Downregulation of androgen, estrogen and progesterone receptor genes and protein is involved in aging-related erectile dysfunction

We hypothesize that downregulation of sex hormone receptors (androgen, estrogen and progesterone receptors) is involved in aging-related erectile dysfunction. To test this hypothesis, we investigated the expression of sex hormone receptors in penile crura of aging rats. A total of 40 rats were divided into four groups based on age (6, 12, 18 and 24 months), and the erectile function was analyzed by the measurement of intracavernous pressure. Gene and protein expressions of sex hormone receptors were analyzed by RT-PCR and immunostaining, respectively. The mean intracavernous pressures of 6-, 12-, 18- and 24-month-old rats were 110.1, 89.6, 73.5 and 42.7 cm H(2)O, respectively. Gene and protein expressions for androgen receptor, estrogen receptor-beta and progesterone receptor were present in similar levels in 6-, 12- and 18-month-old rat crura, but significantly lower or absent in 24-month-old crura. This is the first study to demonstrate that downregulation of sex hormone receptors in aging rat crura is associated with erectile dysfunction.     

HORMONE RECEPTORS IN MALE BREAST CANCER

Hormone receptor assays were performed on specimens of breast cancer from 19 male patients over a six year period. Ninety-four per cent were positive for oestrogen receptor, 93% for progesterone receptor and 57% for androgen receptor. Eight patients had hormonal treatment for advanced disease and five (62.5%) responded. Duration of response ranged from six months to 23 months. There appeared to be no clear relationship between hormone receptor status or quantitative receptor level and response to treatment in this small series. It is unlikely that oestrogen and progesterone receptors will be of value as discriminators because of their high incidence and it is suggested that further study of androgen receptor is indicated.     

Steroid receptors in human brain and spinal cord tumors

Previous investigators have shown evidence of hormonal receptor protein in human brain tumors. In spite of conflicting results, antiestrogen agents (e.g., tamoxifen) have been used in clinical trials of recurrent unresectable meningiomas. In an effort to accrue further comprehensive in vitro data on this subject, we have evaluated 50 human brain and spinal tumors for estrogen, progesterone, and androgen receptor markers. Twenty-nine of the 50 tumors were meningiomas. The other 21 included 11 gliomas of various grades, 5 schwannomas, 3 metastatic carcinomas, 1 angiofibroma, and 1 craniopharyngioma. Only 8 tumors, all meningiomas, were positive for both progesterone and androgen receptors. The 8th tumor was positive for all three receptor proteins. Our study did not find a significant relationship between meningiomas and the presence of steroid receptor protein. We conclude that the use of antiestrogen agents is not indicated in the treatment of meningioma. No significant relationship to sex, menopausal status, tumor type, or tumor location was observed.     

Location and concentration of estrogen,progesterone, and androgen receptors in the bladder and urethra of the rabbit

The objective of this study was to determine location and concentration of estrogen, androgen and progesterone receptors in the bladder and urethra of the rabbit. Two urethral and two bladder specimens were obtained from four 12-week-old female New Zealand white rabbits. Rat monoclonal antibody (AN 1–15) to human androgcn receptor and (H222) to human estrogen receptor and mouse monoclonal antibody (PR6) to chicken progesterone receptor were used. Immunocytochemical staining was performed and specimens were evaluated lor presence and location of steroid receptors. Androgen receptors were found in the highest concentrations in urethral and bladder epithelium. Low to low/moderate concentration were found in smooth muscle. Estrogen receptors were found in moderate to moderate/high concentrations in urethral epithelium and bladder and urethral smooth muscle. Progesterone receptors were not found in appreciable concentrations from any location, though the animals were not pretreated with estrogen. The rabbit model suggests a mechanism by which estrogen therapy can be effective in treating postmenopausal lower urinary tract symptoms. Progesterone receptors were not found in appreciable concentrations, suggesting progesterone therapy may not diminish the effectiveness of estrogen therapy by acting on urethral progesterone receptors. The effect of androgcns on the lower urinary tract needs further investigation to determine if androgen therapy can alleviate lower urinary tract symptoms. © 1995 Wiley-Liss, Inc.     

Elucidation of a Role for Stromal Steroid Hormone Receptors in Mammary Gland Growth and Development Using Tissue Recombinants

The use of tissue recombinants in conjunction with steroid receptor deficient mice is described as a tool to dissect the complex paracrine pathways of sex-hormone-regulated epithelial growth and ductal morphogenesis in the mammary gland and other hormone target organs. The basic methodology involves the construction of the four possible tissue recombinants composed of epithelium (E)⁶ and stroma (S) from wild-type (wt) and knock-out (KO) mice: wt-S + wt-S, wt-S + KO-E, KO-S + KO-E, and KO-S + wt-E. All tissue recombinants are grown as subrenal capsule grafts in nude mice. Following appropriate hormonal challenge epithelial growth can be studied in the four types of tissue recombinants. Such studies using estrogen receptor, androgen receptor and progesterone receptor knockout mice demonstrate that epithelial steroid receptors are neither necessary nor sufficient for hormonal regulation of epithelial proliferation. Instead, hormonal regulation of epithelial proliferation is a paracrine event mediated by hormone-receptor-positive stromal cells.     

Steroid hormone receptors in laryngeal carcinoma

The larynx has long been shown to be a target organ for androgenic steroids in both women and men, and specific androgen receptors have been determined in normal laryngeal mucosa and in laryngeal carcinoma tissue. In this study, samples from 21 primary laryngeal carcinomas, from 4 recurrent laryngeal carcinomas and from 1 cervical metastasis of laryngeal carcinoma were obtained at the time of surgery to assay specific androgen, estrogen, and progesterone receptors. Specific androgen receptors were found in 8 samples (31%). The level of receptors varied from 1.7 femtomoles (fmol) per milligram to 7.3 fmol/mg cytosol protein. Detectable levels of specific estrogen receptors were found in 18 samples (69%) and progesterone receptors in 8 of the 15 samples studied (53%). There was no apparent correspondence with donors' sex, since samples from both females and males contained all kinds of receptors. We know that antiestrogen inhibits the growth of squamous carcinoma cells lines positive for estrogen receptors in vitro and that this effect is reversible with the appropriate hormone. Thus, the relatively high percentage of estrogen and progesterone receptors found in laryngeal carcinoma tissue may open new aspects in the treatment of laryngeal carcinoma with antihormones.     

Correlation of meningioma hormone receptor status with hormone sensitivity in a tumor stem-cell assay

Several investigators have detected progesterone receptors in a high percentage of meningioma specimens and have noted progesterone receptors to be more common than estrogen receptors in these specimens. However, a functional significance of such hormone receptor positivity in control of meningioma growth has not been described. This paper describes a paired test of the estrogen and progesterone receptor assay as the biochemical assay and of the human tumor stem-cell clonogenic assay (HTSCCA) as the functional assay in 17 meningioma specimens. Only one (6%) of the 17 specimens was estrogen receptor-positive, while 11 (69%) of 16 specimens were progesterone receptor-positive. The HTSCCA revealed that only two (15%) of 13 specimens were sensitive to estradiol while five (31%) of 16 specimens were sensitive to progesterone. Comparison of progesterone results for the 15 specimens on which both hormone receptor assay and HTSCCA were performed revealed correlation in a majority of cases; four specimens were positive for both assays and five specimens were negative for both assays. No specimen that was negative for progesterone receptors was sensitive to progesterone by HTSCCA. These results suggest that the hormone receptor and sensitivity pattern of meningiomas may differ from that of breast cancer, and that progesterone addition or ablation may be a reasonable therapeutic approach for meningiomas.     

Lability of steroid hormone receptors following devascularization of breast tumors

Ischemia may invalidate hormone-receptor analyses. This study determined the effects of progressive ischemia on steroid hormone-receptor analyses. Breast cancer was induced in 50- to 60-day-old female Holtzman rats by intragastric administration of 25 mg of 7,12-dimethylbenz[a]anthracene. After 90 days, rats were anesthetized and breast tumors were devascularized in vivo. At 0, 30, 60, 90 and 150 minutes, a biopsy specimen from each tumor was taken and rapidly frozen. Steroid binding capacity for estrogen (ER), progesterone (PR), and androgen (AR) receptors was determined by incubation with tracer receptor ligand. Ischemia decreased ER and AR levels by 30 minutes, whereas PR levels were unchanged through 150 minutes of ischemia. Following mastectomy, tylectomy, or breast biopsy, PR may be the most reliable of the hormone receptors for determining endocrine-responsive breast cancer. However, for accurate determination of all hormone receptors, specimens should be frozen in liquid nitrogen immediately, then preserved at -70 degrees C, or processed immediately.     

Androgen receptor-mediated growth and epidermal growth factor receptor induction in the human prostate cell line LNCaP

Human prostate tumor cells, LNCaP, contain androgen receptors and respond to androgens with increased growth rate. Although other steroid hormone receptors are not detectable in LNCaP cells, progesterone and estradiol stimulate the growth of these cells. The androgen receptor shows considerable cross binding activity with progesterone and estradiol but not with the glucocorticoid triamcinolone acetonide. The latter steroid does not have any effect on cell proliferation. LNCaP cells respond to epidermal growth factor (EGF) with an increased growth rate. Steroids that stimulate LNCaP cell proliferation also increase the number of EGF receptors per cell. In conclusion, LNCaP cells are sensitive to EGF. Different steroids bind to the androgen receptor and stimulate the proliferation of human prostate tumor cells. This stimulation of growth is preceded by an increase in EGF receptor number per cell.     

Progesterone receptor in cystosarcoma phyllodes.

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.     

Loss of hormonal receptors expression from primary breast carcinoma to axillary lymph node metastases

Breast tumors growth is regulated by female sex steroid hormones. The level of the estrogen and progesterone receptors (ER and PR) expression by the malignant cells is important for the evaluation of the tumor prognostic and the benefit of a hormonal therapy. The aim of our study was to identify the expression of estrogen and progesterone receptors in primary breast tumors and in the corresponding axillary lymph nodes metastases, in 24 cases. The results showed that more than 30% of poorly differentiated breast carcinomas lost their expression of hormone receptors from the primary tumors to axillary metastases, an event which can be associated with an aggressive tumoral behaviour and resistance to hormonal therapy.     

Primary, nonviral, hepatocellular carcinoma in patients with prostate cancer treated by hormone therapy: 2 case reports

We studied two cases of primary, hepatocellular carcinoma (HCC) that occurred following hormone therapy (estrogen therapy in one case and total androgen blockade therapy in another) for stage D2 prostate cancer. Prostate cancer is considered to be hormone-dependent, and androgens appear to be important hormonal factors. However, hepatocellular carcinoma has been shown to have both estrogen and androgen receptors, suggesting that this may be dependent on estrogen or androgen. Reported here are two unique cases of hepatocellular carcinoma in patients with prostate cancer; the pathogenesis of HCC in these patients was suspected to be related to diethylstilbestrol (DES) therapy and antiandrogen therapy for their prostate cancer.     

Steroid receptor profile in human prostate cancer metastases as compared with primary prostatic carcinoma

The steroid receptor profile in seven prostate cancer metastases was compared with the profile in seven primary prostate cancers. The secondaries were all lymph node metastases, obtained during pelvic lymphadenectomy, preceding radical prostatectomy or irradiation. Cytosol androgen receptor content was higher in metastases, whereas the nuclear androgen receptor content was only one-fourth that in primary cancer. Cytosol progesterone as well as estrogen receptor contents were markedly lower in metastases compared with primary cancer. The steroid receptor profile differed very little between primary cancer and normal tissue. Primary prostatic carcinoma is usually obtained at early stages of the disease, whereas metastases represent a dedifferentiated, more aggressive cell population. This may explain the low amounts of progesterone, estrogen, and nuclear androgen receptor levels. The total androgen receptor content was similar in metastatic and primary disease, however, with a shift towards a cytosolic predominance in metastases. Possibly androgen receptors in metastatic disease are "deactivated."     

Estrogen and progesterone receptors in normal and varicose saphenous veins.

The presence of estrogen and progesterone receptors was investigated in the walls of normal and varicose veins. Cryostat sections from the saphenous veins of 29 normal individuals, and varicose and normal vein segments of 32 patients with varicose veins, were stained with anti-estrogen or anti-progesterone receptor antibodies. Nuclear stain intensity was scored by three independent observers. Receptors to both hormones were detected in the nuclear regions of the intima and media in females and males. In the adventitia, estrogen and the progesterone receptors were found only in nuclei of the vasa vasorum. Estrogen receptor levels were lower in non-varicose segments of varicose veins compared with normal veins. In varicose segments, estrogen receptors were more abundant than in the non-varicose parts of the same vein, especially in females. Similarly, progesterone receptor levels in the non-varicose portions were higher in females. These gender differences may be related to hormonal action. However, these differences may also be age related. These findings may be related to the involvement of sex-hormones in varicosis, by mechanisms as yet unknown.     

A case of multiple leiomyomatous lesions of the lung: An analysis of flowcytometry and hormone receptors

A 36 year old woman was admitted to our department because of a chest X-ray which showed multiple developing shadows. She underwent bilateral exploratory thoracotomies and a total 5 tumors were resected and pathologically diagnosed as benign metastasizing leiomyoma, the largest of which was positive for the progesterone receptor and negative for the estrogen receptor. A histogram of this tumor using a flow cytometer showed a diploid pattern and 4.6 percent of the S phase which was not more than that of a leiomyoma of the uterus from another patient. Two months later, she underwent a hysterectomy and bilateral salpingo-oophorectomy for treatment of the positive progesterone receptor in the pulmonary lesions. The resected uterine myoma and normal myometrium showed positive estrogen and progesterone receptors. For the subsequent 28 months she has been free of any further symptoms. Benign metastasizing leiomyoma of the uterus is a rare disease and very interesting because of its histological benignity and hormonal dependency. However, according to the literature, it is often confused in entity due to the fact that normal lung tissue also possesses hormone receptors. Considering our data on hormone receptors, it is rational to think that multiple leiomyomatous lesions in the lung should only be diagnosed as benign metastasizing leiomyomas when they possess positive estrogen and progesterone receptors.     

Value of measuring hormone receptor levels of regional metastatic carcinoma of the breast

To assess the value of measuring the estrogen- and progesterone-receptor content of metastatic nodal disease, 38 women with node-positive breast cancer were prospectively evaluated. Receptor content of the primary tumor and a pathologically confirmed positive node were measured simultaneously using a dual-isotope, dextran-coated, charcoal-binding assay. A receptor content of greater than or equal to 10 fmol/mg of cytosol protein was considered positive for both the estrogen-receptor and progesterone-receptor assays. Overall concordance between the primary tumors and the nodal metastases was 82% (31/38 patients) for the estrogen-receptor measurements and 84% (31/37 patients) for the progesterone-receptor measurements. Paired receptor levels were significantly correlated: r = .745 for the estrogen-receptor measurements and r = .805 for the progesterone-receptor measurements. Despite this correlation, 6 (25%) of 24 patients with an estrogen receptor-positive primary tumor had an estrogen receptor-negative nodal metastasis. Four (20%) of 20 patients with a progesterone receptor-positive primary tumor had a progesterone receptor-negative nodal metastasis. Six (24%) of 25 patients with tumors labeled as hormonally sensitive on the basis of the receptor content of the primary tumor had receptor-negative nodal disease. In reflecting the hormonal status of the more aggressive elements of the primary tumor, receptor levels of metastatic nodes may provide more useful information than the levels of the primary tumor as a guideline for further therapy.     

Androgen receptor binding activity in meningiomas

Analyses of androgen receptor binding activity in 54 intracranial, intraspinal, and metastatic meningiomas were performed with a specific radioligand binding technique using [3H]R 1881 as radioligand. [3H]R 5020 was used for the concurrent determination of progesterone receptor binding activity. Moderate concentrations of androgen receptors (33.4 +/- 5.4 fmol/mg protein) were detected in 35 (65%), whereas high levels of progesterone binding components (236 +/- 35 fmol/mg protein) were demonstrated in 48 (89%) tumors. The androgen receptor binding activity was positively correlated with the progesterone receptor binding activity (rs = 0.38, p less than 0.05). This relationship is suggestive of an androgen regulation of the progesterone receptor via the androgen receptor system. The presence of androgen and progesterone receptors in a large proportion of meningiomas, and the tendency for a dependence of androgen receptor and progesterone receptor binding activity on the histological subtype could have implications for tumor therapy.     

Osteoclasts isolated from membranous bone in children exhibit nuclear estrogen and progesterone receptors

Osteoclasts were isolated from membranous bone from four children without metabolic bone disease who were undergoing craniotomy for either tumor or trauma. Both freshly isolated osteoclasts and those cultured for 4-7 days exhibited the following characteristics: production of tartrate-resistant acid phosphatase (9.5-14.8 units), contraction in response to application of 100 mg/ml of human calcitonin, and formation of resorption lacunae on devitalized bone wafers. Nuclear estrogen and progesterone receptors were demonstrated by immunohistochemical techniques and quantitated in two of the patients by radioimmunoassay (estrogen receptor RIA, 23.6 and 23.8 cpm/micrograms protein; progesterone receptor RIA, 36.7 and 74.2 cpm/micrograms protein). The demonstration of sex steroid hormone receptors in the nucleus of osteoclasts derived from children with normal membranous bone has established a potential mechanism whereby direct modulation of bone resorption by the sex steroid estrogen and progesterone may occur.     

Hormone receptor in renal cell carcinoma and correlation with clinical response to endocrine therapy

Analyses of hormone receptors in cytosols from 41 renal cell carcinoma specimens were performed by the dextran-coated charcoal technique, using estradiol, synthetic progestin R5020 and synthetic androgen R1881. Binding data were calculated according to the method of Scatchard. Of 41 renal cell carcinomas estradiol receptor was detected in 11, R5020 receptor in 11 and R1881 receptor in 13. No significant correlation between histopathological findings and hormone receptors was observed. Patients were classified into those positive and negative for receptors. The clinical response of endocrine therapy for 17 with advanced residual or metastatic lesions after nephrectomy was studied in regard to the survival rates. Although there was no complete or partial regression in tumor size, the survival rate of patients with 1 or more receptors was significantly higher than that of patients negative for receptors (p less than 0.01). In conclusion, hormonal manipulation in patients with renal cell carcinoma cannot induce an antitumor effect but seems to increase survival in patients with receptors.     

Aggressive angiomyxoma in the scrotum expressing androgen and progesterone receptors

Aggressive angiomyxoma is a rare benign mesenchymal myxoid tumor that arises from the pelvic soft tissues and perineum in relatively young females. This tumor has the ability to infiltrate locally and has a high risk of local recurrence after extirpation, but no potential to metastasize. We report here a rare case of aggressive angiomyxoma that developed in the scrotum of a 47-year-old male. Immunostaining of the resected specimen revealed that the tumor cell nuclei stained strongly and diffusely for androgen receptors (80% of the tumor cells), and moderately and partly for progesterone receptors (20% of the tumor cells). However, staining was negative for estrogen receptors. It is highly suggested that the growth of aggressive angiomyxoma in males may depend on androgen manipulation, contrary to its frequent and close association with estrogen receptor expression, which has been reported in females.