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Story of Discovery: Finding the Master Reproductive Hormone

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Roger Guillemin and Andrew V. Schally, NICHD grantees, opened the way for current treatments for infertility and cancers of the reproductive system. Working independently of each other, the two isolated hormones from the brain region known as the hypothalamus, which regulates blood pressure, body temperature, fluid balance, and other essential body functions. The magnitude of their contribution was recognized when they received the Nobel Prize in Physiology or Medicine in 1977.

Scientists’ understanding of the hypothalamus grew out of a series of scientific investigations spanning more than80 years. The hypothalamus secretes hormones that stimulate the pituitary, a pea-sized gland beneath the brain. The hypothalamus sends its hormonal signals through a network of blood vessels. In the 1920s scientists took a major step in understanding the gland’s functioning by cutting these vessels in experimental animals. The animals soon lost their reproductive functioning. Scientists knew that a hormone, called luteinizing hormone (LH), acted on the ovaries and testes, leading to ovulation in women and sperm production in men. Observing that the experimental animals lost the capacity to reproduce, the scientists theorized that a second hormone, which they called luteinizing hormone releasing factor (LHRF), stimulated release of LH from the pituitary, thus controlling reproduction. The search for the “master” reproductive hormone that stimulated this release had begun.

Later two fiercely competitive research teams, one led by Guillemin and the other by Schally, independently discovered the hormone. Lacking precise techniques now available for isolating very small quantities of a substance, the teams needed massive quantities of tissue to work with. Guillemin’s team found the hormone by analyzing five million samples from discarded sheep brains. Schally’s group found an identical substance in an equal quantity of pig brain tissue. The hormone they discovered is now known as gonadotropin releasing hormone (GnRH). GnRH was later found in a number of species, including human beings. The next step for researchers was to develop GnRH analogs--substances that are similar to GnRH chemically but, due to minor substitutions in their chemical makeup, might work more effectively than GnRH itself. For example, researchers found that injecting experimental animals with a large dose of a GnRH analog first stimulated a surge of reproductive hormones and then led to their complete suppression. Following up on this discovery, a pharmaceutical company developed another GnRH analog, leuprolide, which became a standard treatment for prostate cancer. Leuprolide also became the standard treatment for precocious puberty (a form of abnormally early sexual maturation). This treatment switches off sex hormone production in a child with this condition, until the child reaches an appropriate age. Other GnRH analogs were developed to treat female infertility. In conjunction with other hormones, these analogs “reset” a woman’s monthly ovulatory cycle and stimulate ovulation. Now, other NICHD-funded researchers are testing a GnRH antagonist, a synthetic substance that causes the body to stop producing GnRH immediately. The new agonist holds potential as a component of a male hormonal contraceptive and may also be useful for treating prostate cancer.

Last Reviewed: 09/01/2006
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