Acquired cystic kidney disease: the hormonal hypothesis.

Based on the reported sex difference in the incidence of acquired cystic kidney disease (ACKD) in patients with chronic renal failure, it is hypothesized that the hormonal derangement, well documented in male and female uremic patients on long-term dialysis, could be responsible for the pathogenesis of ACKD. The decreased androgen/estrogen ratio, and the increased estrogen value could be responsible for an estrogen receptor mediated effect on the tubular epithelial cell proliferation, an event further potentiated by the action of regulatory peptides like epidermal growth factor (EGF). The epithelial stimulation is more pronounced in men because male tissues are less adapted than female tissues to high estrogen values. Furthermore the androgen reduction, more remarkable in male than female patients, is responsible for an up-regulation of EGF-R. Therefore hormones and growth factors, by means of their own receptor in renal tissue (homologous to the two oncogenes c-erb A and c-erb B), may be responsible for the development of ACKD, and may play an important role in the pathogenesis of multiple adenomas and renal carcinomas reported with high incidence among uremic patients with ACKD.

Sex steroid hormones in the pathogenesis of chronic subdural haematoma.

In order to verify whether hormonal factors could be involved in the pathogenesis of Chronic Subdural Haematoma (CSDH), based on clinical and epidemiological demonstration of higher incidence of this disease in male patients and particularly in those with high urinary estrogen values, Estradiol (ER) and Progesterone (PR) Receptors were studied in the Haematoma External Membrane (HEM) in 18 male and 7 female CSDH patients. The observed higher incidence of ER and PR in male rather than in female patients (73% vs 27% and 72% vs 28% for male and female patients respectively), and the higher concentration of ER in the HEM of male rather then female patients (55 +/- 15 S.E. vs 13 +/- 7 S.E. fmol/mg protein) suggest that this pathological process, which affects individuals whose gonadal activity is quiescent, is mainly dependent upon hormonal local effect played by estrogen compounds on the HEM of the male patients. In this sex, in fact, whose tissues are not usually adapted to an estrogen action, the effect of estrogens on a responsive tissue such as the newly-vascularized HEM could lead to an increased formation of tissue Plasminogen Activator (t-PA), a compound that, escaping into the subdural collection, could maintain a local hyperfibrinolysis with formation of Fibrinogen Degradation Products (FDP). Therefore local hyperfibrinolysis enhanced by steroid hormones and the subsequent CSDH may perhaps be influenced by the prophylactic or adjuvant treatment with inhibitors either of the aromatase activity or of the estrogen action at receptor level.

Antiandrogens: clinical applications.

Antiandrogens, preventing androgen action at target tissue level, are used in the treatment of various androgen-dependent diseases. Pharmacologically these substances have either a steroidal structure, like cyproterone acetate (CPA) and spironolactone (SPL), or a non-steroidal structure, like flutamide (FLU). In women with hyperandrogenism (PCO syndrome, idiopathic hirsutism, acne), clinical benefit may be obtained with CPA, which also displays a progestational activity and an antigonadotropic effect. CPA (25-50 mg/day) is used in combination with ethinyl-estradiol (EE) (20-30 micrograms/day) in reversed sequential regimen. SPL, less effective than CPA may be employed in moderate hirsutism and acne at dosages of 100-200 mg/day. During SPL treatment menstrual irregularities are frequent: in this case an association with oral contraceptives is indicated. SPL + bromocriptine (2.5-5 mg/day) has been experienced with success in PCO syndrome. The pure antiandrogen FLU, inducing progressive increase in LH and testosterone secretion, may be used only in combination with oral contraceptives. In men antiandrogens have been tested in BPH and prostatic carcinoma. In BPH the decrease in nuclear receptors and DHT nuclear content during CPA or FLU may represent the rational base of the medical treatment. An improvement in urinary obstructive manifestation has been observed with CPA alone or associated with tamoxifen (100 mg + 100 mg day). In advanced prostatic carcinoma antiandrogens represent a good alternative to estrogen therapy with less side effects and in combination with surgical or medical castration (LH-RH analogues) achieve a complete androgen blockade. An increase in the percentage of remissions and survival has been reported.

Epidermal growth factor binding and steroid receptor content in human benign prostatic hyperplasia.

The receptor for epidermal growth factor (EGF-R) was characterized on membrane fractions from human benign prostatic hyperplasia (BPH). Specific binding of [125I]EGF reached equilibrium after 40 min at 25 degrees C and was stable for up to 120 min. Saturation analysis of EGF-R, performed by incubating the membranes with 0.0156-15 nM [125I]EGF in the presence and in the absence of 100-fold excess of cold EGF for 60 min, revealed the presence of two classes of binding sites with high and low affinities (Kd = 0.35 +/- 0.23 and 9.60 +/- 2.87 nM respectively). Competition experiments revealed that FSH, insulin and calcitonin did not compete with [125I]EGF. The simultaneous determination of EGF-R and that of estradiol (ER), progesterone (PR) and androgen receptors (AR) was performed using the same buffer to homogenate the tissues and to obtain cellular membranes. The steroid receptors (SR) were determined by means of the dextran-coated charcoal method. There was a significant negative correlation between nuclear SR and binding capacity of EGF-R. The presence of specific and high affinity binding sites for EGF and the modulation of the level of these sites by steroid receptors suggest a possible role of EGF in prostatic hyperplasia.

Effects of two different medical treatments on dihydrotestosterone content and androgen receptors in human benign prostatic hyperplasia.

In order to evaluate the biochemical modifications induced by hormonal treatments on human prostatic tissue, the intracellular distribution of tissue DHT and AR were investigated in BPH patients untreated and treated (25-30 days before surgery) with the association of cyproterone acetate (CPA), 100 mg p.o./day plus tamoxifen (TAM), 100 mg p.o./day, or with flutamide (FLU) alone, 750 mg p.o./day. Dextran-coated charcoal and exchange assay in the presence of sodium molybdates (0.2 M) were used for AR determination, employing methyltrienolone as radioligand in the presence of triamcinolone acetonide. Endogenous DHT was measured by RIA, after ether extraction and purification on celite microcolumns. The treatment with CPA plus TAM led to a detection of cytosol AR (ARc) in 50% of the specimens, while nuclear AR (ARn) were never measurable. The FLU treatment did not modify the incidence of ARc, while ARn was not detectable. The cytosolic and nuclear compartmentalization of DHT was scarcely affected by the combined CPA plus TAM treatment, while FLU treatment induced a prevalent cytosolic localization of DHT (DHTc = 283.2 +/- 24.6 S.E. and DHTn = 1138.4 +/- 98.7 S.E. pg/mg DNA in untreated patients; DHTc = 350.4 +/- 97.7 S.E. and DHTn = 589.7 +/- 154.4 S.E. pg/mg DNA in CPA plus TAM treated patients; DHTc = 1101.7 +/- 165.7 S.E. and DHTn = 733.0 +/- 93.9 S.E. pg/mg DNA in FLU treated patients). Both medical treatments, therefore, were able to reduce prostatic growth on account of the reduced value of nuclear DHT content.

Nuclear steroid receptors and dysplasia in adenomatous polyps of the colon as markers of high risk for malignant transformation.

To detect an early colon carcinoma in its stage of carcinoma in situ, colonoscopic examinations with removal of all adenomas of the left colon (particularly of the sigmoid tract and rectum), followed by histological and biochemical evaluations, have been performed on 30 patients. Two-thirds of the adenomas examined presented histological patterns of tubular, tubulovillous, and villous adenomas; those with moderate or severe dysplasia were at high risk of neoplastic transformation. Measurement of estradiol (ER) and progesterone (PR) receptors was performed in the cytosol and in the nuclei of solitary and multiple adenomas and in those with synchronous carcinomas using the dextran-coated-charcoal (DCC) method. Steroid receptors were usually found in the cytosol of the large polyps of male rather than female patients (46% vs 11%) and in the cytosol of the adenomas with moderate or severe dysplasia in male patients. Malignant lesions usually possessed both ER and PR in the cytosol and nuclear fraction. These findings led to hypothesize that patients with adenomas of the colorectal tract with moderate or severe dysplasia and nuclear steroid receptors should be considered at high risk for colon carcinoma and therefore need a special follow-up program.

Hormones and tumours in central nervous system (CNS): steroid receptors in primary spinal cord tumours.

On the basis of the studies reported on steroid receptors in brain tumours, cytoplasmic and nuclear estrogen (ER) and progesterone (PR) receptors have been examined in forty primary spinal cord tumours: fifteen neurinomas, three neurofibromas, nine meningiomas, nine ependymomas, two astrocytomas, one oligodendroglioma and one hemangiopericytoma with the exchange method in the presence of sodium thiocyanate for ER and using the synthetic progestin R5020 for PR. Regardless the type of the tumour, ER have been detected with a higher incidence in male than in female patients (78% versus 59%). PR had the same incidence in male and in female patients. The neurinoma was the oncotype more constantly provided with steroid receptors: nuclear ER, in fact, has been found with an incidence of 75% in male and of 43% in female patients. This oncotype is usually provided in both sexes with PR. Ependymomas is spinal tumour with the highest incidence of cytosol ER both in male and in female patients. On the basis of the above results reported it can be assumed that hormonal factors might be involved in the occurrence as well as in the growth of spinal cord tumours. Therefore it can be hypothesized that hormonal treatment might favourably be used as an adjuvant therapy in some selected patients with receptor positive spinal tumours.

Steroid receptors in CNS: estradiol(ER) and progesterone(PR) receptors in human spinal cord tumors.

To investigate the role of steroid hormones in the occurrence and growth of human spinal cord tumors and to study the biochemical basis of the sex related difference in the incidence of the various spinal oncotypes, ER and PR have been measured in 24 human spinal cord tumors (12 neurinomas, 6 meningiomas, 5 ependymomas and 1 astrocytoma) by means of sodium thiocyanate exchange assay at low temperature and with dextran-coated charcoal method and R5020 for PR. Cytoplasmic and nuclear receptors have been evaluated. Neurinomas are the oncotypes which contained both ER (usually in the nuclear fraction) adn PR: estradiol binding has been found only in one meningioma; ependymomas contained cytoplasmic ER and the astrocytoma had nuclear ER and cytoplasmic PR. The dissociation constant is in favour of a high affinity binding (Kd = 0.15 X 10(-9)M for ERc; Kd = 3.85 X 10(-9)M for ERn; Kd = 8.07 X 10(-9)M for PRc). The overall incidence of steroid receptors in the spinal oncotypes studied is higher in male than in female patients (63.64 vs 46.15% for ER and 100 vs 71.43% for PR). Further studies on a greater number of patients will help to define the correlation between different spinal oncotypes and steroid receptors as well as the possibility of an endocrine therapy as adjuvant treatment for selected patients.

Steroid receptors in the pathogenesis of chronic subdural hematoma.

Chronic subdural hematoma (CSDH), located between the dura mater and the arachnoid and usually characterized by a well-vascularized external capsule (HEM), has a higher incidence in male patients with elevated urinary estrogens than in female patients. In an attempt to increase our understanding of the physiopathogenesis of CSDH, total estrogen receptor (ER) was measured in HEM specimens from four male patients by a sodium thiocyanate exchange assay and cytosol progesterone receptor (PRc) in three specimens by a dextran-coated charcoal adsorption assay. Although no nuclear ER could be detected, ERc and PRc were found in all three specimens examined. The presence of ER in a mesenchymal tissue like HEM could suggest that, in addition to inducing vascular changes, estrogens might act directly on HEM through a receptor-mediated mechanism more pronounced in men than in women, whose vascular network is adapted to high estrogen values.

Results of the Italian interlaboratory quality control program for estradiol receptor assay.

This article presents results of the first Italian quality control program for determining the estradiol receptor on lypophilized guinea pig and calf uteri. Despite considerable variability in quantitative terms, the results concur in ability to define samples as positive or negative for receptor content. One of the parameters that most strongly influences accuracy of determination of receptor concentration is protein assay. The evaluation of several lyophilized preparations at scalar concentrations permitted identification, by linear regression, for each laboratory of the systematic and non-systematic variables. More comparable results will be forthcoming when a standardized methodology program has been fully adopted.

[the oral use of a progestational hormone (Provera 100) as an adjuvant in therapy of adenocarcinoma of the kidney. Preliminary report]. / L'impiego di un progestinico per via orale (Provera 100) come coadiuvante nella terapia dell'adenocarcinoma del rene. Rapporto preliminare.

PIP: The article reports on the positive results obtained with oral treatment of medoxyprogesterone acetate in the therapy of renal adenocarcinoma, whether it is, or it is not, caused by oral contraception. In all cases examined Provera resulted to be an important coadjuvant of surgical treatment. No side effects were reported; it is very important to consider this form of therapy whenever hormonal receptors are present.^ieng

Renal cancer steroid receptors: biochemical basis for endocrine therapy.

Estradiol receptor (ER) and progesterone receptor (PR), found in experimental renal cancer as well as in normal human kidney and in human renal cell carcinoma (RCC), have been measured in 27 RCCs from patients submitted to surgery and endocrine therapy in an attempt to predict the response to progestational therapy. Of these 27 tumors 59% were positive for ER and 59% for PR; 37% were positive and 19% negative for both ER and PR. The follow-up of 23 patients showed that progestational therapy, started in 18 patients, has given favorable results in 14 patients and negative results in 3 patients with ER-PR- renal cancer. Antiestrogenic therapy, started soon after nephrectomy in 1 patient with ER+PR- renal cancer and lung metastases, failed since the patient died 8 months after surgery.

Renal cancer steroid receptors: biochemical basis for endocrine therapy.

The hypothesis of hormone dependence of human renal cancer, based on experimental and clinical data, has recently been supported by estradiol-receptor (ER) and progesterone-receptor (PR) studies. ER and PR, found in experimental renal cancer as well as in normal human kidney and in human renal cell carcinoma (RCC), have been measured in 27 RCCs from patients submitted to surgery and endocrine therapy, in an attempt to predict the response to progestational therapy . Of these 27 tumors, 59% were positive for ER and 59% for PR; 37% were positive and 19% were negative for both ER and PR. The follow-up of 23 patients so far investigated showed that progestational therapy, commenced in 18 patients, has given favorable results in 14 patients and negative results in 3 patients with ER-PR- renal cancer. Antiestrogenic therapy, started after nephrectomy in 1 patient with ER+PR- renal cancer and lung metastases, failed since the patient died 8 months after surgery.