Many people think that scientific progress is as orderly as building a highway. Crews bulldoze rocks and other obstacles out of the way, then level the surface, and then lay down the asphalt so that travelers can proceed steadfastly from one point to another.
But advancing science is more like putting together a thousand-piece jigsaw puzzle. Except that you can’t check the cover of the box to see what the finished scene should look like. And, instead of a thousand pieces, it’s more like several thousand, or even tens of thousands.
On our Web site this month, we’re trying to raise awareness about one such scientific puzzle, the problem of infertility. Most couples who wish to become parents don’t have any serious problems conceiving, and ultimately, of bearing a child. But, underlying this seemingly simple process are layers and layers of complexity. Thousands of genetic and biochemical events must proceed smoothly for a woman to release an egg that can be fertilized, for a man to produce viable sperm, for the sperm to find the egg, and for that fertilized egg to implant in the uterine wall and develop for nine months. Given this complexity, it’s truly amazing that the process succeeds as often as it does.
Because so many things could, potentially, go wrong, it’s often difficult to find the cause of infertility. Still, we’ve been successful in piecing together key pieces of the puzzle. We’ve learned that normal aging, lifestyle, and environmental factors all play roles. So does an individual’s health.
Consider, for example the puzzling disorder known as polycystic ovary syndrome (PCOS). Women with this condition produce high levels of androgens—male hormones. PCOS can result in infertility and also in irregular menstrual cycles, increased facial and body hair, acne, and cyst-like growths in the ovaries. Women with PCOS often have difficulty metabolizing insulin and may be at increased risk for heart disease, high blood pressure, and type 2 diabetes. Although PCOS affects roughly 5 to 7 percent of women of reproductive age, we aren’t sure what causes it, and often lack effective treatments for it.
However, as we report this month, NICHD-funded scientists have uncovered what may be a major piece of the puzzle of this mysterious disorder. The scientists have presented data tying the source of the androgens in PCOS to a protein ordinarily produced by cells in the ovary, DENND1A.V2. Evidence of the protein is also present in the urine of women with PCOS, which opens up the possibility of a more accurate and early diagnosis for the condition. More information about this encouraging finding is available in our news release, Gene linked to excess male hormones in female infertility disorder.
This particular puzzle piece was identified by researchers in an NICHD-supported research network, the Specialized Cooperative Centers Program in Reproduction and Infertility Research (SCCPIR). As anyone who has ever worked on a thousand piece jigsaw puzzle knows, things go faster when several people are working on it, rather than just one person alone. SCCIPR scientists come from a number of different specialties. The objective of the SCCPIR is to improve human reproductive health by fostering collaboration between basic science and clinical investigators. For the DENND1A.V2 protein, researchers in the SCCPIR program began by analyzing a gene first identified in genome wide association scans from women in China. The gene contained information needed to make DENND1A.V2. SCCPIR scientists worked as a team to devise a series of experiments to determine how this protein might contribute to high androgen levels.
When SCCPIR center researchers identify such promising leads, the new information is then applied to improving the medical management of the particular infertility disorder. Once a new test or treatment is ready for a clinical study, it can be evaluated in NICHD’s Reproductive Medicine Network (RMN). The purpose of the RMN is to carry out large scale clinical trials at centers throughout the country. So, for example, if efforts to develop a urine test for DENND1A.V2 are successful, the test might ultimately be evaluated in a clinical trial in the RMN.
Previously, SCCPIR researchers tested the effectiveness of the diabetes drug metformin in helping women with PCOS achieve pregnancy. In addition to high androgen levels, women with PCOS often experience insulin resistance, a pre-diabetic condition in which higher-than-normal amounts of insulin are required to allow glucose to enter tissues. Although metformin showed promise, a follow-up study by the RMN ultimately determined that treatment of PCOS with clomiphene, a drug used to induce ovulation, is more effective in helping women to achieve pregnancy than is metformin. Recently, another RMN study determined that the drug letrozole, which works by a different mechanism from clomiphene, was even more effective than clomiphene in helping women with PCOS achieve pregnancy.
Some SCCPIR researchers are working on other aspects of the PCOS puzzle. A team at the SCCPIR center at the University of Virginia has focused on the possible link between androgens and obesity. They’ve found that girls with obesity in the early stages of puberty are more likely than girls of typical weight to have high androgen levels. Androgen levels were especially high in girls with obesity who entered puberty early—their androgen levels were five times higher than those of girls of typical weight who entered puberty early.
We haven’t been able to solve the puzzle of PCOS just yet. But we believe that our network of researchers have put key pieces of the puzzle into position, and, based on what they’ve assembled so far, will make important advances in the years to come.
Originally posted: April 22, 2014