Overcoming infertility

Vincent Parziale was just 27 years old when he began testosterone replacement therapy. The resident of Southington, Connecticut—then a rookie police officer—had been feeling moody and lethargic much of the time, so he went to a urologist to find out why. The diagnosis: he wasn’t producing enough testosterone, the primary male sex hormone. After starting testosterone treatments, Parziale’s mood and energy levels perked up, but he was warned that he might not be able to father a child as a result of the treatments.

Last year, when he and his wife Jessica decided to get married, he discovered that sure enough, the synthetic testosterone had knocked his sperm count to near zero. Parziale sought help from Stanton Honig, MD, professor of clinical urology and director of Yale Urology’s Men’s Health Program. Honig prescribed clomiphene citrate, an oral medication that increases testosterone but does not have a detrimental effect on sperm production. Parziale began taking it soon after the couple married last September. By January, Jessica was pregnant. Their child is due in September.

Parziale is elated. His advice to other couples with fertility problems: “Go to the best specialists you can find. For them, infertility is as easy to treat as the common cold.”

Of course, it isn’t quite that easy. In fact, some infertility diagnoses and treatments are on the cutting edge of medical science. But infertility is certainly common. An estimated 15% of couples have trouble conceiving. And Parziale is correct that tremendous progress has been made in treating the wide variety of conditions and diseases that cause or contribute to difficulty conceiving.

There are a host of reasons for infertility. It can be caused or triggered by disease, infections, injuries, and genetic defects—plus environmental conditions. Sometimes, minor problems in both partners combine to make conception difficult.

In a sense, the meanings of fertility and infertility have changed in our society in recent years. In the not-too-distant past, if one partner in a heterosexual couple was infertile, the only option was adoption. These days, heterosexual couples, people in same-sex relationships, or a person planning on single parenting have a host of medications and procedures to choose from. Even in more challenging situations, dreams of biological parenthood can often come true—if the people involved have good insurance; if they’re willing to freeze eggs or sperm; or if they’re open-minded about relying on egg donors or surrogates. We’re seeing the emergence of “virtual” fertility.

“We can get just about anybody pregnant,” said Hugh Taylor, MD, HS ’92, FW ’98, chair and the Anita O’Keeffe Young Professor of Obstetrics, Gynecology and Reproductive Sciences. This claim holds true even in situations that seemed to be impossible in the past. If a woman doesn't have a uterus, a surrogate can carry the baby—or the woman can have a uterus transplant, a procedure that is now possible. If a woman doesn’t have viable eggs, a donor can be found. Gay men can use a donated egg and a surrogate. “We’re all about helping to build families,” Taylor said.

The golden age of reproductive sciences began in the late 1970s with the first birth of a child conceived through in vitro fertilization (IVF)—a so-called test-tube baby. The initial success rates for IVF were less than 5%, but better medications were introduced to stimulate egg production; egg and sperm handling methods were improved; and techniques were developed to make it easier for men with very low sperm counts to fertilize eggs.

In the early 1980s, clinicians began offering women the option of using eggs from donors. They have learned to synchronize the ovulation cycles of an infertile woman and her donor. Next, they began using surrogates to carry a woman’s fertilized egg through a full-term pregnancy.

Starting in the late 1980s, women or couples gained the ability to freeze eggs or embryos. That’s useful for people who are about to undergo cancer treatments, or for those in their 30s who are not ready to have a child and are worried that they might not be able to have one later.

But advances in technology and genetics starting in the early 1990s enabled clinicians to perform pre-implantation genetic diagnoses. An embryo contains all of a person’s genetic information. A short time after fertilization of the egg, clinicians remove genetic material and test it for anomalies. If they find that the embryo contains too many chromosomes or has other genetic defects, they won’t transfer it.

As IVF became more successful, women began to have multiple pregnancies—more embryos than they wanted. A major advance in the 21st century is the ability to transfer a single embryo into the womb with similar chances of pregnancy. Another significant advance: the ability to freeze embryos and eggs so that they produce similar success rates in IVF as fresh ones.

“Through all this work, we have come to understand the natural processes—from gametes to fertilization and early pregnancy--in ways that were not possible before, and to use that knowledge to treat infertility,” said Sandra Ann Carson, MD, professor of obstetrics, gynecology and reproductive sciences and the new director of Yale’s Reproductive Endocrinology & Infertility section. “It’s like traveling from Washington, D.C. to Philadelphia by horse, and then all of a sudden you have an airplane. This has really taken off.”

Earlier in Carson’s career, when she was at Alpert Medical School (formerly Brown University School of Medicine), she invented the first artificial human ovary in an effort to mature eggs in culture. The 3D device, designed to re-assemble the multiple cell layers of a human ovary, has been used experimentally to bring human eggs from the immature oocyte stage in the follicle to a mature ovum. The device has helped improve understanding of the ovary’s development and its responses to medications.

Longtime Yale faculty members have also contributed significantly to advances in the infertility field. Taylor, for instance, is a leader in research and treatment of endometriosis, a condition in which cells similar to those in the tissue that lines the uterus grow outside the uterus, most often on the fallopian tubes, the ovaries, and the tissue surrounding the uterus. Endometriosis causes pelvic pain, pain during intercourse, and infertility in 30% to 50% of women diagnosed with the condition.

David Seifer, MD, professor of obstetrics, gynecology & reproductive sciences, is a pioneer in understanding reproductive aging. His work led to an everyday used simple diagnostic blood test targeting the anti-Müllerian hormone (AMH), a glycoprotein hormone secreted by the ovary that helps determine the health of a woman’s ovaries, estimate her egg count, and assess the timing of her biological clock. Today such information assists physicians in choosing an initial infertility treatment and amount of medicine to be used. It also informs physicians about individualization of fertility preservation counseling and strategies for those women not ready to conceive right away but wish to “freezing their eggs” to provide reproductive options when they are ready but older. Tomorrow Dr. Seifer's work offers the potential to lead to the development of a new class of drugs aimed at slowing down ovarian aging (i.e. delaying the onset of menopause), acting as an ovarian chemoprotectant for those women wishing to preserve their fertility when receiving treatment for cancer as well as novel treatments of prevalent reproductive disorders such as polycystic ovarian syndrome (PCOS).

Another expert in reproductive aging, Emre Seli, MD, professor of obstetrics, gynecology & reproductive sciences, has made significant advances in understanding how metabolic dysfunction in eggs can lead to accelerated reproductive aging in females. This knowledge helps researchers understand why some women enter menopause much earlier than others, and it can be used to develop targeted therapies.

Among the urologists on the Yale faculty, Honig has produced groundbreaking advances in treatments addressing male infertility and sexuality. Those include sperm retrieval techniques, medical and surgical treatment of erectile dysfunction and peyronie’s disease, and treatments for low testosterone levels and fertility preservation in transgender females.

Honig applauds the arrival of more accurate home sperm tests—which make it easier for men with potential fertility problems to overcome reluctance to be evaluated. And this testing isn’t just about producing babies. Low sperm counts may indicate other health problems that might be present—now and in the future, such as cancer and brain tumors. “The home tests are a two-edged sword. They get patients to earlier evaluation but can sometimes deliver a false sense of security as most do not test every important sperm function,” said Honig. “If the couple is still not getting pregnant, a formal sperm test and medical evaluation of the male are important.”

Much of patient care for infertility takes place at the Yale Fertility Center, which is the clinical practice of the Reproductive Endocrinology & Infertility (REI) section. It’s one of a few such centers around the country that treat the problems of men and women in one place. That’s significant because it’s often not clear at the outset which partner has fertility issues—or whether both do. Rather than shuttling men and women back and forth between clinics, the Fertility Center treats the couple.

The IVF success rate at the center for new patients under age 35 is 70.7%, compared to 54.8% nationwide, according to the Society for Assisted Reproductive Technology. For women between the ages of 35 and 37, the success rate at Yale is 50.9% compared to 43.5% nationally.

Surgeons affiliated with the center perform some of the most advanced surgical procedures. For instance, Oz Harmanli, MD, professor of obstetrics, gynecology, and reproductive sciences, and chief of urogynecology and pelvic reconstructive surgery, performs surgeries for women with incomplete vaginas that connect the vagina to the uterus, enabling these women to bear children. There are also plans underway to offer uterus transplants.

Since Carson arrived as the new section and clinic director last February, she and her colleagues have undertaken a major reexamination of their work. Building on existing strengths, they plan to focus on three areas in research and clinical practice: recurrent pregnancy failure; third-party reproduction, including the special needs of the LGBTQ community; and ovarian aging. “Our goal is to offer the best clinical practice and the most innovative research in the country,” said Carson. At the same time, the clinic is moving from its current home in New Haven’s Long Wharf district to a new office, clinic, and laboratory space on Yale’s West Campus. The space is already under construction, and the staff plans to move in next January.

Recurrent pregnancy failure is one of their top priorities because so many pregnancies aren’t successful. In fact, according to Carson, about 60% of pregnancies fail even before the woman knows she’s pregnant. Many of these miscarriages are believed to be caused by hormonal changes, genetic abnormalities, and defects in the uterus. By studying failures, researchers hope to be able to better diagnose women’s difficulties in getting pregnant and offer them targeted treatments. “When nature goes wrong, we will be able to detect those errors and address them, so a couple can achieve a healthy term pregnancy,” said Carson.

Many of the improvements in pregnancy success rates at Yale and elsewhere have come about thanks to technological advances. Carson invented a specialized catheter that’s used in pre-implantation diagnosis; and Amir Mor, MD, a second-year fellow in reproductive endocrinology and infertility, won a first prize at Yale Innovation Summit 2019 for his Accurate Cell Injection System (ACIS). The device enables clinicians to implant sperm in eggs more effectively, and to determine whether eggs are viable without aspirating and potentially damaging them.

ACIS uses the principles of electrophysiology to determine whether a catheter has successfully penetrated the outer wall of the egg. Mor produced it in collaboration with Seli and Xiao-Bing Gao, PhD. “This [system] will enable the automation of IVF and significantly improve success rates,” said Mor.

At Yale, research and clinical practice are closely tied. For instance, Taylor and his research associates have been studying the genes that regulate endometrial development and the roles of stem cells in repopulating the uterus. They’re now developing a clinical protocol for introducing stem cells into the uterus to replace or regenerate its lining—so that embryos can attach to the uterus successfully and women can carry fetuses to birth.

Stem cells and genetic engineering are the wave of the future for addressing infertility. Mor foresees a time when clinicians will intervene in the early stages of pregnancies in women who are in their 40s, using genetic engineering to improve the processes of DNA replication and cell division within the embryo. “You could help people with old eggs have completely healthy babies,” he said.

Further out, Taylor sees a time when there will be no need for donor eggs or donor sperm. An individual’s stem cells will be used to create their eggs or sperm. And women of any age will be able to have healthy “young” eggs. “My feeling is that this is the future of infertility treatment,” said Taylor. “A lot of what we do today will be considered very old-fashioned, including IVF, and it will go away.”

In the here and now, however, some policy issues need to be addressed to improve treatments and outcomes for infertility patients, according to Yale faculty members. For one thing, many insurance policies don’t cover infertility treatments. Some insurers consider them to be akin to using plastic surgery for reasons of vanity. Connecticut has an insurance mandate for infertility coverage, but these policies are state specific.

Another challenge is coming to terms with the ethical questions surrounding genetic engineering. Faculty members say the goal should be to create a judicious balance—forbidding practices that are dangerous for individuals or society while at the same time empowering physicians to use gene technologies to combat disease and crippling conditions. This sorting-out is critical, they say, because the egg, the sperm, and the embryo are where many of the next generation of medical miracles will surely take place.