Aromatase inhibitor effective first-line infertility treatment in PCOS

In women with polycystic ovary syndrome, letrozole therapy offers greater chance of a successful pregnancy than clomiphene or in vitro fertilization and should be considered as a first-line therapy, according to a presenter at the annual PCOS Awareness Symposium.

In a presentation highlighting findings from several multicenter clinical trials that included women with PCOS, Richard S. Legro, MD, vice chair of research and professor of obstetrics and gynecology and public health sciences at Penn State College of Medicine, said several randomized controlled trials showed that letrozole increased the live birth rate vs. clomiphene in women with PCOS and infertility. Any data regarding rates of congenital anomalies with letrozole should be compared with the rate with clomiphene, he said, adding that no peer-reviewed data show a pattern of anomalies with use of the drug.

“For anyone who has faced this road [of infertility], we know that, increasingly, we are using IVF for everything,” Legro said, speaking at Thomas Jefferson University. “Ordinarily, if a woman doesn’t ovulate, you would think you don’t need to stick a needle, get eggs out of her ovary, inseminate them in vitro and put the embryos back. You would just give a treatment that would help the women ovulate. But obviously, there are others issues driving this.”

Richard S. Legro

IVF, Legro said, can be expensive and inconvenient, but the procedure also carries specific risks for women with PCOS, who are already at increased metabolic risk for complications.

“Currently, in the United States, the multiple pregnancy risk [with IVF] is about 30% in our most recent reporting,” Legro said. “If you have a woman at very high risk for gestational diabetes or hypertensive disorders during pregnancy, you don’t want to give that woman multiple pregnancies. You’re not helping her or the eventual baby by overloading the uterus.”

A more targeted approach

Metformin, often a first-line therapy for women with PCOS, can improve metabolic health; however, it does not improve fertility, Legro said. Aromatase inhibitors offer a more targeted approach for infertility.

“[Metformin] led us away from solely focusing on metabolic issues and instead saying, let’s focus more on getting the brain to communicate better with the ovary,” Legro said. “And all of our drugs in that area have come from breast or prostate cancer, which have a hormonal component. By blocking the inappropriate communication between the brain and the ovary, we can improve that communication to better stimulate the ovary.”

Recent research has found letrozole improved pregnancy rates by interfering with inappropriate estrogen feedback in the hypothalamus, preventing the production of estrogen, Legro said.

In a 2014 study, Legro and colleagues randomly assigned 750 women aged 18 to 40 years with PCOS, as defined by modified Rotterdam criteria, in a 1:1 ratio to treatment with letrozole or clomiphene for up to five cycles. Patients had at least one patent fallopian tube and a normal uterine cavity.

Women had more cumulative live births with letrozole (27.5%) vs. clomiphene (19.1%; P = .007), with a 1.44 (95% CI, 1.1-1.87) rate ratio for live birth.

A higher cumulative ovulation rate occurred with letrozole at 61.7% vs. clomiphene at 48.3% (P < .001).

The differences between groups were not significant for pregnancy loss (letrozole, 31.8% vs. clomiphene, 29.1%) or twin pregnancy (3.4% and 7.4%, respectively).

Letrozole offers several advantages, according to Legro. It has a shorter half-life vs. clomiphene, meaning less early pregnancy exposure and fewer cumulative effects, and has been shown to have a favorable reproductive effect vs. clomiphene, although the mechanism behind the improved pregnancy rate is unclear. Research has shown improved rates cannot be attributed to increased monofollicular ovulation or more favorable endometrial effects, he said.

In a recent meta-analysis of five randomized controlled trials comparing letrozole with clomiphene by Roque and colleagues published in Gynecological Endocrinology, researchers found an increase in live birth rates in the letrozole groups vs. clomiphene groups (RR = 1.55; 95% CI, 1.26-1.9). No between-group differences were observed for multiple pregnancies, miscarriage or ovulation rates.

“This is interesting because we want to answer, why does letrozole work?” Legro said. “Women developed the same number of follicles on both drugs. The critical thing that changed is, relative to clomiphene, the estradiol level went down and the progesterone level went up. In order of magnitude, the greatest difference was a large decrease in estrogen levels after ovulation with letrozole.”

That decrease in estrogen, Legro said, creates an ideal condition for ovulation.

“What’s unique about letrozole compared to clomiphene is you get a very high progesterone-to-estradiol ratio in the luteal phase when the pregnancy is implanting in the endometrium, and that gives a more favorable chance for implantation than when we artificially elevate the estrogen levels,” Legro said. “One of the big concerns with IVF is we have estrogen levels in the thousands, which just do not occur physiologically. So what are we doing? What does an endometrium do when you have an estradiol level that’s 10-fold higher than a normal cycle? Does that somehow inhibit implantation? I think we could argue it does.”

Adverse effects and safety

Both letrozole and clomiphene can cause adverse effects in patients, with many patients prescribed letrozole reporting fatigue and dizziness, whereas patients prescribed clomiphene often report hot flashes, Legro said. But some studies also have raised concerns regarding congenital anomalies in infants born to mothers prescribed letrozole. In the study conducted by Legro and colleagues, no significant differences were observed in overall congenital anomalies; however, four major congenital anomalies were seen with letrozole vs. one with clomiphene.

In a second randomized controlled trial, Diamond and colleagues also found no significant between-group differences for congenital anomalies for clomiphene (4.2%) and letrozole (3.6%).

“Some people thought letrozole increased the rate for birth defects, and this led to a black box warning, and unfortunately, there were never any publications to support this,” Legro said. “There have been a number of publications done since [the warning] ... that found similar congenital anomaly rates between clomiphene and letrozole.

“Congenital anomaly rates are higher with infertility treatments than on assisted conception,” he said. “The rate of anomaly is comparable between letrozole and clomiphene, and no data support an increased risk for birth defects.”

Prepregnancy steps

Preconception clinical care can be key to achieving a successful pregnancy, Legro said. Women with PCOS who smoke, for example, are 30% less likely to ovulate vs. nonsmokers. In women with PCOS and obesity, lifestyle modification has been shown to improve ovulation rates in women prescribed clomiphene vs. pretreatment with oral contraceptives.

“The weight loss gave them about a 30% to 50% improvement in ovulation,” he said. “We also found a significant trend in improvement in live births in patients who lost weight. This regimen improves ovulation rates with clomiphene. We’re looking forward to other groups replicating [the results].”

Before starting any infertility therapy, Legro said, health care providers should counsel patients regarding common adverse effects, adverse events and any teratogenicity of aromatase inhibitors in the treatment of reproductive disorders. – by Regina Schaffer

Disclosure: Legro reports consulting for AstraZeneca, Bayer, Clarus Therapeutics, Euroscreen, JDS, Kindex, Millendo, Sprout and Takeda, and receiving research funding from AstraZeneca, Ferring, the NIH and Tobacco Settlement Funds PA.

In women with polycystic ovary syndrome, letrozole therapy offers greater chance of a successful pregnancy than clomiphene or in vitro fertilization and should be considered as a first-line therapy, according to a presenter at the annual PCOS Awareness Symposium.

In a presentation highlighting findings from several multicenter clinical trials that included women with PCOS, Richard S. Legro, MD, vice chair of research and professor of obstetrics and gynecology and public health sciences at Penn State College of Medicine, said several randomized controlled trials showed that letrozole increased the live birth rate vs. clomiphene in women with PCOS and infertility. Any data regarding rates of congenital anomalies with letrozole should be compared with the rate with clomiphene, he said, adding that no peer-reviewed data show a pattern of anomalies with use of the drug.

“For anyone who has faced this road [of infertility], we know that, increasingly, we are using IVF for everything,” Legro said, speaking at Thomas Jefferson University. “Ordinarily, if a woman doesn’t ovulate, you would think you don’t need to stick a needle, get eggs out of her ovary, inseminate them in vitro and put the embryos back. You would just give a treatment that would help the women ovulate. But obviously, there are others issues driving this.”

Richard S. Legro

IVF, Legro said, can be expensive and inconvenient, but the procedure also carries specific risks for women with PCOS, who are already at increased metabolic risk for complications.

“Currently, in the United States, the multiple pregnancy risk [with IVF] is about 30% in our most recent reporting,” Legro said. “If you have a woman at very high risk for gestational diabetes or hypertensive disorders during pregnancy, you don’t want to give that woman multiple pregnancies. You’re not helping her or the eventual baby by overloading the uterus.”

A more targeted approach

Metformin, often a first-line therapy for women with PCOS, can improve metabolic health; however, it does not improve fertility, Legro said. Aromatase inhibitors offer a more targeted approach for infertility.

“[Metformin] led us away from solely focusing on metabolic issues and instead saying, let’s focus more on getting the brain to communicate better with the ovary,” Legro said. “And all of our drugs in that area have come from breast or prostate cancer, which have a hormonal component. By blocking the inappropriate communication between the brain and the ovary, we can improve that communication to better stimulate the ovary.”

Recent research has found letrozole improved pregnancy rates by interfering with inappropriate estrogen feedback in the hypothalamus, preventing the production of estrogen, Legro said.

In a 2014 study, Legro and colleagues randomly assigned 750 women aged 18 to 40 years with PCOS, as defined by modified Rotterdam criteria, in a 1:1 ratio to treatment with letrozole or clomiphene for up to five cycles. Patients had at least one patent fallopian tube and a normal uterine cavity.

Women had more cumulative live births with letrozole (27.5%) vs. clomiphene (19.1%; P = .007), with a 1.44 (95% CI, 1.1-1.87) rate ratio for live birth.

A higher cumulative ovulation rate occurred with letrozole at 61.7% vs. clomiphene at 48.3% (P < .001).

The differences between groups were not significant for pregnancy loss (letrozole, 31.8% vs. clomiphene, 29.1%) or twin pregnancy (3.4% and 7.4%, respectively).

Letrozole offers several advantages, according to Legro. It has a shorter half-life vs. clomiphene, meaning less early pregnancy exposure and fewer cumulative effects, and has been shown to have a favorable reproductive effect vs. clomiphene, although the mechanism behind the improved pregnancy rate is unclear. Research has shown improved rates cannot be attributed to increased monofollicular ovulation or more favorable endometrial effects, he said.

In a recent meta-analysis of five randomized controlled trials comparing letrozole with clomiphene by Roque and colleagues published in Gynecological Endocrinology, researchers found an increase in live birth rates in the letrozole groups vs. clomiphene groups (RR = 1.55; 95% CI, 1.26-1.9). No between-group differences were observed for multiple pregnancies, miscarriage or ovulation rates.

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“This is interesting because we want to answer, why does letrozole work?” Legro said. “Women developed the same number of follicles on both drugs. The critical thing that changed is, relative to clomiphene, the estradiol level went down and the progesterone level went up. In order of magnitude, the greatest difference was a large decrease in estrogen levels after ovulation with letrozole.”

That decrease in estrogen, Legro said, creates an ideal condition for ovulation.

“What’s unique about letrozole compared to clomiphene is you get a very high progesterone-to-estradiol ratio in the luteal phase when the pregnancy is implanting in the endometrium, and that gives a more favorable chance for implantation than when we artificially elevate the estrogen levels,” Legro said. “One of the big concerns with IVF is we have estrogen levels in the thousands, which just do not occur physiologically. So what are we doing? What does an endometrium do when you have an estradiol level that’s 10-fold higher than a normal cycle? Does that somehow inhibit implantation? I think we could argue it does.”

Adverse effects and safety

Both letrozole and clomiphene can cause adverse effects in patients, with many patients prescribed letrozole reporting fatigue and dizziness, whereas patients prescribed clomiphene often report hot flashes, Legro said. But some studies also have raised concerns regarding congenital anomalies in infants born to mothers prescribed letrozole. In the study conducted by Legro and colleagues, no significant differences were observed in overall congenital anomalies; however, four major congenital anomalies were seen with letrozole vs. one with clomiphene.

In a second randomized controlled trial, Diamond and colleagues also found no significant between-group differences for congenital anomalies for clomiphene (4.2%) and letrozole (3.6%).

“Some people thought letrozole increased the rate for birth defects, and this led to a black box warning, and unfortunately, there were never any publications to support this,” Legro said. “There have been a number of publications done since [the warning] ... that found similar congenital anomaly rates between clomiphene and letrozole.

“Congenital anomaly rates are higher with infertility treatments than on assisted conception,” he said. “The rate of anomaly is comparable between letrozole and clomiphene, and no data support an increased risk for birth defects.”

Prepregnancy steps

Preconception clinical care can be key to achieving a successful pregnancy, Legro said. Women with PCOS who smoke, for example, are 30% less likely to ovulate vs. nonsmokers. In women with PCOS and obesity, lifestyle modification has been shown to improve ovulation rates in women prescribed clomiphene vs. pretreatment with oral contraceptives.

“The weight loss gave them about a 30% to 50% improvement in ovulation,” he said. “We also found a significant trend in improvement in live births in patients who lost weight. This regimen improves ovulation rates with clomiphene. We’re looking forward to other groups replicating [the results].”

Before starting any infertility therapy, Legro said, health care providers should counsel patients regarding common adverse effects, adverse events and any teratogenicity of aromatase inhibitors in the treatment of reproductive disorders. – by Regina Schaffer

Disclosure: Legro reports consulting for AstraZeneca, Bayer, Clarus Therapeutics, Euroscreen, JDS, Kindex, Millendo, Sprout and Takeda, and receiving research funding from AstraZeneca, Ferring, the NIH and Tobacco Settlement Funds PA.