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Toxicologic Pathology 2005A selective estrogen receptor modulator (SERM) is a nonsteroidal compound with tissue specific estrogen receptor (ER) agonist or antagonist activities. In animals, SERMs...
A selective estrogen receptor modulator (SERM) is a nonsteroidal compound with tissue specific estrogen receptor (ER) agonist or antagonist activities. In animals, SERMs may produce morphologic changes in hormonally-sensitive tissues like the mammary gland. Mammary glands from female rats given the SERM LY2066948 hydrochloride (LY2066948) for 1 month at >or= 175 mg/kg had intralobular ducts and alveoli lined by multiple layers of vacuolated, hypertrophied epithelial cells, resembling in part the morphology of the normal male rat mammary gland. We hypothesized that these SERM-mediated changes represented an androgen-dependent virilism of the female rat mammary gland. To test this hypothesis, the androgen receptor antagonist flutamide was co-administered with LY2066948 (175 mg/kg) to female rats for 1 month. Female rats given SERM alone had hyperandrogenemia and the duct and alveolar changes described here. Flutamide cotreatment did not affect serum androgen levels but completely blocked the SERM-mediated mammary gland change. In the mouse, a species that does not have the sex-specific differences in the mammary gland observed in the rat, SERM treatment resulted in hyperandrogenemia but did not alter mammary gland morphology. These studies demonstrate that LY2066948 produces species-specific, androgen-dependent mammary gland virilism in the female rat.
Topics: Androgen Antagonists; Androgens; Animals; Drug Combinations; Estradiol; Female; Flutamide; Luteinizing Hormone; Male; Mammary Glands, Animal; Mice; Naphthalenes; Piperidines; Rats; Rats, Inbred F344; Selective Estrogen Receptor Modulators; Sex Factors; Species Specificity; Virilism
PubMed: 16263696
DOI: 10.1080/01926230500343902 -
The Journal of Clinical Endocrinology... Mar 1999Idiopathic hirsutism may result from an increase in the androgen receptor (AR)-mediated sensitivity of the hair follicle. The AR gene is located on the X-chromosome and...
Idiopathic hirsutism may result from an increase in the androgen receptor (AR)-mediated sensitivity of the hair follicle. The AR gene is located on the X-chromosome and contains a highly polymorphic trinucleotide repeat (CAGn) in its first exon, whose length and methylation pattern affect both AR expression and function. We analyzed these CAG repeats in the genomic DNA from 16 nonhyperandrogenic hirsute patients (Ferriman score: 16 +/- 4.7, mean +/- SD) and 10 normal controls (Ferriman score: 3 +/- 1.4), who were similar in their hormonal profiles. We found no difference in the number of CAG repeats between hirsute patients and controls, and no correlation between number of repeats and the Ferriman score or hormonal values. However, after DNA digestion with methylation-sensitive HpaII and measurement of the optical density, we found a marked decrease in the hirsute group (P < 0.0001), which was greater than in the control group (P = 0.0003). In addition, in the hirsute patients, the shorter of the two alleles was preferentially less methylated (P = 0.007), suggesting skewing of X-chromosome inactivation in the patients but not in the controls. When the mean optical density of both alleles was correlated with the Ferriman score, we observed a significant negative correlation (P = 0.02, r = -0.45), which became stronger when the shorter alleles were analyzed separately (P = 0.01; r = 0.48). We conclude that nonhyperandrogenic hirsutism is associated with skewing of X-chromosome inactivation in peripheral blood lymphocytes. This leads to the longer of the two AR alleles being preferentially methylated, allowing for the shorter (and presumably, more functional) allele to be expressed on the active X-chromosome. Further studies need to be performed to investigate whether this phenomenon is present in androgen-sensitive tissues in these patients.
Topics: Adult; Androgens; Base Sequence; Drug Resistance; Female; Hirsutism; Humans; Microsatellite Repeats; Receptors, Androgen; X Chromosome
PubMed: 10084600
DOI: 10.1210/jcem.84.3.5540 -
General and Comparative Endocrinology Feb 2015Androgen receptors (ARs) mediate the physiological effects of androgens in vertebrates. In fishes, AR-mediated pathways can be modulated by aquatic contaminants,...
Androgen receptors (ARs) mediate the physiological effects of androgens in vertebrates. In fishes, AR-mediated pathways can be modulated by aquatic contaminants, resulting in the masculinisation of female fish or diminished secondary sex characteristics in males. The Murray-Darling rainbowfish (Melanotaenia fluviatilis) is a small-bodied freshwater teleost used in Australia as a test species for environmental toxicology research. We determined concentration-response profiles for selected agonists and antagonists of rainbowfish ARα and ARβ using transient transactivation assays. For both ARα and ARβ, the order of potency of natural agonists was 11-ketotestosterone (11-KT)>5α-dihydrotestosterone>testosterone>androstenedione. Methyltestosterone was a highly potent agonist of both receptors relative to 11-KT. The relative potency of the veterinary growth-promoting androgen, 17β-trenbolone, varied by more than a factor of 5 between ARα and ARβ. The non-steroidal anti-androgen bicalutamide exhibited high inhibitory potency relative to the structurally related model anti-androgen, flutamide. The inhibitory potency of the agricultural fungicide, vinclozolin, was approximately 1.7-fold relative to flutamide for ARα, but over 20-fold in the case of ARβ. Fluorescent protein tagging of ARs showed that the rainbowfish ARα subtype is constitutively localised to the nucleus, while ARβ is cytoplasmic in the absence of ligand, an observation which agrees with the reported subcellular localisation of AR subtypes from other teleost species. Collectively, these data suggest that M. fluviatilis ARα and ARβ respond differently to environmental AR modulators and that in vivo sensitivity to contaminants may depend on the tissue distribution of the AR subtypes at the time of exposure.
Topics: Androgen Antagonists; Androgens; Animals; Australia; Female; Fishes; Male; Microscopy, Fluorescence; Oxazoles; Phylogeny; Protein Isoforms; Receptors, Androgen; Substrate Specificity; Transcriptional Activation; Trenbolone Acetate; Virilism
PubMed: 25644213
DOI: 10.1016/j.ygcen.2015.01.024 -
Zeitschrift Fur Die Gesamte Innere... Oct 1979Endokrine active tumours of the adrenal cortex are rare diseases in man. Benign as well as malignant tumours of the adrenal cortex can alone excrete cortisol,...
Endokrine active tumours of the adrenal cortex are rare diseases in man. Benign as well as malignant tumours of the adrenal cortex can alone excrete cortisol, aldosterone, androgens or oestrogens. More frequent are, however, tumours with a mixed incretion. Publications about tumours forming sexual hormones are above all descriptions of individual cases. After a short explanation of the most important clinical, diagnostic and therapeutic aspects on androgen-producing tumours of the adrenal cortex four own cases are discussed.
Topics: Adrenal Cortex Neoplasms; Adult; Aged; Aldosterone; Androgens; Estrogens; Female; Humans; Hydrocortisone; Middle Aged; Radiography; Virilism
PubMed: 549298
DOI: No ID Found -
The Journal of Steroid Biochemistry and... Apr 1993The data reviewed in this paper suggest that a factor other than ACTH which is suppressible by treatment with glucocorticoid, plays an essential role in the regulation... (Review)
Review
The data reviewed in this paper suggest that a factor other than ACTH which is suppressible by treatment with glucocorticoid, plays an essential role in the regulation of adrenal androgen production. Adrenal androgen biosynthesis probably takes place exclusively in specific androgen-secreting cells. That availability of androgen substrate alone e.g. 17OH-progesterone, is not sufficient to lead to hyperandrogenaemia is clear from data which was obtained from treated patients with the 21 hydroxylase deficiency type of congenital adrenal hyperplasia. In pituitary ACTH excess, cortisol production is relatively greater than that of androgens. In contrast, in some patients with ectopic ACTH production, the excess production of androgens is relatively greater than that of cortisol. Taken together, these observations suggest that a factor closely related to ACTH, i.e. a POMC fragment other than ACTH, plays an important role in the regulation of adrenal androgen production, that in Cushing's disease the ratio of ACTH to the androgen-stimulating fragment increases, and that in some patients with ectopic ACTH syndrome the ratio of ACTH to the alternative fragment may be decreased. In addition, the data reviewed are consistent with a model for the pathogenesis of idiopathic hirsutism and polycystic ovary syndrome whereby mild adrenal androgen excess is primary to the development of these disorders. However, the identity of the putative adrenal androgen stimulating hormone has yet to be established.
Topics: Adrenal Hyperplasia, Congenital; Adrenocortical Hyperfunction; Androgens; Cushing Syndrome; Female; Hirsutism; Humans; Male; Polycystic Ovary Syndrome
PubMed: 8481335
DOI: 10.1016/0960-0760(93)90130-o -
Clinical Endocrinology Apr 1994
Review
Topics: Adult; Alopecia; Androgens; Animals; Child; Female; Hair; Hirsutism; Humans; Male; Pregnancy; Sex Characteristics
PubMed: 8187311
DOI: 10.1111/j.1365-2265.1994.tb02483.x -
Annual Review of Medicine 1964
Review
Topics: Adrenal Cortex Hormones; Adrenal Gland Neoplasms; Adrenal Insufficiency; Androgens; Asian People; Black People; Blood Chemical Analysis; Cysts; Disorders of Sex Development; Estrogens; Female; Genetics, Medical; Gonadal Steroid Hormones; Hirsutism; Humans; Hypertrichosis; Ovarian Neoplasms; Syndrome; Testosterone; Urine; Virilism; White People
PubMed: 14139936
DOI: 10.1146/annurev.me.15.020164.001531 -
California Medicine Feb 1967In normal females, androstenedione from both the adrenal cortex and ovary, as a result of peripheral conversion, is the source of the majority of biologically active...
In normal females, androstenedione from both the adrenal cortex and ovary, as a result of peripheral conversion, is the source of the majority of biologically active testosterone in the circulation. The control of the secretion of precursor steroid and androgenic hormone (testosterone) in females is not clear at this time. There are a number of possibilities to explain various types of hirsutism and virilization. The presence of true virilization indicates a significant disorder and requires complete investigation. The presence of increased amounts of 17-ketosteroids in the urine implicates the adrenal cortex as a source of the pathologic manifestations. The suppressibility of elevated 17-ketosteroids with cortisol analogues aids in distinguishing between adrenal hyperplasia and autonomous neoplasm of the adrenal cortex. By far the most common entity in this area is simple hirsutism without virilization. Although our knowledge of this disorder is quite incomplete, conservative management is indicated. Further progress in this field is rapidly occurring. An informed clinician can do an adequate job of diagnosis and treatment with the clinical and laboratory tools generally available.
Topics: Androgens; Female; Hirsutism; Humans; Virilism
PubMed: 6044295
DOI: No ID Found -
Special Topics in Endocrinology and... 1984Hirsutism in women may be defined as excessive thick (terminal) hair growth in facial and body regions. It is one of the early manifestations of virilization that... (Review)
Review
Hirsutism in women may be defined as excessive thick (terminal) hair growth in facial and body regions. It is one of the early manifestations of virilization that correlate closely with elevated testosterone production. Testosterone production rates in normal women average 0.2 mg/day, with 25% secreted by the ovaries, 25% by the adrenals, and 50% arising from the peripheral metabolism of prehormones, notably androstenedione. Increased testosterone from adrenal and/or ovarian sources induces 5 alpha-reductase activity within the susceptible hair follicle. This results in the local production of dihydrotestosterone, the potent androgen that is likely responsible for the growth and stimulation of the hair follicle that leads to hirsutism. Activation of the hair follicle by androgens provides a secondary pathway for testosterone metabolism, unfortunately at the expense of undesirable hair growth. Although virilization in women may be caused by exogenous androgens, it occurs primarily from diseases of the adrenals or ovaries. Androgen-producing tumors of the adrenals cause virilization in association with excessive production of a wide variety of C19 androgens. In contrast, ovarian tumors tend to secrete a narrower range of androgens and their presence may be more occult. The most common causes of hirsutism in women arise from nontumorous states, chiefly ovarian in origin. The androgenized ovary syndrome represents a spectrum of abnormalities ranging from idiopathic hirsutism to the polycystic ovary syndrome to ovarian hyperthecosis. These states are associated with mild to severe abnormalities of androgen production and concomitant mild to severe abnormalities of ovarian histology. The pathogenesis of these abnormalities is still speculative, but appears to be related to increased pulsatile and tonic secretion of LH with ovarian hyperstimulation. Of the various laboratory tests to evaluate hirsutism, simple measurements of plasma testosterone, free testosterone, and most recently androstanediol glucuronide seem to provide the best chemical evidence of androgen abnormalities. Treatment of hirsutism/virilism in women is difficult and frequently unsatisfactory. At present, treatment schemes include local methods, suppression of androgens via glucocorticoids or oral contraceptives, and antiandrogens.
Topics: Adrenal Cortex Neoplasms; Adrenal Glands; Androgens; Contraceptives, Oral; Female; Glucocorticoids; Hirsutism; Humans; Ovarian Neoplasms; Ovary; Palliative Care; Progestins; Testosterone; Virilism
PubMed: 6084314
DOI: No ID Found -
Endocrinology Jan 2012One of the hallmarks of polycystic ovary syndrome (PCOS) is increased ovarian androgen secretion that contributes to the ovarian, hormonal, and metabolic features of...
One of the hallmarks of polycystic ovary syndrome (PCOS) is increased ovarian androgen secretion that contributes to the ovarian, hormonal, and metabolic features of this condition. Thecal cells from women with PCOS have an enhanced capacity for androgen synthesis. To investigate whether this propensity is a potential cause, rather than a consequence, of PCOS, we used an ovine prenatal androgenization model of PCOS and assessed ewes at 11 months of age. Pregnant Scottish Greyface ewes were administered 100 mg testosterone propionate (TP) or vehicle control twice weekly from d 62 to 102 of gestation, and female offspring (TP = 9, control = 5) were studied. Prenatal TP exposure did not alter ovarian morphology or cyclicity, or plasma androgen, estrogen, and gonadotropin concentrations, at this stage. However, follicle function was reprogrammed in vivo with increased proportions of estrogenic follicles (P < 0.05) in the TP-exposed cohort. Furthermore, in vitro the thecal cells of follicles (>4 mm) secreted more LH-stimulated androstenedione after prenatal androgenization (P < 0.05), associated with increased basal expression of thecal StAR (P < 0.01), CYP11A (P < 0.05), HSD3B1 (P < 0.01), CYP17 (P < 0.05), and LHR (P < 0.05). This provides the first evidence of increased thecal androgenic capacity in the absence of a PCOS phenotype, suggesting a thecal defect induced during fetal life.
Topics: Androgens; Androstenedione; Animals; Cholesterol Side-Chain Cleavage Enzyme; Disease Models, Animal; Female; Gene Expression; Humans; Hydroxysteroid Dehydrogenases; Hypothalamo-Hypophyseal System; In Vitro Techniques; Ovary; Phosphoproteins; Polycystic Ovary Syndrome; Pregnancy; Prenatal Exposure Delayed Effects; RNA, Messenger; Receptors, LH; Sheep, Domestic; Steroid 17-alpha-Hydroxylase; Testosterone Propionate; Theca Cells; Virilism
PubMed: 22087026
DOI: 10.1210/en.2011-1607