Blaming the woman for a couple's childlessness has a long tradition. But modern-day research has revealed that human infertility -- considered to be an issue when a couple fails to conceive after one year of trying -- is traced to the male just as often as to the female.

For infertile men, the problem can be absent or too-rare sperm, immature sperm, or sperm that just can't seem to find their way. Yet, despite the availability of microscopes for three centuries, widespread recognition that problems with sperm contribute significantly to childlessness did not come about until the 1970s.

That a female scientist should be the first to discover a major genetic cause of male infertility seems like retribution for millennia of blaming the woman, but Renee Reijo-Pera's motivation is to help couples, not to cast blame. In fact, Reijo-Pera, an assistant professor of obstetrics and gynecology and reproductive sciences, addresses not only problems in the male but also waning fertility and menopause in the female. Moreover, she identifies healthy embryos for infertile couples who undergo in vitro fertilization (IVF) procedures at UCSF.

Reijo-Pera made her first discovery of a male infertility gene in the mid-1990s, as a postdoctoral fellow working in the laboratory of David Page at MIT's Whitehead Institute. Those were the glamour days of gene discovery, before lightning-quick DNA-sequencing technologies took some of the glory out of successfully sleuthing for single genes.

"In human genetics, even that recently, there really was a competition just to find something, and once a gene was discovered, often times the game was over and the fun ended," Reijo-Pera says. "But I started looking more closely at the DNA sequence, which led to the recognition that this gene, and its relatives, are special and hold promise for understanding how sperm, and eggs, are made."

About 30 percent of male infertility now is attributed to having no sperm, a condition called azoospermia, or too few sperm, known as oligospermia. The gene discovered on the Y "male" chromosome by Reijo-Pera, called DAZ (for Deleted in AZoospermia), accounts for about 13 percent of all male infertility. DAZ hinders the development of early-stage, immature sperm cells called spermatogonia.

Improving ICSI

A decade ago, clinicians at the UCSF Medical Center and elsewhere began using an odds-defying IVF technique for achieving conception called intracytoplasmic sperm injection (ICSI). Using ICSI, clinicians inject a single sperm, even an imperfectly developed sperm, directly into an egg, enabling men who are oligospermic due to DAZ defects or other problems to father children.

However, even ICSI does not assure childbirth for couples, and, of course, males inherit their father's mutations and infertility. Of even greater concern, recent evidence suggests that children born through ICSI and other IVF procedures may be more prone to birth defects.

"It's not just a matter of delivering the male's DNA to the egg's nucleus," Reijo-Pera says. A particular pattern of DNA modification, or "imprinting," must occur during spermatogenesis to assure that certain genes will be turned on later in the developing embryo to produce needed proteins at the right time, Reijo-Pera notes. That is why two maternal nuclei cannot be used to generate a viable embryo.

Today there are tests to identify defects in DAZ and other genes in infertile men and to screen single cells from early-stage embryos for serious defects prior to implantation in the uterus -- eliminating the wait for amniocentesis in the 15th week of pregnancy. But there are no tests for other problems, such as imprinting defects. Reijo-Pera aims to help identify the genetic origins of problems leading to embryo loss, so that diagnostic tests can be improved.

While DAZ is relatively new on the reproductive scene, Reijo-Pera's research group has turned up what may be the oldest gene in the human DAZ family, on chromosome 2.

Meiotic pathway

The gene, BOULE, plays a crucial role during meiosis, when the progenitors of germ cells replicate their DNA and then divide twice, creating cells with unpaired chromosomes and half the DNA found in other cells. When a mature sperm and egg come together, the chromosomes from these germ cells pair off again in the fertilized egg, reestablishing the normal cellular DNA allotment. Reijo-Pera found that flies with defects in BOULE did not undergo meiosis, but when they were given human BOULE gene replacements, their germ cell progenitors were "rescued" and did undergo meiosis. The similarity of the fly and human BOULE genes points to a common ancestral origin of about 600 million years ago.

Problems in meiosis are implicated in 30 percent of male infertility. Even so, Reijo-Pera did not find any defective variants of BOULE in infertile men. Still, the identification of BOULE has put her research group on the biochemical trail of other genes in the meiotic pathway that might play a role in male infertility.

Many genes play a role in the development of both sperm and eggs, naturally leading Reijo-Pera to her interest in genetic determinants of female as well as male infertility. A major focus is on menopause.

A sexually mature male normally generates new sperm continually, but a female is born with all the eggs she will ever have, about 1 million. When a woman goes through menopause, only about 1,000 eggs remain in her ovaries. About 400 to 500 eggs are ovulated from menarche to menopause; the rest are lost gradually throughout her life due to a kind of biologically programmed cellular suicide. The number of eggs a baby girl is born with and the rate of egg loss determine the age of menopause, but the biological determinants of these two variables are unknown, Reijo-Pera explains.

"Even though epidemiological studies of twins and sisters show that there clearly is a genetic component that helps determine the age of menopause, there are few genetic studies reported in the scientific literature," she says.

The average age of menopause is 51, but earlier menopause is associated with an earlier and steeper decline in fertility, which begins 10 to 15 years before menopause in all women, Reijo Pera notes. To help women plan ahead, she hopes to identify genetic clues and molecular markers that can predict early menopause and waning fertility. "There are women who want to have children who do not realize that, for them, time is running out," she says.

Of her career choices Reijo-Pera says, "I think the fact that I am a woman makes all the difference in the world." She acknowledges the hierarchical, competitive and largely male state of "pure science," joking about the top research ranks being populated by theoretical physicists, the lower by scientists who seek practical applications. "I have chosen this area of research because I care about children's and women's health and infertile couples, but also to do something a bit different," she says. "Maybe someday this will be a big field, but right now we are a small group of researchers with a lot of room to expand."