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Ovarian cancer is responsible for 4% of all cancers in females and 6% of all their cancer deaths. Its mortality rate is greater than that of cervical and endometrial cancer together. The concentration of estrogen receptors (ER) rises and progesterone receptors (PR) falls in malignant ovarian tumors. In fact, ER and PR at present in 61% and 49% of malignant ovarian tumors respectively. 36% of these tumors contain both ER and PR. Further 69-90% of such tumors contain androgen receptors (AR). After (anti)hormonal agent therapy fails, physicians use progestins in combination with the synthetic antiestrogen tamoxifen in progressive or recurrent advanced ovarian cancer. The response rate for this treatment of ovarian cancer is only around 15%. Patients with malignant ovarian tumors with PR levels =or+ 50 fmol/mg tend to have a better prognosis than those with PR levels 50 fmol/mg. Neither age, stage of disease, nor tumor histology affect the prognostic value of PR. In vitro studies demonstrate that pure antiandrogens significantly inhibit about 60% of ovarian tumors. Another study also demonstrates that antiandrogen therapy alone may an effective endocrine therapy. As a result, the Gynecologic Cancer Cooperative Group of the European Organization for Research and Treatment of Cancer if conducting a clinical trial on the effect of the antiandrogen flutamide on advanced or recurrent ovarian cancer. Researchers plan to investigate the effect of combining endocrine therapy with current standard chemotherapy. In fact, they intend to learn if combined chemo-endocrine therapy should be used as 1st line treatment for ovarian cancer.

Estrogen (ER), progesterone (PR), and androgen receptors (AR) were determined by saturation analysis in 100 cases of primary ovarian cancer and correlated with patient survival. The mean follow-up period was 5.4 years (range, 4 to 6.5 years). Positivity for PR was associated with a significantly better survival rate (P less than 0.05). A similar observation was made for AR (P less than 0.05). Tumor ER content did not correlate with survival. Ten patients with tumors that had negative results for both PR and AR all died of the disease. In 91 cases of serous, endometrioid, and mucinous carcinomas, grade, stage, and tumor PR content, but not AR content, were identified as independent prognostic factors with the use of the Cox proportional hazards model. The relative risk of patients with PR-negative tumors was 2.3 times higher than that of patients with tumors containing high (greater than or equal to 30 fmol/mg) PR levels.

The prevalence of nerve growth factor (NGF) production in different human prostatic tumor cell lines (DU145, PC-3, LNCaP-FGC) was investigated using a specific enzyme-linked immunosorbent assay (ELISA) and compared to that of different human and rat prostatic tissue samples. In addition, the biological effects of NGF beta addition to the human prostatic cancer cell cultures were investigated. The ELISA technique showed the DU145 cell line to secrete measurable levels of NGF in the culture medium. When neurite-outgrowth determination in a pheochromocytoma cell line was used as a bioassay, the NGF synthesized by DU145 cells was confirmed to exhibit functional biological activity. No effect of exogenously added NGF could be established on tumor cell proliferation, on the basis of either colorimetric tetrazolium-based staining assay or bromodeoxyuridine incorporation. Also the expression of prostate specific acid phosphatase was not influenced by NGF addition. However, the in vitro invasive capacity (Matrigel) of DU145 cells was significantly increased by inclusion of 50 ng or 100 ng NGF beta/ml culture medium. In view of the clinically well-known perineural invasion of prostate cancer cells, the possible involvement of NGF as a (paracrine) factor in prostatic cancer metastatic behavior should be investigated further.

New active non-toxic therapeutic regimens are warranted in ovarian cancer relapsing after platinum-based chemotherapy. Some investigators have determined that androgen receptors predominated over oestrogen and progesterone receptors in untreated common epithelial ovarian cancer tissue cytosols. In an effort to test its antitumoural activity, 68 pretreated patients with epithelial ovarian cancer were given flutamide 750 mg/day orally for at least 2 months. Of 32 patients who received a minimum of 2 months of therapy, pretreated with at least one platinum-based chemotherapy, and a median of two chemotherapy regimens, two (6.3%) objective responses (one complete and one partial) and nine (28%) disease stabilisations were observed; these lasted 44 and 72 weeks, respectively (for the complete and partial response), and for a median of 24 weeks for stabilisations (range 12-48+). Nausea and vomiting were the most frequent side-effects. These occurred in 19/55 (34.5%) patients evaluable for toxicity. Flutamide has to be considered ineffective in patients extensively pretreated with chemotherapy, and it is not devoid of side-effects.

Prostate tumor cell metastasis to the axial skeleton was induced in male Copenhagen rats using the intravenous injection of syngeneic metastatic R3327-MATLyLu tumor cells and concomitant caval vein clamping. The proliferation of tumor cells in the lumbar region was monitored by the progression, within 19 days post tumor cell injection, of hindleg paralysis which appeared in these animals. Histology confirmed the presence of tumor cells within the lumbar spine in 100% of cases displaying hindleg paralysis. Treatment with either of the bisphosphonate drugs, Cl2MDP or APD, suppressed and delayed the development of hind leg paralysis. Bisphosphonate treatment may be expected to delay the onset of axial skeletal metastasis effects in prostate cancer patients.

Enzyme activities of N-acetylglucosaminyltransferase (GlcNAc-Tase) I–V involved in N-linked complex-type carbohydrate synthesis were determined in a non-metastatic hormone-dependent rat prostate tumor (R3327-H) and a related, hormone-independent variant metastasizing to lymph nodes and lungs (R3327-MatLyLu). In the metastasizing variant a significantly increased activity of both GlcNAc-Tase III and GlcNAc-Tase V was observed, whereas the activities of GlcNAc-Tase I and II were essentially unchanged. The increase in activity of GlcNAc-Tase III is particularly noteworthy since it indicates that elevated expression of this enzyme cannot be considered as an exclusive marker of hepatic malignancy.

A literature review of pregnancy-related vertebral haemangiomas, pregnancy-related haemangiomas outside the nervous system and its coverings, and pregnancy-related meningiomas was performed. All three conditions tended to occur during the first pregnancy, the second or third trimester, to ameliorate postpartum, and to recur during a subsequent pregnancy. These results suggested a hormonal influence on the clinical expression of haemangiomas and meningiomas. To test whether a hormonal factor is also operative in the (not pregnancy related) symptomatic and asymptomatic counterparts of these conditions we also reviewed the literature concerning the symptomatic and asymptomatic haemangiomas and meningiomas for the following: frequency, sex and age distribution. No arguments were found to suggest that steroid hormones are strong factors in the development of asymptomatic and symptomatic lesions. The pregnancy-related counterparts have to be considered as subsets with their own behaviour.

The nuclear DNA content of 47 malignant epithelial ovarian tumours and five ovarian tumours of borderline malignancy was correlated with estrogen (ER), progesterone (PR) and androgen receptor (AR) status. Aneuploidy was observed in 60% of the malignant tumours. The DNA index of poorly differentiated tumours was higher than that of well differentiated tumours (P less than 0.05). Ploidy did not correlate with histological type, stage of disease and ER content. Of the diploid tumours, 74% was PR-positive, in contrast to 36% of the aneuploid tumours (P less than 0.05). In addition, 89% of the diploid tumours had high AR levels (greater than or equal to 30 fmol/mg cytosol protein), in contrast to only 54% of the aneuploid tumours (P less than 0.05). These observations strengthen our previous findings on the prognostic importance of PR and also suggest that androgens may have a role in ovarian cancer.

The histologic, morphometric, immunohistochemical, and ultrastructural study of a malignant Brenner tumor in a postmenopausal women presenting with vaginal bleeding is described. A comparison with transitional cell carcinomas is made, and the use of morphometry in grading the urotheliallike epithelium in malignant Brenner tumors is suggested. High preoperative urinary estrogen, low serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels and histologically confirmed atypical endometrial hyperplasia suggested a hyperestrogenism. The reduction in urinary estrogen and the increase in serum LH and FSH after tumor removal and the presence of aromatase activity detected in tumor microsomes confirmed that the tumor was synthesizing estrogen. Estrogen receptors were undetectable both by biochemical and histochemical analysis in the tumor.Cancer 58:754-760, 1986.

Treatment effects of RU 23908 antiandrogen (Anandron) and estrogen in low doses on hormone-dependent rat prostatic adenocarcinoma (R3327-H) were investigated. Tumor-bearing Copenhagen rats were treated for 6 weeks with 8 micrograms Anandron and 1 microgram estradiol-17 beta every two days. Reduction and counteraction of androgen synthesis and action was established by an observed decline in serum testosterone level and by changes in both histology and weight of androgen target organs. Prostate tumor growth rate was significantly retarded in rats treated with Anandron/Estradiol combination compared to untreated intact control and was equal to the slow growth rate in castrate tumor-bearing animals. Tumor histology changes during treatment correlated with the observed growth rate retardation. Areas of necrosis, metaplasia, and acellularity were more frequently observed in tumors of Anandron/Estradiol-treated compared to castrated rats. These results suggest that low doses of Anandron and estrogen can effectively be combined as a complete androgen counteracting therapy for hormone-dependent prostatic carcinoma with minimal undesired side effects.

A series of progesterone (P)-bovine serum albumin (BSA) conjugates were synthesized by precisely controlling the molar ratios in the reaction mixtures of hemisuccinyloxyprogesterone, isobutyl chloroformate, and BSA. P was conjugated to BSA via the 2α, 11α, or 21 positions. 17β-Estradiol (E2) was conjugated through a 6-carboxymethyloxime side chain to BSA. An additional series of steroid-BSA conjugates was prepared in which fluorescein was attached to the BSA portion. All of the conjugates were tested for binding to rabbit uterine cytoplasmic P and estrogen receptors using charcoal adsorption and sucrose density gradient techniques. P-BSA and E2-BSA conjugates compete against [3H]P and [3H]E2 for the appropriate receptor proteins, but hemisuccinyloxyprogesterones and 6-carboxymethyloximino- E2 do not compete against steroid hormones for the appropriate steroid receptors. 21-P-BSA in the P-BSA series shows the highest degree of competition against [3H]P for P receptor. The maximum competitive activity of 21...

The results of assay for estrogen receptor (ER) in the tumor cytosol and thymidine labeling indices (TLI) of 63 primary invasive carcinomas of the breast were analyzed. The ER assay was performed by using dextran-charcoal to adsorb unbound tritiated estradiol-17beta (E2) in cytosol. The TLI was measured as the number per hundred of neoplastic cell nuclei labeled by tritiated thymidine. A significant association between low TLI and presence of ER was found. Wereas all 19 tumors with TLI less than 2.5 contained ER in the primary lesion or in axillary metastases and ER was found in 25 of 30 tumors with TLI between 2.5 and 10, only 4 of 14 tumors with TLI greater 10 contained ER (p less than 0.001). TLI and saturable binding of E2 were significantly negatively correlated (r=-0.436,P. less than 0.001). It is concluded that dedifferentiation in breast carcinomas is associated with both high TLI and absence of ER, and suggested that the carcinomas with the most rapid proliferative rates will include the highest proportion of tumors unresponsive to hormonal therapy.

A virilizing granulosa cell tumor of the ovary contained large amounts of testosterone and progesterone and small amounts of estrogens. Assays for progesterone receptor were positive, but estrogen receptor could not be detected. The presence of progesterone receptor in the tumor is consistent with recent evidence for a role of the receptor in the physiology of the Graafian follicle, and suggests the possibility that progestational therapy may be effective in advanced stage granulosa cell tumor.

Coordinated estrogen- and progesterone-induced changes regulate biological functions of the endometrium. The uterine deciduoma reaction is used as a model in defining the mechanism of the progesterone-induced endometrial transformations. Uterine progesterone concentrations were determined by radioimmunoassay during three critical periods related to progesterone action: the preparatory period, the initiatory period, and the proliferative period. Tissue progesterone concentration significantly exceeded peripheral plasma concentration during the late afternoon of proestrus and in pseudopregnant animals on the day of maximal sensitivity to deciduoma induction. On the basis of the uterine progesterone concentration at the time of trauma, it was possible to predict whether or not decidualization would occur. Thus, substantiation was obtained for the existence of a specific uterine progesterone receptor, and its presence was related to prior exposure of the uterus to estradiol-17β. Summarized evidence for the existence of specific progesterone binding proteins in uterine tissue from several mammalian species, including the human being, shows a fair degree of uniformity in the properties of these binding proteins, e.g., tissue specificity, ligand specificity, and sensitivity to estrogen stimulation. Although some questions remain as to whether the effectiveness of progesterone therapy in endometrial adenocarcinoma can be considered as being proportional to the degree of resemblance of the cancer to normal endometrium, it is suggested that the possibility of such a relationship makes highly desirable the organization of programs designed to correlate the presence of progesterone receptor with progesterone responsiveness in these tumors.

Juvenile nasopharyngeal angiofibromas (JNA) are rare. They have been frequently treated with estrogens, either solely or as an adjuvant therapy prior to surgery or irradiation. Clinical trials have provided no evidence to explain the objective response to estrogens observed in some tumors. Since the mechanism of steroid hormone action is mediated via specific receptors, we analyzed 8 JNA for tumor cytosol estrogen receptors. None were positive for estrogen receptors. Additionally, all were also negative for progesterone receptors. Nasopharyngeal angiofibromas occur predominantly in adolescent boys at a time when there is a gradual change in androgen availability. Therefore, three latter angiofibromas were also analyzed for the presence of cytosol androgen receptor. Specific testosterone and dihydrotestosterone binding components in the tumor cytosol were detected. This observation raises for the first time the possibility that JNA may be an androgen-dependent tumor. Estrogen may act as an antiandrogen on these tumors, an action similar to that on prostate cancer. Cancer 46:547–551, 1980.

Biochemical study of fibroepithelial tumors of the female breast showed presence of progesterone receptor (PgR) in all five cystosarcoma phyllodes (two malignant, three benign), and in 11 of 13 fibroadenomas tested. Estrogen receptor (ER) was detected in only one of five cystosarcomas and 2 of 13 fibroadenomas. The relative volumes occupied by epithelium and stroma in each tumor were measured from histologic sections. The results were consistent with presence of PgR in the stroma and ER in the epithelium. Different types of cystosarcoma (benign and malignant) and different types of fibroadenomas (intracanalicular, pericanalicular, and mixed) did not differ significantly in content of PgR, and mean levels of PgR in cystosarcoma were comparable with those in fibroadenomas. The presence of PgR in cystosarcomas suggests that progestational therapy, and possibly other forms of hormonal therapy, should be tested in the treatment of advanced, malignant cystosarcoma phyllodes.

Primary renal adenocarcinoma tissue, metastatic deposits, and normal kidney parenchyma from 16 patients were assayed for sex hormone receptors by dextran-coated charcoal adsorption and sucrose gradient centrifugation techniques. Dihydrotestosterone receptors (DHTR) were found in all renal carcinomatous tissue (20/20) and in 93% (13/14) autologous normal kidneys analyzed. Testosterone receptors were found in 84% (16/19) of tumors and 93% (14/15) or normal kidneys analyzed. Estrogen receptors in small amounts (ER) were detected in only 5% (1/19) of tumors and in 7% (1/15) of normal kidneys. Progesterone receptors (PR) in low quantities were detected in 30% (6/20) of renal tumors and in 40% (6/15) of normal kidneys. DHTR levels in high-stage tumors (T3, T4) were significantly elevated over levels in autologous normal kidney, whereas in low-stage tumors localized to the kidney (T1 and T2 tumors) DHTR levels were not significantly different from autologous normal kidney. The mean levels of DHTR in high-stage kidney tumors were significantly elevated over levels in low-stage tumors (P less than 0.001). DHTR estimation in renal neoplasms may help in biologic staging of renal adenocarcinoma and could define a group of patients in whom anti-androgen therapy may be worth a trial.

Fluorescein conjugates to estradiol-17 beta by the sixth carbon (6-FE) and to estrone by the 17th carbon (17-FE) were used to detect estrogen receptors (ERs) in breast cancer tissue sections and in cultured cell lines (human mammary carcinoma MCF-7 and Copenhagen rat prostatic tumor R3327-AT). 17-FE was found to interact with ERs better than 6-FE by biochemical and histochemical techniques. Thin layer chromatography analysis of ethanolic extracts of 17-FE incorporated in tissues and cultured cells showed that over 95% of 17-FE was not metabolized. We concluded that the fluorescence observed in tissue sections and cultured cells was due to 17-FE and not to fluorescein dissociated from the conjugate. Analysis of 65 human breast cancer showed that 74% of the cases were positive for specific 17-FE uptake and 26% were negative. The fluorescence was consistently brighter in the ductal and glandular epithelial cells than in the stroma. specific 17-FE uptake in the nucleoli was observed in MCF-7 and in R3327-AT tumor cells in in vitro cultures, suggesting that these nucleolar estrogen receptors may play a key role in the mechanism of estrogen action. Problems of fluorescence quantitation in tissue sections and cells are discussed.

• A specific receptor for progesterone has been found in a cystosarcoma phyllodes, as determined by charcoal adsorption and sucrose gradient analysis. Similar assays for estrogen receptors were negative. The tumor consisted almost entirely of stroma that contained the progesterone receptors. The epidemiology and natural history of cystosarcoma do not strongly support the hypothesis that it is controlled by female sex hormones, but the presence of the progesterone receptors suggests that some cystosarcomas are hormonally regulated, and thus may be responsive to therapeutic hormonal manipulation. ( Arch Surg 112:620-622, 1977)

Anandron administration (300 mg/daily) to 16 human normal genetic male volunteers (who opted for male to female gender transformation) induced clinical signs of feminisation during 8 weeks of treatment. More than 2-fold increase in blood luteinising hormone and testosterone was measured while follicle stimulating hormone remained without any change in the levels. Prolactin showed a slight but significant increase at 8 weeks of treatment. The prostate size measured in 6 subjects using transrectal ultrasonography before and at 8 weeks of anandron treatment showed no change. The prostate size measured in 6 subjects who received androcur (100 mg/daily) in combination with ethinyl estradiol (100 micrograms/daily) for longer than 18 months did not differ compared to pre-treatment size. However, the prostate histology showed a clear predominance of stromal components with a significant reduction in the number of acini. The epithelial cells appeared atrophic. Histology of the testes showed a readily observable reduction in tubular and interstitial cells. The monodispersed cells prepared from the testes consisted of Leydig and non-Leydig cells. These cells responded to stimuli (hCG and Pregnenolone) in terms of an increase in testosterone synthesis in vitro. Anandron treatment of intact mature male rats increased the blood testosterone level. Estrogen administration dramatically reduced the anandron induced increase in testosterone to castration level. The benefits of a combination of low doses of anandron and estrogen for achieving an effective anti-androgenic action are presented.

A ligand-specific progesterone-binding protein which migrated in sucrose gradients, as a 4–5S complex, has been identified in endometrial cytosol. The association constant (Ka) for progesterone binding to cytosol protein was estimated at 1.2–3.4 i 109 M

Sucrose gradient centrifugation, gel nitration, and charcoal adsorption techniques have been used successfully to isolate and partially characterize progesterone—binding proteins from rabbit uterine cytosol and nuclei. Dissociability in high ionic strength buffers and precipitability in 30% saturated ammonium sulfate differentiated the cytosol binding component from a CBG—like binding protein present in rabbit serum. Progesterone was bound to a 4S complex in uterine cytosol following injection of 3H—progesterone to castrate rabbits; hormone binding increased quantitatively after pretreatment of castrate animals with estradiol– 17β and a qualitative change in the binding pattern became apparent with the appearance of an 8S binding complex in addition to the 4S unit. 0.4M KC1 extraction of the nuclear pellet obtained from estrogen—treated castrates yielded only a 4S binding component. Rabbit uterine cytosol prepared from either castrate or estrogen—treated animals in vitro, when equilibrated with 3Hprogeste...