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DNA Blueprints Guide The Construction Of Specific Human Structures
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The article includes an audio recording of the full interview. Photo courtesy of the UCSD School of Medicine.
| Regulating The Regulator Of Sex Hormone Production |
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| Medicine - Hormones & Meds | |||
| TS-Si News Service | |||
| Wednesday, 30 July 2008 17:00 | |||
St. Louis, MO, USA. The triumvirate of sex hormones — estrogen, progesterone, and testosterone — have cycles of rise and fall in our bloodstreams that influence and respond to other changes in our bodies. The sex hormones are controlled in turn by two other hormones, known as luteinizing hormone (LH) and follicle stimulating hormone (FSH).
Disturbances in the levels of either LH or FSH affect the production of sex hormones and can cause either premature or delayed puberty as well as infertility. This is the starting point for humans even prior to menopause or the administration of sex hormones during cross-sex transition.
Ablation of GalNAc-4-sulfotranferase-1 enhances reproduction by altering the carbohydrate structures of luteinizing hormone in mice. Yiling Mi, Dorothy Fiete and Jacques U. Baenziger. Journal of Clinical Investigation 118(5) 1815-1824. doi: 10.1172 / JCI32467. [ Download PDF ]
An enhanced undrstanding the basic mechanisms involved in native sex hormone concentrations can provide evidence for improved hormone dosages. Moreover, knowing just how the regulator hormones, LH and FSH, are regulated can provide clues on how to stimulate hormone receptors for more efficient processing.
 Jacques Baenziger, M.D., Ph.D., and colleagues at the Washington University School of Medicine in St. Louis, have identified a new mechanism by which levels of LH in the blood are regulated. Changing the sugars attached to a hormone produced in the pituitary gland increased fertility levels in mice nearly 50 percent. The change appears to alter a reproductive "thermostat," unveiling part of an intricate regulatory system that may one day be used to enhance human fertility. The report appears in The Journal of Clinical Investigation.
Sugars are the most common addition to hormones and other proteins after they have been assembled from instructions in DNA. Nearly all proteins in the blood and on the surface of cells have sugars attached. Scientists believe sugar attachments modify and adapt proteins, enabling them to fill more than one job or changing the way they do their jobs in different contexts. But direct demonstration of such changes has been a daunting challeng.
Baenziger found a unique set of sugars consistently added to luteinizing hormone, which is part of a feedback loop between the pituitary, the reproductive organs and the liver. The loop cycles up and down over time, producing periodic peaks in other reproductive hormones and triggering regular events such as the ovaries' release of eggs.
Attached to LH are unique carbohydrate structures that end in a carbohydrate unit known as GalNAc-4-SO4. In the study, mice lacking the protein responsible for adding GalNAc-4-SO4 to the end of the carbohydrates on LH were found to have higher levels of LH in the blood than normal mice.
The authors concluded that the unique carbohydrate structures attached to LH have a crucial role in regulating the levels of this hormone in the blood.
For their study, Baenziger's laboratory genetically disabled one of the enzymes that attaches sugars to luteinizing hormone in mice. This enzyme isn't the only one to add sugars to the hormone, so the alteration changes the mix of sugars rather than eliminating them completely. "To adjust for the right amount of key reproductive hormones such as estrogen and testosterone, we may someday alter the sugars that are added to this hormone or others like it," says Baenziger. "Initially, we didn't seem to see much of a difference in the animals," Baenziger says. "But then someone came to me and said, 'We have too many animals. We're constantly weaning mice!'"
A closer look showed that the mice were having nearly 50 percent more pups than normal, and that the liver removed the altered hormone from the blood more slowly. In addition, female mice were maturing earlier, were always receptive to male overtures for mating and had a disrupted ovulatory cycle. Males had higher levels of testosterone and females had higher levels of estrogen. Surprisingly, the altered female mice were also better mothers: They ate their pups less often.
"One could speculate that fertility problems in some humans may be partly related to a defect somewhere in this very complicated regulatory system," says Baenziger. "They may have the wrong proportion of some of these sugars, or the receptors that clear the sugar-hormone combination from the blood might not bind as well."
Baenziger wants to learn more about the segments in the reproductive hormones that single them out for the addition of unique sugars. He hopes to use that information to search for other proteins that receive similar treatment.
"We know these systems for adding sugars are well-regulated, but we're just starting to get a sense for how they are controlled and how far-reaching their effects can be," he says. "I think we're going to see much more of this kind of alteration and regulation of protein properties via added sugars in many other important areas of biology."
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