Unwinding The Ovarian Clock to Understand Fertility

Researchers at the University of Rochester School of Medicine and Dentistry have uncovered the cell in the ovary that governs the timing of ovulation and plays a major role in fertility. This finding could unlock clues to remedy infertility among people who have altered sleep schedules due to shift work or frequent jet lag, for example.

Michael Sellix, Ph.D., assistant professor of Medicine found that theca cells, which aid the development and release of eggs from the ovary, are important for maintaining a cyclic window of sensitivity to the hormone that incites ovulation, or egg release. Theca cells control the ovary’s ability to respond to luteinizing hormone (LH) by ramping up production of the receptor for LH at precisely the right time.

Theca cells use a circadian clock to control the timing of LH receptor production.  Circadian rhythms, or biological processes that occur on a 24 hour cycle, exist in nearly all of the cells that make up the human body and can even be found in single celled organisms, like bacteria. These “clocks” allow organisms to make predictions about changes in their environment like when food, light, or mates will be available.

Female reproduction – especially ovulation – relies heavily on circadian rhythms and can suffer if these rhythms are disrupted.  “Negatively affecting the timing system through bad sleep habits, shift work, or jet lag is all clinically linked to fertility issues,” says Sellix. “The timing system and how these things are coordinated is such a critical feature of normal function among women.  We need to use basic experiments like this one to think about how to target this system to aid in recovery from those detriments to fertility.”

In his study, published in Endocrinology, Sellix genetically disrupted the clock mechanism in theca cells or granulosa cells, which together make up the ovarian follicle, in mice. They also blocked LH signaling in the mice so they could administer their own LH surge to induce ovulation at specific times.  Animals with disrupted clocks in theca cells had altered timing of LH receptor production in the ovary and were less sensitive to LH. This resulted in lower rates of ovulation, smaller litter sizes, and fewer litters than control animals whose clock mechanisms were not disrupted. By comparison, none of these negative effects were observed when the clock was disrupted exclusively in the granulosa cells.

This discovery is surprising because the clock mechanisms in the brain and pituitary gland have been thought to govern all cyclic events in the female reproductive system. Only recently have clock mechanisms in organs like the ovary been appreciated. In Sellix’s words, “We used to think that the clock in the brain told the pituitary gland what to do, which told the ovary what to do. Now, our data has shifted that paradigm to the idea that the clock in the ovary is as important for sensing what the brain is telling it as the brain is for telling it in the first place.”

Sellix hopes that this new knowledge will lead to theca-cell-targeted therapies that may help women with disrupted circadian rhythms start a family.

To read the full study, click here.

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