UMLS:C0001430 - FACTA Search

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Query: UMLS:C0001430 (adenoma)
21,222 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

5 cases of extremely rare testicular tumours are related in the subject, 2 cases of non hodgkinian malignant Lymphoma, 1 case of leiomyosarcoma in the testis and epididymis , Leydig, Cell. Tumour, Pick's Adenoma. These cases result from the study of a series of investigated testicular tumours between 1960 and 1970. This delay of publication enables the adequate set back for some cases. A 3% frequency of rare tumours in the study of the testicular tumours investigated from 1955 to 1978. The scientific study has been brought up to date, but it is necessary to remember the different possibilities of investigation and treatment which were very limited with regard to the large range of possibilities Actually at our disposal.
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PMID:[5 rare tumors of the testicle]. 667 83

A male patient followed from the age of 3 to 25 years was eventually diagnosed as having Proteus syndrome. He was born with linear epidermal nevi of the neck and forearm and presented with macrodactyly of the right hand and progressive hemihypertrophy of the right lower limb recurring after multiple reduction operations. The bone ends showed disorderly overgrowth of hyaline and fibrocartilage mixed with collagen and bone, and early differential diagnoses included Ollier's disease. The child also had vertebral anomalies, scoliosis, a bony protrusion of the cranial vertex, and strabismus. In the second decade he developed gyriform swelling of the soles, retinopathy, bilateral papillary cysts of the epididymis, and a giant cyst of the left kidney with complex glandular foci. At 22 years a 3-cm meningioma containing adipose tissue was resected, and at 24 years a 3-cm cellular nodule of the rete testis with hyperchromatic foci, probably an adenoma, was removed. The features of Proteus syndrome were those of hyperplasia and neoplasia of mostly mesodermal tissues. Unlike other reported cases, overgrowth of a finger recurred at 25 years.
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PMID:Pathology of osseous and genitourinary lesions of Proteus syndrome. 810 99

Gestational and lactational exposure to di(n-butyl) phthalate (DBP) at >/=250 mg/kg/day disrupts male rat reproductive development and function. Although this indicates an antiandrogenic mechanism, DBP and its biologically active metabolite do not interact with the androgen receptor (AR) in vitro. In the present study, we compared the effects of DBP and the antiandrogen flutamide using a shorter exposure during the prenatal period of male sexual differentiation in rats. Pregnant CD rats received DBP at 0, 100, 250, or 500 mg/kg/day po (n = 10) or flutamide at 100 mg/kg/day po (n = 5) from Gestation Days 12 to 21. In F1 males, DBP (500 mg/kg/day) and flutamide caused hypospadias; cryptorchidism; agenesis of the prostate, epididymis, and vas deferens; degeneration of the seminiferous epithelium; and interstitial cell hyperplasia of the testis. Flutamide and DBP (250 and 500 mg/kg/day) also produced retained thoracic nipples and decreased anogenital distance. Interstitial cell adenoma occurred at 500 mg DBP/kg/day in two males. The only effect seen at 100 mg DBP/kg/day was delayed preputial separation. In contrast to flutamide, DBP caused a low incidence of prostate agenesis and hypospadias with no vaginal pouch. The low incidence of DBP-induced intraabdominal testes contrasted with the high incidence of inguinal testes seen with flutamide. Thus prenatal male sexual differentiation is a sensitive period for the reproductive toxicity of DBP. A no observed adverse effect level was not established and the lowest observed (adverse) effect level was 100 mg/kg/day. Flutamide and DBP disrupted the androgen signaling necessary for male sexual differentiation but with a different pattern of antiandrogenic effects. DBP is an example of an environmental antiandrogen that disrupts androgen-regulated male sexual differentiation without interacting directly with the AR, as does flutamide.
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PMID:Disruption of androgen-regulated male reproductive development by di(n-butyl) phthalate during late gestation in rats is different from flutamide. 1103 75

Di(n-butyl) phthalate (DBP) is a commercially important plasticizer and ubiquitous environmental contaminant. Since previous, limited dose-response studies with DBP that reported alterations in male reproductive development and function failed to establish a NOAEL (no-observed-adverse-effect level), an extensive dose-response study was conducted. Pregnant CD rats were given DBP by gavage at 0, 0.5, 5, 50, or 100 mg/kg/day (n = 19-20) or 500 mg/kg/day (n = 11) from gestation day 12 to 21. In male offspring, anogenital distance was decreased at 500 mg DBP/kg/day. Retained areolas or nipples were present in 31 and 90% of male pups at 100 and 500 mg/kg/day, respectively. Preputial separation was not delayed by DBP treatment in males with normal external genitalia, but cleft penis (hypospadias) was observed in 5/58 rats (4/11 litters) at 500 mg/kg/day. Absent or partially developed epididymis (23/58 rats in 9/11 litters), vas deferens (16/58 animals in 9/11 litters), seminal vesicles (4/58 rats in 4/11 litters), and ventral prostate (1/58 animals) occurred at 500 mg/kg/day. In 110-day-old F(1) males, the weights of the testis, epididymis, dorsolateral and ventral prostates, seminal vesicles, and levator ani-bulbocavernosus muscle were decreased at 500 mg/kg/day. At 500 mg/kg/day, widespread seminiferous tubule degeneration was seen in 25/58 rats (in 9/11 litters), focal interstitial cell hyperplasia in 14/58 rats (in 5/11 litters), and interstitial cell adenoma in 1/58 rats (in 1/11 litters). For this 10-day prenatal (embryonic and fetal) exposure to DBP, the NOAEL and LOAEL (lowest-observed-adverse-effect level) were 50 and 100 mg/kg/day, respectively. This is currently the lowest NOAEL described for the toxicity of DBP.
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PMID:Dose-dependent alterations in androgen-regulated male reproductive development in rats exposed to Di(n-butyl) phthalate during late gestation. 1078 69

CDw60 is a recently described T-cell antigen, which functionally delivers a costimulatory signal in T-cell activation. In addition, CDw60 has been regarded as a melanoma-associated antigen. To date, only limited information exists on the distribution of CDw60 in other normal and pathologically altered tissues in human. In the present study, the expression of CDw60 was analysed immunohistologically in a large panel of formalin-fixed and paraffin-embedded normal and pathological human tissues. The antigen was detected in several normal tissues, such as epithelia of the reproductive system, exocrine and endocrine glands, glial cells and neurons of the central and peripheral nervous systems, and lymphoid cells. These showed different subcellular distribution patterns, i.e. (1) cell surface labelling of peripheral lymphocytes and lymphocytes of the lymph node and thymus, (2) diffuse cytosolic staining in lymphocytes, subpial glial processes, and the outer plexiform layer of the retina, (3) granular cytoplasmic staining associated with the Golgi apparatus in epithelial cells of certain endocrine and exocrine glands, of the ductus epididymis and deferens, neurons of the peripheral and central nervous system, and lymphocytes and megakaryocytes of the bone marrow. In exocrine glands, e.g. of the prostate and uterine corpus, CDw60-positive Golgi fields were located in the juxtaluminal cell compartment, thus reflecting a polarized distribution. In some malignant tumours, the neoplastic cells contained CDw60-immunolabelled Golgi complexes, which were disorderly distributed throughout the cytoplasm, thus reflecting a loss of epithelial polarity. Only in mammary carcinomas was abnormal cell surface labelling detected. A putative de novo expression of CDw60 was observed in pleomorphic adenoma and mucoepidermoid carcinoma of the parotid gland, seminoma, embryonal and teratocarcinoma of the testis, small cell carcinoma of the lung, and malignant melanoma. These results define the CDw60 determinant as a broadly distributed antigen within a large panel of normal human tissues. The antigen is also detectable in some previously undescribed benign and malignant tumours, which may give importance to CDw60 as a possible diagnostic marker.
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PMID:CDw60: an antigen expressed in many normal tissues and in some tumours. 1098 8

We investigated 115 testicular and 3 epididymal tumors and 6 cases of the complete androgen insensitivity syndrome (AIS) for the expression of inhibin-alpha, CD99, HEA125, PLAP, and chromogranin, using monoclonal antibodies and standard immunhistochemical techniques. Ihibin-alpha was detected in the neoplastic cells in 27 of 27 primary Leydig cell tumors (LCTs), 1 of 1 metastatic LCT, 6 of 20 Sertoli cell tumors (SCTs), 4 of 5 juvenile granulosa cell tumors (GCTs), and 2 of 5 unclassified sex cord-stromal tumors (USCSTs). Except for 2 choriocarcinomas, the choriocarcinomatous component of 1 mixed germ cell tumor, and a small focus of inhibin-positive syncytiotrophoblast in 1 embryonal carcinoma, inhibin-a immunoreactivity was not present in the neoplastic cells of the 38 remaining testicular germ cell tumors; 11 B-cell and 1 T-cell lymphomas; 1 granulocytic sarcoma; and 1 rhabdomyosarcoma of the testis; 1 adenoma of the rete testis, and 3 adenomatoid tumors of the epididymis. Inhibin-alpha immunoreactivity was present in the Sertoli cells and Leydig cells in 5 testicular hamartomas and in 1 Sertoli cell adenoma in 6 cases of AIS; both Sertoli and Leydig cells were also positive in the extranodular testicular parenchyma present in 2 of these cases. CD99 was detected in 10 of 15 primary LCTs, 1 of 7 SCTs, 3 of 5 JGCTs, and in 1 of 5 USCSTs but was not found in any tumor outside the sex cord-stromal category. HEA125 immunostaining was not detected in sex cord-stromal tumors; however, 3 of 12 seminomas, 3 of 12 embryonal carcinomas, 6 of 8 yolk sac tumors, and 1 of 2 teratomas were HEA125 positive. PLAP was not detected in sex cord-stromal tumors except for 4 of 15 primary LCTs but was present in most germ cell tumors. Chromogranin immunostaining was present in the sex cord-like element in 1 of 5 USCSTs, 1 of 8 YSTs, 1 of 2 teratomas, and in 1 of 1 rete adenoma, and in normal adjacent rete testis. In conclusion, although inhibin-alpha and PLAP, and, to a somewhat lesser extent, CD99 and HEA125 immunostaining are helpful in the differential diagnosis of certain testicular neoplasms that are difficult to distinguish on morphologic grounds, chromogranin is far less helpful in this context.
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PMID:Inhibin-alpha CD99, HEA125, PLAP, and chromogranin immunoreactivity in testicular neoplasms and the androgen insensitivity syndrome. 1101 71

Employing postpubertal testicular tissue, we determined the cDNA coding sequence of a truncated canine relaxin-like factor (RLF) consisting of a signal peptide of 28 amino acids (aa), a B-domain of 23 aa, a truncated C-domain of 34 aa, and an A domain of 26 aa, respectively. Within the B-domain of canine RLF, the putative relaxin receptor binding motif contained a single substitution with the C-terminal arginine replaced by a serine residue, and the putative RLF receptor binding motif was truncated. Leydig cells specifically expressed RLF in the normal postpubertal and cryptochid testis as well as in testicular Leydig cell adenoma. The epididymis was an additional source of RLF in the dog. In the female reproductive tract, expression of immunoreactive RLF and relaxin were compared. Within the ovary, RLF, but not relaxin, was detected in follicular theca interna and granulosa cells and the corpus luteum. In the nonpregnant uterus, luminal and glandular epithelium coexpressed RLF and relaxin. Uteroplacental tissue at early stages of gestation revealed RLF expression in the proliferative fetal villous cytotrophoblast and in maternal uterine cells. In the mature canine placenta, the trophoblast surrounding the maternal blood vessels and the hemophagous cytotrophoblast of the paraplacental zone expressed RLF. Canine relaxin was absent in the paraplacental areas. Western analysis of placental tissue extracts revealed the presence of specific immunoreactive bands likely resembling unprocessed and enzymatically cleaved RLF. Differential expression of RLF and relaxin appears to reflect distinct autocrine and paracrine functions of RLF in canine reproductive tissues.
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PMID:Canine relaxin-like factor: unique molecular structure and differential expression within reproductive tissues of the dog. 1115 45

In recent years advances have been made in the clinical and genetic aspects of von Hippel-Lindau disease (VHL). Retinal capillary hemangioma is the most common manifestation of VHL disease and, therefore, ophthalmologists are frequently involved in the care of patients with this disease. The incidence of VHL disease is approximately 1 in 40,000 live births. It is estimated that there are approximately 7000 patients with VHL disease in the USA. The inheritance of VHL disease is autosomal dominant with high penetrance. Depending on the clinical circumstances, retinal capillary hemangioma may be managed by observation, laser photocoagulation, cryotherapy, and plaque radiotherapy. Typical extraocular lesions associated with VHL disease are central nervous system hemangioma, renal cyst, renal carcinoma, pancreatic cysts and adenoma, pancreatic islet cell tumors, pheochromocytoma, endolymphatic sac tumor of the inner ear, and cystadenoma of the epididymis and the broad ligament. The life expectancy of affected individuals may be improved by early detection and treatment of varied manifestations with the use of surveillance protocols. Identification of the VHL gene on chromosome 3p25-26 has now made it possible for suspected individuals to undergo genetic testing with a high degree of accuracy. We review herein the ophthalmic manifestations and treatment of retinal capillary hemangioma and systemic findings of the VHL disease.
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PMID:von Hippel-Lindau disease. 1157 46

Methyleugenol is used as a flavoring agent in jellies, baked goods, nonalcoholic beverages, chewing gum, candy, pudding, relish, and ice cream. It is also used as a fragrance in perfumes, creams, lotions, detergents, and soaps. Methyleugenol has also been used as an insect attractant in eradication programs and as an anesthetic in rodents. Methyleugenol was nominated for testing because of its widespread use and because of its structural resemblance to safrole, a known carcinogen, and isosafrole and estragole. Male and female F344/N rats and B6C3F1 mice received methyleugenol (approximately 99% pure) in 0.5% methylcellulose by gavage for 14 weeks or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and mouse peripheral blood erythrocytes. 14-WEEK STUDY IN RATS: Groups of 9 or 10 male and 10 female F344/N rats were administered 0, 10, 30, 100, 300, or 1,000 mg methyleugenol/kg body weight in 0.5% methylcellulose by gavage 5 days per week for 14 weeks. A water control group of 10 male and 10 female rats received deionized water by gavage. All rats survived until the end of the study. The final mean body weights of 300 and 1,000 mg/kg males and of all dosed groups of females were significantly less than those of the vehicle controls. Erythrocyte microcytosis was demonstrated by decreased mean cell volumes in 300 mg/kg males and 1,000 mg/kg males and females. There was evidence of a thrombocytosis at all time points, demonstrated by increased platelet counts in the 100 mg/kg or greater groups. The serum activities of alanine aminotransferase and sorbitol dehydrogenase were increased in the 100 mg/kg or greater rats at various time points, suggesting hepatocellular injury. Additionally, bile acid concentrations were generally increased in the 300 and 1,000 mg/kg groups at all time points, consistent with cholestasis or altered hepatic function. A hypoproteinemia and hypoalbuminemia, evidenced by decreased total protein and albumin concentrations, occurred in rats in the 300 and 1,000 mg/kg groups at all time points. Liver weights of 100, 300, and 1,000 mg/kg males and 300 and 1,000 mg/kg females and testis weights of 1,000 mg/kg males were significantly increased. Increased incidences of liver lesions occurred in 300 and 1,000 mg/kg males and females and hepatocellular adenoma occurred in one 1,000 mg/kg male. The incidences of atrophy and chronic inflammation of the mucosa of the glandular stomach were significantly increased in rats administered 300 or 1,000 mg/kg. Increased incidences of adrenal gland cortical hypertrophy and/or cytoplasmic alteration in the submandibular gland occurred in the 100 mg/kg or greater groups. 14-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice received methyleugenol in 0.5% methylcellulose by gavage at doses of 0, 10, 30, 100, 300, or 1,000 mg/kg, 5 days per week for 14 weeks. A water control group of 10 male and 10 female mice received deionized water by gavage. All but one male and all females receiving 1,000 mg/kg died before the end of the study. The mean body weight gains of mice in the 300 mg/kg groups were significantly less than those of the vehicle controls. The only clinical finding was toxicity manifested as generalized morbidity in mice administered 1,000 mg/kg. Liver weights of 30, 100, and 300 mg/kg males and of 300 mg/kg females were significantly increased. Male mice administered 10 or 30 mg/kg had significantly lower cauda epididymis, epididymis, and testis weights; males receiving 100 mg/kg had significantly lower spermatozoal concentrations. Increased incidences of liver lesions occurred in 1,000 mg/kg males and 300 and 1,000 mg/kg females. The incidences of lesions of the glandular stomach were increased in one or more groups administered 30 mg/kg or greater. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats received methyleugenol in 0.5% methylcellulose by gavage at doses of 37, 75, or 150 mg/kg, 5 days per week for 105 weeks; groups of 60 male and 60 female rats received the 0.5% me60 female rats received the 0.5&percnt; methylcellulose vehicle only. Stop-exposure groups of 60 male and 60 female rats received 300 mg/kg in 0.5&percnt; methylcellulose by gavage for 52 weeks followed by just the 0.5&percnt; methylcellulose vehicle for the remaining 53 weeks of the study. Special study groups of 10 male and 10 female rats administered 36, 75, 150, or 300 mg/kg were designated for toxicokinetic studies. Survival and Body Weights: All 150 and 300 mg/kg males died before the end of the study, and survival of 150 mg/kg females was slightly less than that of the vehicle controls. Mean body weights of all dosed groups of rats were less than those of the vehicle controls throughout most of the 2-year study. Pathology Findings: Chemical-related liver neoplasms occurred in all dosed groups of rats and included hepatocellular adenoma, hepatocellular carcinoma, hepatocholangioma, and hepatocholangiocarcinoma; at 2 years, there were positive trends in the incidences of hepatocellular adenoma, carcinoma, and adenoma or carcinoma (combined) in core study rats and in the numbers of rats with multiple liver neoplasms. Nonneoplastic lesions included eosinophilic and mixed cell foci, hepatocellular hypertrophy, oval cell hyperplasia, cystic degeneration, and bile duct hyperplasia (females); the incidences of these lesions in dosed groups of male and female rats were increased at 6 months, 12 months, and/or 2 years. Chemical-related neoplasms and nonneoplastic lesions of the glandular stomach included benign and malignant neuroendocrine tumors in the 150 and 300 mg/kg groups and females in the 75 mg/kg group. In all dosed groups of rats at all time points, the incidences of mucosal atrophy were significantly greater than in the vehicle controls. Neuroendocrine cell hyperplasia was observed in females at 6 months and males and females at 12 months and at 2 years. In core study female rats, there was a positive trend in the incidences of squamous cell papilloma or carcinoma (combined) of the forestomach, and the incidence in the 150 mg/kg group exceeded the historical control range. The incidences of renal tubule proliferative lesions in male rats were suggestive of a neoplastic effect in the kidney. Therefore, additional step sections of the kidneys of male rats were prepared. The incidences of renal tubule hyperplasia and adenoma in the extended evaluation and the combined incidences of standard and step sections in the 75, 150, and 300 mg/kg groups were greater than those in the vehicle controls. The incidences of nephropathy were increased in all dosed groups of females, and the increase was significant in the 300 mg/kg group. In dosed groups of male rats, there was a positive trend in the incidences of malignant mesothelioma, and the incidences were significantly greater in 150 and 300 mg/kg males than in the vehicle controls. The incidences of mammary gland fibroadenoma in 75 and 150 mg/kg males were significantly increased. The incidences of fibroma of the subcutaneous tissue in 37 and 75 mg/kg males and the combined incidences of fibroma or fibrosarcoma in 37, 75, and 150 mg/kg males were significantly increased. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice received methyleugenol in 0.5&percnt; methylcellulose by gavage at doses of 0, 37, 75, or 150 mg/kg for 105 weeks. Special study groups of 10 male and 10 female mice administered 37, 75, or 150 mg/kg were designated for toxicokinetic studies. Survival and Body Weights: Survival of all dosed groups of male mice was similar to that of the vehicle controls. Survival of dosed groups of females was significantly less. Mean body weights of dosed mice were generally less than those of the vehicle controls throughout the studies. Pathology Findings: Chemical-related increases in the incidences of liver neoplasms and nonneoplastic lesions in mice included hepatocellular adenoma and carcinoma, hepatoblastoma, hepatocholangiocarcinoma, eosinophilic foci, oval cell hyperplasia, bile duct hyperplasia, hemosiderin pigmentation, chronic active inflammation, and hematopoietic cell proliferation. In all dosed groups ofmales and females, the incidences of hepatocellular neoplasms and the multiplicity of neoplasms were generally greater than in the vehicle controls. The incidences of hepatoblastoma were significantly increased in all dosed groups of females and slightly increased in 150 mg/kg males. Hepatocholangiocarcinoma was observed in 150 mg/kg females. The incidences of eosinophilic foci, oval cell hyperplasia, portal hypertrophy, hepatocyte necrosis, hematopoietic cell proliferation, bile duct hyperplasia, and hemosiderin pigmentation were significantly increased in two or more dosed groups of male and/or female mice. The incidences of glandular ectasia, mucosal atrophy, chronic active inflammation, epithelial hyperplasia, and neuroendocrine cell hyperplasia of the glandular stomach were increased in one or more dosed groups of male and female mice. In addition, malignant neuroendocrine tumors were observed in the glandular stomach of two 150 mg/kg male mice; one male in this group had a carcinoma. TOXICOKINETIC STUDIES: Methyleugenol is rapidly absorbed following oral administration to rats and mice. The kinetic data are consistent with rapid clearance from the blood, metabolism in the liver, and excretion of the parent and various metabolites in the urine. GENETIC TOXICOLOGY: Methyleugenol was not mutagenic in S. typhimurium strain TA98, TA100, TA1535, or TA1537, with or without exogenous metabolic activation (S9). In cytogenetic tests with cultured Chinese hamster ovary cells, methyleugenol induced sister chromatid exchanges in the presence of S9, but no induction of chromosomal aberrations was noted in cultured Chinese hamster ovary cells following exposure to methyleugenol, with or without S9. In vivo, no increase in the frequency of micronucleated normochromatic erythrocytes was seen in male or female mice administered methyleugenol by gavage for 14 weeks. PHYSIOLOGICALLY BASED PHARMACOKINETIC MODEL: A physiologically based pharmacokinetic (PBPK) model resulting from intravenous and oral exposure was created to characterize tissue concentrations of methyleugenol in rats and mice. Data used to create the model were obtained from the literature or from current studies. The primary conclusions that can be reached from the PBPK model are: 1) absorption of oral doses of methyleugenol in rats and mice is rapid and complete, 2) distribution of methyleugenol to tissues is not hampered by capillary permeability, and 3) metabolism of methyleugenol is saturable and must have some extrahepatic component in the mouse. Model-based plasma methyleugenol concentrations were not found to be good dosimeters for evaluating neoplasm dose-response data. CONCLUSIONS: Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenic activity of methyleugenol in male and female F344/N rats based on the increased incidences of liver neoplasms and neuroendocrine tumors of the glandular stomach in male and female rats and the increased incidences of kidney neoplasms, malignant mesothelioma, mammary gland fibroadenoma, and subcutaneous fibroma and fibroma or fibrosarcoma (combined) in male rats. A marginal increase in the incidence of squamous cell neoplasms of the forestomach may have been related to methyleugenol administration in female rats. There was clear evidence of carcinogenic activity of methyleugenol in male and female B6C3F1 mice based on the increased incidences of liver neoplasms. Neuroendocrine tumors of the glandular stomach in male mice were also considered related to methyleugenol administration. In male and female rats and mice, methyleugenol administration caused significant increases in nonneoplastic lesions of the liver and glandular stomach. Synonyms: 1-Allyl-1,2-dimethoxybenzene; 4-allylveratrole; 4-allyl-1,2-dimethoxy-benzene; 1,2-dimethoxy-4-allylbenzene; 3,4-dimethoxyallylbenzene; ENT 21040; 1-(3,4-dimethoxyphenyl)-2-propene; eugenol methyl ether; 1,3,4-eugenol methyl ether; veratrole methyl ether.
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PMID:NTP Toxicology and Carcinogenesis Studies of Methyleugenol (CAS NO. 93-15-2) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1256 49

Oxymetholone is a synthetic anabolic steroid used to treat a variety of conditions, including hypogonadism and delayed puberty. It is also used to correct hereditary angioneurotic edema, manage carcinoma of the breast, promote a positive nitrogen balance following injury or surgery, and stimulate erythropoiesis. Considerable amounts of androgens are consumed by athletes in attempts to improve athletic performance. The National Institute of Environmental Health Sciences and the National Cancer Institute nominated oxymetholone for study based on its extensive illicit pharmaceutical use and the limited evidence that it is a potential human carcinogen. Male and female F344/N rats received oxymetholone (greater than 99% pure) in 0.5% methylcellulose by gavage for 16 days, 14 weeks, or 2 years, and male and female B6C3F1 mice received oxymetholone in 0.5% methylcellulose by gavage for 16 days or 14 weeks. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and mouse peripheral blood erythrocytes. 16-DAY STUDY IN RATS: Groups of five male and five female F344/N rats were administered 0, 160, 315, 625, 1,250, or 2,500 mg oxymetholone/kg body weight in 0.5% methylcellulose by gavage for 16 days. All male rats survived to the end of the study; one 2,500 mg/kg female died on day 14. The mean body weights of all dosed groups of males were significantly less than those of the vehicle controls, while those of 160 and 315 mg/kg females were significantly greater. 16-DAY STUDY IN MICE: Groups of five male and five female B6C3F1 mice were administered 0, 320, 630, 1,250, 2,500, or 5,000 mg/kg in 0.5% methylcellulose by gavage for 16 days. All mice survived to the end of the study. The final mean body weights of all dosed groups of females were greater than those of the vehicle controls. 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were administered 0, 80, 160, 315, 625, or 1,250 mg/kg in 0.5% methylcellulose by gavage for 14 weeks. One male rat each in the 625 and 1,250 mg/kg groups died before the end of the study. The mean body weights of males administered 160 mg/kg or greater were significantly less than those of the vehicle controls; in contrast, the mean body weights of all dosed groups of females were significantly greater. A dose-related erythrocytosis, evidenced by increases in erythrocyte counts, total hemoglobin concentrations, and hematocrit values, occurred in dosed groups of rats at week 14. A dose-related hypocholesterolemia occurred at all time points in all dosed groups of rats. Dose- and time-related decreases in 5 -nucleotidase activity occurred in treated rats. There was a transient, treatment-related increase in the activity of alanine aminotransferase in males and females. For male rats administered oxymetholone, cauda epididymis, epididymis, and testis weights and spermatid counts and total spermatid heads per testis were significantly less than those of the vehicle controls, and total spermatid heads per gram testis were significantly greater. Female rats in the 80 mg/kg group spent more time in diestrus and less time in estrus than did the vehicle controls. Kidney weights of males and females and liver and uterus weights of females were increased compared to vehicle controls in rats that received 315 mg/kg or greater; thymus weights of males and females and sartorius muscle and testis weights of males were less. Compared to the vehicle controls, rats that received 160 mg/kg or greater had increased incidences of nonneoplastic lesions of the kidney and mammary gland, and the incidences of hydrometra of the uterus and dysgenesis of the ovary were increased in dosed groups of females. Female rats administered 315 mg/kg or greater had increased incidences of cytoplasmic vacuolization of the adrenal gland and myocardial degeneration of the heart. The severities of these lesions generally increased with increasing dose. 14-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were administered 0, 160, 320, 630, 1,250, or 2,500 mg/kged 0, 160, 320, 630, 1,250, or 2,500 mg/kg in 0.5&percnt; methylcellulose by gavage for 14 weeks. All mice administered oxymetholone survived until the end of the study. The mean body weights of all dosed groups were similar to those of the vehicle controls. The percentages of motile sperm in 1,250 and 2,500 mg/kg males were significantly less than those of the vehicle controls. The estrous cycle lengths of 630, 1,250, and 2,500 mg/kg females were significantly longer, and females in the 1,250 and 2,500 mg/kg groups spent more time in diestrus and less time in estrus. Kidney and liver weights of males and females were greater and thymus weights of females were less than those of the vehicle controls. All dosed females had hyperplasia of the clitoral gland, metaplasia of the parietal layer epithelium of the Bowman's capsule in the kidney, and cytoplasmic alteration of the submandibular gland; these lesions were not observed in the vehicle control group. The incidences of hypoplasia of the ovary in 320 mg/kg or greater females and of parotid gland atrophy in 1,250 and 2,500 mg/kg females were increased. The results of the 14-week oral gavage studies were generally similar in rats and mice, but rats were much more sensitive to oxymetholone. Because it was not likely that a long-term mouse study would provide significant additional toxicity information, the NTP decided to conduct a 2-year study in rats only. 2-YEAR STUDY IN RATS: Groups of 90 male F344/N rats were administered 0, 3, 30, or 150 mg/kg in 0.5&percnt; methylcellulose by gavage, and 90 female F344/N rats were administered 0, 3, 30, or 100 mg/kg in 0.5&percnt; methylcellulose by gavage for up to 104 weeks, with 9 or 10 rats per group evaluated at 3, 6, 12, or 18 months. Survival and Body Weights: Survival of all dosed groups was similar to that of the vehicle controls. The mean body weights of the 30 mg/kg male group were generally within 10&percnt; of those of the vehicle controls, but those of the 150 mg/kg group were markedly decreased. Mean body weights of 3 and 30 mg/kg females were generally greater than those of the vehicle controls throughout the study. Determinations of Oxymetholone in Plasma: The concentrations of oxymetholone in plasma of male and female rats receiving 3 mg/kg for 6, 12, or 18 months were generally below the limits of quantification; therefore, all plasma concentrations in the 3 mg/kg group are considered to be estimates (Table 8). The plasma concentrations at 30 mg/kg were approximately one order of magnitude greater than those of the estimates for males and females receiving 3 mg/kg. There were no dose-related differences in plasma concentrations in female rats receiving 30 or 100 mg/kg, but plasma concentrations in males were significantly elevated in the 150 mg/kg group. It was concluded that oxymetholone kinetics was saturated at 30 mg/kg in female but not male rats. Pathology Findings: A wide spectrum of neoplasms and nonneoplastic lesions was seen in rats administered oxymetholone for 2 years. The incidences of hepatocellular adenoma and hepatocellular adenoma or carcinoma (combined) were significantly increased in 100 mg/kg females as were the incidences of basophilic and clear cell foci in 150 mg/kg males and 100 mg/kg females compared to vehicle controls. The incidences of alveolar/bronchiolar adenoma and adenoma or carcinoma (combined) were significantly increased in 30 mg/kg females. The incidences of mineralization in the lung of 150 mg/kg males and 30 and 100 mg/kg females were significantly increased. The incidence of keratoacanthoma was increased in 30 mg/kg females, and the combined incidence of squamous cell papilloma, keratoacanthoma, basal cell adenoma, squamous cell carcinoma, or carcinoma of the sweat gland was significantly increased in 100 mg/kg females. The incidences of subcutaneous tissue fibroma and fibroma or fibrosarcoma (combined) were significantly increased in 3 mg/kg males. At 2 years, the incidences of benign pheochromocytoma and benign or malignant pheochromocytoma (combined) of the adrenal gland in 150 mg/kg males and medullary hyperplasia in 100 mg/kg females were significantly increased. The incidences of cytoplasmic vacuolization of adrenal cortical cells were significantly increased in 30 and 150 mg/kg males at 18 months and 2 years and in 100 mg/kg females beginning at 12 months and in 30 mg/kg females at 2 years. The incidences of renal tubule adenoma in 3 and 150 mg/kg males were slightly increased. An extended evaluation of the kidney was conducted, and additional incidences of renal tubule adenoma were observed in step sections in vehicle control and dosed male rats. The combined single- and step-section incidence of renal tubule adenoma was significantly increased in 3 mg/kg males. The incidences of nephropathy were significantly increased in 30 and 150 mg/kg males at 2 years and in 100 mg/kg females beginning at 3 months. The severities of nephropathy were significantly increased in dosed groups of males at 2 years and in 100 mg/kg females at 18 months and 2 years. The incidences of mineralization of the kidney were significantly increased in 150 mg/kg males at all time points. The incidences of ovarian dysgenesis were significantly increased in 100 mg/kg females beginning at 3 months and in 30 mg/kg females beginning at 6 months, and severities increased with increasing dose. The incidences of chronic myocardial degeneration (cardiomyopathy) were significantly increased in 100 mg/kg females at 6 months and 2 years and the severity was increased at 2 years. The incidences of lobular hyperplasia were increased in 150 mg/kg males at 18 months and 2 years and in 30 and 100 mg/kg females at all time points. The incidences of seminiferous tubule degeneration were significantly increased in 30 and 150 mg/kg males at 2 years, and the incidences of mineralization of the testis were increased in 150 mg/kg males at 12 months and in 30 mg/kg males at 18 months and at 2 years. Decreased incidences of neoplasms occurred in male and female rats. The incidence of uterine stromal polyp or stromal sarcoma (combined) was significantly decreased in 100 mg/kg females at 2 years. The incidences of mammary gland fibroadenoma and fibroadenoma or carcinoma (combined) were significantly decreased in all dosed groups of females. The incidences of pituitary gland pars distalis adenoma were significantly decreased in 30 and 100 mg/kg females at 2 years. The incidences of testicular interstitial cell adenoma were significantly decreased in 30 and 150 mg/kg males at 18 months and in all dosed groups at 12 months and 2 years. The incidences of mononuclear cell leukemia were significantly decreased in 30 and 150 mg/kg males and 100 mg/kg females at 2 years. GENETIC TOXICOLOGY: Oxymetholone was not mutagenic in S. typhimurium strain TA97, TA98, TA100, or TA1535, with or without S9 metabolic activation. It did not induce chromosomal aberrations in cultured Chinese hamster ovary cells, with or without S9, and no increase in the frequency of micronucleated normochromatic erythrocytes was noted in peripheral blood samples from male or female mice treated for 14 weeks with oxymetholone. CONCLUSIONS: Under the conditions of this 2-year gavage study, there was equivocal evidence of carcinogenic activity of oxymetholone in male F344/N rats based on increased incidences of subcutaneous tissue fibromas and fibromas or fibrosarcomas (combined) of the skin, variably increased incidences of benign and benign or malignant pheochromocytomas (combined) of the adrenal gland, and increased incidences of renal tubule adenomas. There was clear evidence of carcinogenic activity of oxymetholone in female F344/N rats based on increased incidences of hepatocellular neoplasms. Increased incidences of alveolar/bronchiolar neoplasms and skin neoplasms in female rats were also related to oxymetholone administration. Decreased incidences of alveolar/bronchiolar neoplasms and testicular interstitial cell adenomas in males; uterine stromal polyps or stromal sarcomas (combined), mammary gland neoplasms, and pituitary gland pars distalis adenomas in females; and mononuclear cell leukemia in males and females were related to oxymetholone administration. In addition, gavage administration of oxymetholone to male and female F344/N rats resulted in a spectrum of nonneoplastic effects frequently reported with administration of synthetic anabolic androgens. Synonyms: Adroidin; anadroyd; anasteron; anasteronal; anasterone; androstan-3-one, androstano[2,3-c]1,2,5-oxadiazol-17-ol, 17-methyl-, (5-a,17-b)-; becorel; 4,5-dihydro-2-hydroxymethylene-17-a-methyltestosterone; dynasten; HMD; 17b-hydroxy-2- (hydroxymethyl)-17-methyl-5-a-androstan-3-one; 17-hydroxy-2-(hydroxymethylene)-17-methyl-(5-a,17-b)-; 17-hydroxy- 2-(hydroxymethylene)-17-methyl-5-a-17-b-androst-3-one; 17b-hydroxy-2-(hydroxymethylene)-17-a-methyl-5-a-androstan-3-one; 17b-hydroxy-2-(hydroxymethylene)-17-methyl-5a-androstan-3-one; 17-hydroxy-2-(hydroxymethylene)-17-methyl-5-a-17- b-androstan-3-one; 17b-hydroxy-2-hydroxymethylene-17a-methyl-3-androstanone; 2-hydroxymethylene-17-a-methyl-5- a-androstan-17-b-ol-3-one; 2-hydroxymethylene-17a-methyl dihydrotestosterone; 2-hydroxymethylene-17-a-methyl-17-b- hydroxy-3-androstanone; methabol; 17a-methyl-2-hydroxymethylene-17-hydroxy-5-a-androstan-3-one; oximetholonum; oximetolona; oxitosona-50; oxymethenolone; roboral; zenalosyn Trade names: Adroyd; Anadrol; Anapolon; Anapolon 50; Nastenon; Pardroyd; Pavisoid; Plenastril; Protanabol; Synasteron
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PMID:NTP Toxicology and Carcinogenesis Studies of Oxymetholone (CAS NO. 434-07-1) in F344/N Rats and Toxicology Studies of Oxymetholone in B6C3F1 Mice (Gavage Studies). 1257 78

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