Yale Researcher: Hunger Plays a Role in Infertility

Calorie restriction is known to add years to animals’ lives. Now, a recent study has shown that calorie restriction may play a role in infertil­ity as well.

The study, published in the Proceedings of the National Academy of Sciences by Meenakshi Alreja, Associate Professor of Psychiatry at the Yale School of Medicine, looked into the molecular interactions that link hunger and infertility. The findings revealed a molecular pathway that shuts down the activity of brain cells that control the reproductive axis during conditions of negative energy balance.

The reproductive axis is a complex pathway that con­trols the production of sex hormones in both males and females, regulating the onset of puberty, ovulation, and fertility. Signaling for the pro­duction of these sex hormones begins in the hypothalamus, a small almond-shaped part of the brain located just above the brain stem. It is here where the gonadotropin-releasing hormone (GnRH) producing cells, the master regulators of the productive axis, reside.

When activated by action potentials, these neurons secrete GnRH, which travels to the pituitary glands. The pituitary glands then produce luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which target the gonads, or sex organs.

With the uptake of LH and FSH, the gonads produce the sex hormones needed for ovulation and fertility. Thus, any inhibition during this delicate signaling pathway could lead to decreased production of sex hormones, triggering infertility.

Alreja’s group focused on a protein in the hypo­thalamus called melanin-concentrating hormone (MCH). MCH secretion is activated by negative energy balance caused by calorie restriction, with animals put on a starvation diet observed to have increased levels of MCH.

The Yale researchers showed that MCH pre­vents kisspeptin, a key reproductive hormone that triggers puberty and sustains ovulation, from triggering the release of GnRH from GnRH-producing neurons. MCH achieves this by binding to its MCH 1 receptor, opening the potassium channels. MCH is so effective at silencing GnRH that four seconds of MCH stimulation inhibits the secretion of GnRF for over 30 minutes.

To conduct the study, the group measured the effect of MCH on the membrane potential of GnRH-producing neurons. The difficulty of the experiment lay in identifying the approximately 800 GnRH-producing neurons among the millions of other cells in the brain. To solve this problem, Alreja’s group observed that MCH-producing neurons have fibers that aggregate around the GnRH-producing neu­rons, intricately linking the two types of cells together. Thus, the scientists were able to observe the effect of MCH on GnRH in vitro.

MCH was found to polarize neural membranes to such a degree that it became difficult for the neurons to fire and thereby release GnRH. This novel result demonstrated which neurons MCH specifically inhibited.

Additionally, as MCH effects did not notice­ably differ between the sexes, the findings also confirmed clinical beliefs that the hormone is not sexually dimorphic.

Alreja plans to further research by studying how MCH and other neuroproteins, such as leptin and Neuropeptide Y, affect kisspeptin and the repro­ductive axis. This research may ultimately lead to the development of a drug that prevents these proteins from affecting the neurons, potentially reversing infertility.

For now, by identifying the unique popula­tion of neurons that is inhibited by MCH, Yale researchers have opened up a new field of research on GnRH neurons that has shed more light on the causes of infertility.