RF9 Rescues Cortisol-Induced Repression of Testosterone Levels in Adult Male Macaques
Open accessAbstract
Cortisol inhibits hypothalamic-pituitary-gonadal (HPG) axis whereas RF9, a potent agonist of kisspeptin receptor (GPR54) activates HPG-axis during fasting-induced stress and under normal physiological conditions. However, the effect of RF9 on the cortisol-induced repressed HPG-axis is not studied yet. This study investigated whether exogenous cortisol-induced repression of the HPG-axis can be rescued by RF9. Six intact adult male rhesus monkeys (Macaca mulatta) habituated to chair-restraint were administered hydrocortisone sodium succinate at a rate of 20 mg/kg of body weight (BW) per day for 12 days. Single blood sample was taken by venipuncture from each animal on alternate days for hormones analyses. On experimental day 12, hydrocortisone treated monkeys received a single intravenous bolus of RF9 (n = 3) and vehicle (n = 3). The animals were bled for a period of 4 h at 60 min intervals from an indwelling cannula in the saphenous vein. RF9 was administered intravenously at the dose of 0.1 mg/kg BW immediately after taking 0 min sample. Plasma cortisol and testosterone concentrations were measured by using specific enzyme immunoassays. Hydrocortisone treatment increased plasma cortisol levels (P ≤ 0.0001) and decreased plasma testosterone (P ≤ 0.0127) levels. Interestingly, compared to vehicle, RF9 treatment significantly increased plasma testosterone levels at 120 min (P ≤ 0.0037), 180 min (P ≤ 0.0016), and 240 min (P ≤ 0.0001) intervals in the hydrocortisone treated monkeys. From these results, we concluded that RF9 administration relieves the suppressed HPG-axis in term of plasma testosterone levels in the cortisol treated monkeys.
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In vertebrate models, stress-induced glucocorticoids repress the HPG axis by inhibiting GnRH neurons or stimulating neurons releasing GnIH.
“In vertebrate models, stress-induced glucocorticoids repress the HPG axis by inhibiting GnRH neurons or stimulating neurons releasing gonadotropin-inhibitory hormone (GnIH) [89–91].”
From Fibromyalgia pathogenesis explained by a neuroendocrine multistable model (2024) · cites this paper as [91]
The Introduction says glucocorticoids inhibit gonadotropin secretion and that the HPA axis inhibits GnRH neurons. The Discussion says cortisol may act directly on GnRH neurons or indirectly through GnIH neurons, but presents these routes as possibilities, not demonstrated mechanisms; it also says the affected component of the HPG axis remains unknown. No page numbers are provided in our copy's passages. (LLM, conf=0.86)
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Rivier, C., & Rivest, S. (1991) · Biology of Reproduction · doi:10.1095/biolreprod45.4.523 · Cited by 799 · see citing works
Rivier, C., Rivier, J., & Vale, W. (1986) · Science · doi:10.1126/science.3003907 · Cited by 531 · see citing works
Structural and functional evolution of gonadotropin‐releasing hormone in vertebrates
Okubo, K., & Nagahama, Y. (2008) · Acta Physiologica · doi:10.1111/j.1748-1716.2008.01832.x · Cited by 271 · see citing works
Simonin, F., Schmitt, M., Laulin, J., Laboureyras, E., Jhamandas, J. H., MacTavish, D., Matifas, A., Mollereau, C., Laurent, P., Parmentier, M., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0502090103 · Cited by 232 · see citing works
Dubey, A. K., & Plant, T. M. (1985) · Biology of Reproduction · doi:10.1095/biolreprod33.2.423 · Cited by 217 · see citing works
Rizwan, M. Z., Poling, M. C., Corr, M., Cornes, P. A., Augustine, R. A., Quennell, J. H., Kauffman, A. S., & Anderson, G. M. (2012) · Endocrinology · doi:10.1210/en.2012-1133 · Cited by 172 · see citing works
Suppression of the Hypothalamic-Pituitary-Ovarian Axis in Normal Women by Glucocorticoids1
Saketos, M., Sharma, N., & Santoro, N. F. (1993) · Biology of Reproduction · doi:10.1095/biolreprod49.6.1270 · Cited by 145 · see citing works
Pineda, R., García-Galiano, D., Sanchez-Garrido, M. A., Romero, M., Ruíz-Pino, F., Aguilar, E., Dijcks, F. A., Blomenröhr, M., Pinilla, L., van Noort, P. I., et al. (2010) · Endocrinology · doi:10.1210/en.2009-1259 · Cited by 95 · see citing works
Thibier, M., & Rolland, O. (1976) · Theriogenology · doi:10.1016/0093-691x(76)90168-0 · Cited by 92 · see citing works
Samuels, M. H., & McDaniel, P. A. (1997) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.82.11.4376 · Cited by 87 · see citing works
Caraty, A., Blomenröhr, M., Vogel, G. M. T., Lomet, D., Briant, C., & Beltramo, M. (2012) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2012.02283.x · Cited by 76 · see citing works
Wahab, F., Shahab, M., & Behr, R. (2015) · Journal of Endocrinology · doi:10.1530/joe-14-0688 · Cited by 55 · see citing works
Self-citationTurner, A. I., Hemsworth, P. H., Canny, B. J., & Tilbrook, A. J. (1999) · Biology of Reproduction · doi:10.1095/biolreprod61.3.614 · Cited by 54 · see citing works
Effect of adrenal steroids on testosterone and luteinizing hormone secretion in the ram
JUNIEWICZ, P. E., JOHNSON, B. H., & BOLT, D. J. (1987) · Journal of Andrology · doi:10.1002/j.1939-4640.1987.tb02430.x · Cited by 43 · see citing works
Wahab, F., Aziz, F., Irfan, S., Zaman, W.-U., & Shahab, M. (2008) · Life Sciences · doi:10.1016/j.lfs.2008.09.001 · Cited by 40 · see citing works
Self-citationRF9 Excitation of GnRH Neurons Is Dependent Upon Kiss1r in the Adult Male and Female Mouse
Liu, X., & Herbison, A. E. (2014) · Endocrinology · doi:10.1210/en.2014-1517 · Cited by 37 · see citing works
RF9 Acts as a KISS1R Agonist In Vivo and In Vitro
Min, L., León, S., Li, H., Pinilla, L., Carroll, R. S., Tena‐Sempere, M., & Kaiser, U. B. (2015) · Endocrinology · doi:10.1210/en.2015-1635 · Cited by 36 · see citing works
Wahab, F., Bano, R., Jabeen, S., Irfan, S., & Shahab, M. (2010) · Hormone and Metabolic Research · doi:10.1055/s-0030-1252016 · Cited by 33 · see citing works
Self-citationTurner, A. I., Hemsworth, P. H., Canny, B., & Tilbrook, A. J. (1999) · Journal of Endocrinology · doi:10.1677/joe.0.1630477 · Cited by 31 · see citing works
Ullah, R., Shen, Y., Zhou, Y.-D., Huang, K., Fu, J.-F., Wahab, F., & Shahab, M. (2016) · Neuropeptides · doi:10.1016/j.npep.2016.05.004 · Cited by 30 · see citing works
Self-citationHayashi, K. T., & Moberg, G. P. (1987) · American Journal of Primatology · doi:10.1002/ajp.1350120304 · Cited by 30 · see citing works
Batool, A., Naz, R., Wazir, M. A., Azam, A., Ullah, R., Wahab, F., & Shahab, M. (2014) · Hormone and Metabolic Research · doi:10.1055/s-0034-1387788 · Cited by 14 · see citing works
Self-citationUllah, R., Batool, A., Wazir, M., Naz, R., Rahman, T. U., Wahab, F., Shahab, M., & Fu, J. (2017) · Neuropeptides · doi:10.1016/j.npep.2017.07.005 · Cited by 10 · see citing works
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Mbiydzenyuy, N. E., Hemmings, S. M. J., Shabangu, T. W., & Qulu-Appiah, L. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e27501 · Cited by 21 · see citing works
Fibromyalgia pathogenesis explained by a neuroendocrine multistable model
Demori, I., Losacco, S., Giordano, G., Mucci, V., Blanchini, F., & Burlando, B. (2024) · PLOS ONE · doi:10.1371/journal.pone.0303573 · Cited by 14 · see citing works
Mechanisms of Male Reproductive Sterility Triggered by Dysbiosis of Intestinal Microorganisms
Wei, M., Liu, H., Wang, Y., Sun, M., & Shang, P. (2024) · Life · doi:10.3390/life14060694 · Cited by 12 · see citing works
Santos, L. C., Cordeiro, J. M. D. A., Santana, L. D. S., Barbosa, E. M., Santos, B. R., Mendonça, L. D., Cunha, M. C. D. S. G., Machado, W. M., Santana, L. R., Kersul, M. G., et al. (2023) · Scientific Reports · doi:10.1038/s41598-023-44056-z · Cited by 10 · see citing works
Fraile‐Μartinez, O., Ortega, M. A., & Montero, C. G. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27020692 · Cited by 9 · see citing works
Testosterone in long-term sedentary aging males: Effect of antiaging strategies
Abdel-Sater, K. A. (2025) · Physiology International · doi:10.1556/2060.2024.00486 · Cited by 5 · see citing works
The role of anti-aging approaches in managing hypogonadism in sedentary older males
Abdel-Sater, K. A. (2024) · Frontiers in Aging · doi:10.3389/fragi.2024.1514438
Kamijima, J., Ikeda, A., Charvat, H., Maruyama, K., Tomooka, K., Kawamura, R., Takata, Y., Osawa, H., Tatsukawa, M., Yoshida, M., et al. (2026) · Neuroepidemiology · doi:10.1159/000550694
- Authors
- Ullah, R., Naz, R., Batool, A., Wazir, M., Rahman, T. U., Nabi, G., Wahab, F., Fu, J., & Shahab, M.
- Affiliations
- Children's Hospital of Zhejiang University (CN)
- Quaid-i-Azam University (PK)
- Hebei Normal University (CN)
- Pak-Austria Fachhochschule: Institute of Applied Sciences and Technology (PK)
- Corresponding author
- Fu, Junfen
- Shahab, Muhammad
- Venue
- Frontiers in Physiology
- Publisher
- Frontiers Media SA
- Published
- 2021-02-25
- Volume
- 12
- Pages
- 630796-630796
- ISSN
- 1664-042X (ISSN-L)
- PMC
- PMC7946976
- OpenAlex
- W3133439188
- Cited by
- 8
- References
- 23
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 4 · 2023: 1
- FWCI
- 1.08
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Physiology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (81570759, 2016YFC1305301, 81270938)
- Quaid-i-Azam University
- National Key Research and Development Program of China (No. 2016YFC1305301, 2016YFC1305301, 81270938, 81570759)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- kisspeptin, cortisol, hypothalamic-pituitary-gonadal axis, testosterone, male reproduction, rhesus monkeys
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