The Experts below are selected from a list of 72 Experts worldwide ranked by ideXlab platform
P J Selman - One of the best experts on this subject based on the ideXlab platform.
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binding specificity of medroxyprogesterone acetate and Proligestone for the progesterone and glucocorticoid receptor in the dog
Steroids, 1996Co-Authors: P J Selman, Jeannette WolfswinkelAbstract:Abstract The use of the synthetic progestin medroxyprogesterone acetate (MPA) for estrus prevention in the dog can result in overproduction of growth hormone, suppression of plasma glucocorticoid levels, and the induction of mammary tumors. Proligestone (PROL) was claimed to be devoid of these unwanted side effects. In the present study, the binding characteristics of MPA and PROL for the canine progesterone receptor (PR) and glucocorticoid receptor (GR) were investigated. The apparent inhibition constants for the PR and GR of MPA and PROL were compared with those of progesterone, ORG 2058, and a number of corticosteroids. MPA and PROL had high affinities for both the PR and the GR. The rank order for displacement of the binding of the PR ligand [3H]ORG 2058 from the canine uterine receptor was: MPA ≈ ORG 2058 > PROL > progesterone ⪢ cortisol, dexamethasone, and spironolactone. The rank order for displacement of the specific binding of the GR ligand [3H]dexamethasone from the canine liver receptor was: dexamethasone > cortisol > MPA > PROL > progesterone ⪢ aldosterone ≈ spironolactone. The apparent inhibition constants of PROL for both the PR and the GR were approximately 10 times higher than those of MPA. The ratios of the inhibition constants for the GR and PR appeared to be equal for PROL and MPA. It is concluded that although MPA has higher affinities for the PR and GR than PROL, both progestins have a similar in vitro binding specificity, which is less than that of progesterone. These findings are consistent with suppression of the adrenal cortex and the induction of growth hormone secretion in the mammary gland after MPA and PROL treatment in dogs.
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comparison of the histological changes in the dog after treatment with the progestins medroxyprogesterone acetate and Proligestone
Veterinary Quarterly, 1995Co-Authors: P J Selman, E Van Garderen, T S G A M Van Den InghAbstract:Abstract Administration of progestins in the dog may result in overproduction of growth hormone, suppression of the hypothalamic‐pituitary‐adrenocortical axis, and insulin resistance. In this paper we present a comparison of the histological findings in control dogs and dogs treated with either medroxyprogesterone acetate (MPA) or Proligestone (PROL). Depot preparations of MPA or PROL were administered (SC) at 3‐week intervals in two groups of seven ovariohysterectomized beagle dogs, after which three dogs of each group were killed. After a 6‐month period without hormone treatment during which recovery was studied, the remaining dogs received five additional injections at the same interval and were subsequently killed. Tissue samples of four intact female beagle dogs served as controls. Progestin treatment resulted in atrophy of the adrenal cortex. In both MPA‐ and PROL‐treated dogs, the thickness of the combined zona fasciculata and reticularis was significantly smaller than in control animals. In the ma...
Ad Rijnberk - One of the best experts on this subject based on the ideXlab platform.
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New insights in the molecular mechanism of progestin-induced proliferation of mammary epithelium: Induction of the local biosynthesis of growth hormone (GH) in the mammary gland of dogs, cats and humans
The Journal of Steroid Biochemistry and Molecular Biology, 1999Co-Authors: E Van Garderen, Gerard R. Rutteman, Ad RijnberkAbstract:In contrast to the protective, anti-proliferative, action of progestins on the development of endometrium cancer, progestins may have local stimulatory and inhibitory effects on the proliferation of mammary epithelium. Until now there was no final molecular explanation of this discrepancy. Prolonged treatment of dogs with depot medroxyprogesterone acetate (DPMA) or with Proligestone (PROL) results in enhanced plasma concentrations of growth hormone (GH), insulin-like growth factor (IGF)-I, IGF-II and IGF-binding proteins, together with the development of benign mammary tumours. The stimulated plasma GH levels do not have the typical pulsatile secretion pattern, and are not sensitive to stimulation with GHRH or to inhibition with somatostatin. The autonomous secretion can be inhibited by the anti-progestin RUU-486. The source of progestin-induced plasma GH levels has been demonstrated to be the canine mammary gland where progestins induce the expression of the gene encoding GH. The expression of the GH gene is restricted to focal areas of hyperplastic epithelium as shown by immunohistochemistry, and is predominantly located in single positive epithelial cells with an intermediate position between luminal- and myo-epithelium. Progestin-induced fibroadenomatous changes in the mammary gland of cats are also associated with locally enhanced GH expression. In both normal, benign and malignant mammary tumours of humans GH mRNA expression has been demonstrated by RT-PCR. The presence of GH mRNA is associated with the presence of immunoreactive GH as shown by immunohistochemistry. Sequence analysis revealed 100% homology to the pituitary expressed GH gene. In malignant mammary tumours of humans and dogs GH expression is also found in specimens negative for progesterone receptors as measured by ligand binding. It is concluded that the gene encoding GH is expressed in the mammary gland of a variety of species, including man. This appears to represent a contribution to the molecular explanation of the action of progestins on proliferation of mammary epithelium. It needs, however, to be proven whether this local biosynthesis of GH in the mammary gland is the cause of the local stimulatory effect of progestins on the proliferation of mammary epithelium.
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Effects of Progestin Administration on the Hypothalamic-Pituitary-Adrenal Axis and Glucose Homeostasis in Dogs
Journal of reproduction and fertility, 1997Co-Authors: P J Selman, E Van Garderen, T S G A M Van Den Ingh, Gerard R. Rutteman, Ad RijnberkAbstract:: The effects of medroxyprogesterone acetate (MPA) and Proligestone (PROL) on the hypothalamic-pituitary-adrenocortical axis and glucose homeostasis were studied in two groups of eight ovariohysterectomized beagle bitches. In addition, the binding characteristics of MPA and PROL for the progesterone and glucocorticoid receptor were investigated. The administration of both progestins resulted in suppression of the hypothalamic-pituitary-adrenal axis. Whereas basal plasma concentrations of adrenocorticotrophic hormone (ACTH) were only moderately affected, the basal plasma concentrations of cortisol and the cortisol:creatinine ratio in urine were significantly decreased after the first administration of both progestins. In the group given MPA the increase of ACTH after stimulation with corticotrophin-releasing hormone (CRH) remained normal but it was suppressed in the group treated with PROL. In both treatment groups the increase of cortisol after stimulation with CRH was lower. After cessation of progestin administration both basal and stimulated plasma ACTH concentrations returned to pretreatment concentrations within a few weeks. In contrast, it took 6 month to restore the basal plasma cortisol concentrations and cortisol:creatinine ratios in urine. Paradoxically, the stimulated cortisol concentrations returned to normal shortly after the cessation. Histological examinations revealed a severe atrophy of the zona fasciculata and reticularis of the adrenal gland in all treated dogs and a steroid-induced hepatopathy in 50% of them. During the first half of the progestin treatment, glucose homeostasis was maintained by increased plasma concentrations of insulin in both groups. After prolonged treatment the response to a glucose load became impaired. None of these parameters improved during the 6 month recovery period. Histological changes in the pancreas, characteristics of diabetes mellitus, were found in two dogs of each group. Most probably, the glucocorticoid action of the progestins is not the sole explanation for the insulin resistance since progestin treatment resulted in a concomitant increase in plasma concentrations of growth hormone which has diabetogenic properties. Experiments in vitro confirmed the strong glucocorticoid component of MPA and PROL. The inhibition constants (Ki) of PROL for both the progesterone receptor (PR) and the glucocorticoid receptor (GR) were approximately then times higher than those of MPA. Nonetheless, the ratios of the Ki for the GR and PR indicated that the specificity of MPA and PROL was only slightly different but considerably smaller than that of progesterone. It is long-term treatment with high doses of these progestins may result in a iatrogenic Cushing's syndrome and diabetes mellitus.
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Progestin treatment in the dog. II. Effects on the hypothalamic-pituitary-adrenocortical axis.
European Journal of Endocrinology, 1994Co-Authors: P J Selman, Gerard R. Rutteman, Ad RijnberkAbstract:: The effects of two synthetic progestins, medroxyprogesterone acetate (MPA) and Proligestone (PROL), on the hypothalamic-pituitary-adrenocortical (HPA) axis were studied in two groups of eight ovariohysterectomized dogs each. Eight injections of long-acting progestins were administered at 3-week intervals. Recovery of the HPA axis was studied in four dogs of each group in the following 6 months. Basal levels of adrenocorticotrophin (ACTH) and cortisol in plasma and the urinary corticoid/creatinine ratio were measured. The responsiveness of the HPA axis was investigated by stimulation with ovine corticotrophin-releasing hormone. Both MPA and PROL caused sawtooth patterns of suppression of basal ACTH and cortisol levels in plasma, synchronous with the time of administration. The suppression of the adrenocortical component of the HPA axis was most pronounced. Adrenocorticotrophin production also was affected but to a lesser extent and occurred especially in PROL-treated dogs. Soon after the cessation of progestin administration ACTH levels increased, sometimes with a rebound. In both groups basal cortisol levels and urinary corticoid/creatinine ratios did not return to pretreatment levels until 6 months after the last progestin injection. It is concluded that MPA and PROL act as glucocorticoid agonists and suppress the HPA axis. The suppression at the adrenocortical level may last for 6 months.
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Progestin treatment in the dog I. Effects on growth hormone, insulin-like growth factor I and glucose homeostasis
European Journal of Endocrinology, 1994Co-Authors: P J Selman, Gerard R. Rutteman, Ad RijnberkAbstract:: The effects of two synthetic progestins, medroxyprogesterone acetate (MPA) and Proligestone (PROL), on the release of growth hormone (GH) and glucose metabolism were studied in two groups of eight ovariohysterectomized dogs. Eight injections of long-acting progestins were administered at 3-week intervals. Recovery was studied in four dogs of each treatment group in the 6 months following cessation of progestin administration. Treatment with both MPA and PROL resulted in similar increases in plasma levels of GH and insulin-like growth factor I (IGF-I). The GH responses to both clonidine and growth hormone-releasing hormone became impaired. In neither treatment group did the elevated plasma GH levels decrease after administration of the synthetic somatostatin analogue SMS 201-995. The size and shape of the pituitary gland were not changed by progestin treatment. After cessation of progestin administration, basal plasma levels of GH and IGF-I did not return to pretreatment values. The GH response to growth hormone-releasing hormone remained impaired for at least 6 months after the last progestin administration. In both treatment groups, glucose homeostasis was sustained initially by increased insulin production. Prolonged treatment with MPA and PROL resulted in glucose intolerance. No amelioration was observed during the recovery period in either group. A small number of dogs developed diabetes mellitus. In more than 50% of the dogs in both treatment groups small mammary tumours developed. The recently discovered local production of GH probably played a role in mammary tumorigenesis.(ABSTRACT TRUNCATED AT 250 WORDS)
Jeannette Wolfswinkel - One of the best experts on this subject based on the ideXlab platform.
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binding specificity of medroxyprogesterone acetate and Proligestone for the progesterone and glucocorticoid receptor in the dog
Steroids, 1996Co-Authors: P J Selman, Jeannette WolfswinkelAbstract:Abstract The use of the synthetic progestin medroxyprogesterone acetate (MPA) for estrus prevention in the dog can result in overproduction of growth hormone, suppression of plasma glucocorticoid levels, and the induction of mammary tumors. Proligestone (PROL) was claimed to be devoid of these unwanted side effects. In the present study, the binding characteristics of MPA and PROL for the canine progesterone receptor (PR) and glucocorticoid receptor (GR) were investigated. The apparent inhibition constants for the PR and GR of MPA and PROL were compared with those of progesterone, ORG 2058, and a number of corticosteroids. MPA and PROL had high affinities for both the PR and the GR. The rank order for displacement of the binding of the PR ligand [3H]ORG 2058 from the canine uterine receptor was: MPA ≈ ORG 2058 > PROL > progesterone ⪢ cortisol, dexamethasone, and spironolactone. The rank order for displacement of the specific binding of the GR ligand [3H]dexamethasone from the canine liver receptor was: dexamethasone > cortisol > MPA > PROL > progesterone ⪢ aldosterone ≈ spironolactone. The apparent inhibition constants of PROL for both the PR and the GR were approximately 10 times higher than those of MPA. The ratios of the inhibition constants for the GR and PR appeared to be equal for PROL and MPA. It is concluded that although MPA has higher affinities for the PR and GR than PROL, both progestins have a similar in vitro binding specificity, which is less than that of progesterone. These findings are consistent with suppression of the adrenal cortex and the induction of growth hormone secretion in the mammary gland after MPA and PROL treatment in dogs.
V. A. Andryushina - One of the best experts on this subject based on the ideXlab platform.
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SYNTHESIS AND BIOLOGICAL ACTIVITY OF SYNTHETIC 17a-HYDROXYPROGESTERONE DERIVATIVES
2020Co-Authors: O. A. Zeinalov, V. V. Yaderets, M. A. Petrosyan, T. S. Stytsenko, V. A. AndryushinaAbstract:Gestagenic and contraceptive (in combination with estrogen) activities of megestrol acetate, Proligestone, and two esters of mepregenol acetate (butyrate and hemisuccinate) were studied. The absence of a correlation between the gestagenic and contraceptive activity (CA) of the synthetic derivatives of 17-hydroxyprogesterone was established. Of two compounds (Proligestone and megestrol acetate) showing the maximum (100%) CA (in combination with ethynylestradiol), Proligestone was practically devoid of gestagenic activity while megestrol acetate was a highly active gestagen. It was confirmed that the gestagenic activities of injected megestrol acetate and mepregenol acetate tended to exceed their peroral activities. Pure estrogen was found to contribute to the CA of the mepregenol esters.
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14α hydroxylation of steroids by mycelium of the mold fungus curvularia lunata vkpm f 981 to produce precursors for synthesizing new steroidal drugs
Pharmaceutical Chemistry Journal, 2013Co-Authors: V. A. Andryushina, V. V. Yaderets, M. A. Petrosyan, T. S. Stytsenko, N E Voishvillo, A V Druzhinina, O. A. ZeinalovAbstract:Five 14α-hydroxylated derivatives of androstane and pregnane steroids were obtained using mycelium of the mold fungus Curvularia lunata (VKPM F-981). The conditions for microbiological transformation of androst-4-en-3,17-dione that enabled its 14α-hydroxy analog to be obtained in yields up to 60% with substrate loading 6 g/L were determined. The 21-acetoxy analog of Proligestone was synthesized from 14α-hydroxycortexolone that was formed simultaneously with hydrocortisone during hydroxylation of cortexolone by C. lunata. The resulting 14α- and 14α,21-hydroxysteroids could be used as precursors for the synthesis of new drugs.
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Synthesis and biological activity of synthetic 17α-hydroxyprogesterone derivatives
Pharmaceutical Chemistry Journal, 2012Co-Authors: O. A. Zeinalov, V. V. Yaderets, M. A. Petrosyan, T. S. Stytsenko, V. A. AndryushinaAbstract:Gestagenic and contraceptive (in combination with estrogen) activities of megestrol acetate, Proligestone, and two esters of mepregenol acetate (butyrate and hemisuccinate) were studied. The absence of a correlation between the gestagenic and contraceptive activity (CA) of the synthetic derivatives of 17α-hydroxyprogesterone was established. Of two compounds (Proligestone and megestrol acetate) showing the maximum (100%) CA (in combination with ethynylestradiol), Proligestone was practically devoid of gestagenic activity while megestrol acetate was a highly active gestagen. It was confirmed that the gestagenic activities of injected megestrol acetate and mepregenol acetate tended to exceed their peroral activities. Pure estrogen was found to contribute to the CA of the mepregenol esters.
O. A. Zeinalov - One of the best experts on this subject based on the ideXlab platform.
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SYNTHESIS AND BIOLOGICAL ACTIVITY OF SYNTHETIC 17a-HYDROXYPROGESTERONE DERIVATIVES
2020Co-Authors: O. A. Zeinalov, V. V. Yaderets, M. A. Petrosyan, T. S. Stytsenko, V. A. AndryushinaAbstract:Gestagenic and contraceptive (in combination with estrogen) activities of megestrol acetate, Proligestone, and two esters of mepregenol acetate (butyrate and hemisuccinate) were studied. The absence of a correlation between the gestagenic and contraceptive activity (CA) of the synthetic derivatives of 17-hydroxyprogesterone was established. Of two compounds (Proligestone and megestrol acetate) showing the maximum (100%) CA (in combination with ethynylestradiol), Proligestone was practically devoid of gestagenic activity while megestrol acetate was a highly active gestagen. It was confirmed that the gestagenic activities of injected megestrol acetate and mepregenol acetate tended to exceed their peroral activities. Pure estrogen was found to contribute to the CA of the mepregenol esters.
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14α hydroxylation of steroids by mycelium of the mold fungus curvularia lunata vkpm f 981 to produce precursors for synthesizing new steroidal drugs
Pharmaceutical Chemistry Journal, 2013Co-Authors: V. A. Andryushina, V. V. Yaderets, M. A. Petrosyan, T. S. Stytsenko, N E Voishvillo, A V Druzhinina, O. A. ZeinalovAbstract:Five 14α-hydroxylated derivatives of androstane and pregnane steroids were obtained using mycelium of the mold fungus Curvularia lunata (VKPM F-981). The conditions for microbiological transformation of androst-4-en-3,17-dione that enabled its 14α-hydroxy analog to be obtained in yields up to 60% with substrate loading 6 g/L were determined. The 21-acetoxy analog of Proligestone was synthesized from 14α-hydroxycortexolone that was formed simultaneously with hydrocortisone during hydroxylation of cortexolone by C. lunata. The resulting 14α- and 14α,21-hydroxysteroids could be used as precursors for the synthesis of new drugs.
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Synthesis and biological activity of synthetic 17α-hydroxyprogesterone derivatives
Pharmaceutical Chemistry Journal, 2012Co-Authors: O. A. Zeinalov, V. V. Yaderets, M. A. Petrosyan, T. S. Stytsenko, V. A. AndryushinaAbstract:Gestagenic and contraceptive (in combination with estrogen) activities of megestrol acetate, Proligestone, and two esters of mepregenol acetate (butyrate and hemisuccinate) were studied. The absence of a correlation between the gestagenic and contraceptive activity (CA) of the synthetic derivatives of 17α-hydroxyprogesterone was established. Of two compounds (Proligestone and megestrol acetate) showing the maximum (100%) CA (in combination with ethynylestradiol), Proligestone was practically devoid of gestagenic activity while megestrol acetate was a highly active gestagen. It was confirmed that the gestagenic activities of injected megestrol acetate and mepregenol acetate tended to exceed their peroral activities. Pure estrogen was found to contribute to the CA of the mepregenol esters.
