Heavier women are less fertile. For each unit increase above a body mass index (BMI) of 25, where the “normal” weight range tops out, there’s a 3 percent drop in fertility in a given month.

That may not sound like much, but it means a woman at the bottom of the obese range – with a BMI of 30 – is 15 percent less fertile than someone of normal weight. And fertility keeps dropping from there even as other problems mount.

“It takes longer to get pregnant, there’s more pregnancy loss, more cesarean sections, more surgical complications from C-sections, and there’s double the risk of having an obese child,” said Nanette Santoro, MD, chair of the University of Colorado School of Medicine’s Department of Obstetrics and Gynecology.

With more than one-third of U.S. women of childbearing age being obese, this is a problem of epidemic proportions. Long ago, Santoro, who sees patients at UCHealth’s Reproductive Medicine – Stapleton, asked the simple question: why?

Nearly 15 years later, she’s closing in on an answer – with help from a new study explicitly excluding overweight and obese women. It could, she hopes, lead to treatments that improve fertility without requiring extreme weight loss, something few manage to achieve, much less sustain over time.

Hormones the culprit

As it is with science, Santoro’s work started with that of others – in this case, the Study of Women’s Health Across the Nation, or SWAN. In the mid-2000s, she and colleagues parsed the data and noted that, as she put it, “the bigger you are, the lower your reproductive hormones.”

She followed that insight up with a study that measured reproductive hormones among women who lost 25 percent or more of their body weight after bariatric surgery. Reproductive hormone levels returned towards normal in those patients, she and colleagues found. So there was definitely a connection. Now came the hard part: where along the reproductive hormone-producing chain was the problem? The hypothalamus in the brain? The pituitary gland hanging just below the hypothalamus? The ovaries themselves?

The hypothalamus, deep in the brain and producing dozens of molecules related to appetite and reproduction, would make for a difficult target, Santoro knew. The pituitary, below the blood-brain barrier and less prolific, would be somewhat more accessible, so to speak. The chain of interest involved both: the hypothalamus produces gonadatropin-releasing hormone (GnRH). GnRH then prods the pituitary to release two key gonadotropins: luteinizing hormone (LH), which triggers ovulation; and follicle-stimulating hormone (FSH), which helps control egg production by the ovaries as well as the menstrual cycle.

Santoro’s team found that, among obese women, the pituitary gland was the weak link: essentially, weight-based dose of GnRH led to less LH and FSH production with increasing weight. The question then was what was causing the pituitary gland to fail these women?

Help from a friend

Santoro suspected that the pituitary was capitulating due to inflammation caused by some combination of floods of sugar-processing insulin as well as free fatty acids such as cholesterol in the bloodstreams of obese women. But, as Santoro put it, “We had enough for a hypothesis, but not enough for anybody to give me a grant” to put the hypothesis to the scientific test.

“Then we got lucky,” she said.

It happened that Irene Schauer, PhD, a CU School of Medicine endocrinologist, was doing a diabetes study. It included healthy controls – cyclists – who were taking six-hour infusions of free fatty acids and insulin. Santoro and colleagues tested them and found that, indeed, the cholesterol and insulin caused cyclists’ FSH and LH levels to plunge.

The team reported those results in the journal Obesity in February. It was the evidence they needed for a four-year, $1 million grant leading to her new study of non-obese women to understanding the obesity-fertility link. The study, involving about 30 women, is being done in two stages.

The first, like the work with Schauer that led to it, infuses women with insulin and free fatty acids while monitoring the pituitary’s output of FSH and LH. Genie Hendley, 33, is one of those women. She works in accounting at the CU School of Medicine’s Department of Pathology and learned about the study through an email blast.

“I’m interested in science and the evolutionary part of medicine, and if I can do my part, that’s awesome,” Hendley said.

Her part included being infused with saline for six hours as someone did a blood draw every ten minutes, with a repeat – this time with infusions of insulin and free fatty acids and blood checks every five minutes – scheduled for this month.

“I pretty much sit in a bed for six hours,” Hendley said. “It’s really not that bad.”

While the study is ongoing, Santoro says study subjects’ data so far have backed up the conclusions of the team’s previous work, Santoro said.

Bacon

The study’s second phase will put women on a closely controlled high-fat diet for a month. It’s heavy on things like potato chips, eggs, cheese, bacon, pork chops, peanut butter and peanuts. Santoro tried it herself first.

“I’m a vegetarian, but I ate bacon for science for two weeks,” she said. The diet is no higher in calories than more standard fare, she added. “That was important, because nobody’s going to do it if they’re going to gain weight.”

The research team will measure daily urine samples for a full suite of reproductive hormones along the way. They think the added fat – largely in the form of inflammation-producing omega-6 rather than anti-inflammatory omega-3 fatty acids – may also bump up insulin levels. That would naturally create the pituitary-unfriendly combination delivered by the study’s infusions.

The work, as Santoro put it, “is at the interface of metabolism and reproduction.”

If Santoro and colleagues’ hunches are correct, an interesting question arises: what if it’s not obesity per se, but rather the diets of obese women that are stressing so many pituitaries and suppressing fertility? That may be a good thing, in fact. Should the results from Hendley and her fellow non-obese study volunteers prove out as hypothesized, Santoro and colleagues would follow up with studies of treatments that could be as simple as cutting back on bad fats, boosting omega-3 intake, or even just taking anti-inflammatories such as baby aspirin or low-dose steroids.

“If we’re going to fix this and try to improve reproductive function, we really want to target the pituitary gland,” Santoro said. “That’s way easier than making obese people un-obese.”