Method of prevention of benign prostatic hyperplasia (bph) in men with partial age-related androgen deficiency (padam)

 

(57) Abstract:

The invention relates to medicine, in particular to urology and endocrinology. How is that lower levels of prolactin, somatotrophic hormone (STH), insulin-like growth factor-1 (IGF-1), adrenocorticotropic hormone (ACTH), cortisol, 17-estradiol, 5-dihydrotestosterone, insulin, glucagon, glucose in the blood plasma of fasting, 1,25(OH)2D3, epidermal growth factor (EGF), the main fibroblast growth factor (bFGF), tumor necrosis factor , interleukin 1, interleukin 1, interleukin 6, increase the level of transforming growth factor- (TGF) by individual selection of doses of testosterone to normalize the levels of luteinizing hormone (LH), total testosterone, free testosterone, globulin that binds sex hormones, index of free androgens, 5-dihydrotestosterone, 17-estradiol, recovery pulse secretion of LH and total testosterone. The way you can affect pathogenetic aspects of prevention of BPH.

The invention relates to medicine, in particular to urology and endocrinology.

The prototype of the invention is the purpose of finasteride (proscar) with prostatic hyperplasia (E. Stoner The clinical effects of 5-reductase inhbitor, linasteride, on benign prostatia hyperplasia // J. Urol. - 1992. - V. 147. - P. 1298-1302).

The disadvantage of the prototype is that it does not affect endocrine regulation in men with PADAM, violation of which largely determines the development of benign prostatic hyperplasia (BPH) in aging men.

The purpose of the invention is to develop a pathogenetic method of prevention of BPH in men with partial age-related androgen deficiency (PADAM).

The invention consists in the decrease in men with partial age-related androgen deficiency (PADAM) levels of prolactin, somatotrophic hormone (STH), insulin-like growth factor-1 (IGF-1), adrenocorticotropic hormone (ACTH), parathyroid hormone (PTH), cortisol, 17-estradiol, 5-dihydrotestosterone, insulin, glucagon, glucose, 1,25(OH)2D3, epidermal growth factor (EGF), transforming growth factor - (TGF), platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF), fibroblast growth factor-7 (FGF-7), tumor necrosis factor , tumor necrosis factor , interleukin 1, interleukin 1 , interleukin 6, to increase the level of transforming growth factor- (TGF) in plasma revelation of one of the drugs testosterone with individual selection of doses to normalize the levels of LH, total testosterone, free testosterone, bioavailable testosterone, globulin that binds sex hormones, index of free androgens, 5-dihydrotestosterone, 17-estradiol, recovery pulse secretion of LH and total testosterone.

The daily dose of testosterone is divided into two steps: 2/3 - in the morning (7-8 hours) and 1/3 - day (16 hours). With persistent elevated levels of 5-dihydrotestosterone, 17-estradiol, globulin that binds sex hormones, LH and low levels of total testosterone, free testosterone, bioavailable testosterone and index of free androgens (or a combination of these changes with normal values of LH and total testosterone), as well as the absence or reduced pulse rhythm education total testosterone, LH dose of testosterone increase. These criteria are more fully reflect partial age-related androgen deficiency and can be used for diagnostic PADAM, and to monitor the effectiveness of androgen-replacement therapy.

A significant part of the tissue has testosterone receptors and can be considered as targets for androgens. Testosterone is involved in Protel C. M., Arch R. A. Pathophysiology of the endocrine system. - SPb-M.: Nevsky dialect, 2001.- S. 232-233). Age-related decline in the production of testosterone (PADAM) violates the natural development cycle of cells with androgenove receptors. This is manifested in the decrease in the intensity of cell multiplication in a number of tissues during ageing (Farber E. Cell proliferation as a major risk factor for cancer: a concept of both doubtful validity // Cancer Res., 1995. - Vol. 55. - P. 3759-3762; Spom, M. B. The war on cancer // Lancet., 1996. - Vol. 347. - R. 1377-1381; Bershtein L. M. Hormonal carcinogenesis. - SPb.: Science, 2000.-S. 31, 65). The transition androgenization transtorno-proliferating cells in androgen pool of transitional cells (Lopatkin N.A. Manual of urology. - M.: Medicine, 1998. - So 3. - S. 377-378), requiring further development, the presence of physiologically required levels of testosterone, accompanied by the disruption of the process of their differentiation. Increases the risk of neoplastic transformation (Russo j, Russo I. H. Differentiation and breast cancer // Medicina (b Aires), 1997. - Vol. 57, suppl. 2.- P. 81-91; Bershtein L. M. Hormonal carcinogenesis. - SPb.: Science, 2000.- S. 31). PADAM, hindering the passage of the preceding stages, natural violates the onset of the last stage of development testosteronemycelex cells of their natural death (apoptosis).

For isotopically reactions affecting both endocrine and paracrine autocrine levels.

There is a kind of contact and intersection (cross-talk) peptization and steroid-dependent mechanisms of regulation (Bershtein L. M. Hormonal carcinogenesis. - SPb.: Science, 2000.- S. 51). The severity of compensatory-adaptive reactions is proportional to the degree of age-related decline in testosterone. These changes are aimed mainly at increasing mitotic activity of the cells.

Partial age-related androgen deficiency leads to compensatory increase production in some tissues of 5-dihydrotestosterone and 17-estradiol. The activity of aromatase and 5-a reductase depends on the level of testosterone, which remains low, so the production of 5-dihydrotestosterone and 17-estradiol is higher than normal (Pechersk A. C., Mazur C. I., Semiglazov C. F., Karpischenko A. I., Mikhailichenko centuries, Udintsev A. C. Open No. 175 “Regularity reduce the formation of 5-dihydrotestosterone and 17-estradiol in men with partial age-related androgen deficiency (PADAM) and benign prostatic hyperplasia when changing the level of testosterone in blood plasma” Decision of 10 September 2001, Moscow. Per. No. 208). The main enologia. - M.: The Practice, 1999.- S. 372). The increased activity of 5-reductase accompanying the formation of BPH (Stoner E. The clinical effects of 5-reductase inhbitor, linasteride, on benign prostatia hyperplasia // J. Urol. -1992. - V. 147. - P. 1298-1302). In the transient zone, the content of 5-dihydrotestosterone in BPH in 2-3 times above, than in other areas of the body (Lopatkin N.A. Manual of urology. - M.: Medicine, 1998. - So 3. - S. 378).

Most aromatase activity in the prostate with benign hyperplasia was also observed in the transient zone, in which is revealed the accumulation of 17-estradiol and estrone. Estrogen receptors are found in cells of the stroma and epithelium of the prostate gland with predominant localization in the stroma. Stimulation of growth of stromal cells induces proliferation of the epithelium with glandular formation of new structures (Lopatkin N.A. Manual of urology. - M.: Medicine, 1998. - So 3. - S. 377-380, 394-395). Cellular hypertrophy can be caused not only by increased mitotic activity. When hormonal imbalance is observed volume change of cells. In the glandular epithelium of the prostate increases with age, the average size of the cells (Bershtein L. M. Hormonal carcinogenesis. - SPb.: Science, 2000.- S. 31) that sposobem the receptors (H. Burrows, Homing E. Oestrogens and neoplasia. Sprifield; Illinois: Charles C. Thomas Publ. - 1952. - P. 189). 5-dihydrotestosterone along with testosterone binds to the same cellular receptor (Avalanches H. Endocrinology.- M: Practice, 1999.- S. 345) and stimulates the proliferative activity of cells (Satarov E. G., Severin, E. S. Molecular mechanisms of carcinogenesis of the prostate.// News. Russian Academy of medical Sciences, 1998.-№5.- S. 29-35). Insulin, along with IGF-1 also increases the mitotic activity of the cells. The increase in the latter is characteristic for the stage of promotion of tumor growth (Yam D., Fink, A., A. Mashiah, BenHur E. Hyperinsulinemia in colon, stomach and breast cancer patients // Cancer Lett., 1996. - Vol. 104. - P. 129-132; Gamajunova V. C., Bobrov Ju. F., Tsyrlina E. V., Evtushenko T. P., Berstein L. M. Comparative study of blood insulin levels in breast and endometrial cancer // Neoplasma, 1997. - Vol. 44. - P. 123-126; Bershtein L. M. Hormonal carcinogenesis. - SPb.: Science, 2000. - S. 69).

Increased levels and, accordingly, the mitotic activity of 5-dihydrotestosterone and 17-estradiol supplemented by the activation of a number of hormones, cell growth factors and cytokines. Produced by the cells of peptide growth factors is performed in order autocrine and paracrine regulation, compensating the lack of endocrine activators reproduction (Vasiliev, Y. M. Social behavior of normal cells and anti-social behaviour the op is 000. - S. 51). 5-dihydrotestosterone induces the synthesis of insulin-like growth factors, epidermal growth factor, fibroblast growth factor, transforming growth factor- (Satarov E. G., Severin, E. S. Molecular mechanisms of carcinogenesis of the prostate.// News. Russian Academy of medical Sciences, 1998. No. 5. - S. 29-35). Estrogens induce the expression of a series estrogenzawisimy genes, which include genes peptide growth factors, receptors, progesterone and oncogenes (Bershtein L. M. Hormonal carcinogenesis. - SPb.: Science, 2000. - S. 57-58). Estrogen receptors detected on the surface of lymphocytes and macrophages (Jakob F., Tony H.-P., H. Thole Immunological detection of the oestradiol receptor protein in cell lines derived from the lymphatic system and the haematopoietic system: variability of specific hormone binding in vitro // J. Endocrinol. 1992,-Vol. 134.-P. 397-404; Cutolo m, Accardo S., Villaggio Century, Barone A., L. Castagnetta Androgen and estrogen receptors are present in primary cultures of human synovial macrophages // J. Clin. Endocrinol.and Metabol., 1996-Vol. 81.-P. 820-827). Clone Thi (T-helpers) secretes the tumor necrosis factor P, a Th2-clone - interleukin-6.

At the same time, insulin-like growth factor - 1 (IGF-1), transforming growth factor , platelet and epidermal growth factors have a stimulating effect on aromatase (Mendelson, S. R., Simpson E. R. Regulation of estrogen biosynthesis by human adipose cells in vitro // Molec. and Cell. Endocrinol., 1987. - Vol. 52. - P. Ara L. M. Sneganna production of estrogen. - SPb.: Science, 1998.-S. 86).

Cytokines can not only modulate antitumor resistance, autoimmune, inflammatory and allergic reactions, but also to influence the biosynthesis of steroids, including aromatase activity (Purohit a, Ghilchik, M. W., Duncan L., Wang D., Reed, M. J. Aromatase activity /and interleukin-6 production by normal and malignant breast tissues // J. Clin. Endocrinol and Metabol., 1995. -Vol. 80. - P. 3052-3058; Reed, M. J., Purohit, A., Singh, A., Roberts C. J., Potter, B. V. L. The role of cytokines, and sulphatase inhibitors in regulating oestrogen synthesis in breast tumours // J. Steroid Biochem. and Molec. Biol., 1995. - Vol. 53. - P. 413-420; Abbas, A. K., Murphy K. M., Sher A. Functional diversity of helper T-lymphocy // Nature., 1996. - Vol. 383. - P. 787-793; Bershtein L. M. Sneganna production of estrogen. SPb.: The science. -1998. - S. 70).

It controls the activity of aromatase include interleukin 1 and tumor necrosis factor - (Belizario J. E., Katz, M., Chenker E., Raw I. the Bioactivity of skeletal muscle proteolysis-inducing factor (PIF) in the plasma proreins from cancer patients with weight loss // Brit. J. Cancer., 1991. - Vol. 63. - P. 705-710; McPheron A. C., Lawler, A. M., Lee S. J. Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member // Nature., 1997. - Vol. 387. - P. 83-86, L. Bershtein M Sneganna production of estrogen. - SPb.: Science, 1998. - S. 61).

Increased secretion of interleukin-1, interleukin-1 correlates with increased activity of aromatase (Pacific R., Brown, S., E. Puscheck, Friedrich E., Slatopolsky E., Avioli L. V. J Effect of surgical menopause and estrogen replacement gain: 17-estradiol and 5-dihydrotestosterone stimulates the formation of cellular growth factors and cytokines, the latter, in turn, increase the secretion of 17-estradiol and 5-dihydrotestosterone. Aromatase activity is increased under the influence of insulin (Lueprasitsakul P., Longcope C. Aromatase activity of human adipose tissue stromal cells: effects of thyroid hormones and progestogens // Proc. Soc. Exp. Biol. and Med., 1990. - Vol. 194. - P. 337-341). Glucocorticoids stimulate the activity of aromatase in the culture of stromal cells isolated from adipose tissue (Santner, S. J., Kaseta J., Berstein L., Pauley, R. J., Smith H., R. J. Santen Regulation ofaromatase in the stromal cells from human breast cancer and peripheral breast tissue: effects of dexamethasone, phorbol esters and cAMP // Proc. 77th An-nual Endocrine Soc. (USA) Meeting. Washington, 1995. - P 2-654). 1,25 (OH)2D3enhances this effect (Jakob F., Homann D., Seufert J., Schneider D., Kohrle J. Expression and regulation ofaromatase cytochrome P450 in THP1 human myeloid leukemia cells // Molec. and Cell. Endocrinol., 1995. - Vol. 110. - P. 27-33; M. Shozu, Akasofa K., Harada T., Kubota Y. A new cause of female pseudoher-maphroditism: placenta aromatase deficiency = MKD // J. Clin. Endocrinol. and Metabol., 1991. - Vol. 72. - P. 560-666; Bershtein L. M. Sneganna production of estrogen. - SPb.: Science, 1998. -S. 77).

Transforming growth factor - role astromedia mediation effect of estradiol, as well as ligand of the receptor for epidermal growth factor (Lippman M. E., Dickson, R. C. Mechanisms of normal and malignant brev ast epithelial growth regulation // J. Steroid Biochem., 1989. - Vol. 34. - P. 107-121; Bershtein L. M. Hormonal carcinogenesis. SPb.: The science.-2000.-S. 51). Astromedia are also the disease is receiving. Their effect is due to stimulation of phosphorylation of estrogen receptor (Bershtein L. M. Hormonal carcinogenesis. SPb.: The science.-2000. - S. 129).

Increased levels of progesterone determines the shift in the sensitivity of tissues from steroids to peptide growth factors that cause the development of tissue resistance to steroid hormones (Lange S. A., Richer, J. K., Horwitz, K. C. Hypothesis: progesterone primes breast cancer cells for crosstalk with proliferative or antiproliferative signals // Mol. Endocrinol., 1999. - Vol. 13. - P. 829-836, Bershtein L. M. Hormonal carcinogenesis. - SPb.: Science, 2000.-S. 128). This restructuring of the regulation characteristic of PADAM.

These changes combined with the inhibition of the formation of the factors responsible for the sequential passage of cell stages of differentiation and the onset of apoptosis (Bershtein L. M. Hormonal carcinogenesis. - SPb.: Science, 2000. - S. 17). In particular, the decrease of the level of transforming growth factor-(TGF) (Lopatkin N.A. Manual of urology. - M.: Medicine, 1998. - So 3. - S. 385).

Changing levels of the above factors, as well as improve the education of basic fibroblast growth factor (bFGF) and fibroblast growth factor-7 (FGF-7) are pivotal in the pathogenesis of BPH (Lopatkin N.A. Manual of urology. - the local decrease the production of testosterone, in addition to increasing the production of LH, gonadotropin-releasing hormone violation of their physiological pulse mode of education, affects the entire endocrine regulation (Lavin N. Endocrinology, - M: Practice, 1999.- S. 370-371, 877-898).

Estrogens have a direct activating effect on the secretion of pituitary prolactin (Pankov A. Y. Prolactin //bed, M.: Soviet encyclopedia, 1983. - So 21. - S. 134). The increase in production of 17-estradiol causes a decrease in the content prolactinemia factor of dopamine in the hypothalamus (Lavin N. Endocrinology. - M.: The Practice, 1999. - S. 160; cattail C. M., Arch R. A. Pathophysiology of the endocrine system. -SPb-M.: Nevsky dialect, 2001.- S. 38). Increased level of prolactin, in turn, causes an increase in the activity of aromatase, and the vicious circle (Mendelson, S. R., Simpson E. R. Regulation of estrogen biosynthesis by human adipose cells in vitro // Molec. and Cell. Endocrmol., 1987. - Vol. 52. - P. 169-176; Lueprasitsakul P., Longcope C. Aromatase activity of human adipose tissue stromal cells: effects of thyroid hormones and progestogens // Proc. Soc. Exp. Biol. and Med., 1990. - Vol. 194. - P. 337-341).

In men with PADAM increases the sensitivity of cells near the thyroid gland to calcium, resulting in disrupted the mechanism of suppression of PTH secretion in response to hypercalcemia. As a result, the cells of the parathyroid glands Secretary-1 and others) (Lavin N. Endocrinology. - M.: The Practice, 1999. - C. 414, 417, 418, 420, 426, 464).

With the increase in 17-estradiol is associated with increased levels STH. This is confirmed by the results of functional tests with estrogen, in which there is increased secretion of STH (Lavin N. Endocrinology.-M: Practice, 1999.- S. 95, 552). Increased levels STH strengthens the formation of IGF-1. The receptor for IGF-1 is similar to the insulin receptor, therefore, IGF-1 can bind to insulin receptors and activate them. Increased levels of IGF-1 and insulin in patients with PADAM is a compensatory response to the development of insulin resistance. Increased levels of IGF-1-binding protein inhibits the interaction of IGF-1, insulin receptor and thereby inhibits their action on target cells (Lavin N. Endocrinology.- M: Practice, 1999.- C. 42,43, 102, 104, 691). A decrease in IGF-1 - binding proteins, on the contrary, enhances the action of IGF-1 and insulin (Cohen, P., Peehl, D. M., Graves N. C. R., Rosenfeld R. G. Biological efects of prostate specific antigen as an insulin-like growth factor binding protein-3 protease // J. EndocrinoL, 1994. - Vol. 142. - P. 407-415; Bershtein L. M. Hormonal carcinogenesis. - SPb.: Science, 2000.-S. 139). Insulin inhibits the synthesis of IGF-1-binding proteins (Rutanen, E. M., Nyman T., Lehtovirta P., Ammala M, Pekonen F. Sup-pressed by the expression of insulin-like growth factor binding protein-1 mRNA in the endometrium: a molecular mechanism associating endometrial cancer Kim way hyperinsulinism to a certain extent, helps to reduce insulinresistance. Some serine protease (prostate-specific antigen (PSA), inhibitor-1 plasminogen activator) destroy IGF-binding protein-3 (Alessi, M. C., Peiretti f, Morange p, Henry m, Juhan-Vague I. Pro-4 duction of plasminogen activator inhibitor 1 by human adipose tissue: possible link with visceral fat accumulation // Diabetes., 1997. - Vol. 46. - P. 860 - 867; Bershtein L. M. Hormonal carcinogenesis. - SPb.: Science, 2000.-S. 50).

Elevated levels of 5-dihydrotestosterone not only induces the synthesis of insulin-like growth factor-1, but also through the stimulation of education PSA potentiates the action of IGF-1 in the prostate gland (Satarov E. G., Severin, E. S. Molecular mechanisms of oncogenesis// News. Russian Academy of medical Sciences, 1998. No. 5. -S. 29-35).

Thus, with increasing education 5-dihydrotestosterone and 17-estradiol is due to the increased influence of STH, IGF-1, insulin, possessing a strong mitogenic effect (Yam D., Fink, A., A. Mashiah, BenHur E. Hyperinsulinemia in colon, stomach and breast cancer patients // Cancer Lett. 1996. Vol. 104. P. 129-132; Bershtein L. M. Hormonal carcinogenesis. - SPb.: Science, 2000. - S. 50-51, 69). Stimulation aromatase and 5-reductase activity is accompanied by compensatory hyperplasia tissues containing these enzymes. In particular, there adenomatous giperplazirovanne insulin resistance, stimulate the secretion of somatoliberin and corticoliberin, inhibit the secretion of somatostatin (Lavin N. Endocrinology.- M: Practice, 1999.- S. 91, 95; cattail C. M., Arch R. A. Pathophysiology of the endocrine system. - SPb-M.: Nevsky dialect, 2001.- S. 175). Somatoliberin stimulates the secretion continuarea hormone - STH and therefore IGF-1. Corticoliberin causes the release of ACTH, which increases the secretion of another continuarea hormone cortisol in the adrenal cortex. (Lavin N. Endocrinology. - M.: The Practice, 1999.- S. 866, 966).

Increased levels of glucocorticoids potentiates the effect of estrogen. According to Tsai et al. the corticosteroid receptors homologous parts of the estrogen receptor. They can turn into a form that activates as corticosteroidscortisone and estrogenically elements of the genome (Tsai, M. J., J. dark, Schrader, W. T., O'malley C. W. Mechanisms of action of hormones that act as reduced-regulatory factors // Williams text book of endocrinology Ed. by J. D. Wilson etc. Philadelphia: W. B. Saunders, 1998. P. 55-87; Bershtein L. M. Hormonal carcinogenesis. SPb.: Science, 2000. - S. 128-129).

In patients with insulin resistance, despite the activation of gluconeogenesis and glycogenesis, the level of glucose in the blood plasma may remain within the normal range (or slightly previsit is s N.N. The obesity. M: Malpractice - M., 2002. - S. 55-88). Therefore, the main result of the development of insulin resistance is increased levels of insulin and its mitotic activity.

The purpose androgenzamestitelnoy therapy to men with partial age-related androgen deficiency (PADAM) leads to lower levels of prolactin, somatotrophic hormone (STH), insulin-like growth factor-1 (IGF-1), parathyroid hormone (PTH), adrenocorticotropic hormone (ACTH), cortisol, 17-estradiol, 5-dihydrotestosterone, insulin, glucagon, glucose, 1,25(OH)2O3, epidermal growth factor (EGF), transforming growth factor - (TGF), platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF), fibroblast growth factor-7 (FGF-7), tumor necrosis factor , tumor necrosis factor , interleukin 1, interleukin 1, interleukin 6, increase the level of transforming growth factor- (TGF) in plasma fasting, recovery pulse mode STH secretion, ACTH, cortisol, insulin, which promotes the prevention of BPH.

Method of prevention of benign prostatic hyperplasia (BPH) in men with partial age-related androgen deficiency (PADAM), requires that the F-1), adrenocorticotropic hormone (ACTH), cortisol, 17-estradiol, 5-dihydrotestosterone, insulin, glucagon, glucose in the blood plasma of fasting, 1,25(OH)2ABOUT3, epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), tumor necrosis factor , interleukin 1, interleukin 1, interleukin 6, increase the level of transforming growth factor- (TGF) by individual selection of doses of testosterone to normalize the levels of luteinizing hormone (LH), total testosterone, free testosterone, globulin that binds sex hormones, index of free androgens, 5-dihydrotestosterone, 17-estradiol, recovery pulse secretion of LH and total testosterone.

 

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