EXPERT ANALYSIS FROM ENDO 2017

ORLANDO (FRONTLINE MEDICAL NEWS) – Fertility preservation techniques pioneered in young cancer patients may someday allow some women with Turner syndrome to give birth to their own children, without relying on donated eggs.

Spontaneous conception and live birth are exceedingly rare among women with the genetic disorder. Until very recently, adoption was the only practical way for most to grow a family. In the last decade, however, fertility specialists in Europe and the United States have had good success with in vitro fertilization using donated eggs. Now, those clinicians are aiming for a higher goal: babies born from a patient’s own eggs, cryopreserved either individually or within whole ovarian tissue.

These are not pipe dreams, according to experts interviewed for this story. Autologous oocyte freezing is well established in healthy women and is now coming of age in cancer patients, with recent reports of live births. Ovarian tissue freezing and reimplantation is a much newer technique, also pioneered in cancer patients. To date, more than 70 live births have occurred from ovarian cortical tissue conservation and later transplantation in adults. Last December brought the first report of a live birth to a childhood cancer survivor who had prepubertal ovarian tissue frozen before chemotherapy. And a 2015 report detailed the case of a girl with primary ovarian failure secondary to sickle cell anemia treatment. At 25, she gave birth to a healthy child conceived from ovarian tissue removed when she was 14 years old.

Not all clinicians so enthusiastically embrace this future, however. A new set of consensus guidelines for the management of girls and women with Turner syndrome is in the works and will recommend a more conservative clinical approach, according to Nelly Mauras, MD, chief of endocrinology, diabetes, and metabolism at the Nemours Children’s Health System in Jacksonville, Fla.

A group of academic and patient advocacy stakeholders is cooperatively honing the document based on a meeting last summer in Cincinnati. These groups include the European Society of Endocrinology, the Endocrine Society, the U.S. Pediatric Endocrine Society, the European Society for Pediatric Endocrinology, Cardiology, and Reproductive Endocrinology, as well as Turner syndrome patient advocacy groups.

Dr. Mauras said the guideline will be “less discouraging” than the existing one issued in 2012 by the American Society of Reproductive Medicine. In its 2012 guidelines, the society identified Turner syndrome as a relative contraindication to pregnancy and an absolute contraindication in those with documented cardiac anomalies. However, greater experience has since been accrued in reproductive techniques of oocyte donation in Turner, with better outcomes.

The upcoming guidelines, however, will still recommend strongly against ovarian stimulation for fertility preservation for girls younger than 12, Dr. Mauras said, and will not recommend ovarian tissue conservation. “We just do not have the safety data and pregnancy outcomes that we need to give strong recommendations for these treatments,” she said. “These are still considered experimental treatments for girls with Turner syndrome.”

Turner syndrome, caused by a deletion of one X chromosome, throws a unique curve into the game – very early ovarian failure. Those with a complete deletion (45,X) begin losing their primordial ovarian follicles even before birth. Most will never experience spontaneous puberty; even if they do, their egg reserve is virtually gone soon after. Ovarian reserve may not be completely lost in girls with mosaicism, however, who have the X deletion in only a portion of their cells (46,XX/45,X). Some will enter puberty, and about 5% may even conceive spontaneously in younger years. But of the majority of Turner girls eventually experience complete ovarian failure.

This means that fertility preservation can’t be a wait-and-see issue, according to Kutluk Oktay, MD, PhD, a fertility specialist on the leading edge of this issue in the United States.

“We have to be proactive,” said Dr. Oktay, professor of obstetrics and gynecology at New York Medical College, Valhalla. “If we wait until girls are 12 or 13 to address this, a majority will have totally depleted their ovarian reserve by then. They will have no option other than an egg donor or adoption. We are suggesting that they should be screened as soon as they are diagnosed, and if they and their parents wish it, something should be done before it’s too late.”

Dr. Oktay is also the founder of fertilitypreservation.org , which specializes in advanced fertility treatments for cancer patients. He is one of a handful of physicians in the United States who advocate early oocyte harvesting in peripubertal girls and ovarian tissue harvesting in prepubertal girls with Turner syndrome. Last year, in conjunction with the Turner Syndrome Foundation, he and his colleagues published a set of guidelines for preserving fertility in these patients.

The paper recommends fertility assessment pathways for pre- and postpubertal girls. For both groups, Dr. Oktay employs serial assessments of ovarian reserve by monitoring several hormones, including follicle-stimulating hormone, luteinizing hormone, and antimüllerian hormone (AMH). Produced by primordial follicles, AMH declines as egg reserve declines over a lifetime, and is considered an accurate marker of ovarian reserve. When a girl experiences two consecutive AMH declines, egg depletion is probably accelerating. “This is the time to consider fertility preservation,” he said.

If a girl is peri- or postpubertal, the choice would probably be ovarian stimulation with the goal of retrieving mature oocytes. For prepubertal girls, the best choice is probably ovarian tissue cryopreservation. But because the egg reserve may already be spotty inside the ovary, he recommended freezing it en bloc, rather than preserving just cortical sections.

Because these techniques are only beginning to be used in young Turner patients, neither has been tested yet to see if it would result in a pregnancy. However, Dr. Oktay said, more than 80 babies have been born to women with other disorders who had ovaries frozen as adults. And European women with Turner syndrome have been successfully bearing children with donated oocytes for years.

“I don’t differentiate Europe from the U.S.,” he said. “We have no reason to believe Turner syndrome girls would be any different here than they are there.”

Pregnancy rates by egg donation in Turner syndrome patients are about half that typically seen in an otherwise healthy infertile woman, according to numerous sources; with a take-home baby rate of about 18%. There are numerous reasons for this. The miscarriage rate in Turner patients is about 44%. Women with Turner tend to have smaller uteri, with thinner endometrium, mostly because of the lack of estrogen.

But with careful management, those who do conceive can safely deliver a healthy baby, said Outi Hovatta, MD, a Finnish fertility specialist who has done extensive work in the area. “In Europe, we have been doing this quite liberally for years, and haven’t had a bad experience,” she said in an interview.

A 2013 review summarized both the success and the risks of these pregnancies. It examined obstetric and neonatal outcomes among 106 women with Turner syndrome who gave birth via egg donation from 1992 to 2011 in Sweden, Finland, and Denmark.

Most (70%) had a single embryo transferred, as virtually all guidelines recommend. Women with Turner are prone to cardiac and aortic defects that can worsen under the strain of pregnancy, or even present for the first time during gestation. Aortic dissection is a real threat; up to a third of patients with Turner experience it during adulthood, and it’s a major cause of death among them. In the Nordic series, 10 women (9%) had a known cardiac anomaly.

The multiple birth rate was 7%. More than a third (35%) developed a hypertensive disorder, including preeclampsia (20%). Four women had potentially life-threatening complications, including one with aortic dissection, one who developed mild regurgitation of the tricuspid and mitral valve, one with a mechanical heart valve who developed HELLP syndrome (hemolysis, elevated liver enzymes, low platelets), and one who underwent a postpartum hysterectomy because of severe hemorrhaging.

The infants, nevertheless, did well. The preterm birth rate was 8%, with 9% of the singleton infants having a low birth weight. About 4% had a major birth defect. Of the 131 born, three died (2.3%), including a set of extremely preterm twins.

Close follow-up and cross-specialty cooperation are what make these positive outcomes possible, said Dr. Hovatta, who is now a professor emeritus at the Karolinska Institute, Sweden.

“We do everything we can to exclude things that could cause bad outcomes.” That includes extremely rigorous cardiac testing before pregnancy and continuous monitoring during it. “If a woman has any sign of cardiac anomaly, she is advised not to become pregnant. If she shows any signs of aortic dilation, we follow her extremely carefully with experienced cardiologists.”

Like Dr. Oktay, Dr. Hovatta and her European colleagues make fertility preservation an early topic of conversation. Unlike in the United States, where many girls aren’t diagnosed with the disorder until they fail to enter puberty, almost all Turner girls in Europe are identified very early in childhood. They receive early growth hormone treatment, and there is frequent consultation with interdisciplinary specialists. Fertility is spoken of early and often.

Early oocyte retrieval is common, Dr. Hovatta said. “Yes, it’s possible to wait until puberty, but for so many girls, most of the eggs have disappeared by then, so we typically don’t wait. We start looking at that option around 11 years, which is the same time we think about cryopreserving ovarian tissue.”

However, she added, as in the United States, the outcomes of these procedures are still unknown. But the existing data in other populations, the ability to carefully shepherd women through a successful pregnancy, and the willingness of families to provide the option all support further exploring them. Dr. Hovatta was at the Cincinnati gathering last summer and said she did not agree with the conservative tone she heard. Dr. Oktay also does not agree.

“This evidence we have so far is good evidence,” he said. “Look, where we are right now with Turner girls is where we were 15 years ago with cancer patients. People thought, ‘They have cancer. They should just be worrying about surviving cancer, not about their fertility.’ Now fertility counseling is a very important part of cancer care. We have all these tools available to us for cancer patients who don’t want to lose their fertility. This accumulated experience that has already been applied in other medical conditions … why not use that for Turner syndrome? This is my point: With all the data out there about the potential benefits and the ways to manage the risks, we shouldn’t have to tell girls, ‘Well, you have to become menopausal, and maybe you can adopt someday.’ That doesn’t sit well with parents any more. We want these girls to thrive. Not just to survive, but to have as close to a normal quality of life as possible.”

msullivan@frontlinemedcom.com

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