[Granulosa and theca cell tumors and vaginal smear].
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A granulosa-theca-cell tumour in a 17-month-old girl with isosexual precocity and hirsutism is described. Following removal of the tumour, pubertal signs and hirsutism gradually subsided. Serum alpha-fetoprotein was very high (1800 ng/ml) before, but not any longer detectable after the removal of the tumour and on repeated measurements for the subsequent 34 months, at which time the clinical condition of the child has been very good.
In view of the increasing need for laboratory primates in biomedical research it is desirable to develop appropriate primate-specific cell culture models that could prevent or significantly reduce the increasing use of primary cultures and experiments with living animals. Follicular granulosa and theca cells are essential for the control of hormone-dependent processes such as the ovarian cycle and pregnancy, but also for the occurrence of hormone-dependent diseases. For this reason it is of great interest to know more about control mechanisms existing in these follicular cell types and the effect of pharmacological or toxicological agents on them. An immortalisation protocol for the two ovarian cell types of the marmoset monkey (Callithrix jacchus) has been developed. All cell lines established so far were examined with regard to the maintenance of known, tissue-specific features (e.g. hormone responsiveness and enzyme expression). The results obtained indicate that it is worth while cloning and characterising the cell lines in more detail so that they could be used after an adequate validation as a defined test system both for basic research as well as for pharmacological or toxicological screening.
A 21 year old thoroughbred mare with granulosa theca cell tumor (GTCT) in the right side and atrophic contralateral ovary was investigated in this study. After arrival at our laboratory on 10th December 1999, the clinical diagnosis of GTCT was examined by rectal palpation and ultrasonographic image of ovaries. Plasma from peripheral blood was collected in the breeding and non-breeding seasons for hormonal analysis. The results showed that the contralateral ovary regained normal activity without any treatment of the GTCT affected ovary and contained follicles showing different sizes 19 months later. However, the affected right ovary, which became smaller after 4 months, was totally inactive without any follicle. The observations clearly demonstrate that without any treatment of the GTCT affected ovary, a mare can return to her normal estrous cycle within a certain period in some GTCT cases.
Granulosa theca cell tumor (GTCT) in the premenarche accounted for 7% of all ovarian tumors treated at the Children's Hospital Medical Center from 1928 through 1979. The average age of the ten girls at the time of diagnosis was 5 years (range 11 months-121/2 years) with precocious "pseudopuberty" and an abdominal mass being the most common presentation. GTCTs were solitary (five right, five left) with an average diameter of 12.1 cm. Histologic examination showed a predominantly diffuse or solid pattern with prominent luteinization; Call-Exner bodies and folded ("coffee-bean") nuclei were inconspicuous. Ultrastructural examination of one GTCT confirmed the presence of both granulosa and theca components with the latter showing extensive luteinization; estradiol, testosterone and prolactin were demonstrated in the same tumor using immunologic techniques. The average follow-up time was 21 years with nine of the ten patients being followed for more than ten years. Salpingo-oophorectomy resulted in cures despite the occurrence of tumor spillage in two patients. The prognosis for GTCTs in the premenarche appears more favorable than for those occurring in adulthood, but further study is needed to completely define their full biologic potential; the significance of subsequent breast cancer in two long-term survivors merits further investigation as well.
The juvenile-type of granulosa theca cell tumour in a young girl is reported. The child presented with pain, vaginal bleeding, distension of the abdomen and enlarged breasts and exhibited pubic and axillary hair, i.e. signs of oestrogenic and androgenic effects and overproduction of luteinizing hormone--an unusual phenomenon. Discussion includes the differences between the juvenile and adult types of this tumour. Salpingo-oophorectomy of the affected side is recommended in such cases. A recurrence many years after surgery has been reported, so long-term follow-up is envisaged in this case.
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We have investigated the mRNA expression of the Ets-1 and Ets-2 genes in murine gonads and found expression in adult ovaries. In situ hybridization experiments show that the Ets genes are predominantly expressed in theca cells and cells of ovarian interstitium. By gel retardation experiments we detected DNA binding proteins in ovaries that specifically bind to the ETS motif, suggesting the expression of Ets or Ets-related proteins. Our results raise the possibility of Ets-2 involvement in ovarian pathology seen in patients with Down's syndrome.
During the period 1923 to 1972, 62 women with theca-cell tumors were treated at Radiumhemmet. The mean age at diagnosis was 59.5 years. Concomitant endometrial carcinoma was found in 13 patients. At 1978, after a mean observation time of 15.5 years, 30 patients were alive. No patient died from thecoma. Malignant disease caused death in 7 women. No difference in survival was found between 20 patients and 40 controls matched by age and place of residence.
From 1976 to 1989, 29 cases of ovarian theca cell tumors were diagnosed at the Pathology Department of our Hospital. Their clinical and histologic features were reviewed. The main presenting symptom in postmenopausal patients was uterine bleeding, whereas in premenopausal women, abdominal swelling and the findings of ultrasonographic examination were the diagnostic keys. Different surgical procedures were the cornestone of treatment, although in 12 cases the indication for surgery was not apparently related to an adnexal condition.
The FecB (Booroola) mutation, which leads to increased ovulation rates and multiple births in sheep, is now known to occur in the signaling domain of the bone morphogenic protein (BMP)-1B receptor. We examined the effect of the mutation on the responsiveness of granulosa (GC) and theca cells (TC) to BMPs and other local regulators using tissue from animals with (Fec(B/B)) and without (Fec(+/+)) the FecB mutation. Experiments examined the effect of BMP-2, -4, and -6 (0.005-50 ng/ml), and their interaction with IGF-I (0.1-10 ng/ml LR3 analog) and gonadotropins, on the proliferation and differentiation of GCs and TCs isolated from small (<2 mm) antral follicles and maintained in serum-free culture for up to 8 d. Dose-finding studies using ovaries from wild-type sheep obtained from the abbattoir showed no difference among the different BMPs in stimulating (P < 0.001) estradiol (E2) production by GCs cultured with FSH (10 ng/ml), but there was a clear interaction (P < 0.001) with IGF-I. BMPs had no effect on GC proliferation or the sensitivity of GCs to FSH. In contrast, higher doses of BMPs (5-50 ng/ml) inhibited LH-stimulated androstenedione production by TCs, whereas lower doses (0.005-0.05 ng/ml) stimulated TC proliferation (P < 0.01). Regardless of dose of IGF-I, at the end of culture (96-192 h) hormone production by GCs (E2, inhibin A) and TCs (androstenedione) was 4- to 5-fold greater (P < 0.001) by cells from Fec(B/B), compared with Fec(+/+) ewes exposed to the same dose of gonadotropin. In the presence of low concentrations of IGF-I (0.1 ng/ml), the maximum increase in the production of E2 and inhibin A by GCs from FF ewes in response to BMPs was observed at doses that were 3- to 10-fold lower (3-10 ng/ml) than ++ (30 ng/ml; P < 0.001). Low doses of BMPs stimulated proliferation of TCs from ++ (P < 0.01) but not FF ewes. Immunohistochemistry confirmed BMP-6 protein expression in the oocyte, granulosa, and thecal layers of antral follicles from both genotypes. These results confirm a major role for BMPs in controlling ovarian somatic cell function in sheep and provide evidence to support the hypothesis that the FecB mutation increases the BMP response of somatic cells when stimulated to differentiate by gonadotropins.
The amounts of lysophospholipase D (LPLD) and the ovarian protein kinase C delta (PKCdelta) increase during the course of pregnancy. Because LPLD is involved in the production of the bioactive phospholipid lysophosphatidic acid (LPA), we examined whether stimulation with LPA would influence PKCdelta in the ovary. We used immunoblotting and immunohistochemical methods to show that stimulation of bovine theca cells with LPA leads to an unexpected redistribution of PKCdelta from the cytosol to the perinuclear area and that in the presence of LH, LPA induces a complete nuclear translocation of PKCdelta. These effects of LPA are dose dependent, can be mimicked by phorbol ester, and are inhibited by a PKCdelta inhibitor, rottlerin. Concomitantly, under the same experimental conditions both LPA and the phorbol ester PMA (4beta-phorbol-12-myristate-13-acetate) augment LH-stimulated progesterone accumulation in this cell system. This functional effect of LPA and PMA is abolished in cells pretreated with rottlerin. It is unclear whether the nuclear localization of PKCdelta indicates a specific function of the enzyme in the bovine ovary. Because PKCdelta supports a luteotropic function in rodent models, a similar role in the bovine ovary is also likely.
Theca (T) cells modulate steroid secretion by granulosa (G) cells in vitro. This investigation was undertaken to see whether the cytoskeleton is involved in this process. Monocultures of G cells alone, T cells alone and GT co-cultures were viewed by light microscopy. Microtubules were visualized using monoclonal Ab against tubulin. The specificity of the Ab was checked by Western blotting. One group of cells was treated with colchicine, a microtubule disrupting drug, to show its influence on oestradiol secretion by cultured cells. Microtubule arrangement was monitored using a fluorescence microscope. In monoculture of G cells a diffuse pattern of immunocytochemical staining of tubulin was noted while in T cells cultured alone the microtubule were arranged in a network of delicate fibres. In co-culture the microtubule arrangement changed in G cells and became very fine and less numerous than in theca fibres. Oestradiol secretion by colchicine-treated cultures different from control secretions. The E2 secretion declined in cultures of G cells (48.9 pg/10(5) cells in control vs 19.4 pg/10(5) cells in colchicine cells), and in T cells cultures alone (490 pg i n control vs 171 pg/10(5) cells in colchicine treated cells) while in co-culture a dose-dependent increase of this steroid was detected after the addition of colchicine (2,008 pg vs 1,269 pg/10(5) cells in control). It is conceivable that microtubules affect transport of androgens from their production site in T cells to G cells where this substrate is aromatized resulting in increased preovulatory oestradiol secretion.
To clarify the endocrinological characteristics of the mares with granulosa theca cell tumor (GTCT), peripheral plasma samples from the 6 mares affected with GTCT were collected before and after the surgical removal of the affected ovary. Concentrations of testosterone (T), follicle stimulating hormone (FSH), luteinizing hormone (LH), immunoreactive-inhibin (ir-INH), progesterone (P) and estradiol-17beta (E(2)) in the plasma samples were measured by radioimmunoassay. Before removal of GTCT in all cases, the concentrations of T were significantly higher than those of normal mares at the breeding and non-breeding seasons, whereas plasma concentrations of FSH, LH, ir-INH, P and E(2) were lower. After surgical removal of the affected ovary, the circulatory concentrations of T was declined, but the concentrations of other hormones were constantly low as compared with those of normal mares. The present study suggests that 1) the source of higher T may be due to the abnormal follicles in ovary of GTCT, 2) in the case of GTCT the elevated level of T is observed due to the lack of aromatase, and 3) the high level of T is a typical characteristics for GTCT in mares. It is also suggested 4) due to the elevated levels of T the concentrations of gonadotropins may be suppressed.
An analysis of 936 women with granulosa- and theca-cell tumors reported to the Swedish Cancer Registry between 1958 and 1972 showed crude annual incidence rates for these lesions of 0.72 and 0.74, respectively, pre 100 000 of the female population, unchanged during the period. The age-specific incidence rates, both groups taken together, increased almost linearly from 35 to 69 years. The women displayed an increased risk of developing endometrial carcinoma and malignant lymphoma, possibly also breast, colon and thyroid carcinoma.
A retrospective study of 51 thecomas and granulosa-theca cell tumors of the ovary seen at Confederate Memorial Medical Center in Shreveport, Louisiana, is presented. Endometrial tissue was available for study in 38 of the 51 patients. The relation of these tumors to endometrial morphology suggests an excessive estrogenic stimulation in most cases. The microscopic pattern and degree of pleomorphism was of no value in predicting which tumors would behave in a malignant fashion. The incidence of endometrial malignancy associated with these tumors was only 7.8%, which was less than was anticipated. The addition of irradiation and/or chemotherapy is, in our opinion, difficult to evaluate since many of the women with these tumors die of unrelated causes before a recurrence is evident.