Identifying genetic mutations that delay puberty in a small number of children may also lead to better infertility treatment and birth control, says a Medical College of Georgia physician-scientist.
"Irreversible, delayed puberty is fortunately rare," said Dr. Lawrence C. Layman, chief of the MCG Section of Reproductive Endocrinology, Infertility and Genetics. "But if we can find mutations in genes in these patients, that shows the genes are important for normal puberty so they could be useful in infertility treatment as well. You also could block them and make a contraceptive. So there are a lot of possibilities."
Dr. Layman recently received a $1 million grant from the National Institutes of Health, the second NIH grant he has to tackle the laborious task of studying the some 100 genes believed to have a role in puberty and reproduction. He'll look at the numerous potential mutations of each and find whether they cause idiopathic hypogonadotropic hypogonadism, an unfortunate series of genetic circumstances that forestall the sex steroids or hormones that transform children into reproductive adults.
Boys usually begin puberty by age 10 or 11 and girls age 8 or 9, when the hypothalamus in the brain begins releasing gonadotropin releasing hormone, which stimulates the pituitary gland to make follicle stimulating hormone, FSH, and luteinizing hormone, LH. FSH and LH, in turn, prompt the ovaries to produce estrogen and eggs and the testes to produce testosterone and sperm.
"When patients present to us with delayed puberty, it usually means they are not making either estrogen or testosterone," said Dr. Layman. "And, if you then measure the levels of FSH and LH, and they are low, that means the problem is in the brain, either the hypothalamus or the pituitary."
These adolescents receive hormone replacement therapy throughout their reproductive lives. If they decide to have children, they will need comparatively expensive gonadotropin (FSH and LH) injections to stimulate ovulation in women and sperm production in men.
Mutations of nine genes have been found that contribute to about 20 percent of the cases of delayed puberty. Dr. Layman's studies have contributed to identification of two of these mutations, including those on the GNRH receptor and FSHB, but the total list of contributors could be in the hundreds, he said.
Now Dr. Layman is using the Affymetrix GeneChip machine in the MCG Genomics Core Facility, which was developed with the support of the Georgia Research Alliance, to handle the massive task of looking at suspect genes and possible mutations.
Each custom-made chip, configured by Affymetrix of Santa Clara, Calif., has six suspect genes along with all their possible mutations, which include a seemingly infinite number of combinations of the bases adenine, guanine, cytosine and thymine. The sequence of these bases determines gene function by determining the protein it produces; genetic mutations occur when the order is altered, changing gene function.
"We are working our way through the genes we think could cause this and screening them for mutations at every possible base," said Dr. Layman. The gene chip machine dramatically increases the speed of this arduous endeavor. "It should be a high-throughput way to screen for mutations," he said. But that is just the beginning.
"If it looks like we have a mutation, we sequence it and then you have to determine if it affects the protein. You have to study it, put it in a cell line, compare it to the normal protein and see if it causes problems," Dr. Layman said. Sometimes a harmless change in a base does not affect gene function; in fact, everyone has these variations, called polymorphisms.
When the researchers find a base change that does affect the protein expressed, they have to look for that base change in the DNA of both normal people and those with delayed puberty. Dr. Layman has DNA from about 300 patients with delayed puberty he has helped treat in the last 15 years.
"Somebody who has normal puberty shouldn't have that base change at that particular place. If they do, then it's not causing the disease," Dr. Layman said. Then, the researchers put the normal gene and the mutation into cells where they can function and make FSH; mutations should make decreased amounts.
Delayed puberty, which affects about 1 percent of the population, can be a devastating problem for children and families, Dr. Layman said, although most respond well to treatment. The disease can run in families and may have associated problems including stunted growth, a cleft lip and palate and some central nervous system abnormalities, such as balance problems.
He hopes his studies will provide better insight into the cause of delayed puberty and normal puberty, for that matter, which also is not well understood, and ultimately lead to better treatment. He said some of these genes "absolutely" have a role in fertility as well, which could one day mean better infertility treatments and birth control as well.
Dr. Iqbal Khan, MCG embryologist, is a co-investigator on the studies. Dr. Layman also sees patients with a wide variety of reproductive problems, including pubertal disorders, menstrual abnormalities, genetic diseases, menopause and offers reproductive conserving surgery as well as all aspects of infertility treatment. His colleagues, Drs. Adelina M. Emmi and Daksha Chudgar, see patients at Reproductive Medicine and Infertility Associates, 810 Chafee St., Augusta.