Science explores new contraceptive pathways

Family planning clinicians are familiar with the hormones that regulate human reproduction. Research has identified a new hormone that suppresses reproduction, which opens the door to possible development of a new class of contraceptive.1

The hormone, gonadotrophin inhibitory hormone (GnIH), has the opposite effect from gonadotrophin-releasing hormone (GnRH), a key reproductive hormone. While GnRH triggers a cascade of hormones that prime the body for sex and procreation, GnIH halts the process.

GnIH was discovered in 2000 in quail and has been studied in other birds, as well as in mice and in sheep.2 Scientists have been challenged to identify its role in humans. While the human genome contains the gene for GnIH, scientists have not been sure when and where the protein hormone is produced and whether it affects reproduction.

In the current research paper, neuroscientists at the University of California, Berkeley extracted two versions of the hormone from human brains. Findings indicate the hormones are present in the hypothalamus region of the brain, the area that controls reproduction, and affect nerve cells that secrete GnRH. Based on their findings, the scientists believe the hypothalamus and pituitary — two key parts of the reproductive axis in the brain — have receptors for the hormones.1

GnIH pushes the pause button on reproduction, but in a variety of ways, says George Bentley, PhD, assistant professor of integrative biology at the university and a co-author of the study. It can act on GnRH neurons in the hypothalamus and inhibit GnRH release; it can act directly on pituitary; or it can influence the gonads directly. The overall effect is to inhibit reproduction, but at different levels of the reproductive axis, he notes.

The identification of a hormone in humans that inhibits reproduction opens the door to possible contraceptive development; however, researchers have a long way to go, notes Bentley. Berkeley scientists continue to investigate how GnIH acts in humans, as well as in starlings and zebra finches.

Gel study moves forward

In other news, progress has been reported in research of a novel contraceptive gel containing the progestin Nestorone and estradiol that uses an advanced transdermal delivery system. Scientists have concluded a dose-finding Phase II trial for the gel, which is being developed by Antares Pharma of Ewing, NJ, and the Population Council, based in New York City. The patented transdermal delivery system is used in another Antares Pharma product, Elestrin, which is used as hormone replacement therapy (HRT) in postmenopausal women.

Scientists designed the current research as a dose-finding, open-label, crossover study to evaluate the effect of the transdermal gel on ovulation suppression in normal women of fertile age. Eighteen women participated in the trial, which took place in three sites: Los Angeles; Santo Domingo, Dominican Republic; and Santiago, Chile. Each woman completing the study received each of the three doses of the gel for 21 days, separated by a washout month in which no products were administered, which allowed the women to return to normal ovulation.

Research was focused on determining the lowest acceptable dose of the gel to achieve ovulation suppression, as measured by progesterone levels and ultrasound evaluation of follicular development. Scientists also looked at determining the plasma profile of estradiol and the evaluation of bleeding patterns, as well as examined the gel's general safety and tolerability. "We have demonstrated that the transdermal gel combining Nestorone and estradiol is able to suppress ovulation at all doses tested, and we determined the dose that gave the most stable levels of hormones to the subjects," says Régine Sitruk-Ware, MD, executive director for research and development in the Population Council's reproductive health program. "Most women who participated in the study found the gel very easy to use and convenient."

Antares Pharma and the Population Council look to partner with a worldwide or regional pharmaceutical company to take the contraceptive gel to full commercial development. Dario Carrara, PhD, Antares senior vice president and managing director and the inventor of the ATD system, says, "The advantage of using transdermal delivery has been seen with HRT products where recent studies have shown a reduced side-effects profile when compared to orally administered products. The system offers a patient-friendly, fast-drying, and cosmetically appealing gel product that can be easily applied daily."

Reference

  1. Ubuka T, Morgan K, Pawson AJ, et al. Identification of human GnIH homologs, RFRP-1 and RFRP-3, and the cognate receptor, GPR147 in the human hypothalamic pituitary axis. PLoS One 2009; 4:e8400.
  2. Tsutsui K, Saigoh E, Ukena K, et al. A novel avian hypothalamic peptide inhibiting gonadotrophin release. Biochem Biophys Res Commun 2000; 275:661-667.