Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:APRD00627 (MAP)
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Both the gonads and the adrenal cortex secret steroids with anabolic activity. It should be realized that the most intense anabolism occurs during infancy and childhood at which time the concentration of steroid hormones with anabolic activity is extremely low. By far the most important anabolic steroid is in testosterone followed by androstenedione, androsterone and dehydroepiandrosterone. Also, estrogens have a generalized anabolic effect, although these hormones have their greatest anabolic action in their respective target organs. In males, after a short period of relatively high T levels immediately after birth, T levels during infancy and childhood are low (+/- 20--30 ng/100 ml); the increase of T levels in one of the first objective signs of puberty and over a period of 3--4 years adult T levels are reached. The latter vary between 380 and 1,000 ng (mean 660 ng/100 ml); the increase in the protein-free, non-protein bound testosterone is even more impressive as the concentration of testosterone binding globulin decreases sharply at puberty. Testosterone levels remain constant up to the 7th decade of life, and decrease rapidly thereafter; free testosterone levels decrease already after the age of 40. T secretion rates in adult males vary between 4 and 10 mg/24 hrs (-/m: 6.6 mg/24 hrs); in males over 65 years the mean T secretion is 4.2 mg/24 hrs: this decrease is a consequence of a decrease in plasma levels and a slowing down of the metabolism. T in adult males originates practically exclusively from the testes. Decreased T levels and secretion rates are observed in hypogonadism and under stressful conditions (anaesthesia, anxiety, hangover, exhaustion, undernutrition) as well as ACTH stimulation. DHT levels parallel generally T levels. Androstenedions (A) in adult males originates in about equal parts from the testes and adrenals. Androstenedione production rates in adult males vary between 1.4--2.1 mg/24 hrs. Dehydroepiandrosterone (DHEA) levels are low in infants and young children. They increase in the immediate pre-pubertal period to reach adult levels after completion of puberty. ACTH as well as stressful situations increase DHEA levels. The mean DHEA production rate is +/- 70 mg/24 hrs. Androsterone is a metabolite of T, A, DHEA, and 170HP, and circulates in plasma essentially as the 3-sulphate and to a lesser extent as the 3-glucuronide. In females, androgen levels before puberty are grossly similar to levels in male children. Pre- and post-menopausal levels of T, DHT, DHEA and their rates of production are discussed. Estrogens have also some anabolic effects. Levels of estradiol (E2) and estrone (E1) in cycling and post-menopausal women are also given. In post-menopausal women E2 levels are extremely low. E2 production rates in post-menopausal women are of the order of 5--20 mug/24 hrs. Progesterone does not appear to have an anabolic effect...
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PMID:Plasma levels and secretion rate of steroids with anabolic activity in man. 13 98

The relationship between the cellular uptake of glucocorticoid hormones, the binding of these hormones to specific in vitro receptors, and the induction of mouse mammary tumor viruses in an established mouse mammary tumor cell line was highly correlated. These results suggest that the induction of mouse mammary tumor virus by glucocorticoid hormones is a physiological process acting through a mechanism of high affinity, saturable steroid-receptors. A temperature-sensitive or salt-dependent step following glucocorticoid-receptor interaction was required for nuclear uptake of the steroid. Induction studies with different adrenocorticoids indicate that the synthetic glucocorticoid, dexamethasone (1,4-pregnadiene-9-fluor-16alpha-methyl-11beta,17alpha,21-triol-3,20-dione), is the most potent inducer of mouse mammary tumor viruses and all steroids which caused significant induction were glucocorticoids. Other glucocorticoids appear to stimulate murine mammary tumor virus production by a mechanism similar to that of dexamethasone; for example, corticosterone competes with dexamethasone for binding to the glucocorticoid receptor and blocks the uptake of dexamethasone into cells. Progesterone also blocks the cellular uptake of dexamethasone and can bind to the glucocorticoid receptor at low concentrations (10-7 to 10-8 M) but progesterone does not consistently induce virus at hormone concentrations even as high as 10-4 M. Thus, in this system, binding to a cytoplasmic receptor is necessary but not sufficient for induction by glucocorticoids. Estrogens and androgens interfere with receptor binding and cellular uptake of dexamethasone but only at much higher concentration (10-4 M) than progesterone, and do not induce mammary tumor virus production. Although there was a positive correlation between steroid structure, binding, and biologic induction, other factors clearly affect the physiological manifestations of steroid actions. Mouse cells with comparable cytoplasmic receptor levels and comparable nuclear uptake differed absolutely in their degree of murine mammary tumor virus induction following hormone treatment. Although all mouse cells examined contain comparable levels of murine mammary tumor virus DNA, only cells producing constitutive levels of murine mammary tumor virus RNA could be induced to higher levels by a variety of glucocorticoids.
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PMID:Glucocorticoid-receptor interaction and induction of murine mammary tumor virus. 16 67

Although sex steroids were known to play a role in the control of LH, FSH, TSH and prolactin secretion, in vivo experiments could not discriminate between hypothalamic and pituitary sites of action. In this study, the specific action of sex steroids at the anterior pituitary level could be achieved using rat adenohypophyseal cells in primary culture. While estrogens stimulated the sensitivity of the LH and FSH responses to LHRH, androgens had differential effects on the secretion of the two gonadotropins: marked inhibition of LH and stimulation of FSH secretion. Progesterone, on the other hand, while having no effect in the absence of estrogens, could reverse the stimulatory effect of estrogens on LH release while it led to a stimulation of FSH secretion. Estrogens and thyroid hormone exert respective stimulatory and inhibitory effects on TSH secretion by a direct action at the pituitary level. These effects appear to be mediated changes of the level of adenohy-pophyseal TRH receptors. A close correlation was observed between the specificity of binding of the dopamine agonist (3H)dihydroergocryptine and the control of prolactin release in cells in culture, thus supporting the physiological importance of the dopamine receptor in the control of prolactin release. The high degree precision of this system permits assessment of activity of not only dopamine agonists and antagonists, but also of compounds having mixed agonist-antagonistic activity. Preincubation of anterior pituitary cells with 17beta-estradiol not only stimulated basal and TRH-induced prolactin release but, more unexpectedly, led to an almost complete reversal of the inhibitory effect of dopamine agonists on prolactin secretion. Besides its own interest, the adenohypophyseal cell culture system could well be used as a model system for study of the interaction between estrogens and dopaminergic action.
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PMID:[Specific role of sex steroids on the pituitary level. Sex steroids and anterior pituitary secretion]. 20 92

An overview of the sex hormones is presented. Testosterone is a natural androgen produced in the testes, adrenal glands, and ovaries. It has anabolic as well as androgenic effects. Testosterone is used to treat inoperable breast cancer and osteoporosis, and to stimulate erythropoesis. Androgens are absolutely counterindicated in cases of prostate cancer. Estrone, estradiol, and estriol are natural estrogens produced in the ovaries, placenta, testes, and adrenal glands. These hormones also influence the production of gonadotropins by the pituitary gland. Estrogens are used to treat menopausal disorders, ovarial insufficiency, estrogen-independent breast cancer, prostate cancer, and in some cases pregnancy disorders. Estrogens and progestagens are 2 components used in oral contraceptives. Progesterone, a natural progestagen, is produced by the corpus luteum. It promotes the proliferation phase of the endometrium, fertilization, and nidation, and it works to maintain pregnancy. Progesterone is used to treat spontaneous abortion, corpus luteum insufficiency, and endometrial cancer.
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PMID:[Sex hormones]. 24 26

This presentation is limited to the three groups of steroid sex hormones which alone or in combination have been shown to be anabolic when used in farm animals. It seems essential for realistic evaluation of public health aspects of use of these hormones that the discussions include naturally occurring levels of the hormones. The following topics will be dealt with for each group of hormones: 1. Types and sources; 2. Production rates; 3. Plasma levels; 4. Tissue concentrations; 5. Metabolism and excretion. Gestagens. Progesterone and 20-dihydroprogesterones are mainly produced in ovaries and placenta. Production rates are estimated to 10 and 14 mg/24 hrs in pregnant goats and sheep, respectively. Plasma levels during the luteal phase are of the order of 2--10 ng/ml, during pregnancy somewhat higher. Muscular tissue from calves contain 0.25 mg/g. In dairy cows progesterone is excreted with the milk which contains up to 30 ng/ml; butterfat up to 300 mg/g. In ruminants progesterone is metabolized mainly to androgens excreted with faeces. In pigs large parts are metabolized to pregnanediols excreted with urine. Androgens. Testosterone is mainly secreted by testes. Boar testes also produce large amounts of dehydroepiandrosterone and its sulphate. Production rates have been estimated to be 10 mg and 40--50 mg/24 hrs. in boars and bulls respectively. Plasma levels in bulls and rams are generally 2--10 ng/ml, in boars 2--25 ng/ml. Adipose tissue levels up to 22 ng/g are reported for bulls. In ruminants epitestosterone seems to be a major metabolite excreted mainly with faeces. In boars, urinary 11-deoxy-17-ketosteroids are major metabolites of testicular dehydroepiandrosterone. Castration shows elimination to be rapid. Estrogens. 17beta-Estradiol and estrone are produced in ovaries and placenta and, in large amounts, in boar and stallion testes. Production rates in late pregnancy are estimated to 10 mg oestrone/24 hrs. in goats, 2 mg estrone and up to 28 mg 17beta-estradiol/24 hrs. in sheep. In cows much higher values are found. Boars and stallions produce huge amounts daily. Plasma levels in non-pregnant animals are at the pg/ml level. In late pregnancy levels of 2--4 thousand pg/ml are encountered in sows and cows, in sheep and goats lower levels. Calf muscular tissue contains up to 410 and 610 pg/g of estrone and 17beta-estradiol respectively. In muscle from pregnant heifers corresponding values were 120 and 860 pg/g in the 4th month and 2100 and 370 pg/g in the 9th month of pregnancy. Ruminants in large measure metabolize 17 beta-estradiol and estrone to 17alpha-estradiol which possesses low estrogenic activity. In pigs estrone dominates in blood and urine. Major routes of elimination arre with faeces in ruminants, with urine in pigs and horses. Elimination rates are high. Results obtained during the last few years clearly show that all three groups of steroid sex hormones occur in considerable concentrations in plasma and tissue...
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PMID:Endogenous anabolic agents in farm animals. 78 66

A great variety of drugs is reported to induce gallbladder disease by various pathogenetic mechanisms. Early epidemiological studies indicated a doubled risk of gallbladder disease in women taking oral contraceptives. More recent studies, however, have failed to confirm those findings; these conflicting results might be explained by the different methods used to define gallbladder disease. It was shown that the lithogenic index of the bile is increased during intake of oral contraceptives. Estrogens cause hypersecretion of cholesterol in bile, due to increase in lipoprotein uptake by the hepatocyte. Progesterone inhibits acyl coenzyme A-cholesterol acyl transferase (ACAT) activity, causing delayed conversion of cholesterol to cholesterol esters. Of the lipid lowering drugs, only clofibrate has been shown to increase the risk for gallstone formation. The other fibric acid derivatives have similar properties, but clinical experience is not as extensive. They seem to be inhibitors of the ACAT enzyme system, thereby rendering bile more lithogenic. Conflicting epidemiological data exist regarding the induction of acute cholecystitis by thiazide diuretics. Ceftriaxone, a third-generation cephalosporin, is reported to induce biliary sludge in 25 to 45% of patients, an effect which is reversible after discontinuing the drug. The sludge is occasionally a clinical problem. It was clearly demonstrated that this sludge is caused by precipitation of the calcium salt of ceftriaxone excreted in the bile. Long term use of octreotide is complicated by gallstone formation in approximately 50% of patients after 1 year of therapy, due to gallbladder stasis. Hepatic artery infusion chemotherapy by implanted pump is shown to be associated with a very high risk of chemically induced cholecystitis. Prophylactic cholecystectomy at the time of pump implantation is therefore advocated. Some drugs, such as erythromcyin or ampicillin, are reported to cause hypersensitivity-induced cholecystitis. Furthermore, there are reports on the influence of cyclosporin, dapsone, anticoagulant treatment, and narcotic and anticholinergic medication in causing gallbladder disease.
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PMID:Drug-induced gallbladder disease. Incidence, aetiology and management. 153 97

Estrogens (estrone [E1] and estradiol [E2]), their sulfates and progesterone receptor (PR) were evaluated in patients with uterine leiomyomata nontreated and treated with Decapeptyl (D-Trp6-gonadotropin-releasing hormone [GnRH]; Ipsen Biotech, Paris, France). Estrogen concentrations are very high in the leiomyoma (secretory phase, pg/g tissue [mean +/- SEM]: n = 10; E1: 147 +/- 24; E2: 850 +/- 116; E1-sulfate: 1,668 +/- 808; E2-sulfate: 718 +/- 126). Decapeptyl treatment provokes a significant decrease in E2 and particularly in E1 and E2 sulfates. Progesterone receptors were higher in the leiomyoma than in the myometrium; after a long treatment (3 to 4 months) a significant decrease in both tissues is observed. The decrease provoked by D-Trp6-GnRH on estrogens (unconjugated and sulfates) and in PR in the leiomyoma after long treatment, supports the hypothesis that estrogens are implicated in the cause of these tumors.
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PMID:Effect of Decapeptyl, an agonistic analog of gonadotropin-releasing hormone on estrogens, estrogen sulfates, and progesterone receptors in leiomyoma and myometrium. 214 Sep 91

Bird oviduct development is controlled by sex steroid hormones. Estrogens (E) induce cell proliferation, formation of tubular glands by epithelial cell evagination and cell differentiation. Progesterone (P) strongly increases secretory processes in E-treated quails, but inhibits cell proliferation and cell evagination. The balance between E and P is very critical for the development and morphogenesis of the oviduct. After six daily injections of low doses of E (10 micrograms day-1) and high doses of P (5 mg day-1) into ovariectomized quails, cell proliferation and secretory process are stimulated but cell evagination is totally inhibited and distribution of striated collagen is perturbed. Using antibodies against type I collagen the stroma, which is mainly composed of fibroblasts, is brightly stained, as are some regions within the epithelium. Electron microscopy shows that bundles of striated collagen fibrils appear in extracellular spaces between the lateral membranes of the epithelial cells or between the basal lamina and the epithelial basal membrane. After in situ hybridization using a 35S riboprobe specific for mRNA of the alpha 2 chain of type I collagen, mRNA was detected only in the fibroblasts of the stroma and not in epithelial cells. Furthermore electron microscope studies of collagen bundles in serial sections clearly show collagen fibrils passing through the basal lamina. It is assumed that the type I collagen between epithelial cells originates from mesenchymal cells. In the oviduct of immature birds or after physiological E + P stimulation, striated collagen is localized only in the stroma and never within the epithelium. These results indicate a modulation of extracellular matrix by sex steroid hormones in the quail oviduct.
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PMID:Origin of type I collagen localized within oviduct epithelium of quail hyperstimulated by progesterone. 235 4

The osteoporosis is a common problem among postmenopausal women causing at least 1.5 million fractures each year in the USA. Osteoporotic fractures are also common in women with other hypo-estrogenic states. Bone mass among females is fairly constant until the 5th decade and then begins to decline at all skeletal sites. This fall coincides with the gradual onset of ovarian failure. We were able to demonstrate reduced bone mass within three years of oopharectomy, but not in hysterectomized women with intact ovarian function. Estrogen therapy has been shown in a variety of studies to prevent the loss of bone that follows menopause. Cessation of therapy results in restoration of bone loss. The use of estrogen preparations in women with intact uterus requires the addition of a progestogen to protect against the deleterious long-term effects of unopposed estrogen on the endometrium. This does not interfere with the effects of estrogens on the skeleton, but does result in the return of menses, which reduces compliance among the older female population. In our group estrogens are usually prescribed orally (0.625 mg Premarin or its equivalent, or by another route (percutaneous transdermal), provided estradiol levels can be maintained in the modfollicular range. Estrogens are given continuously and- for women with intact uterus--a progestogen is added (Provera 5 mg per day) for 12-14 days each month, starting on the first day of each calendar month. All women should be followed by a gynecologist and have mammography appropriate to their age range. Reduced bone mass at the time of menopause probably indicated an individual who is at increased risk of osteoporosis and should be treated. As alternatives to estrogens calcitonin and diphosphonates can be prescribed to women who do not wish to take estrogen treatment.
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PMID:Estrogens in prevention and treatment of osteoporosis. 253 84

The safety and efficacy of a daily combination of micronized estradiol (E2) (0.7-1.05 mg) and progesterone (200-300 mg) were evaluated in ten menopausal women with moderate to severe vasomotor symptoms and/or vaginal atrophy over a 12-month study interval. For comparison, five similar women were placed on conjugated estrogens, 0.625 mg daily, and medroxyprogesterone acetate, 10 mg daily, for the first 10 days of each calendar month for 12 months. Patients were evaluated at 0, 1, 3, 6, and 12 months. Estrogens rose significantly from baseline in both groups (P less than .01). Progesterone increased significantly above baseline in the E2 and progesterone group (P less than .01), but did not change in the conjugated estrogens and medroxyprogesterone acetate users. All women on E2 and progesterone had a decrease in total cholesterol and an increase in high-density lipoprotein cholesterol from baseline (P less than .01). Those on conjugated estrogens and medroxyprogesterone acetate had no significant change from baseline in total cholesterol; however, they did have an increase in high-density lipoprotein cholesterol values (P less than .01). In the E2 and progesterone group, the endometrial histology became completely quiescent and there was no uterine bleeding after 6 months of observation. Four of five women on conjugated estrogens and medroxyprogesterone acetate continued regular withdrawal bleeding throughout the study period, but no endometrial hyperplasia was encountered. This study demonstrates that the daily administration of a combination of micronized E2 and progesterone results in symptomatic improvement, minimal side effects, an improved lipid profile, and amenorrhea without endometrial proliferation or hyperplasia in menopausal women.
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PMID:Menopausal hormone replacement therapy with continuous daily oral micronized estradiol and progesterone. 253 87


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