Cover Story

Rising obesity rates impact fertility among young adults

Many adolescents and young adults may believe that obesity-related diseases, such as heart disease, diabetes and osteoarthritis, are concerns of old age. But excess weight can have detrimental effects on fertility, a consequence younger adults may not recognize until they want to start a family.

Although age is the greatest predictor of fertility among women, obesity has a substantial effect on the likelihood of pregnancy. For example, the likelihood of pregnancy may be similar between a young woman with BMI greater than 30 kg/m2 and a woman aged older than 35 years, according to Nanette Santoro, MD, the E. Stewart Taylor Endowed Chair in the department of obstetrics and gynecology and professor in the division of reproductive endocrinology at the University of Colorado Denver Anschutz Medical Campus.

“So, if she were 25 years old, she would have the fertility of a woman approaching 40 years, in her ability to get pregnant per month,” Santoro told Endocrine Today.

Obesity has effects throughout the hypothalamic-pituitary-gonadal axis in both men and women, according to Rhoda H. Cobin, MD. Source: Jean Whiteside Photo; printed with permission.

Further, “there is a 3% drop in monthly fecundability for each BMI unit above 25 kg/m2. So, for a woman with a BMI of 35 kg/m2, she has a 30% drop in her fertility by this measure,” she said. “There is a ‘dose-response’ relationship — the greater the obesity, the more likely the infertility.”

Obesity affects not only fecundability — the probability of pregnancy in a given month — but it also is associated with increased risk for spontaneous abortion, congenital anomalies, gestational diabetes and preeclampsia, according to a 2015 American College of Obstetricians and Gynecologists (ACOG) Obesity in Pregnancy Practice Bulletin. Risk for stillbirth, although low, is increased by 30% for women with BMI 30 kg/m2 to 34.9 kg/m2 and almost doubles with BMI 40 kg/m2 and higher, according to the bulletin.

Maternal obesity may also affect the long-term health of children, elevating their risks for metabolic syndrome and childhood obesity, according to ACOG. However, separating prenatal effects from influences after birth is difficult.

Obesity is not a concern only for women; men with obesity may also have decreased fertility.

“We tend to think of this as a women’s issue, but it actually takes two people to make a baby,” Rhoda H. Cobin, MD, clinical professor of medicine in the division of medicine, endocrinology and bone disease at the Icahn School of Medicine at Mount Sinai School, told Endocrine Today. “Obesity affects men’s fertility as well as women’s fertility, so when people talk about infertility, they’re really talking about a couple.”

Rajeshwari Sundaram

In a study conducted by Rajeshwari Sundaram, PhD, senior investigator in the division of intramural population health research at NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development, and colleagues, the average time to pregnancy was longer among couples in which both partners had BMI at least 35 kg/m2 compared with couples in which either or both partners had BMI less than 25 kg/m2.

“Many studies have focused largely on the female,” Sundaram told Endocrine Today. “Our results underscore the importance of including both partners when assessing couple fecundity.”

Multifactorial effects

Obesity affects female fertility in several ways; however, the underlying mechanisms are not all well understood, according to experts Endocrine Today interviewed.

“There are a number of variables that affect the brain — the hypothalamic-pituitary axis — but also problems within the ovary itself that are felt to be due to problems with oxidative stress caused by lipid disorders, problems with mitochondrial dysfunction and problems with actual death of the granulosa cells,” Cobin said. “The effect of obesity is felt throughout the hypothalamic-pituitary-gonadal axis in both men and women.”

At the behavioral level, women with overweight or obesity may have body image concerns or more psychologically based sexual dysfunction.

“[Women with obesity may be] less interested in sex, so intercourse frequency could be one factor,” Richard S. Legro, MD, physician and professor of obstetrics and gynecology and public health services at Penn State College of Medicine, M.S. Hershey Medical Center in Hershey, Pennsylvania, told Endocrine Today. “When women lose weight, their energy improves [and] their sexual function improves, so that in and of itself could be one reason” for the association between obesity and fertility, he said.

Increasing weight is also associated with ovulatory disorders, Legro said. The most common associated ovulatory disorder is polycystic ovary syndrome, although Legro cautioned that elevated weight does not cause PCOS.

“What we’ve shown is that morbidly obese women tend to have longer menstrual cycles,” he said. During a longer menstrual cycle, eggs take longer to develop and ovulation is less frequent throughout the year, thus providing fewer opportunities for pregnancy and making timing of intercourse for conception more difficult.

Other women with “simple obesity” — not associated with PCOS — and normal-length menstrual cycles may have abnormally low hormone levels due to lack of pituitary response to gonadotropin-releasing hormone, according to Santoro. She and fellow researchers are actively investigating candidates for circulating factors that might suppress the pituitary gland.

Nanette Santoro

“It looks like the signals coming from the pituitary gland are lower and do not stimulate the ovary as effectively in obesity,” Santoro said. “What we’re doing now is looking at the combined effect of insulin and free fatty acids. They together, but not alone, seem to reproduce this adverse effect on the pituitary when we give them to normal-weight women.”

Following findings from a preliminary study published this year in Obesity, Santoro and colleagues have almost completed a short study infusing insulin and free fatty acids together in normal-weight women without PCOS. The researchers are planning a longer-term real-world trial to determine whether they can reproduce the menstrual cycle hormonal changes seen in women with obesity in normal-weight women consuming a high-fat diet.

Fertility issues in men

Robert E. Brannigan

Obesity can have an adverse effect on male fertility through a number of mechanisms, and the level of impairment can vary from no effect to substantial negative impact, according to Robert E. Brannigan, MD, professor in the urology department at Northwestern University, Feinberg School of Medicine.

“We’ve seen such a big uptick in this issue of obesity over the last several decades. It doesn’t have just one effect; it has multifaceted effects. Ultimately, these effects can be manifest to varying degrees in different patients,” Brannigan told Endocrine Today.

For example, he said, “obesity will rarely by itself result in azoospermia, though we do think it can be a significant negative factor driving down a number of key components for normal fertility.”

In men, obesity is associated with increased estradiol and decreased testosterone levels, which can suppress libido, impair sexual functioning and decrease sperm quantity and quality, Brannigan said.

Furthermore, obesity is often related with metabolic disorders that can affect the hypothalamic–pituitary axis. Diabetes has been linked to abnormally low levels of luteinizing hormone, which affects testosterone production. Dyslipidemia has been linked to changes in levels of free radicals, which can cause sperm DNA damage.

Body size alone can also affect obesity, according to Brannigan.

“Obese men can develop fat deposits in the medial thighs, the suprapubic area and the spermatic cord,” Brannigan said. “Optimal sperm production happens at a degree or two below core body temperature, and this fat can literally engulf the scrotum and testicles and substantially raise that intrascrotal and testicular temperature and diminish sperm production. These changes can markedly diminish sperm production. These are some of the multifaceted effects obesity can have on fertility.”

Effects of weight loss unclear

Certainly, weight loss improves overall health of women and men with obesity, but whether it increases fertility remains unanswered.

“There are a number of studies looking at this in men, and I would say that they are so heterogenous that it’s hard to know the exact extent of the benefit for fertility,” Brannigan said. “The take-home message is that with weight loss, many men — but not all — will exhibit optimization of semen parameters or sperm quality.”

Studies of the effects of weight loss on women with obesity and infertility have also reached mixed conclusions.

“Generally, we advise some weight loss for women, but it is more based on evidence of benefit to the pregnancy and the baby than for its benefit for fertility,” Santoro said.

One study conducted by Legro and colleagues — a post hoc analysis of data from two trials in 329 women with PCOS and obesity — suggested that weight loss can improve ovulation and likelihood of pregnancy. The researchers found that weight loss with lifestyle modification followed by infertility treatment with clomiphene was associated with 2.5 times the number of live births compared with immediate clomiphene therapy alone.

“That gives us some hope, because we’ve had a couple of studies showing that weight loss before trying to get pregnant is not helpful,” Santoro said. “In one study published last year in The New England Journal of Medicine, it looked like it was bordering on harmful. That was crazy. We looked at that one and said, ‘What is going on?’”

In that study, Meike A.Q. Mutsaerts, MD, PhD, from the department of obstetrics and gynecology at University Medical Center Groningen, University of Groningen, in the Netherlands, and colleagues found no benefit of preconception weight loss on the number of live births. After 24 months, more babies were born to women with obesity who received immediate infertility treatment with clomiphene (n = 100 live births to 285 women) than to those who underwent a 6-month weight-loss intervention before receiving clomiphene (n = 76 live births to 289 women; P = .04).

“That shocked a lot of people,” Legro said. “But that also may be the reality.”

That study reported only modest weight loss, Legro said, and perhaps women require substantially more weight loss to greatly benefit reproduction.

Santoro raised the possibility that the stress of the weight-loss intervention contributed to lower fertility in that group. She said she does not believe, as some do, that the obesity caused irreversible metabolic and reproductive changes.

Santoro and Cobin

Bariatric surgery as an option

Dramatic weight loss via bariatric surgery appears to have a positive effect on the fertility of obese young adults.

In a study published in 2009, Santoro and colleagues found gonadotropins and ovarian hormones tended to shift toward normal levels in women who lost 25% of their body weight after bariatric surgery.

“That led us to hope that weight loss by any means was going to make fertility better, but that may not always be the case,” Santoro said.

Women who lose a substantial amount of weight after bariatric surgery often achieve more regular menstrual cycles, according to Stacy Brethauer, MD, FASMBS, staff physician in laparoscopic and bariatric surgery at Cleveland Clinic, director of bariatric surgery at Fairview Hospital, and president of the American Society for Metabolic and Bariatric Surgery.

“Once they lose that weight, women get back into a regular rhythm in terms of their fertility to the point where we tell most of our patients, for a variety of reasons, that they’re much more fertile after they have their bariatric operation,” Brethauer told Endocrine Today.

Stacy Brethauer

Women are typically advised to wait at least 18 months after surgery before becoming pregnant, he said.

“Even if they want to start a family, we ask that they get their weight off and get stable before they have children,” Brethauer said. “Now, I’ve had patients get pregnant in the first 6 months, and they do fine, but it’s not ideal.”

The main concern, Brethauer said, is nutritional support for the fetus. Once pregnant, women who have lost weight after surgery have fewer pregnancy complications than women with obesity, he said.

In a case-control study comparing pregnancy outcomes for 670 women who had previously undergone bariatric surgery and five controls matched for presurgical BMI for each case, Kari Johansson, PhD, a research assistant at the Karolinska Institutet in Sweden, and colleagues found that the women who underwent weight-loss surgery had 25% lower odds of gestational diabetes and 33% lower odds of delivering an infant large for gestational age.

However, the odds of delivering a small for gestational age infant were more than doubled in the surgery group. The odds for preterm delivery were not significantly different between the groups, but there was an increased prevalence among the women who had lost the most weight.

Richard S. Legro

“Our greatest perinatal public health issues are small babies and preterm births,” Legro said. “So, against common sense, women [in the Johansson study] who lost the most weight actually were at a greater risk for a preterm birth of a small baby than women who would proceed at their full weight with pregnancy.”

Unanswered questions

Despite active research on the link between weight and fertility, many questions remain.

The effects of obesity and weight loss pose unaddressed concerns for families beyond infertility.

As weight regain is typical, questions remain about how much weight a woman should gain during pregnancy and whether she should attempt to lose weight during lactation, for example.

“We shouldn’t say, ‘If you lose weight, you’re going to have a safe and healthy pregnancy,’ because it’s more complex than that,” Legro said.

Also concerning are the potential effects of parents’ obesity on their child’s metabolic health.

“It’s a public health concern when one generation follows the next follows the next,” Cobin said. “As we get heavier and heavier, you see the snowballing into the next generation, if we don’t do something about it now.”

Perhaps the only recommendation is to take steps to avoid excess weight and strive for a healthy lifestyle.

“If I were a teenager or young woman who’s thinking about starting a family, I might take the evidence that obesity is dangerous more seriously if I realized that it was going to hamper my efforts to get pregnant or reduce my likelihood of having a healthy baby, or bringing a baby into this world who has got several strikes against him metabolically to start with,” Cobin said. – by Jill Rollet

Disclosures: Brethauer, Brannigan, Cobin, Legro, Santoro and Sundaram report no relevant financial disclosures.

Click here to read the POINTCOUNTER, "Which has greater influence on childhood obesity, prenatal or postnatal environment?"

Many adolescents and young adults may believe that obesity-related diseases, such as heart disease, diabetes and osteoarthritis, are concerns of old age. But excess weight can have detrimental effects on fertility, a consequence younger adults may not recognize until they want to start a family.

Although age is the greatest predictor of fertility among women, obesity has a substantial effect on the likelihood of pregnancy. For example, the likelihood of pregnancy may be similar between a young woman with BMI greater than 30 kg/m2 and a woman aged older than 35 years, according to Nanette Santoro, MD, the E. Stewart Taylor Endowed Chair in the department of obstetrics and gynecology and professor in the division of reproductive endocrinology at the University of Colorado Denver Anschutz Medical Campus.

“So, if she were 25 years old, she would have the fertility of a woman approaching 40 years, in her ability to get pregnant per month,” Santoro told Endocrine Today.

Obesity has effects throughout the hypothalamic-pituitary-gonadal axis in both men and women, according to Rhoda H. Cobin, MD. Source: Jean Whiteside Photo; printed with permission.

Further, “there is a 3% drop in monthly fecundability for each BMI unit above 25 kg/m2. So, for a woman with a BMI of 35 kg/m2, she has a 30% drop in her fertility by this measure,” she said. “There is a ‘dose-response’ relationship — the greater the obesity, the more likely the infertility.”

Obesity affects not only fecundability — the probability of pregnancy in a given month — but it also is associated with increased risk for spontaneous abortion, congenital anomalies, gestational diabetes and preeclampsia, according to a 2015 American College of Obstetricians and Gynecologists (ACOG) Obesity in Pregnancy Practice Bulletin. Risk for stillbirth, although low, is increased by 30% for women with BMI 30 kg/m2 to 34.9 kg/m2 and almost doubles with BMI 40 kg/m2 and higher, according to the bulletin.

Maternal obesity may also affect the long-term health of children, elevating their risks for metabolic syndrome and childhood obesity, according to ACOG. However, separating prenatal effects from influences after birth is difficult.

Obesity is not a concern only for women; men with obesity may also have decreased fertility.

“We tend to think of this as a women’s issue, but it actually takes two people to make a baby,” Rhoda H. Cobin, MD, clinical professor of medicine in the division of medicine, endocrinology and bone disease at the Icahn School of Medicine at Mount Sinai School, told Endocrine Today. “Obesity affects men’s fertility as well as women’s fertility, so when people talk about infertility, they’re really talking about a couple.”

PAGE BREAK
Rajeshwari Sundaram

In a study conducted by Rajeshwari Sundaram, PhD, senior investigator in the division of intramural population health research at NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development, and colleagues, the average time to pregnancy was longer among couples in which both partners had BMI at least 35 kg/m2 compared with couples in which either or both partners had BMI less than 25 kg/m2.

“Many studies have focused largely on the female,” Sundaram told Endocrine Today. “Our results underscore the importance of including both partners when assessing couple fecundity.”

Multifactorial effects

Obesity affects female fertility in several ways; however, the underlying mechanisms are not all well understood, according to experts Endocrine Today interviewed.

“There are a number of variables that affect the brain — the hypothalamic-pituitary axis — but also problems within the ovary itself that are felt to be due to problems with oxidative stress caused by lipid disorders, problems with mitochondrial dysfunction and problems with actual death of the granulosa cells,” Cobin said. “The effect of obesity is felt throughout the hypothalamic-pituitary-gonadal axis in both men and women.”

At the behavioral level, women with overweight or obesity may have body image concerns or more psychologically based sexual dysfunction.

“[Women with obesity may be] less interested in sex, so intercourse frequency could be one factor,” Richard S. Legro, MD, physician and professor of obstetrics and gynecology and public health services at Penn State College of Medicine, M.S. Hershey Medical Center in Hershey, Pennsylvania, told Endocrine Today. “When women lose weight, their energy improves [and] their sexual function improves, so that in and of itself could be one reason” for the association between obesity and fertility, he said.

Increasing weight is also associated with ovulatory disorders, Legro said. The most common associated ovulatory disorder is polycystic ovary syndrome, although Legro cautioned that elevated weight does not cause PCOS.

“What we’ve shown is that morbidly obese women tend to have longer menstrual cycles,” he said. During a longer menstrual cycle, eggs take longer to develop and ovulation is less frequent throughout the year, thus providing fewer opportunities for pregnancy and making timing of intercourse for conception more difficult.

Other women with “simple obesity” — not associated with PCOS — and normal-length menstrual cycles may have abnormally low hormone levels due to lack of pituitary response to gonadotropin-releasing hormone, according to Santoro. She and fellow researchers are actively investigating candidates for circulating factors that might suppress the pituitary gland.

PAGE BREAK
Nanette Santoro

“It looks like the signals coming from the pituitary gland are lower and do not stimulate the ovary as effectively in obesity,” Santoro said. “What we’re doing now is looking at the combined effect of insulin and free fatty acids. They together, but not alone, seem to reproduce this adverse effect on the pituitary when we give them to normal-weight women.”

Following findings from a preliminary study published this year in Obesity, Santoro and colleagues have almost completed a short study infusing insulin and free fatty acids together in normal-weight women without PCOS. The researchers are planning a longer-term real-world trial to determine whether they can reproduce the menstrual cycle hormonal changes seen in women with obesity in normal-weight women consuming a high-fat diet.

Fertility issues in men

Robert E. Brannigan

Obesity can have an adverse effect on male fertility through a number of mechanisms, and the level of impairment can vary from no effect to substantial negative impact, according to Robert E. Brannigan, MD, professor in the urology department at Northwestern University, Feinberg School of Medicine.

“We’ve seen such a big uptick in this issue of obesity over the last several decades. It doesn’t have just one effect; it has multifaceted effects. Ultimately, these effects can be manifest to varying degrees in different patients,” Brannigan told Endocrine Today.

For example, he said, “obesity will rarely by itself result in azoospermia, though we do think it can be a significant negative factor driving down a number of key components for normal fertility.”

In men, obesity is associated with increased estradiol and decreased testosterone levels, which can suppress libido, impair sexual functioning and decrease sperm quantity and quality, Brannigan said.

Furthermore, obesity is often related with metabolic disorders that can affect the hypothalamic–pituitary axis. Diabetes has been linked to abnormally low levels of luteinizing hormone, which affects testosterone production. Dyslipidemia has been linked to changes in levels of free radicals, which can cause sperm DNA damage.

Body size alone can also affect obesity, according to Brannigan.

“Obese men can develop fat deposits in the medial thighs, the suprapubic area and the spermatic cord,” Brannigan said. “Optimal sperm production happens at a degree or two below core body temperature, and this fat can literally engulf the scrotum and testicles and substantially raise that intrascrotal and testicular temperature and diminish sperm production. These changes can markedly diminish sperm production. These are some of the multifaceted effects obesity can have on fertility.”

PAGE BREAK

Effects of weight loss unclear

Certainly, weight loss improves overall health of women and men with obesity, but whether it increases fertility remains unanswered.

“There are a number of studies looking at this in men, and I would say that they are so heterogenous that it’s hard to know the exact extent of the benefit for fertility,” Brannigan said. “The take-home message is that with weight loss, many men — but not all — will exhibit optimization of semen parameters or sperm quality.”

Studies of the effects of weight loss on women with obesity and infertility have also reached mixed conclusions.

“Generally, we advise some weight loss for women, but it is more based on evidence of benefit to the pregnancy and the baby than for its benefit for fertility,” Santoro said.

One study conducted by Legro and colleagues — a post hoc analysis of data from two trials in 329 women with PCOS and obesity — suggested that weight loss can improve ovulation and likelihood of pregnancy. The researchers found that weight loss with lifestyle modification followed by infertility treatment with clomiphene was associated with 2.5 times the number of live births compared with immediate clomiphene therapy alone.

“That gives us some hope, because we’ve had a couple of studies showing that weight loss before trying to get pregnant is not helpful,” Santoro said. “In one study published last year in The New England Journal of Medicine, it looked like it was bordering on harmful. That was crazy. We looked at that one and said, ‘What is going on?’”

In that study, Meike A.Q. Mutsaerts, MD, PhD, from the department of obstetrics and gynecology at University Medical Center Groningen, University of Groningen, in the Netherlands, and colleagues found no benefit of preconception weight loss on the number of live births. After 24 months, more babies were born to women with obesity who received immediate infertility treatment with clomiphene (n = 100 live births to 285 women) than to those who underwent a 6-month weight-loss intervention before receiving clomiphene (n = 76 live births to 289 women; P = .04).

“That shocked a lot of people,” Legro said. “But that also may be the reality.”

That study reported only modest weight loss, Legro said, and perhaps women require substantially more weight loss to greatly benefit reproduction.

Santoro raised the possibility that the stress of the weight-loss intervention contributed to lower fertility in that group. She said she does not believe, as some do, that the obesity caused irreversible metabolic and reproductive changes.

PAGE BREAK

Santoro and Cobin

Bariatric surgery as an option

Dramatic weight loss via bariatric surgery appears to have a positive effect on the fertility of obese young adults.

In a study published in 2009, Santoro and colleagues found gonadotropins and ovarian hormones tended to shift toward normal levels in women who lost 25% of their body weight after bariatric surgery.

“That led us to hope that weight loss by any means was going to make fertility better, but that may not always be the case,” Santoro said.

Women who lose a substantial amount of weight after bariatric surgery often achieve more regular menstrual cycles, according to Stacy Brethauer, MD, FASMBS, staff physician in laparoscopic and bariatric surgery at Cleveland Clinic, director of bariatric surgery at Fairview Hospital, and president of the American Society for Metabolic and Bariatric Surgery.

“Once they lose that weight, women get back into a regular rhythm in terms of their fertility to the point where we tell most of our patients, for a variety of reasons, that they’re much more fertile after they have their bariatric operation,” Brethauer told Endocrine Today.

Stacy Brethauer

Women are typically advised to wait at least 18 months after surgery before becoming pregnant, he said.

“Even if they want to start a family, we ask that they get their weight off and get stable before they have children,” Brethauer said. “Now, I’ve had patients get pregnant in the first 6 months, and they do fine, but it’s not ideal.”

The main concern, Brethauer said, is nutritional support for the fetus. Once pregnant, women who have lost weight after surgery have fewer pregnancy complications than women with obesity, he said.

In a case-control study comparing pregnancy outcomes for 670 women who had previously undergone bariatric surgery and five controls matched for presurgical BMI for each case, Kari Johansson, PhD, a research assistant at the Karolinska Institutet in Sweden, and colleagues found that the women who underwent weight-loss surgery had 25% lower odds of gestational diabetes and 33% lower odds of delivering an infant large for gestational age.

However, the odds of delivering a small for gestational age infant were more than doubled in the surgery group. The odds for preterm delivery were not significantly different between the groups, but there was an increased prevalence among the women who had lost the most weight.

Richard S. Legro

“Our greatest perinatal public health issues are small babies and preterm births,” Legro said. “So, against common sense, women [in the Johansson study] who lost the most weight actually were at a greater risk for a preterm birth of a small baby than women who would proceed at their full weight with pregnancy.”

PAGE BREAK

Unanswered questions

Despite active research on the link between weight and fertility, many questions remain.

The effects of obesity and weight loss pose unaddressed concerns for families beyond infertility.

As weight regain is typical, questions remain about how much weight a woman should gain during pregnancy and whether she should attempt to lose weight during lactation, for example.

“We shouldn’t say, ‘If you lose weight, you’re going to have a safe and healthy pregnancy,’ because it’s more complex than that,” Legro said.

Also concerning are the potential effects of parents’ obesity on their child’s metabolic health.

“It’s a public health concern when one generation follows the next follows the next,” Cobin said. “As we get heavier and heavier, you see the snowballing into the next generation, if we don’t do something about it now.”

Perhaps the only recommendation is to take steps to avoid excess weight and strive for a healthy lifestyle.

“If I were a teenager or young woman who’s thinking about starting a family, I might take the evidence that obesity is dangerous more seriously if I realized that it was going to hamper my efforts to get pregnant or reduce my likelihood of having a healthy baby, or bringing a baby into this world who has got several strikes against him metabolically to start with,” Cobin said. – by Jill Rollet

PAGE BREAK

Disclosures: Brethauer, Brannigan, Cobin, Legro, Santoro and Sundaram report no relevant financial disclosures.

Click here to read the POINTCOUNTER, "Which has greater influence on childhood obesity, prenatal or postnatal environment?"