Without changing overall levels of hormones, altering how hormones are packaged and shipped out from cells in the body can affect how they act. For women undergoing fertility treatments, delivering reproductive hormones in a new way could be key to improving their egg production. Genetically engineered female mice that released follicle-stimulating hormone (FSH) from dense storage granules—rather than directly into blood as usual—produced a higher number of mature, healthy eggs each cycle than in other normal mice. The observation was reported in a recent PNAS paper.
“We are not changing the FSH protein synthesis in the cell, just how it is coming out of the cell,” says molecular biologist and a pituitary hormone expert Rajendra Kumar of the University of Kansas Medical Center, senior author of the new paper. “But more eggs are coming, and their quality is good.”
In some primitive vertebrate organisms, a single gonadotropin hormone is released from the pituitary gland of females to spur the development of eggs—many at once. Sometime during the evolution of modern animals, however, two different gonadotropins emerged: FSH, and luteinizing hormone (LH). Rather than both hormones being released at once, each of the new gonadotropins had a different pattern of release from the pituitary. At the same time, newly evolved animals began releasing fewer eggs at once.
Kumar and his colleagues wondered why FSH and LH—despite being extremely similar at the molecular level and being produced by the same cells—had evolved such different mechanisms of release from the pituitary. FSH is released in a more or less steady fashion, while LH builds up in so-called “dense core granules” before being released in a pulse. FSH encourages a collection of follicles—immature eggs in a woman’s ovaries—to start the maturation process during each menstrual cycle. When LH peaks, a select number of those follicles—most often one in a human and about eight in a mouse—are ovulated, released as eggs into the fallopian tubes where they can be fertilized. The rest of the follicles that had begun maturing break down through a process called atresia.
To test whether the release mechanism of the hormones mattered to the functions of FSH and LH, Kumar’s team added a tag from LH to the FSH gene in mice, making cells package FSH into granules like those that contain LH. Rather than being steadily released from the pituitary throughout the estrus cycle, FSH was suddenly released from the granules, presumably in periodic bursts. The change had immediate implications for the female mice.
“When the FSH started being secreted through the LH pathway, the ovarian function dramatically increased,” Kumar says. In the ovaries of the mice, the same number of follicles began to mature each cycle, but many more survived—rather than undergoing atresia—and were released as eggs. Moreover, the plentiful eggs were healthy, able to be fertilized, and able to implant when put into a recipient mouse’s uterus.
“If we could devise a protocol that mimics what we’ve done in the mouse, it could be very beneficial to women,” says Kumar. Many women undergoing fertility treatments are set back by limited number of eggs that can be collected. While engineering the genes of women to change how FSH is released isn’t feasible, clinicians could develop a way—such as an under-the-skin drug-release device—to ensure that FSH levels fluctuate at regular intervals throughout a menstrual cycle rather than giving the hormone as shots as they normally do, Kumar says.
The newly realized importance of how FSH and LH are released, rather than just their levels, also should shed light on why some women are experiencing fertility problems to begin with, he says. “There are many women in the clinic whose FSH and LH appear normal when you take a snapshot of levels, but their patterns of release could be abnormal.”
Kumar’s team plans to continue studying how the interplay of FSH and LH release can be used to maximize women’s fertility. They want to know, for example, whether changing the pattern of release of LH, as well as FSH, could also explain the basis for abnormal fertility. Kumar says their results could shed light on other hormone secretion systems in the body—insulin, for example, is released in pulses and studying how cells package and release it could lead to new ways to understand and treat diabetes.