DUNEDIN, New Zealand—Scientists at the University of Otago have shown for the first time the key ovulation-triggering role of kisspeptin, a small protein molecule in the brain, a discovery that could lead to new treatments for infertility.
In a study published Aug. 27 in The Journal of Neuroscience, a team of researchers from the University of Otago School of Medical Sciences' Centre for Neuroendocrinology and Department of Physiology collaborated with the University of Cambridge's Department of Physiology, Development and Neuroscience, to offer the first evidence that kisspeptin signaling in the brain is essential for ovulation to occur in adults.
In previous research, kisspeptin was shown to be vitally important in the onset of puberty. In this latest study, the researchers studied female mice and found that signaling between kisspeptin and its cell receptor, GPR54, was essential to activate gonadotrophin-releasing hormone (GnRH) neurons, the nerve cells known to initiate ovulation.
"This is an exciting finding, as people have been trying to find out precisely how the brain controls ovulation for more than 30 years," says Dr. Allan Herbison, a professor in the University or Otago's Physiology Department.
Using mouse models, the researchers addressed whether kisspeptin and GPR54 have a key role in the activation of GnRH neurons to generate the luteinizing hormone (LH) surge responsible for ovulation. Dual-label immunocytochemistry experiments showed that 40 to 60 percent of kisspeptin neurons in the rostral periventricular area of the third ventricle (RP3V) expressed estrogen receptor and progesterone receptors. Using an ovariectomized, gonadal steroid-replacement regimen, which reliably generates an LH surge, nearly 30 percent of RP3V kisspeptin neurons were found to express c-FOS in surging mice compared with none in nonsurging controls. A strong correlation was found between the percentage of c-FOS-positive kisspeptin neurons and the percentage of c-FOS-positive GnRH neurons.
To evaluate whether kisspeptin and/or GPR54 were essential for GnRH neuron activation and the LH surge, Gpr54- and Kiss1-null mice were examined. Whereas wild-type littermates all exhibited LH surges and c-FOS in nearly 50 percent of their GnRH neurons, none of the mutant mice from either line showed an LH surge or any GnRH neurons with c-FOS.
"These observations provide the first evidence that kisspeptin-GPR54 signaling is essential for GnRH neuron activation that initiates ovulation," the researchers wrote. "This broadens considerably the potential roles and therapeutic possibilities for kisspeptin and GPR54 in fertility regulation."
Herbison says he is optimistic that within the next five years, a new drug treatment could be developed to help overcome infertility problems arising from a "miscommunication between the brain and the ovaries."
"We're doing this research to make a difference to the health of people," he says. "Targeting drugs to this chemical switch to make it work properly may help some people who are infertile, while finding compounds that can block this switch could lead to new contraceptives."
The study, Kisspeptin–GPR54 Signaling Is Essential for Preovulatory Gonadotropin-Releasing Hormone Neuron Activation and the Luteinizing Hormone Surge, was supported by the Health Research Council of New Zealand and the Marsden Fund. DDN
In a study published Aug. 27 in The Journal of Neuroscience, a team of researchers from the University of Otago School of Medical Sciences' Centre for Neuroendocrinology and Department of Physiology collaborated with the University of Cambridge's Department of Physiology, Development and Neuroscience, to offer the first evidence that kisspeptin signaling in the brain is essential for ovulation to occur in adults.
In previous research, kisspeptin was shown to be vitally important in the onset of puberty. In this latest study, the researchers studied female mice and found that signaling between kisspeptin and its cell receptor, GPR54, was essential to activate gonadotrophin-releasing hormone (GnRH) neurons, the nerve cells known to initiate ovulation.
"This is an exciting finding, as people have been trying to find out precisely how the brain controls ovulation for more than 30 years," says Dr. Allan Herbison, a professor in the University or Otago's Physiology Department.
Using mouse models, the researchers addressed whether kisspeptin and GPR54 have a key role in the activation of GnRH neurons to generate the luteinizing hormone (LH) surge responsible for ovulation. Dual-label immunocytochemistry experiments showed that 40 to 60 percent of kisspeptin neurons in the rostral periventricular area of the third ventricle (RP3V) expressed estrogen receptor and progesterone receptors. Using an ovariectomized, gonadal steroid-replacement regimen, which reliably generates an LH surge, nearly 30 percent of RP3V kisspeptin neurons were found to express c-FOS in surging mice compared with none in nonsurging controls. A strong correlation was found between the percentage of c-FOS-positive kisspeptin neurons and the percentage of c-FOS-positive GnRH neurons.
To evaluate whether kisspeptin and/or GPR54 were essential for GnRH neuron activation and the LH surge, Gpr54- and Kiss1-null mice were examined. Whereas wild-type littermates all exhibited LH surges and c-FOS in nearly 50 percent of their GnRH neurons, none of the mutant mice from either line showed an LH surge or any GnRH neurons with c-FOS.
"These observations provide the first evidence that kisspeptin-GPR54 signaling is essential for GnRH neuron activation that initiates ovulation," the researchers wrote. "This broadens considerably the potential roles and therapeutic possibilities for kisspeptin and GPR54 in fertility regulation."
Herbison says he is optimistic that within the next five years, a new drug treatment could be developed to help overcome infertility problems arising from a "miscommunication between the brain and the ovaries."
"We're doing this research to make a difference to the health of people," he says. "Targeting drugs to this chemical switch to make it work properly may help some people who are infertile, while finding compounds that can block this switch could lead to new contraceptives."
The study, Kisspeptin–GPR54 Signaling Is Essential for Preovulatory Gonadotropin-Releasing Hormone Neuron Activation and the Luteinizing Hormone Surge, was supported by the Health Research Council of New Zealand and the Marsden Fund. DDN
