Agonistic and Antagonistic Effects of Clomiphene Citrate and Its Isomers1
Abstract
The agonistic and antagonistic properties of clomiphene citrate (CL) and its isomers were examined in the rat uterus. Immature rats (21 days old) were injected with various doses of estradiol benzoate (EB), CL, zuclomiphene (ZUC, cis isomer), and enclomiphene (ENC, trans isomer), and uterine weight or epithelial cell height was measured. EB treatment produced a typical dose-response curve for uterine weight with a steep slope, while the curves resulting from treatment with CL, ZUC, or ENC were attenuated with a very shallow slope. These differences in shapes of the dose-response curves render the determination of relative potency estimates inaccurate and misleading. In contrast, the shapes of the dose-response curves for epithelial cell hypertrophy were similar for all four compounds. EB was more potent than any form of clomiphene; however, the maximum extent of cellular hypertrophy was not as great. The half maximal dose for each compound was EB, 0.35 ± 0.04 µg; ENC, 25.0 ± 2.0 µg; CL, 35.0 ± 3.1 µg; and ZUC, 65.0 ± 7.1 µg. The ability of these drugs to antagonize the action of EB was examined by injecting EB plus CL, ZUC, or ENC and measuring the uterine weight or epithelial cell hypertrophy 72 h later. All three forms of the drug were antagonistic to EB-induced uterine weight gain over the same dose ranges in which they were agonistic by themselves. No antagonistic effects were observed on estradiol stimulation of epithelial cell hypertrophy. These data show that CL and its isomers are fully capable of stimulating epithelial cell hypertrophy in the rat uterus, and thus, valid relative potency estimates can be obtained with this response. This is not true when uterine weight gain is used because differential cell stimulation is not taken into account. In addition, CL and its isomers are agonistic and antagonistic over the same dose ranges when uterine weight gain is used; however, no antagonism of estrogen-stimulated cellular hypertrophy is measured. Therefore, broad generalizations concerning the estrogenicity or anti-estrogenicity of these compounds are not warranted and can be made only when specific end-points are evaluated.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Enclomiphene is the trans-isomer of clomiphene and a relatively pure oestradiol antagonist.
“Enclomiphene, the trans-isomer of clomiphene is a relatively pure oestradiol antagonist, 113”
From Hypogonadism and male obesity: Focus on unresolved questions (2018) · cites this paper as [113]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Induction of Ovulation with MRL/41: Preliminary Report
Greenblatt, R. B. (1961) · JAMA · doi:10.1001/jama.1961.03040410001001 · Cited by 343 · see citing works
Female sex steroids: receptors and function.
Clark, J. H., & Peck, E. J. (1979) · PubMed · Cited by 273 · see citing works
Self-citationHYPERTROPHY AND HYPERPLASIA IN THE MOUSE UTERUS AFTER OESTROGEN TREATMENT: AN AUTORADIOGRAPHIC STUDY
Martin, L. J., Finn, C. A., & TRINDER, G. (1973) · Journal of Endocrinology · doi:10.1677/joe.0.0560133 · Cited by 268 · see citing works
Oestrogen receptors and antagonism of steroid hormone action
Clark, J. H., Peck, E. J., & Anderson, J. N. (1974) · Nature · doi:10.1038/251446a0 · Cited by 244 · see citing works
Self-citationClark, J. H., Hardin, J. W., Padykula, H. A., & Cardasis, C. A. (1978) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.75.6.2781 · Cited by 52 · see citing works
Self-citationMarkaverich, B. M., Upchurch, S., McCormack, S. A., Glasser, S. R., & Clark, J. H. (1981) · Biology of Reproduction · doi:10.1095/biolreprod24.1.171 · Cited by 51 · see citing works
Self-citationModulation of uterine morphology and growth by estradiol-17beta and an estrogen antagonist.
Kang, Y., Anderson, W. A., & DeSombre, E. R. (1975) · The Journal of Cell Biology · doi:10.1083/jcb.64.3.682 · Cited by 44 · see citing works
Ernst, S., Kite, G. F., Cantrell, J. S., Richardson, A., & Benson, H. D. (1976) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.2600650140 · Cited by 38 · see citing works
Alteration of LH and FSH release in rats treated with clomiphene or its isomers
Schally, A. V., Carter, W. H., Parlow, A. F., Saito, M. T., Arimura, A., Bowers, C. Y., & Holtkamp, D. E. (1970) · American Journal of Obstetrics and Gynecology · doi:10.1016/s0002-9378(15)30364-1 · Cited by 36 · see citing works
Aspects on the Mode of Action of Antiestrogens and Antiprogestogens
Terenius, L. Y., & Ljungkvist, I. (2010) · Gynecologic Investigation · doi:10.1159/000301746 · Cited by 30 · see citing works
BOYAR, R. M. (1970) · Endocrinology · doi:10.1210/endo-86-3-629 · Cited by 24 · see citing works
CYTOPLASMIC OESTROGEN RECEPTOR REPLENISHMENT: OESTROGENS VERSUS ANTI-OESTROGENS
Baudendistel, L. J., Ruh, M. F., Nadel, E. M., & Ruh, T. S. (1978) · European Journal of Endocrinology · doi:10.1530/acta.0.0890599 · Cited by 23 · see citing works
Contrasting Actions of Cis- and Trans-Clomiphene on the Release of FSH and FSH-RF in the Female Rat
Nagel, S., Baier, H., & Taubert, H. ‐. (1970) · Hormone and Metabolic Research · doi:10.1055/s-0028-1095051 · Cited by 12 · see citing works
Jn, K., & Mehrotra, P. K. (1973) · PubMed · Cited by 12 · see citing works
Studies on the Anti-Oestrogenic and Oestrogen-Like Action of Clomiphene Citrate. Animal experiments
Schulz, K.-D., August, S., Gasde, K., & Kramer, G. (2010) · Gynecologic Investigation · doi:10.1159/000301750 · Cited by 10 · see citing works
EMMENS, C. W., & CARR, W. L. (1973) · Reproduction · doi:10.1530/jrf.0.0340029 · Cited by 10 · see citing works
Poteat, W. L., & Bo, W. J. (1971) · The Anatomical Record · doi:10.1002/ar.1091690410 · Cited by 8 · see citing works
Jordan, V. C., DIX, C. J., & Prestwich, G. (1979) · Advances in experimental medicine and biology · doi:10.1007/978-1-4757-6589-2_7 · Cited by 7 · see citing works
Poteat, W. L., & Bo, W. J. (1977) · American Journal of Anatomy · doi:10.1002/aja.1001490203 · Cited by 7 · see citing works
THE EFFECT OF PROMETHAZINE AND CLOMIPHENE ON GONADOTROPHIN SECRETION IN THE RAT
Koch, Y., Dikstein, S., Superstine, E., & Sulman, F. G. (1971) · Journal of Endocrinology · doi:10.1677/joe.0.0490013 · Cited by 6 · see citing works
Effect of clomiphene on fertility in female rats.
Sp, K., & Mr, P. (1967) · PubMed · Cited by 6 · see citing works
AGONISTIC AND ANTAGONISTIC PROPERTIES OF CLOMIPHENE
Clark, J. H., Guthrie, S. C., McCormack, S. A., & Markavarich, B. M. (1982) · De Gruyter eBooks · doi:10.1515/9783111506753-007 · Cited by 2 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 1
- Bliss, C. I. (1952). The Statistics of Bioassay. Aca- demic Press, New York. pp. 488-494.
Cited by
Sorted by citations
The Science behind 25 Years of Ovarian Stimulation for in Vitro Fertilization
Macklon, N., Stouffer, R. L., Giudice, L. C., & Fauser, B. C. J. M. (2006) · Endocrine Reviews · doi:10.1210/er.2005-0015 · Cited by 561 · see citing works
Jordan, V. C. (2003) · Journal of Medicinal Chemistry · doi:10.1021/jm020449y · Cited by 414 · see citing works
The agonistic-antagonistic properties of clomiphene: A review
Clark, J. H., & Markaverich, B. M. (1981) · Pharmacology & Therapeutics · doi:10.1016/0163-7258(81)90055-3 · Cited by 220 · see citing works
Self-citationHypogonadism and male obesity: Focus on unresolved questions
Grossmann, M. (2018) · Clinical Endocrinology · doi:10.1111/cen.13723 · Cited by 164 · see citing works
Structure-Activity Relationships of Estrogens
Jordan, V. C., Mittal, S., Gosden, B., Koch, R. J., & Lieberman, M. E. (1985) · Environmental Health Perspectives · doi:10.1289/ehp.856197 · Cited by 134 · see citing works
Lieberman, M. E., Gorski, J., & Jordan, V. C. (1983) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)32484-0 · Cited by 132 · see citing works
Young, S. L., Opsahl, M. S., & Fritz, M. A. (1999) · Fertility and Sterility · doi:10.1016/s0015-0282(98)00537-8 · Cited by 111 · see citing works
Lyttle, C. R., Damián‐Matsumura, P., Juul, H., & Butt, T. R. (1992) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/0960-0760(92)90108-u · Cited by 93 · see citing works
Jordan, V. C., & Gosden, B. (1982) · Molecular and Cellular Endocrinology · doi:10.1016/0303-7207(82)90095-8 · Cited by 86 · see citing works
Kim, E. D., McCullough, A., & Kaminetsky, J. (2016) · BJU International · doi:10.1111/bju.13337 · Cited by 81 · see citing works
Kaminetsky, J., Werner, M., Fontenot, G., & Wiehle, R. D. (2013) · The Journal of Sexual Medicine · doi:10.1111/jsm.12116 · Cited by 78 · see citing works
Drugs in infertility and fetal safety
Elizur, S. E., & Tulandi, T. (2008) · Fertility and Sterility · doi:10.1016/j.fertnstert.2008.02.092 · Cited by 77 · see citing works
Endocrine pathology of estrogens: Species differences
Hart, J. E. (1990) · Pharmacology & Therapeutics · doi:10.1016/0163-7258(90)90087-i · Cited by 75 · see citing works
Gap junction amplification in rat ovarian granulosa cells
Burghardt, R. C., & Matheson, R. L. (1982) · Developmental Biology · doi:10.1016/0012-1606(82)90084-7 · Cited by 62 · see citing works
Jordan, V. C., Koch, R. J., Langan-Fahey, S. M., & McCague, R. (1988) · Endocrinology · doi:10.1210/endo-122-4-1449 · Cited by 46 · see citing works
The Stimulation of Uterine Complement Component C3 Gene Expression by Antiestrogens
Sundstrom, S. A., Komm, B. S., Xu, Q. S., Boundy, V. A., & Lyttle, C. R. (1990) · Endocrinology · doi:10.1210/endo-126-3-1449 · Cited by 44 · see citing works
Nelson, E., Barnes, A. B., Wiehle, R. D., Fontenot, G. K., Hoenen, T., & White, J. M. (2016) · Viruses · doi:10.3390/v8080206 · Cited by 43 · see citing works
Superovulation Strategy Before In Vitro Fertilization
Hillier, S. G., Afnan, A. M. M., Margara, R. A., & Winston, R. M. L. (1985) · Clinics in Obstetrics and Gynaecology · doi:10.1016/s0306-3356(21)00142-4 · Cited by 43 · see citing works
Kronenberg, M. S., & Clark, J. H. (1985) · Endocrinology · doi:10.1210/endo-117-4-1480 · Cited by 41 · see citing works
Self-citationClomiphene citrate in the twenty-first century
Nasseri, S., & Ledger, W. J. (2001) · Human Fertility · doi:10.1080/1464727012000199212 · Cited by 40 · see citing works
Keeping, H. S., & LYTTLE, R. C. (1982) · Endocrinology · doi:10.1210/endo-111-6-2046 · Cited by 27 · see citing works
Swaby, R. F., & Jordan, V. C. (2008) · Clinical Breast Cancer · doi:10.3816/cbc.2008.n.012 · Cited by 24 · see citing works
CYP2D6 is primarily responsible for the metabolism of clomiphene.
Ghobadi, C., Gregory, A., Crewe, H., Rostami-Hodjegan, A., & Lennard, M. (2008) · Drug Metabolism and Pharmacokinetics · doi:10.2133/dmpk.23.101 · Cited by 24 · see citing works
Shimoya, K., Tomiyama, T., Hashimoto, K., Moriyama, A., Kawamoto, A., Tokugawa, Y., Ohashi, K., Saji, F., & Murata, Y. (1999) · Gynecologic and Obstetric Investigation · doi:10.1159/000010116 · Cited by 23 · see citing works
Chapter 19. Estrogen Receptor Modulators: Effects in Non-Traditional Target Tissues
Grese, T. A., & Dodge, J. A. (1996) · Annual reports in medicinal chemistry · doi:10.1016/s0065-7743(08)60458-3 · Cited by 23 · see citing works
Grunert, G., Neumann, G., Porcia, M., & Tchernitchin, A. N. (1987) · Biology of Reproduction · doi:10.1095/biolreprod37.3.527 · Cited by 22 · see citing works
Chakraborty, P. K., Brown, J. L., Ruff, C. B., Nelson, M. F., & Mitchell, A. (1991) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/0960-0760(91)90297-i · Cited by 22 · see citing works
Predicting the Predisposition to Osteoporosis
Abbasi, R. (1986) · JAMA · doi:10.1001/jama.1986.03370120078026 · Cited by 22 · see citing works
A chemical classification of nonsteroidal antagonists of sex-steroid hormone action
Miquel, J. F., & Gilbert, J. (1988) · Journal of Steroid Biochemistry · doi:10.1016/0022-4731(88)90004-0 · Cited by 20 · see citing works
Differential effects of isomers of clomiphene citrate on reproductive tissues in male mice
Fontenot, G. K., Wiehle, R. D., & Podolski, J. S. (2015) · British Journal of Urology · doi:10.1111/bju.13244 · Cited by 17 · see citing works
The estrogenic effects of clomiphene during the neonatal period in the rat
Clark, J. H., & Guthrie, S. C. (1983) · Journal of Steroid Biochemistry · doi:10.1016/0022-4731(83)90124-3 · Cited by 17 · see citing works
Self-citationGalman, M. S., Sundstrom, S. A., & Lyttle, C. R. (1990) · Journal of Steroid Biochemistry · doi:10.1016/0022-4731(90)90218-h · Cited by 15 · see citing works
Hormonal Regulation of Rat Uterine Secretory Protein Synthesis
Lyttle, C. R., Wheeler, C., & Komm, B. S. (1987) · Advances in experimental medicine and biology · doi:10.1007/978-1-4684-1297-0_7 · Cited by 15 · see citing works
Budinetz, T. H., Benadiva, C. A., Griffin, D. W., Engmann, L. L., NULSEN, J. C., & DiLuigi, A. J. (2015) · Fertility and Sterility · doi:10.1016/j.fertnstert.2014.12.088 · Cited by 12 · see citing works
Estrogenic and antiestrogenic properties of clomiphene citrate in laboratory mice
Kumar, A. B., & Pakrasi, P. L. (1995) · Journal of Biosciences · doi:10.1007/bf02703306 · Cited by 11 · see citing works
Topipat, C., Choktanasiri, W., Jultanmas, R., Weerakiet, S., Wongkularb, A., & Rojanasakul, A. (2008) · Gynecological Endocrinology · doi:10.1080/09513590801895609 · Cited by 10 · see citing works
Polycystic Ovary Syndrome and Ovulation Induction
Yildiz, B. O., & Azziz, R. (2007) · Humana Press eBooks · doi:10.1007/978-1-59745-179-6_35 · Cited by 9 · see citing works
Enclomiphene Citrate Stimulates Serum Testosterone in Men With Low Testosterone Within 14 Days
Wiehle, R. D., Fontenot, G. K., Willett, M. S., Garcia, W. D., & Podolski, J. S. (2014) · Journal of Men s Health · doi:10.1089/jomh.2014.0006 · Cited by 7 · see citing works
Rateb, S. A., El-Hamid, I. S. A., Khalifa, M. A., Ibrahim, N. H., Younis, F., & El-Rayes, M. (2019) · Small Ruminant Research · doi:10.1016/j.smallrumres.2019.04.005 · Cited by 7 · see citing works
Lewis-Wambi, J. S., & Jordan, V. C. (2007) · Elsevier eBooks · doi:10.1016/b0-08-045044-x/00294-7 · Cited by 7 · see citing works
Karadeolian, A., Emmett, M. R., Souza, F. E. S., Chung, A. D., Blazecka, P. G., Sueur, R. L., Patel, D., Zhao, Y., Rey, A. W., & Green, S. (2022) · Organic Process Research & Development · doi:10.1021/acs.oprd.1c00366 · Cited by 6 · see citing works
Fluoro-clomiphene and its synthetic precursors: Synthesis and receptor binding
Gazit, A., Livshitz, T., & Shani, J. (1986) · Steroids · doi:10.1016/0039-128x(86)90042-5 · Cited by 5 · see citing works
Dolginova, E. M., Kadatskii, G. M., Гриненко, Г. С., Filipenko, T. Y., Shchedrina, R. N., Fanchenko, N. D., Minina, L. S., Terekhina, A. I., & Gorenburgova, E. I. (1984) · Pharmaceutical Chemistry Journal · doi:10.1007/bf00779898 · Cited by 4 · see citing works
Diamond, M. P., Herbert, C. M., Maxson, W. S., & Wentz, A. C. (1986) · Fertility and Sterility · doi:10.1016/s0015-0282(16)49281-2 · Cited by 4 · see citing works
Reappraisal of the use of clomifene for ovulation induction
Bekhit, M., & Greenwood, P. (2005) · The Obstetrician & Gynaecologist · doi:10.1576/toag.7.1.014.27037 · Cited by 2 · see citing works
Fontenot, G. K. (2017) · Cited by 2 · see citing works
Selective Estrogen Receptor Modulators
Luniwal, A., Jetson, R. R., & Erhardt, P. (2012) · doi:10.1002/9783527651085.ch7 · Cited by 2 · see citing works
Canpolat, L. (1999) · DergiPark (Istanbul University) · Cited by 1 · see citing works
Synthesis of carbon‐14 labeled clomiphene
Rao, P. N., & Cessac, J. W. (1985) · Journal of Labelled Compounds and Radiopharmaceuticals · doi:10.1002/jlcr.2580220306 · Cited by 1 · see citing works
Kogo, H., & Hikikoshi, A. (1992) · The Japanese Journal of Pharmacology · doi:10.1254/jjp.58.197
13 Future directions: anti-hormones in reproductive medicine
Steingold, K. A., & Hodgen, G. D. (1988) · Baillière s Clinical Obstetrics and Gynaecology · doi:10.1016/s0950-3552(88)80054-3
Hormonal Regulation of Uterine Complement
Isaacson, K., Pruksananonda, K., Hasty, L. A., & Lyttle, C. R. (1991) · Springer eBooks · doi:10.1007/978-1-4615-3380-1_12
Predicting Predisposition to Osteoporosis: GnRH Antagonist for Acute Estrogen Deficiency
Hodgen, G. D., Kenigsberg, D., & Abbasi, R. (1987) · Springer eBooks · doi:10.1007/978-94-009-3229-6_31
Rd, W. (2015) · International Journal of Endocrinology and Metabolic Disorders · doi:10.16966/2380-548x.114
Al-Waeli, A. M., Al-Yawer, M. A., & Haddad, F. Y. S. (2011) · Iraqi Journal of Community Medicine
Gibson, M. (2010) · Springer eBooks · doi:10.1007/978-1-4419-1436-1_35
Kogo, H., & Hikikoshi, A. (1992) · The Japanese Journal of Pharmacology · doi:10.1016/s0021-5198(19)39764-1
Dodge, J. A., Richardson, T. I., & Wallace, O. B. (2007) · Elsevier eBooks · doi:10.1016/b0-08-045044-x/00208-x
- Authors
- Clark, J. H., & Guthrie, S. C.
- Affiliations
- Baylor College of Medicine (US)
- ORCID
- Clark, James H.
- Venue
- Biology of Reproduction
- Publisher
- Oxford University Press (OUP)
- Published
- 1981-10-01
- Volume
- 25
- Issue
- 3
- Pages
- 667-672
- ISSN
- 0006-3363 (ISSN-L)
- 1529-7268
- OpenAlex
- W2012256669
- Cited by
- 58
- References
- 22
- Citations by year
- 2022: 1 · 2019: 1 · 2018: 1 · 2017: 1 · 2016: 1 · 2015: 4 · 2014: 1 · 2013: 1 · 2012: 1
- FWCI
- 2.00
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biology of Reproduction (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Effects and risks of endocrine disrupting chemicals
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- clomiphene citrate, estradiol benzoate, uterine weight, dose-response curves, relative potency, estrogen antagonism, estrogenic activity, immature rats
- MeSH terms
- Animals, Clomiphene, Dose-Response Relationship, Drug, Epithelium, Estradiol, Female, Isomerism, Rats, Inbred Strains, Uterus, Estradiol Congeners, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
