and genetic testing, coupled with new insights into the molecular basis of immune dysfunction in some patients with CVID, have enabled advances in the clinical classification of this heterogeneous disease.

Effects of granulosa cell-specific deletion of Rb in Inha-alpha null female mice.

Our laboratory is interested in the gonadal growth regulatory properties of inhibins, members of the TGFbeta superfamily. We have previously shown that female mice lacking inhibins (Inha(-/-)) develop granulosa cell tumors and that concurrent loss of p27 accelerates tumor development. It has also been shown that the retinoblastoma protein RB regulates the G(1) to S phase transition of the cell cycle by controlling the activity of transcription factors and stabilizing the levels of the cell cycle inhibitor P27. Based on these data, we hypothesized that concurrent loss of Rb and inhibins in the ovary will exacerbate tumor formation. To test this hypothesis, we generated an ovarian granulosa cell conditional knockout (cKO) of Rb using the Cre/lox recombination system in the background of Inha(-/-) mice. Inha(-/-)/Rb cKO females show a modest increase in mortality rates compared with Inha(-/-) females. Although histologically similar to Inha(-/-) ovarian tumors, tumors from Inha(-/-)/Rb cKO females show increased number of mitotic figures and apoptotic rates. Interestingly, P27 levels are decreased in Inha(-/-)/Rb cKO ovarian tumors, likely due to the combined effect of Rb loss and increased Skp2 expression, which targets P27 to the proteosome. We propose that Rb loss may cause cell cycle delay or arrest, followed by apoptosis and that increases in p107 and p130 levels may compensate for Rb loss. These findings confirm the importance of P27 as a cell cycle regulator in granulosa cells and suggest functional compensation between RB-like proteins in ovarian tumorigenesis.

Granulosa cell tumors of the equine ovary.

The granulosa cell tumor is the most common ovarian tumor in mares. A clinical diagnosis can be made based on the presence ofa unilaterally enlarged ovary and a small inactive contralateral ovary. Endocrine testing may be beneficial to confirm a diagnosis. Surgical removal of the tumor eliminates the adverse effect on pituitary function and results in resumption of follicular development and ovulation in the opposite ovary over time.

[Personal observations of puberty in girls after unilateral ovariectomy]. / Wlasne obserwacje dotyczace przebiegu okresu dojrzewania u dziewczat po jednostronnej owariektomii.

The authors present the course of puberty in three girls after surgery because of hormonally active ovarian tumours diagnosed and operated at the age of 3, 6 and 9 years, respectively. In the youngest patient with folliculoma ovari chemotherapy was also given, and girl No. 3 with luteinic capsule was treated for one year with decapeptyl because idiopathic precocious puberty was diagnosed. At present all three girls are in good physical condition with age-adequate development and puberty.