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Food Safety (Tokyo, Japan) Dec 2017Food Safety Commission of Japan (FSCJ) conducted a risk assessment of melengestrol acetate (MGA, CAS No. 2919-66-6), a synthetic hormone, based on results from various...
Food Safety Commission of Japan (FSCJ) conducted a risk assessment of melengestrol acetate (MGA, CAS No. 2919-66-6), a synthetic hormone, based on results from various studies. MGA was recognized to have no genotoxicity relevant to human health, and it enabled FSCJ to specify an acceptable daily intake (ADI) in the assessment. studies using various human hormone-receptors showed that MGA exerts biological action primarily as progestogens and secondarily as glucocorticoids. Major adverse effects of MGA observed were mammary gland hyperplasia, endometrial hyperplasia, and a lack of corpora lutea, accompanying the elevated level of serum prolactin. Increased incidence of mammary gland tumor was observed in C3Han/f mice at the dose of 1.5 mg/kg bw/day in a carcinogenicity study. The increase was presumably due to MGA-induced hyperprolactinemia, but not a direct effect of MGA from the experiment, using a prolactin inhibitor. Inhibitions of estrus and ovulation, in addition to dystocia, were observed in female animals in the reproductive and developmental toxicity studies. Malformations such as cleft palate, clubfoot, umbilical hernia, and defective skeletal ossification were observed in rabbits at doses of 0.8 and 1.6 mg/kg bw/day in a developmental toxicity study. However, these were likely due to the corticosteroidal (glucocorticoid) action of MGA. The no-observed-adverse-effect level (NOAEL) was obtained from a rhesus monkey study given orally 1.5 µg/kg bw/day of MGA over the one menstrual-cycle. The value was, however, the result of the study using the large common ratio of 10. In another study, the lowest-observed-adverse-effect level (LOAEL) of 5 µg/kg bw/day, obtained from a cynomolgus monkey given MGA over the three menstrual-cycles. The LOAEL value was estimated close to the biological threshold, because of no obvious hormonal disorders despite of minimal change of menstrual cycle. Therefore, FSCJ considered it appropriate to specify an ADI on the basis of the LOAEL obtained from a cynomolgus monkey study over the three menstrual-cycles, and to add an additional safety factor of 2. Consequently, FSCJ specified the ADI of 0.025 µg/kg bw/day by applying a safety factor of 200 to the LOAEL of 5 µg/kg bw/day in a cynomolgus monkey study over the three menstrual-cycles.
PubMed: 32231940
DOI: 10.14252/foodsafetyfscj.2017009s -
Zoo Biology Mar 2021Melengestrol acetate (MGA) implants are progestin-based reversible contraceptives used to manage fertility in zoo populations. Although it is recommended that MGA...
Melengestrol acetate (MGA) implants are progestin-based reversible contraceptives used to manage fertility in zoo populations. Although it is recommended that MGA implants should be replaced every 2 years, the duration of efficacy has not been systematically evaluated in most species. Anecdotal reports for Old World monkeys indicate that reproduction may be suppressed longer if the implant is not removed. This study uses Guereza colobus monkey (Colobus guereza) as a model Old World monkey species to examine the effects of MGA implants on reproductive potential. In particular, we investigate whether the probability of reproducing (pR) and rates of stillbirth differ among (1) non-implanted females, (2) females who have had MGA implants removed, and (3) females whose implants were left in past expiration. We found no significant difference in pR between non-implanted and implant-removed groups, but when implants were left in past expiration, the pR was significantly lower than in other groups. Both parity and age significantly impacted pR for the non-implanted group (i.e., younger females and those who were parous increased pR), but neither were significant factors for the implant-removed group. Stillbirth rates were significantly higher post-contraception as compared with pre-contraception. These results support similar analyses in other taxa that show a shorter time to reversal after MGA contraception when implants are removed, making this a good contraceptive option for females likely to receive a breeding recommendation, especially when a more predictable time to reversal is important.
Topics: Animals; Animals, Zoo; Colobus; Contraception; Contraceptive Agents, Female; Drug Implants; Female; Melengestrol Acetate; Pregnancy; Reproduction; Stillbirth
PubMed: 33238048
DOI: 10.1002/zoo.21581 -
Journal of Animal Science Aug 1989Expanded use of artificial insemination in the beef cattle industry depends on successful application of treatments designed to synchronize estrus. Regulation of estrous... (Review)
Review
Expanded use of artificial insemination in the beef cattle industry depends on successful application of treatments designed to synchronize estrus. Regulation of estrous cycles is associated with control of the corpus luteum (CL), whose life span and secretory activity are subject to trophic and lytic mechanisms. The advantages of melengestrol acetate (MGA) in estrous synchronization incorporate ease of administration, lower cost relative to other estrous synchronization products, and potential for use to induce estrus in prepubertal heifers. Treatments first designed to synchronize estrous cycles of normally cycling heifers by feeding MGA were imposed daily for 14 to 18 d at levels of .5 to 1 mg. The minimal daily effective dose required to inhibit ovulation was .42 mg. Longer feeding periods of MGA were associated with low fertility at the first synchronized estrus, but at the second estrus, conception was normal. Low fertility at the synchronized estrus resulted in development of alternative treatment practices, which combined feeding of MGA with injections or implants of estradiol-17 beta, estradiol cypionate, luteinizing hormone, human chorionic gonadotropin, pregnant mare serum gonadotropin, or oxytocin. Estrus was synchronized after MGA and estradiol-17 beta or estradiol cypionate treatments, but fertility was low. Short-term feeding of MGA (5 to 7 d) combined with prostaglandin F2 alpha or its analogs (PGF) on the last day of MGA reduced fertility at the synchronized estrus. The reduced conception at first service occurred in animals that began treatment after d 12 of the estrous cycle. However, feeding MGA for 14 d and then injecting PGF 17 d later avoided problems with reduced conception. Fertility of animals after this treatment was similar to that of contemporaries synchronized with Syncro-Mate-B. However, the length of the treatment period creates a need for increased management and may extend management beyond practical limits. Further research is warranted to address problems associated with reduced fertility after short-term treatment with MGA.
Topics: Animals; Cattle; Estrus Synchronization; Female; Melengestrol Acetate; Pregnadienes
PubMed: 2676933
DOI: 10.2527/jas1989.6781895x -
Journal of Animal Science Dec 2009Melengestrol acetate (MGA) has been used in the United States for nearly 40 yr to enhance feedlot heifer performance, yet unequivocal studies have not been conducted to...
Melengestrol acetate (MGA) has been used in the United States for nearly 40 yr to enhance feedlot heifer performance, yet unequivocal studies have not been conducted to discover the mechanism of action. Our hypothesis was that MGA may induce various populations of muscle-derived cells (MDC) to the adipogenic pathway in both a bovine and murine cell culture model. To determine this, MDC were digested from the semimembranosus muscle tissue of six 14-mo-old crossbred steers. The addition of insulin, oleic acid, and ciglitizone (IOC) with cultured bovine MDC resulted in morphological differences compared with control cultures. Multilocular lipid droplets stained with Oil Red O were seen not only in single MDC, but also in fused myotubes. An increase (P < 0.05) in relative PPARgamma messenger RNA (mRNA) levels was measured in MDC incubated with IOC. However, myogenin mRNA levels in MDC incubated with IOC were repressed (P < 0.05) compared with nontreated MDC. Cultures of MDC treated with 10 microM insulin, 10 microM oleic acid, 10 microM ciglitizone, 10 nM estradiol-17beta (E2), and 10 nM MGA resulted in cultures with highly distributed lipid droplets not only in single cells, but also in the multinucleated myotubes. Relative C/EBPbeta and PPARgamma mRNA levels in total RNA isolated from MDC treated with MGA increased (P < 0.05) compared with control cultures. Estradiol treatment had no effect (P > 0.05) on these mRNA levels. The addition of both E2 and MGA to MDC increased (P < 0.05) C/EBPbeta mRNA levels and tended (P = 0.06) to increase the PPARgamma mRNA level. There was no difference (P > 0.10) in relative myogenin mRNA among the control, E(2), and MGA treatments. Relative C/EBPbeta, PPARgamma, and myogenin mRNA levels were investigated in murine C2C12, C3H 10T 1/2, and 3T3-L1 cells. Treatment of cultures with 10 nM MGA increased C/EBPbeta levels (P < 0.05) in C2C12 myoblasts and tended (P = 0.08) to increase C/EBPbeta levels in 3T3-L1 preadipocytes. These data indicate that populations of cells are present in postnatal skeletal muscle that, under the appropriate stimuli in a culture model, express adipogenic genes and accumulate lipids. In addition, the synthetic progestogen MGA appeared to upregulate the genes necessary for conversion to the adipogenic pathway.
Topics: 3T3 Cells; Adipogenesis; Animals; Cattle; Cells, Cultured; Estradiol; Gene Expression; Growth Substances; Hypoglycemic Agents; Insulin; Lipids; Male; Melengestrol Acetate; Mice; Muscle, Skeletal; Oleic Acid; PPAR gamma; RNA, Messenger; Thiazolidinediones
PubMed: 19684257
DOI: 10.2527/jas.2008-1645 -
Shokuhin Eiseigaku Zasshi. Journal of... 2024The present study verified that it is possible to analyze melengesterol acetate using the existing multi-residue method. Melengestrol acetate was extracted from...
The present study verified that it is possible to analyze melengesterol acetate using the existing multi-residue method. Melengestrol acetate was extracted from livestock products using acidic acetonitrile acidified with acetic acid in the presence of n-hexane and anhydrous sodium sulfate. The crude extracts were cleaned up using an octadecylsilanized silica gel cartridge column. Separation by HPLC was performed using an octadecylsilanized silica gel column with linear gradient elution of 0.1 vol% formic acid and acetonitrile containing 0.1 vol% formic acid. For the determination of the analyte, tandem mass spectrometry with positive ion electrospray ionization was used. In recovery tests using four livestock products fortified with maximum residue limits levels of melengestrol acetate (0.001-0.02 mg/kg), the truenesses ranged from 82% to 100%, and the repeatabilities for the entire procedure ranged from 0.5 RSD% to 5.6 RSD%. In recovery tests using 11 livestock products fortified with 0.0005 mg/kg of melengestrol acetate, the truenesses ranged from 88% to 99%, and the repeatabilities ranged from 1.3 RSD% to 5.4 RSD%. The limit of quantification for melengestrol acetate in livestock products was 0.0005 mg/kg.
Topics: Animals; Liquid Chromatography-Mass Spectrometry; Melengestrol Acetate; Chromatography, Liquid; Livestock; Silica Gel; Tandem Mass Spectrometry; Acetonitriles; Formates
PubMed: 38432897
DOI: 10.3358/shokueishi.65.15 -
Bioorganic Chemistry Nov 2020Glomerella fusaroide, and Rhizopus stolonifer were effectively able to transform the steroidal hormone melengestrol acetate (MGA) (1) into four (4) new metabolites,...
Glomerella fusaroide, and Rhizopus stolonifer were effectively able to transform the steroidal hormone melengestrol acetate (MGA) (1) into four (4) new metabolites, 17α-acetoxy-11α-hydroxy-6-methyl-16-methylenepregna-4,6-diene-3,20-dione (2), 17α-acetoxy-11α-hydroxy-6-methyl-16-methylenepregna-1,4,6-triene-3,20-dione (3), 17α-acetoxy-6,7α-epoxy-6β-methyl-16-methylenepregna-4,6-diene-3,20-dione (4), and 17α-acetoxy-11β,15β-dihydroxy-6-methyl-16-methylenepregna-4,6-diene-3,20-dione (5). All these compounds were structurally characterized by different spectroscopic techniques. The objective of the current study was to assess the anti-inflammatory potential of melengestrol acetate (1), and its metabolites 2-5. The metabolites and the substrate were assessed for their inhibitory effects on proliferation of T-cells in vitro. The substrate (IC = 2.77 ± 0.08 µM) and its metabolites 2 (IC = 2.78 ± 0.07 µM), 4 (IC = 2.74 ± 0.1 µM), and 5 (IC = < 2 µM) exhibited potent T- cell proliferation inhibitory activities, while compound 3 (IC = 29.9 ± 0.09 µM) showed a moderate activity in comparison to the standard prednisolone (IC = 9.73 ± 0.08 µM). All the metabolites were found to be non-toxic against 3T3 normal cell line. This study thus identifies some potent compounds active against T-cell proliferation. Their anti-inflammatory potential, therefore, deserves to be further investigated.
Topics: 3T3 Cells; Animals; Biotransformation; Cell Proliferation; Dose-Response Relationship, Drug; Fermentation; Humans; Melengestrol Acetate; Mice; Molecular Structure; Phyllachorales; Rhizopus; Seeds; Structure-Activity Relationship; T-Lymphocytes
PubMed: 33142425
DOI: 10.1016/j.bioorg.2020.104313 -
Regulatory Toxicology and Pharmacology... Apr 2013Some synthetic chemicals are suspected to be responsible for adverse effects on endocrine function. Sex hormones administered to farm animals are of particular interest...
Plasma concentrations of melengestrol acetate in humans extrapolated from the pharmacokinetics established in in vivo experiments with rats and chimeric mice with humanized liver and physiologically based pharmacokinetic modeling.
Some synthetic chemicals are suspected to be responsible for adverse effects on endocrine function. Sex hormones administered to farm animals are of particular interest because of their regulatory role in developmental processes. To predict concentrations in humans of the synthetic growth promoter melengestrol acetate (17α-acetoxy-6-methyl-16-methylenepregna-4,6-diene-3,20-dione), a forward dosimetry approach was carried out using data from no-observed-adverse-effect-level doses orally administered to mice or rats and from in vitro human and rodent experiments. Human liver microsomes preferentially mediated 2-hydroxylation of melengestrol acetate, but rodent livers produced additional unidentified hydroxymetabolites. Adjusted animal biomonitoring equivalents for melengestrol acetate from mouse and rat studies were scaled to human biomonitoring equivalents using known species allometric scaling factors and human metabolic data with a simple physiologically based pharmacokinetic (PBPK) model. Melengestrol acetate elimination in humans was estimated to be slow compared with elimination in rodents. The disposition of melengestrol acetate in humans was evaluated using chimeric TK-NOG mice with humanized liver. The results suggest the usefulness of simplified PBPK modeling combined with in vitro and in vivo experiments and literature resources as well as a future interest in estimating by a full PBPK modeling using another bottom up system. This model may also be useful for risk evaluation and for simulating plasma concentrations resulting from exposure to low doses of melengestrol acetate and related compounds.
Topics: Animals; Cells, Cultured; Chimera; Glucocorticoids; Hepatocytes; Humans; Liver; Male; Melengestrol Acetate; Mice; Mice, Transgenic; Microsomes, Liver; Models, Biological; No-Observed-Adverse-Effect Level; Rats; Rats, Sprague-Dawley
PubMed: 23395687
DOI: 10.1016/j.yrtph.2013.01.008 -
Journal of Animal Science Nov 2006In vitro experiments were performed to investigate the effects of melengestrol acetate (MGA) or progesterone (P4) on bovine muscle satellite cells and C2C12 myoblasts....
In vitro experiments were performed to investigate the effects of melengestrol acetate (MGA) or progesterone (P4) on bovine muscle satellite cells and C2C12 myoblasts. Addition of MGA at physiological and supraphysiological concentrations resulted in a dose-dependent decrease (P < 0.05) in DNA synthesis as measured by [3H]-thymidine incorporation (TI). Similarly, P4 addition (0.01 nM) reduced (P < 0.05) TI. Addition of MGA (10 nM) increased (P < 0.05) IGF-I mRNA abundance but did not affect myogenin mRNA. Progesterone addition (10 nM) increased myogenin mRNA abundance (P < 0.05). In C2C12 cultures, P4 addition resulted in a dose-dependent decrease in TI. The antiprogestin RU486, in combination with MGA or P4, also resulted in reduced (P < 0.05) TI. Treatment with RU486 alone had a negative effect (P < 0.05) on TI that was similar to the progestins. Treatment of C2C12 myoblasts with MGA (100 nM) resulted in an increase (P < 0.05) in myogenin mRNA. These studies suggest that progestins may reduce satellite cell proliferation, ultimately affecting carcass composition.
Topics: Animals; Cattle; Cell Proliferation; Cells, Cultured; Female; Insulin-Like Growth Factor I; Male; Melengestrol Acetate; Mifepristone; Muscle, Skeletal; Myogenin; Progesterone; RNA, Messenger; Satellite Cells, Skeletal Muscle
PubMed: 17032788
DOI: 10.2527/jas.2005-726 -
Journal of Animal Science May 2002We tested the hypothesis that melengestrol acetate (MGA), an orally active progestin, blocks estrus and the preovulatory surge of luteinizing hormone (LH) in beef...
We tested the hypothesis that melengestrol acetate (MGA), an orally active progestin, blocks estrus and the preovulatory surge of luteinizing hormone (LH) in beef heifers. Cycling yearling Angus heifers were divided randomly into two groups: MGA-treated (n = 6) and control (n = 5). All heifers received injections of prostaglandin F2alpha (PGF) on d -25, -11, and 0 to synchronize estrus. Following the last PGF injection on d 0, heifers were fed either 0.5 mg MGA in a carrier or the MGA carrier each day for 8 d. At 4-h intervals on d 1 through 6, all heifers were observed for expression of estrous behavior, and blood samples were collected and assayed for LH. Daily blood samples were collected at 0800 on d 1 through 10 and assayed for circulating progesterone concentrations. All control heifers exhibited estrus and a preovulatory surge of LH. In each case, this was followed by increases in circulating concentrations of progesterone indicative of ovulation and normal luteal function. In contrast, none of the MGA-treated heifers exhibited estrus, LH surges, or evidence of ovulation. The results of this experiment show that MGA prevents ovulation in cattle by inhibiting the preovulatory surge of LH.
Topics: Animals; Cattle; Dinoprost; Estrus; Estrus Synchronization; Female; Luteinizing Hormone; Melengestrol Acetate; Ovulation; Progesterone; Progesterone Congeners; Random Allocation
PubMed: 12019616
DOI: 10.2527/2002.8051280x -
Journal of the American Veterinary... Dec 1970
Review
Topics: Acetates; Animal Feed; Animals; Birth Weight; Breeding; Cattle; Chickens; Dogs; Escherichia coli Infections; Estrus; Feeding Behavior; Female; Fertility; Horses; Humans; Mice; Milk; Ovulation; Pregnancy; Pregnanes; Rabbits; Rats; Sheep; Swine; Weaning
PubMed: 4922188
DOI: No ID Found