The Quantitative Assay of “Follicle Stimulating” Substances1

Levin, Louis; Tyndale, H. H.

doi:10.1210/endo-21-5-619

Cited by 86 publications

(22 citation statements)

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“…Groups of five animals were used routinely. Levin and Tyndale (1937) used the intact, immature mouse. Mice were treated by sc injection for 3 consecutive days starting on pnd 21 and sacrificed 20 to 24 hours after the last injection.…”

Section: Assay Based On Uterine Weight Increase After Consecutive Dosesmentioning

confidence: 99%

Critical Review and Evaluation of the Uterotrophic Bioassay for the Identification of Possible Estrogen Agonists and Antagonists: In Support of the Validation of the OECD Uterotrophic Protocols for the Laboratory Rodent

Owens

Ashby

2002

Critical Reviews in Toxicology

112

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A current issue for regulatory agencies is endocrine-related modes of action such as those mediated by the estrogen, androgen, and thyroid nuclear receptors. At the national and international levels, the consensus recommendation for the assessment of such modes of action is a tiered series of in vitro and in vivo protocols. The tiered framework begins with screens for structural alerts and then moves to rapid, mechanistic in vitro screening assays, and then to in vivo screening bioassays. The objective of these screens is to identify substances that may warrant testing for endocrine-mediated adverse effects. The final framework tier as needed is to test these substances in long-term bioassays for adverse endocrine-mediated reproductive and/or developmental effects. The subject of this review, the rodent uterotrophic bioassay, is intended to be a rapid in vivo screening bioassay for possible estrogen agonists and based on the response of the estrogen-sensitive uterus. The central metric of bioassay is a statistically significant increase in the weight of the uterus after 3 consecutive days of test substance administration. The extensive background literature is summarized in this review on the mode of action underlying the bioassay and the uterine response to estrogens. The review includes the bioassay's history of development and how its employment has changed and evolved over time. The review describes two major uterotrophic bioassay versions, the intact, immature female and the mature, ovariectomized female, and the protocol factors likely to influence relevance, reproducibility, and reliability of bioassay. The emphasis of the review is the ability of the uterotrophic bioassay to identify the substances of current interest: weak estrogen agonists with binding affinities relative to the natural 17beta-estradiol in the log 0 to log -3 range. Using selected model substances having RBAs in this target range, the bioassay's performance in a hierarchical, tiered approach is evaluated, including the predictive capability of the uterotrophic bioassay based on available reproductive and developmental testing data. The review concludes that the uterotrophic bioassay is reliable and can identify substances that may act via an estrogen-mode of action, supporting the validity of the uterotrophic bioassay and its regulatory use as an in vivo mechanistic screening bioassay for estrogen agonists and antagonists.

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Section: Assay Based On Uterine Weight Increase After Consecutive Dosesmentioning

confidence: 99%

Critical Review and Evaluation of the Uterotrophic Bioassay for the Identification of Possible Estrogen Agonists and Antagonists: In Support of the Validation of the OECD Uterotrophic Protocols for the Laboratory Rodent

Owens

Ashby

2002

Critical Reviews in Toxicology

112

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“…The mouse uterine weight gain bioassay (Levin & Tyndale 1937) was used in a modified form (Das et al 1976) to test the in vivo hCG-neutralizing capacity of the antipeptide antibodies. Prepubertal female mice of the Swiss strain, 20-22 days old and weighing 7-8 g, were placed in groups of five to six mice each.…”

Section: Mouse Uterine Weight Gain Bioassaymentioning

confidence: 99%

A detailed study of the L2beta long-loop region of human chorionic gonadotrophin suggests it to be spatially close to, but not part of, the receptor-binding site

Jagtap¹,

Mahale²,

Mishra³

et al. 2002

Journal of Endocrinology

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An in-depth study of the L2 long-loop region of human chorionic gonadotrophin (hCG), earlier identified to be a conformational bioneutralization epitope and receptorbinding site of the hormone, was carried out. The linear 38-57 hCG peptide and the corresponding cyclic disulphide peptide were synthesized and antipeptide antibodies developed. Binding studies with antibodies to the linear peptide, and with hCG , hCG and human LH suggest that part of the region is buried at the / interface and part exposed in hCG. Observation of the surface exposure of residues 47-53 from the crystal structure of hCG was confirmed by epitope mapping studies of the region. The region is not unique to hCG as a majority of the antibodies to both the linear and cyclic peptides did not exhibit the required specificity. Competitive inhibition studies with the linear and cyclic peptides failed to show inhibition of radiolabelled hCG binding to its receptors. However, both the antipeptide antibodies were able to bioneutralize the hormone in an in vivo assay. Taken together, these results seem to indicate that the L2 long-loop region is not a receptor-binding site of hCG but spatially close to it.

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“…This is due to both a lower binding affinity, which might reduce the residence time of the receptor on the oestrogen response element and a faster rate of elimination from the body. This possibility of a temporal 'decay' in uterine weight increase was first raised by Levin and Tyndale (1937), who observed that extending the time of necropsy to ~48 hours resulted in a 60-70% reduction in the uterine weight increase otherwise observed at 20-24 hours. (Tables 1-3 of Welsh et al, 1969).…”

mentioning

confidence: 99%

Detailed Background Review of the Uterotrophic Bioassay

2004

OECD Series on Testing and Assessment

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The Quantitative Assay of “Follicle Stimulating” Substances1

Cited by 86 publications

References 0 publications

Critical Review and Evaluation of the Uterotrophic Bioassay for the Identification of Possible Estrogen Agonists and Antagonists: In Support of the Validation of the OECD Uterotrophic Protocols for the Laboratory Rodent

Critical Review and Evaluation of the Uterotrophic Bioassay for the Identification of Possible Estrogen Agonists and Antagonists: In Support of the Validation of the OECD Uterotrophic Protocols for the Laboratory Rodent

A detailed study of the L2beta long-loop region of human chorionic gonadotrophin suggests it to be spatially close to, but not part of, the receptor-binding site

Detailed Background Review of the Uterotrophic Bioassay

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