The researchers found four patients who had mutant copies of a gene that contains the information for Phosphodiesterase 11A (PDE11A). Phosphodiesterases are a family of enzymes involved in “switching off” a cell’s response to hormones, Dr. Stratakis explained.
For a hormone to affect the cell, it must first bind to a molecule, or receptor, on the cell’s surface, analogous to how a key fits into a lock. This action triggers the cell to produce substances known as cyclic nucleotides. These function as “second messengers,” often stimulating the cell to begin an activity. In the case of adrenal cells, cyclic nucleotides, such as cyclic AMP and cyclic GMP, may stimulate cell growth or other activities. Once the activity has ended, phosphodiesterases degrade the cyclic nucleotides, thereby halting the cell’s response to the hormone.
In the study, the patients’ tumors were made up of cells that were deficient in the enzyme PDE11A. This enzyme halts cyclic nucleotide production in adrenal cells as well as in
other kinds of cells in the body. Because they lacked PDE11A, the patients’ adrenal cells had higher levels of cyclic nucleotides. The researchers believe that these higher cyclic nucleotide levels led to the formation of tumors.
The gene for PDE11A contains the information needed to make 4 slightly different forms of the enzyme. The form of the enzyme that was mutated in the patients who took part in the study was found in large amounts in normal adrenal glands and in even larger amounts in normal prostate glands, Dr. Stratakis added. Other forms of PDE11A are found in several other tissues, including the testes, skeletal muscle, and the heart.
Dr. Stratakis noted that although the evidence associating the mutation in the gene for PDE11A to the development of adrenal tumors was very strong, the study was not capable of proving that the mutation actually caused the tumors.
In their article, the researchers wrote that drugs used to treat erectile dysfunction interfere with the functioning of PDE11A. The researchers noted that PDE11A “is partially inhibited” by the drug tadalafil and “weakly” inhibited by sildenafil. They added that there are no reports in the medical literature of malfunctioning adrenal glands or increased adrenal cell growth in users of these drugs.
“However, detailed clinical studies addressing this potential complication are currently lacking,” they wrote.
Dr. Stratakis and his colleagues are currently planning studies to determine if differences in the gene for PDE11A might influence an individual’s cancer risk.
The NICHD sponsors research on development, before and after birth; maternal, child, and family health; reproductive biology and population issues; and medical rehabilitation. For more information, visit the Institute’s Web site at http://www.nichd.nih.gov/.
The National Institutes of Health (NIH) — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov. |
