Treatment provides new options for women with unexplained infertility
Six doctors and nurses, Kimberly Brolin and her husband, Nick Brolin, were wedged in the examining room around an ultrasound machine. Everyone was quiet, anxiously watching the screen. When they saw the white flicker inside a small black circle, they erupted in cheers.
A heartbeat. No, two heartbeats. Twins. Kimberly Brolin began to cry, and so did a couple of nurses. Brolin’s pain and perseverance were not in vain. After six miscarriages and six rounds of in vitro fertilization, she was having twins.
It had only been a few months since Brolin learned the reason for her miscarriages: endometriosis, a disease where tissue that normally lines a woman’s uterus grows outside of it, causing cysts and scarring in reproductive organs.
Endometriosis can cause cramps, heavy periods and pain around the pelvis. It affects 10 percent of American women, and causes infertility in 40 percent of those women, according to the National Infertility Association. In fact, endometriosis likely accounts for 30 to 50 percent of unexplained infertility cases, according to the American Society for Reproductive Medicine, with many patients feeling no pain.
Brolin was one of them. Aside from heavy periods, there was no sign of the disease except infertility.
Until a few months ago, the only way to diagnose endometriosis in patients with no pain symptoms was through laparoscopic surgery. Doctors make incisions 2- to-5 millimeters long in the abdomen and insert a tiny camera to see and remove the cysts and scars.
“It’s hard for us to understand the disease when we don’t know who’s got it and who doesn’t unless we do surgery,” said Dr. Steven Young, a professor in reproductive endocrinology and infertility at the University of North Carolina at Chapel Hill.
But that’s changing. In January, Young and Dr. Bruce Lessey, who treated Brolin, released ReceptivaDx, the first diagnostic test for endometriosis. For many women with unexplained infertility, this test offers answers. With the diagnosis comes an endometriosis treatment plan that could save years of emotional pain and tens of thousands of dollars.
For women like Brolin, treatment brings the potential to turn their hope into reality: the possibility of a pregnancy.
Young rips open a sterile bag and pulls out the instrument he uses to conduct the ReceptivaDx test — a white plastic catheter as thin as the ink reservoir in a ballpoint pen, wrapped in a clear plastic tube with a small hole in the top.
During the procedure, called an endometrial biopsy, a doctor pushes the catheter through the vagina to scrape a tissue sample from the lining of the uterus, where a fertilized embryo will attach itself and — if successful — begin to grow into a fetus. It only takes five seconds, but it is painful, and women typically have cramps for five to 10 minutes afterward.
“You might be saying a few f-bombs when I do the test,” Dr. Aimee Eyvazzadeh, a reproductive endocrinologist based in San Francisco, tells her patients. “And that’s totally OK.”
The doctor places the sample in a formaldehyde solution and ships it to the lab, where technicians study it under a microscope. They’re looking for BCL6, a protein that appears in high levels in the uterine tissue of women with endometriosis.
Young pointed to two images of what someone would see while analyzing the cell samples. They looked a bit like 16th-century nautical maps — with a couple of large circles resembling islands and smaller circles creating a sea-like background.
One image was made up of black lines, while the other was mostly red. Young said the red marks BCL6; the redder the sample, the more likely that woman has endometriosis. The technicians calculate a BCL6 score, and if that score is above a certain threshold, the patient’s ReceptivaDx test is positive, meaning it is almost certain she has endometriosis.
Young and Lessey have been developing the test for five years, since they found a research study on how one protein correlated to endometriosis diagnosis. The two started tracking down other proteins that might have a similar relationship. After months of work, they found BCL6. Young recalls Lessey saying this was “the most startlingly clear result that we’ve ever seen.”
That’s when they realized they could use the protein to develop a test.
The next step was taking it to market. Chris Jackson, president and CEO of CiceroDx, a diagnostics company that is marketing ReceptivaDx, said the company has sold kits to conduct the ReceptivaDx test to 100 doctor’s offices in the United States.
One cycle of in vitro fertilization costs $12,000 to $17,000 at least, according to the American Pregnancy Association; for women under 35, an IVF cycle’s success rate is 41 to 43 percent on average, and that declines with age. And in women with endometriosis, Eyvazzadeh said the success rate is about half of that without treatments.
That’s why Eyvazzadeh recommends the test to all of her patients before they do an in vitro cycle. Most of her patients are 39 and older, so every genetically healthy egg is invaluable. Eyvazzadeh tests them before they use one of those eggs so their path to pregnancy is as clear as possible before spending the time and money on in vitro.
“Fertility shouldn’t be something where someone looks at you and be like, ‘I just don’t know,’” Eyvazzadeh said.
Even after the onset of pain, Dr. Hugh Taylor, chief of obstetrics and gynecology at Yale-New Haven Hospitals, said endometriosis normally is not on a primary care doctor’s radar. Because the disease is so misunderstood, diagnosis can be delayed from seven to 11 years. For women trying to get pregnant, the delayed diagnosis can cost thousands of dollars in failed IVF cycles.
Still, Young is conservative in recommending it.
“I’m reluctant to give it to a lot of people, because — I don’t know, it’s my test, and I feel like I’m biased towards it,” he said.
Part of his hesitancy stems from a lack of research. Taylor commended the studies behind the test, but Young wants more supporting information to prove that the test works, particularly in women with unexplained fertility.
Young’s test poses a possible treatment for endometriosis, which has no cure. If BCL6 levels are this strongly connected to endometriosis, maybe cutting off the pathway to build that protein could treat the disease — or even cure it. As he continues studying ReceptivaDx in the coming years, he will explore that possibility.
Young would also like to make the test less uncomfortable. Taylor has developed a test that can diagnose endometriosis using a saliva sample. He detects the disease using micro-RNA found in saliva and blood that is related to endometriosis. He said the test will come on the market in a couple of months.
Since ReceptivaDx has become available, Eyvazzadeh has had several patients with unexplained infertility test positive for endometriosis. After trying to get pregnant for years, they succeeded after a couple of months of treatment.
“The treatments that I use for this aren’t treatments that I would’ve ever thought of before having the results or the access to a test like this,” Eyvazzadeh said.
“Oh, are you pregnant yet?” Brolin said her friends kept asking when she was trying to conceive. But the well-intentioned small talk only reminded Brolin of her emotional pain — the years of miscarriages and failed IVF attempts.
When she was trying to conceive, she spent her money on fertility treatments instead of going to doctors dentist appointments, and started monogramming and making jewelry to sell. Still, Brolin persisted. She wanted a family. Her hope rose and receded, but never disappeared.
Shortly after the birth of her twins, Ava and Stella, Brolin realized she wanted another child. She did two in vitro cycles — one failed to take, and the other led to a miscarriage. That’s when Lessey began to suspect her endometriosis had returned.
Lessey offered ReceptivaDx to Brolin a few months before it came on the market.
“It’s kind of a running joke between me and him,” Brolin said. “He always says that I was his guinea pig,”
She agreed to do the test, which costs $790, to avoid the riskier laparoscopic surgery, which can cost from $1,700 to $5,000 without insurance and has a one- to two-week average recovery time.
Brolin tested positive, so she treated her endometriosis with a laparoscopy and three months of medication. Then she did another IVF cycle — the last one. She couldn’t endure the heartache of a long road to fertility twice.
She was shopping on Black Friday when she got the phone call — she was pregnant again. And again, twins. She was shocked, the nurses laughed, and then she was filled with excitement. By now, she knew all about twins.
Ava and Stella are now 5 years old; her younger twins, Lily and Wyatt, are 15 months. Now that Brolin is done with fertility treatment, having endured nine rounds of IVF and nine miscarriages, she can focus on raising her family.
She is grateful to Lessey for these moments — when she watches her daughters playing in the yard, or when she admires how her twins seem to share a secret language.
As she raises the family she persevered for, the thought passes through her head:
“If it wasn’t for him, I wouldn’t have this. I wouldn’t be able to experience all this,” she said.