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Behavioral Endocrinology: Kisspeptins' affects on Sex Hormones

Figure 1: Lordosis in mice

Kisspeptin is a peptide hormone that is formed by the cleavage of the peptides created by the KISS1 gene. Some functions of kisspeptins are signalling the release of gonadotropin-releasing hormone (GnRH) and suppressing metastasis in breast cancer and in melanoma. Kisspeptin in terms of sexual and social encounters act as a promoter for GnRH secretion. This pathway occurs in the limbic system which encompasses the structural components of the orbitofrontal cortex, hippocampus, cingulate cortex, amygdala, hypothalamus, thalamus, and the ventral striatum.The limbic system controls emotions and behavioral actions based on social cues. The main structural components of the limbic system that control specifically processing emotions is primarily the amygdala, hypothalamus, cingulate cortex, and the prefrontal cortex.Kisspeptin modulates the production of GnRH and the products of GnRH propose a negative feedback mechanism towards kisspeptin.

When looking at the effect of kisspeptin on behavior, researchers tested the function of kisspeptin by examining animals that lack the KISS1 gene and animals that have acquired activating mutations of the KISS1 gene. The results showed that the animal lacking KISS1 gene failed to go through puberty and the animal expressing the activating mutations of KISS1 gene went through precocious puberty. These result indicate the crucial role kisspeptin has on activators of the HPG axis and the role of sexual and emotional processing in the brain. Another study that confirmed the connection between the amygdala and HPG axis was administering kisspeptin or antagonist to kisspeptin directly into the amygdala and monitoring the LH output. The results showed that when kisspeptin was injected into the amygdala that the LH output increased, whereas when the antagonist was injected into the amygdala the LH output decreased as well as decrease in pulsitility. Behaviorally, the administration of kisspeptin triggered lordosis behavior in female rats and increase the amount of time a male would be interesting the females odors. When male rats were injected with kisspeptin in the median amygdala, it caused erections. Kisspeptin also is shown to have effects on behavior based on motivation due to the way it interacts with behavioral neuropeptides.

Pathway of Kisspeptin for Sex Hormone Secretion

When the amygdala is stimulated, the hypothalamus secretes kisspeptin from its' neurons which travel to kisspeptin receptors. Kisspeptin receptors are under the class of G-protein coupled receptors, These receptors are called Kiss1r receptors and are also formerly known as GPR54. When kisspeptin hormones are released, the kisspeptin receptors are activated on the GnRH neurons and in return triggers the release of GnRH. When GnRH is secreted, this hormone travels to the anterior pituitary to and binds to receptors that trigger the release of LH and FSH. When these hormones are secreted, they travel to the gonads to signal the production of sex hormones like testosterone, estrogen, and progesterone. The products caused through the release of the GnRH activate a feedback loops on the release of kisspeptin. The negative feedback that is caused by the release of sex hormones inhibits the kisspeptin neurons on the ARC. The kisspeptin neurons on the ARC are also known to be responsible for the pulsitility in GnRH. The positive feedback loop that is caused by the presence of sex hormones stimulates kisspeptin neurons in the RP3V (Rostal periventricular area of the third ventricle).

Kisspeptin Affects on Social Behavior

Figure 2: An active human amygdala

In animal studies researching the role of kisspeptin in behavior, the amygdala was shown to be the core processing center of emotions according to MRI images. This was tested by placing the rat underneath the MRI and showing sexual and non-couple bonding images. The result showed high activity in the amygdala which concluded that the amygdala is the core processing for social interactions, non-couple bonding as well as mating. The hypothalamus is known for working collaboratively with the amygdala because when the amygdala is stimulated, there is a direct increase in GnRH, which is secreted by the hypothalamus. While the amygdala processes emotions and the hypothalamus secretes GnRH, they work together to connect emotional processing and reproductive pathways.

• Acts as an antidepressant in males.
• Reduces fear in males.
• Can induce or reduce anxiety in males.
• Increases male brain activity in processing parts of the brain for sex drive.
• Increased activity in brain for male bonding.

Alterations of KISS1 Gene

When the KISS1 gene was studied to identify the its' importance, it was discovered that without having this gene the species would fail to go through puberty and had infertility. Inversely, when the KISS1 genes were mutated, this triggered precocious puberty. Some studies suggest that with this information that the KISS1 genes are essential for reproduction not only in sex drive but in fertility and puberty. In situations Hypogonadotropic Hypogonadism, behavioral effects mainly surround libido and attraction. When looking at studies preformed on mice without kisspeptin or administration of kisspeptin antagonists, the mice become less interested in each other, sexually and socially, as well as having lower sex drives. In situations of activating mutations in the KISS1 gene, the behavioral effects that result from this are mood swings and emotional changes.

Hypogonadotropic Hypogonadism

This disorder occurs when the KISS1 gene is not present. The absence of the KISS1 gene prevents kisspeptin from being created and released which would usually proceed down the normal pathway to create sex hormones by stimulating the ovaries or testes. Normally kisspeptin would travel to receptors on the hypothalamus which in turn would release GnRH. GnRH would usually bind to receptors on the anterior pituitary to release FSH and LH. FSH and LH would usually bind to the receptors on the ovaries or testes which would then release sex hormones like estrogen and testosterone. This process does not occur without the KISS1 gene which leads to the lack of sex hormones produced. Having a lack of sex hormones affects behavior due to the loss of sex drive, irritability, and depression.

Symptoms

• Regression of secondary sex characteristics
• Anemia
• Muscle mass reduction

• Osteoporosis
• Reduced libido
• Depressed/Increased Irritability
• Difficulty concentrating
• Infertility
• Hot flashes

Treatment

The main route of treatment involves hormone replacement therapy for both men and women. Pre-menupausal women and men generally take hormone pills, patches, chewing gum, or injections in order to replace the hormones they cannot make themselves. Younger women who have not had their uterus's removed take progesterone, estrogen, and low-dose testosterone to prevent endometrial cancer and to increase sex drive.

Central Precocious Puberty (CPP)

This disorder occurs when there is a mutation in the KISS1 gene that stimulates the GnRH secretion in children, specifically girls before the age of 8 and boys before the age of 9. In children who have central precocious puberty tend to have behavioral issues because of the increase in sex hormones in their bodies.

Symptoms

• Pubic hair
• Underarm hair
• Growth spurt
• Acne
• Breast development in girls
• Menstruation in girls
• Penis growth in boys
• Deepening of the voice in boys
• Physiological problems
• Behavioral problems

Treatments

• GnRH agonist
  • GnRH agonist induce a negative feedback system that helps the anterior pituitary stop signalling from the hypothalamus that try to stimulate ovaries and testes to make sex hormones.

Discovery

Kisspeptin was discovered by the lab of Dr. Danny Welch in 1996. While they were studying metastasis of cancer cells, they discovered that a cell would not undergo metastasis when human chromosome 6 was added. This discovery was proven when chromosome 6 was added to melanoma cells and they did not metastasize. They named this gene KISS1 because it was discovered in Hershey Pennsylvania which is where Hershey Kisses were founded.