SYR: How sheep can help us understand why girls are reaching puberty at younger ages

michelle-bedenbaughThis guest post is the second written by Michelle Bedenbaugh, a Ph.D. student in the Physiology and Pharmacology Department at West Virginia University. Check out her first post on the benefits of using large animal models to study reproduction. It is also part of our Speaking of Your Research series of posts where scientists discuss their own research. In this post, Michelle discusses some of the cells and signaling pathways that are important for controlling the timing of puberty and how the use of sheep as a model is beneficial for this type of research. If you would be willing to write a guest article for Speaking of Research, please contact us here.

For those of you who have been watching the news in the United States over the past 5-10 years, you have probably heard a few discussions about the fact that girls are reaching puberty at younger ages.  In the 1980s, girls normally reached puberty around the age of 13.  In 2010, the average age of girls reaching puberty had dropped to 11 and has since continued to decline.  Reaching puberty at earlier ages is associated with several adverse health outcomes, including polycystic ovary syndrome (PCOS), metabolic syndrome, obesity, osteoporosis, several reproductive cancers and psychosocial distress.  The public and researchers have pointed fingers at several potential culprits, including an unhealthy diet, chemicals that disrupt the body’s normal hormonal environment, and an individual’s genetic predisposition to disease.  In reality, a combination of factors have probably led to the decrease in the age at which girls reach puberty, but I don’t want get into a discussion about these factors today.  Instead, I want to talk about some of the signaling molecules in the body that these factors may be influencing to affect the initiation of puberty.

As with many processes in the human body, the brain plays a critical role in the control of reproduction and the timing of puberty.  Within a specific area of the brain called the hypothalamus, several populations of neurons (specialized cells in the brain) exist that control reproduction.  The activity of these neurons is influenced by various factors that are communicated from other parts of the body and outside environment to the brain, including nutritional status, concentrations of sex steroids (like estrogen and testosterone), genetics, and many other external factors.  All of these factors tell the brain when an individual has obtained the qualities necessary to successfully reproduce and therefore undergo pubertal maturation.  Gonadotropin-releasing hormone (GnRH) neurons found in the hypothalamus are the final step in this chain of communication and are essential for the initiation of puberty.

A GnRH neuron present in the hypothalamus.

A GnRH neuron present in the hypothalamus.

Most of these nutritional, hormonal, genetic and environmental signals are not directly communicated to GnRH neurons.  Instead, they are conveyed through other types of neurons that then relay this information to GnRH neurons which either stimulates or inhibits the release of GnRH.  Because GnRH is a signaling molecule that ultimately stimulates the maturation of male (sperm) and female (egg) gametes, stimulating GnRH in turn stimulates reproductive processes while inhibiting GnRH inhibits reproductive processes.  The perfect balance of stimulatory and inhibitory inputs is needed for GnRH to be released and for puberty to be initiated.  Consequently, if stimulatory inputs signal to increase GnRH prematurely, puberty will occur earlier, which may result in several of the health concerns that were mentioned above later in life, including reproductive cancers and psychosocial distress.  In contrast, if inhibitory inputs block the release of GnRH, puberty will never occur and result in infertility.

My research looks at some of these stimulatory and inhibitory inputs and how they communicate with each other, as well as with GnRH neurons.  Two of the stimulatory signaling molecules that we research are kisspeptin and neurokinin B (funny names, I know).  We also study dynorphin (another funny name), a molecule that inhibits GnRH release.  These three molecules can all individually affect GnRH release and therefore reproduction.  However, the really cool thing about these three molecules are that they are actually present together in a special type of neuron that is only found in one small and highly specific area of the hypothalamus.  Because these neurons contain kisspeptin, neurokinin B, and dynorphin, they are often called KNDy (pronounced “candy”) neurons.  The fact that kisspeptin, neurokinin B, and dynorphin are all present in these KNDy neurons together allows for them to communicate directly and affect each other’s release.  This communication then ultimately affects the release of GnRH.  Before puberty, inhibitory inputs, like dynorphin, dominate and don’t allow for adequate amounts of GnRH to be released to stimulate reproduction.  As an individual matures, stimulatory inputs, like kisspeptin and neurokinin B, begin to outweigh inhibitory inputs, and GnRH can be released in adequate amounts to support reproductive processes.  Below is a figure that summarizes how we think all of this works within the body.  However, there is still a lot that we don’t know about how kisspeptin, neurokinin B and dynorphin interact with each other that is waiting to be discovered!

Hypothesized model for the initiation of puberty. (1) Internal and external factors are communicated to the body. (2) Next, these factors are relayed through various signaling pathways to stimulatory and inhibitory molecules present in neurons located in the hypothalamus. (3) Stimulatory and inhibitory molecules travel to GnRH neurons and affect the release of GnRH. (4) GnRH stimulates reproductive processes that are critical for the initiation of puberty. (5) Once all of the proper conditions are met, reproductive maturity is attained.

Hypothesized model for the initiation of puberty. (1) Internal and external factors are communicated to the body. (2) Next, these factors are relayed through various signaling pathways to stimulatory and inhibitory molecules present in neurons located in the hypothalamus. (3) Stimulatory and inhibitory molecules travel to GnRH neurons and affect the release of GnRH. (4) GnRH stimulates reproductive processes that are critical for the initiation of puberty. (5) Once all of the proper conditions are met, reproductive maturity is attained.

To complete all of these studies, we use sheep as our model.  I know what some of you are thinking.  “How in the world would sheep serve as a good model for how puberty is initiated in humans?  I don’t think I am similar to a sheep at all!”  In fact, sheep are actually an excellent model in which to do this research.  The signaling pathways that affect the release of GnRH in sheep are very similar to the signaling pathways in humans, and in some cases, are even more similar to the human pathways than the pathways present in mice or rats.  In humans and sheep, neurokinin B has only been found to stimulate GnRH release.  However, in rodents, there have been reports of neurokinin B both stimulating and inhibiting GnRH release.  Since neurokinin B is one of the main signaling molecules that we study, using sheep instead of mice or rats is more beneficial for modeling what is occurring in humans.

sheep-in-reproduction-research

Because we have to collect several blood samples from the sheep in order to measure hormone concentrations, having an animal with a larger blood volume is also advantageous.  Several hormones in the body (including GnRH) are released in a pulsatile manner, meaning one minute GnRH concentrations are high and a few minutes later they are low.  Therefore, in order to appropriately measure GnRH, blood samples need to be taken every 10-12 minutes for several hours.  This is not feasible in rodents.  If you took blood samples as frequently in rodents as is possible in sheep, you would risk killing the animal.  Some scientists who use rodents as their research model attempt to get around this issue by taking blood samples less frequently.  However, this means their hormone measurements are less accurate.

These are just a few of the many reasons why we conduct our research in sheep (to learn more about the advantages of using sheep and other large animal models to conduct research involving reproduction, see my previous post).

While most people (including myself) do not look back fondly on our awkward pubertal years, I absolutely love studying the signaling pathways the body uses to determine when it is ready to successfully reproduce.  We have discovered quite a bit over the past few decades concerning how different internal and external factors affect pubertal maturation, but there are still so many unknowns left to be determined.  I look forward to hopefully discovering some of these unknowns and improving our understanding of how puberty is initiated in both humans and livestock species.

Michelle Bedenbaugh

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