G. Concolino

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.

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.

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.

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.

Human kidney steroid receptors

Abstract Saturation analyses, binding kinetics and agar gel electrophoresis performed on normal human kidney tissue revealed the presence of a specific progesterone receptor in all the specimens studied and in one, a specific estradiol receptor was observed, Progesterone binding had a rapid association and a slow dissociation reaction. The binding capacity for estradiol and progesterone was not significantly different, whereas the binding affinity for progesterone was lower than that for estradiol. These results on progesterone receptors in the cytosol of normal human kidney tissue offer an interesting field of investigation considering the estrogen-induced renal adenocarcinoma in animals and the possibility of progestational therapy for tumour regression in humans.

Progestational therapy in human renal carcinoma and steroid receptors

Abstract Normal human kidney and human renal adenocarcinoma have been studied for progesterone and estradiol receptors by means of agar gel electrophoresis technique. Progesterone receptor was found in the eytosol fraction of all the normal kidneys and of the adenocarcinoma studied, while estradiol cytosol receptor was found only in some of the tissues examined. No correlation between the degree of the differentiation of the tumours and the progesterone binding capacity has been detected. Furthermore the binding affinity for estradiol was greater than that for progesterone. The low affinity of progesterone receptor could explain the large mass (pharmacological doses) of progesterone needed to obtain a marked tumour regression as well as a favorable effect on the clinical course of the advanced renal cancer. Like human breast cancer, responsive to endocrine ablation when both estradiol and progesterone receptors are present, it could be hypothesized that progestational therapy may be useful in the treatment of renal adenocarcinoma in which both estradiol and progesterone receptors are present.

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 androgen receptor as marker of responsiveness to medroxyprogesterone acetate in human renal cell carcinoma

Abstract The presence of steroid receptors in human renal cell carcinoma (RCC) has been reported by many authors. However some controversy exists regarding the response of human RCC to medroxyprogesterone acetate (MPA). The hypothesis that the MPA effect on tumor growth might be due to the androgenic action of the progestin was suggested since 1976. Based on the recent report that in mouse kidney the androgenic action of progestins correlates with nuclear uptake but not with cytosol androgen receptor (AR c ), 24 human RCC were studied for the presence of AR c and 14 for the presence of AR c and nuclear androgen receptor (AR n ) in order to establish a parameter more suitable to define the tumor responsiveness to MPA. Tritiated methyltrienolone (R1881) plus cold triamcinolone acetonide and R1881 was employed with the dextran-coated charcoal method. AR c was detected in 19 out of 38 (50%) and AR n in 8 out of 14 (57%) of the tumors examined. Therefore androgen receptors not only help to define, with estrogen and progesterone receptors, the hormone-dependent human RCC, but may also be useful in the selection of patients to be treated with MPA. In fact, the androgenic activity of MPA could counteract the promoting action of estrogens on tumor growth only in the patients with AR n positive tumor.

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.