Professor Emerita, Biology Department
Phone: (250) 721-7143
Research area: molecular endocrinology of growth and reproduction
We've come a long way in understanding how the brain controls the release of sex hormones. If fact, when Dr. Nancy Sherwood first started studying reproduction in the sixties, people knew the brain played a role but they didn’t know how it controlled the pituitary gland, which produces hormones that act on gonads, stimulating them to produce sex steroids such as estrogen, progesterone and testosterone.
However, early researchers had an inkling that the brain must be involved at some level, Sherwood explains. For instance, many species of birds lay a certain number of eggs, and if you take one egg away from a bird, it will lay a new one to replace it. That bird must be sensing the number of eggs and transmitting that information to the pituitary gland to stimulate the production of another egg. Likewise, temperature, light, smell and stress all affect the output of sex hormones in animals, including humans. How are those signals being sensed, processed and transmitted to the pituitary if not through the brain?
The answer is the hypothalamus, which in humans is about the size of an almond and sits just above the brain stem and the pituitary gland. The hypothalamus controls many autonomic functions like respiration, body temperature, hunger and circadian rhythms, as well as the onset of puberty, ovulation, and the formation of sperm, just to name a few of its roles. Neurons in the hypothalamus collect signals from many parts of the central nervous system, and responds by secreting small neurohormones that act on the pituitary gland. To underline the point here, neurohormones are produced by neurons, explaining the mechanism by which the brain controls the endocrine system.
Sherwood has been fascinated by this mechanism and has focused her career on reproductive neurohormones, especially gonadotropin-releasing hormone (GnRH).
GnRH causes the pituitary gland to secrete follicle-stimulating hormone and luteinizing hormone, which act on the ovaries and testes to produce sex steroids that control such things as menstruation, lactation and sperm formation. In a classic feedback loop, sex steroids inhibit secretion of GnRH, completing the cycle to the brain.
These days Sherwood is interested in GnRH receptors. There are several reasons why this work is important; for one, the more researchers look, the more forms of GnRH receptors they find in different areas of the body, suggesting a wider role than just controlling ovaries and testes via the pituitary gland.
For example, one of Sherwood's graduate students, Javier Tello, discovered a GnRH receptor in the hind brain of zebra fish, suggesting GnRH is affecting motor functions directly through the hind brain, perhaps controlling sexual behaviour. (Tello received the Governor General’s gold award for best pHD thesis at UVic for 2008 for his GNRH receptor work).
His discovery is exciting because in Sherwood’s experience, if you see a neurohormone mechanism in a simple animal, chances are you’ll see a related mechanism in humans. With the wealth of completed genomes (with more coming each year), it is becoming increasingly clear just how true this is, with related forms of human neurohormones being discovered in the genome of the simplest animals -- and vice versa. That is why Sherwood and her team can use animals such as fish, amphioxus and sea squirts as models for understanding puberty and fertility in humans.
One thing that intrigues Sherwood is why most animals have two or more closely related forms of GnRH and GnRH receptors. So far, it is not clear what all the different forms do. For instance, Sherwood recently discovered that the humble sea squirt has six forms of GnRH and four forms of the receptor, prompting her to ask: “What is all this for?” Humans, by comparison, have only two forms of the neurohormone and one form of the receptor. Sherwood is not sure whether higher animals lost the other forms of GnRH or if sea squirts evolved further forms after higher animals branched off. She is testing to see if all six forms are active. All three tested so far are active.
Sherwood also created a mouse model to study the role of GnRH in mammal development. She wanted to know at which stage of development GnRH becomes necessary. For instance, does it affect fetal development? Does it affect sexual differentiation? To answer these questions, Sherwood and her team developed a mouse strain where they blocked the expression of the GnRH receptor genes. (Removing the receptors is the most complete way of making the hormone unavailable; without receptors, fetal mice can not even respond to their mother’s hormone in the womb).
The mice were born healthy, and remained normal until puberty, but did not mature sexually. The mouse model provides a good base for future studies to begin to distinguishing more subtle problems with GnRH and its receptors, which are seen in human disorders, affecting puberty and fertility.
Lately, Sherwood has branched to look at nonreproductive neurohormones. She recently found that mice lacking PACAP (a member of the secretin superfamily) are unable to regulate their temperature. Young mice lacking PACAP die at room temperature, finding it too cool. This was surprising because although PACAP was known to control the distribution of fat, no one knew it also helped mammals control body temperature.
The multiple effects of PACAP are typical of neurohormones and underlines the challenge of treating hormonal dysfunctions: namely, it is hard to treat one hormonal effect in isolation, and given our knowledge so far, side effects are hard to predict. Sherwood’s work helps fill in the necessary background.
When she is not in the lab, Sherwood enjoys tutoring students in UVic’s Island Medical Program, helping them work through mock case studies of endocrine and metabolism disorders. She also co-edited the book, Hormones and Their Receptors in Fish Reproduction, published in 2005.