Parents – At Last!

Young, healthy and in love, Lynne and David Stawicki* were eager to start what they hoped would be a large family. A year passed, then another. By the third year without a pregnancy, the couple nervously sought medical testing. The results stunned them: David’s sperm sample proved to contain no sperm at all. Zero. “I was shocked,” says David, 34.

Further tests revealed the reason: David was born missing both vas deferens, the two tubes that ferry sperm from the epididymis, behind the testicles, to the ejaculatory ducts. Genetic testing found that he was a carrier of cystic fibrosis, a chronic – often fatal – disease of the lungs and digestive system. While David didn’t have the illness or any apparent symptoms of it, the lack of vas deferens (causing certain infertility) is common to all men who have the disease. “He had sperm,” says Lynne, 32, “but no way for it to get where it needed to go.”

The Stawickis’ doctor referred them to Dr. Keith Jarvi, a urologist specializing in male infertility and a professor of surgery at U of T. Toronto was a distant 1,400 kilometres from the couple’s northern Ontario home, but it was their best hope. As Jarvi says, “There’s a huge infertility infrastructure here, and Toronto is a world leader in cystic fibrosis and male infertility research.” In a precisely synchronized series of procedures, doctors used a syringe to extract sperm directly from David’s testes; they then retrieved mature eggs from Lynne’s ovaries. Several days after the eggs were successfully fertilized in a Petri dish, two embryos were transferred to Lynne’s uterus. The couple are now the parents of healthy 16-month-old twin boys. “It’s pretty amazing,” says David. “We know how fortunate we were to get that referral.”

Toronto has one of the country’s highest concentrations of infertility experts, and many of them are associated with U of T. The university’s division of reproductive endocrinology and infertility, in the department of obstetrics and gynecology, includes 15 infertility specialists, three basic scientists, four reproductive endocrinologists and a clinical embryologist. Many of these men and women also run fertility clinics in Toronto and engage in various strands of research that investigate the causes, diagnoses and treatments of infertility – a disturbingly common condition that afflicts 10 to 20 per cent of Canadian couples, or approximately one in six.

Because infertility was scarcely talked about a generation or two ago, we don’t know if the problem is becoming worse, and, if so, how much worse. But Ted Brown, the division’s academic head and a professor in obstetrics and gynecology and physiology, says, “It seems to be increasing. Couples are waiting longer to have children, as careers take time to become established, and fertility declines with age.”

But there’s a host of other reasons that people can’t produce or sustain a pregnancy. The causes can be structural, such as absent, blocked or deformed Fallopian tubes, uterus or vas deferens; or hormonal, including thyroid or sex hormone imbalances. They can be genetic, causing chromosomal aberrations in the egg, sperm or embryo; or the result of infections, such as from sexually transmitted diseases, which produce inflammation or scarring. Exposure to smoke, excessive alcohol, toxins, extreme stress or, in men, excessive heat to the genitals, such as that experienced by chefs or long-distance cyclists, are also factors. Then there’s the most frustrating reason of all: undetermined. While infertility problems have traditionally been blamed on the woman, in fact men may account for up to 50 per cent of the problem, says Brown.

But if infertility is on the increase, so is the range of treatments available, thanks in part to the work of many U of T–affiliated clinicians and researchers. Last year Mount Sinai Hospital consolidated its fertility programs into a new multidisciplinary, state-of-the-art facility. One of the centre’s many features is a quarantined lab for infertile couples in which one partner has a viral infection such as hepatitis B or C or HIV-AIDS. “Although the centre is a hospital program, it’s a soothing, off-site environment, so we have the best of both worlds,” says medical director Dr. Ellen Greenblatt, a professor in obstetrics and gynecology at U of T. Patients seeking help for infertility aren’t required to share waiting rooms with pregnant patients. The centre has about 18,000 clinic visits a year.

One common infertility problem is recurrent early miscarriage. That’s a particular area of interest for Dr. Sony Sierra, co-founder of First Steps Fertility clinic and a professor at U of T in obstetrics and gynecology. Almost half of all pregnancies miscarry before six weeks, Sierra says, chiefly because of random genetic error. But when a woman miscarries three pregnancies in a row, there’s often another reason. And sometimes the treatment can be surprisingly low-tech.

Case in point: Chloe Prasad,* a university professor herself, sought help from Sierra during her second pregnancy, which, like her first, ended in miscarriage. The 35-year-old was quickly diagnosed with polycystic ovarian syndrome, a common endocrine disorder affecting about seven per cent of infertile women and linked to diabetes. “I felt in perfect health, but I did have irregular periods and there is diabetes in my family,” Prasad says. After Prasad’s second miscarriage, Sierra put her on a course of metformin, a diabetes drug to help regulate insulin levels. “It worked like a charm,” Prasad says. “My husband and I have a beautiful, perfect, healthy son born last year.” She recently underwent another course of metformin and is pregnant again, due this fall.

While recurrent early miscarriage often has a physical or hormonal cause, Sierra says that something as simple as regular ultrasounds may help overcome some of these obstacles. A 2006 study (for which Sierra was a co-author) of 1,800 couples who had experienced at least two miscarriages found that simply by giving the patient two additional, reassuring ultrasounds in the course of a pregnancy increased the rate for successful completion from 15 per cent to 71 per cent, without the help of in vitro fertilization (IVF) or any other reproductive technology. “The mind-body connection is powerful, and psychological stress plays a huge role,” Sierra says. Using highly complex microarray technology, she is also conducting research into what she calls the “black box of pregnancy” – the two weeks after a woman releases an egg – to investigate exactly what happens to the endometrial lining to make it receptive or hostile to implantation.

There’s also a growing emphasis on preserving fertility in people who are at risk of losing it, such as cancer patients. Chemotherapy, radiation and surgery can compromise fertility, sometimes permanently, by damaging delicate testicular cells and some cell DNA. Dr. Kirk Lo, a urologist, a professor in the department of surgery at U of T and a surgeon investigator at Mount Sinai, sees boys and young men in their teens, 20s and 30s before cancer treatment to discuss options. The easiest is to take a few sperm samples – either through ejaculation or extraction – and freeze them, a process that leaves sperm viable for at least 20 years. But Lo says up to half of all oncologists don’t even discuss the issue with their young male patients or families. “Sperm preservation is not difficult, but awareness is a major issue, both among health professionals and the general public,” Lo says. He’d like every cancer centre to have one staff member specializing in fertility issues.

Taking the issue a step further, Lo’s lab is investigating ways to protect sperm cells from chemotherapy damage, even in males too young to produce sperm. Lo has been able to remove testicular stem cells from cancerous mice before chemotherapy and then inject them back afterward, restoring fertility. The way of the future, he suggests, will be to take stem cells from skin and reprogram them to become sperm cells. Lo and colleague Jarvi are also world leaders in identifying the more than 2,000 different proteins in semen, some of which may be markers for everything from infertility to prostate cancer.

Preserving fertility in females is a greater challenge. Extracting an egg for freezing can require weeks of preparation, and cancer patients often don’t have the luxury of time. Teresa Lee* was 25 when she developed non-Hodgkin’s lymphoma, a cancer of the lymphatic system. There was such an emphasis on saving her life that there was no time or opportunity to extract and freeze her eggs. Lee is now 28 and healthy again, but has a lower “ovarian reserve.” She and her husband have gone through three cycles of IVF, with no pregnancy. While drugs to help protect ovaries during chemotherapy are still experimental, Lee urges women to investigate their options. “You don’t realize how important fertility is until it’s taken away from you,” she says.

Infertile couples who do undergo successful IVF treatments often have another challenge to deal with: multiple pregnancy. To ensure that at least one embryo will “take,” IVF specialists often transfer two into a patient simultaneously (or more, as in the case of California’s “Octomom,” who gave birth to eight babies last year). Couples who have struggled to have a baby may think that multiples will be a bonus. But almost half of all twins and 90 per cent of all triplets, quads and quints are born premature, and multiples are five times more likely than single babies to have birth defects and disabilities.

A hot area of research is therefore the quest for the “best” egg to fertilize or the “best” embryo to transfer – which is tricky, considering that at least half of the eggs of an average, healthy young woman are abnormal. Dr. Robert Casper, professor of obstetrics and gynecology and medical director of the Toronto Centre for Advanced Reproductive Technology, is working on developing a quick, inexpensive test for egg selection. Since a healthy egg when it matures casts off half of its 46 chromosomes into an outlying structure called a polar body, a test that finds more or fewer than 23 castoffs in the polar body would suggest that the egg may be abnormal and therefore not a good choice for IVF. “If we can select which embryos to put back, it would allow us to put back fewer,” Casper says.

Casper adds that while the eggs of a woman in her late 20s or early 30s are optimal, by the mid-30s the eggs don’t always have the energy to separate their chromosomes properly. His lab has been working on reversing that process in mice by treating them with the naturally occurring compound co-enzyme Q10, which revs up mitochondria, the cell’s “batteries.” He says, “We were quite surprised that the eggs of these animals, who were 52 weeks old, looked 10 weeks old again.” He’s begun a randomized clinical trial in women over 35, with results expected next year. More than a decade ago, Casper and his team were the first to use aromatase inhibitors, drugs that block estrogen, instead of clomiphene to induce ovulation. Now standard therapy in many clinics, aromatase inhibitors are as effective as the older drug, but with fewer side effects to mother and baby.

Future research on infertility will almost certainly include more studies to find genetic links and identify molecular pathways of development for eggs, sperm and embryos. “I’m really interested in trying to identify what factors are required for embryo development and why some embryos grow slowly or fragment,” says Andrea Jurisicova, a scientist at Mount Sinai and a professor in obstetrics and gynecology and physiology at U of T. Jurisicova, whose lab works on egg cells from mice, says she’s excited that our increasing knowledge of genetics will vastly improve our understanding of infertility.

Meanwhile, Jurisicova has shown just how fragile fertility can be. In 2007 she headed a study that found that female mice exposed to the environmental pollutants called polycyclic aromatic hydrocarbons, even before they got pregnant, dramatically reduced fertility in their offspring. The chemical, found in cigarette smoke, car exhaust, charred and smoked food, and fumes from wood stoves, caused a two-thirds drop in the number of egg-producing follicles in their female offspring. Fewer eggs mean lower fertility and earlier menopause.

“There may be a message here for young girls who are thinking about starting to smoke,” Jurisicova says. “It’s possible that the impact of these chemicals on fertility could be much more long term than people think.”

*The names of couples seeking infertility treatment have been changed.