We have The Pill. Do we really need new contraceptives? Yes, said Allan Rosenfield, dean of the School of Public Health at Columbia University, as he introduced an international symposium to survey New Frontiers in Contraceptive Research, held July 15–16 in Washington, D.C.

In a world where 40 to 60% of pregnancies are estimated to be unwanted, where as many as 200 million women worldwide have unmet needs for contraceptives, and where men have only condoms and vasectomy, there is an emphatic need for new approaches to contraception. Yet R&D in the pharmaceutical industry "lost its energy" years ago, Rosenfield lamented.

Most drug companies abandoned R&D completely as more than 50 oral contraceptive brands saturated the market. Worry about liability lawsuits if new contraceptives have side effects continues to hinder research, as does the desire to avoid the politics of abortion symbolized by the post-coitus pill RU486 (mifepristone).

So hope for innovative contraceptives depends especially on basic research from academia, Rosenfield said. Two approaches to identifying molecules controlling spermatogenesis and oocyte maturation, sperm–egg fusion, and endometrial implantation of the early embryo are already suggesting new routes to contraceptives. One applies genomics and proteomics technology. The other uses genetic analysis of model organisms.

At Washington State University, Michael Griswold and his colleagues use DNA microarrays to collect gene expression data on mouse testis cell types (including Sertoli cells, types A and B spermatogonia, pachytene spermatocytes, round spermatids, and peritubular myoid cells). Their work reveals that FSH (follicle-stimulating hormone) primarily activates genes, while testosterone primarily represses. So far they've found about 250 genes with testis-specific expression. Perhaps these potential regulators of spermatogenesis will suggest new targets for male contraceptives, Griswold said.

At the University of Virginia, John C. Herr and his colleagues are sequencing the human sperm and mouse egg proteomes. They use tandem mass spectrometry to sequence peptides from sperm and oocyte proteins isolated by high-resolution two-dimensional gel electrophoresis. Comparing peptide sequences with gene databases then reveals which genes are expressed. Applying two-dimensional gel proteomics to the sperm membrane has produced an investigational sperm vaccine for women.

The vaccine combines four proteins associated with the acrosomal reaction (in which hydrolytic enzymes in the sperm's acrosomal granule help the sperm penetrate the egg's outer layer, the zona pellucida). In vitro studies with antibodies demonstrate that the proteins are necessary for sperm–egg binding or fusion. The vaccine is safe and immunogenic in female baboons, Herr said.

A tidbit to titillate the gang at happy hour: A sperm from Drosophila melanogaster is longer than the entire fly. Its enormous tail makes it the "Olympic champion" of sperm, said Barbara Wakimoto of the University of Washington. Wakimoto uses Drosophila as a model organism to dissect genetic control of male fertility.

Her team has identified nearly 2400 male sterile mutations. Phenotypes include defects in spermatogenesis, meiosis, mating, sperm storage, sperm–egg recognition, and oocyte penetration. As the researchers move from phenotypes to genes to proteins, they hope to uncover essential mechanisms of male fertility. A mutation in which sperm are defective after penetration suggests a new view of the Drosophila acrosome: that it is not essential for fertilization but is required to form the male pronucleus.

Oocyte growth and development require paracrine regulatory factors secreted by the somatic granulosa cells that surround it. Similarly, paracrine factors from the oocyte support granulosa cells. This oocyte–granulosa cell regulatory loop is "a ripe source of potential contraceptive targets," said John Eppig of the Jackson Laboratory in Bar Harbor, Maine. Eppig will identify proteins in the loop with a yeast-based selection system. The system captures signal peptide sequences targeting oocyte and granulosa proteins for secretion or membrane insertion.

His project, still in the signal sequence library building stage, has trapped several known secreted proteins and found two others present only in oocytes. Loop regulatory factors might reveal numerous avenues for contraceptive intervention: at meiosis, ovulation, sperm attraction, fertilization, or embryonic development.

Even leptin, a hormonal protein much studied for controlling obesity, may in different guise be the key to an anti-implantation contraceptive, according to Ruben Gonzalez of the Boston Biomedical Research Institute. Besides regulating food intake, leptin also regulates implantation and placentation. Exogenous addition of leptin restores fertility to leptin-deficient mice. OB-R, leptin's receptor, increases in the endometrium during the menstrual cycle secretory phase. In subfertile women, endometrial OB-R and leptin decrease.

In a mouse model, Gonzalez is studying a leptin peptide antagonist (LPA2) that binds OB-R without activating signal transduction. His hypothesis is that blocking OB-R will block implantation of the early embryo into the endometrium.

The symposium was organized by a committee of the US Institute of Medicine, which intends to issue a report on the topic in early 2004.