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A better way to treat infertility?
Estrogen produced in the brain is necessary for ovulation to begin in monkeys, according to research at the University of Wisconsin-Madison which has upended our traditional understanding of the hormonal cascade leading to release of an egg from the ovaries. The findings may reveal the cause of some undiagnosed infertility problems and point the way to new methods of birth control.
The work is published in the journal Proceedings of the National Academy of Science (PNAS)
For decades, scientists have known that a group of neurons in a part of the brain called the hypothalamus and cells in the pituitary gland control the menstrual cycle. The brain stimulates the pituitary to make hormones that, early in the menstrual cycle, spur the ovaries to produce estrogens — predominantly a type of estrogen called estradiol.
Estradiol builds in the bloodstream until it reaches a concentration that causes a surge of the hypothalamic and pituitary hormones, including one called luteinizing hormone, which in turn triggers an ovary to release an egg.
"It's a feedback loop, and scientists have thought for some time that it was all to do with the estrogen from the ovaries. Then, in 2013, we discovered the hypothalamus was releasing estradiol just as the ovaries do. We were so surprised. We knew it had to be important."
Now, Terasawa, Brian Kenealy (who earned his doctorate in Terasawa's lab) and colleagues have worked out just how important by studying the brains of rhesus macaque monkeys. After removing their ovaries, macaques were implanted with capsules under their skin which released estradiol, fooling their brains into thinking their ovaries were preparing for ovulation. At the same time, the animals were kept from making any of their own estrogens by inhibiting the enzyme, aromatase, critical to estrogen production. Without the help of estradiol, release of luteinizing hormone fell short of the full surge required to spark ovulation.
To zero in on where estrogen was doing its work, researchers repeated the process, but this time blocking estradiol production in the monkey hypothalamus. They anticipated the release of hypothalamic hormones — gonadotropin-releasing hormone and kisspeptin — which indicate neurons are about to cue up a luteinizing hormone surge. However, the releases of all three ovulation-signaling hormones was reduced, this indicated the brain is where estradiol effects are occuring.
"Ovarian estrogen starts the surge, but brain estrogen allows the surge to continue. When we block the production of brain estrogen, we still start the surge, but basically we cut the top off the mountain and the surge is drastically reduced."
"This shows the brain's estrogen is a huge helper, necessary for the release of an egg that makes pregnancy possible," says Terasawa, whose work was funded by the National Institutes of Health. "We have to modify our concept of the feedback loop."
"Maybe doctors can use this to figure out a better way to treat people dealing with fertility issues," Kenealy adds. "We've filled in some of the gaps we didn't know before, and hopefully that will help people in the future."
This new picture of the hormonal progression to ovulation could eventually have clinical applications.
The concept that ovarian cycles in female mammals are regulated by gonadal steroids released from the ovary is well-established dogma. The findings of this study, however, showing that the removal of neuroestradiol synthesis in the median eminence of the hypothalamus by the aromatase inhibitor, letrozole, greatly attenuates estrogen-induced gonadotropin releasing hormone and luteinizing hormone surges in ovariectomized female monkeys, indicate that neuroestradiol locally synthesized and released in the hypothalamus is an integral part of the ovary-initiated positive feedback mechanism of estradiol.
Negative and positive feedback effects of ovarian 17?-estradiol (E2) regulating release of gonadotropin releasing hormone (GnRH) and luteinizing hormone (LH) are pivotal events in female reproductive function. While ovarian feedback on hypothalamo–pituitary function is a well-established concept, the present study shows that neuroestradiol, locally synthesized in the hypothalamus, is a part of estrogen’s positive feedback loop. In experiment 1, E2 benzoate-induced LH surges in ovariectomized female monkeys were severely attenuated by systemic administration of the aromatase inhibitor, letrozole. Aromatase is the enzyme responsible for synthesis of E2 from androgens. In experiment 2, using microdialysis, GnRH and kisspeptin surges induced by E2 benzoate were similarly attenuated by infusion of letrozole into the median eminence of the hypothalamus. Therefore, neuroestradiol is an integral part of the hypothalamic engagement in response to elevated circulating E2. Collectively, we will need to modify the concept of estrogen’s positive feedback mechanism.
Authors: Haruko Nakano Itsunari Minami Daniel Braas Herman Pappoe Xiuju Wu Addelynn Sagadevan Laurent Vergnes Kai Fu Marco Morselli Christopher Dunham Xueqin Ding Adam Z Stieg James K Gimzewski Matteo Pellegrini Peter M Clark Karen Reue Aldons J Lusis Bernard Ribalet Siavash K Kurdistani Heather Christofk Norio Nakatsuji Atsushi Nakano
Key words: auditory system cochlea hair cell planar cell polarity primary cilium
This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R21HD077447 and R01HD015433), and by the National Institutes of Health (OD011106).
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Current portrayal of hormonal regulation of the female reproductive system.
Image credit: Lumen Learning