With Pouneh K. Fazeli, MD, and Tamara Wexler, MD, PhD
Subclinical hypothyroidism may have an association with unexplained infertility in women, according to a team of researchers from Harvard Medical School who believe the finding could point to an “economical first step” in treating people trying to conceive.1
“We were surprised by the strength of the association. Importantly, our results held up even after controlling for variables that may affect TSH levels including body mass index (BMI) and age,” Pouneh K. Fazeli, MD, a neuroendocrinologist at Harvard Medical School, and senior author told EndocrineWeb.
“I think the strength of our study was the fact that our population was very carefully selected. We did not include anyone with a history of abnormal levels of thyroid-stimulating hormone (TSH) and all of the patients included in our study had normal fertility evaluations, except that patients in the control group had a male partner with a very low sperm count,” Dr. Fazeli said.
Although previous work has linked severe hypothyroidism to difficulty in conceiving,2 this study is the first to show that even slightly depressed levels of thyroid hormone may impair the ability to become pregnant.1
The researchers determined that low thyroid function was twice as common among women with unexplained infertility as it was among those without the condition. The study can be accessed online ahead of print in the Journal of Clinical Endocrinology & Metabolism.
Between 7% and 15.5% of women of reproductive age in the United States experience infertility, which is considered the inability to conceive a child after 12 months of sex without use of birth control, according to the Centers for Disease Control and Prevention.3 The source of the difficulty was identifiable for most of these women; for roughly 10%-30% the infertility is unexplained.3
The link between thyroid hormone and female fertility is well-documented. Laboratory data show that the hormone plays an important role in the proper development and implantation of eggs. Data also indicate that infertility affects nearly half of women with Hashimoto’s thyroiditis and Graves’ disease, both of which are marked by low thyroid function.
The American Thyroid Association recommends that physicians evaluating women for infertility assess TSH levels for severe abnormalities. However, no such guidance exists for infertile women with thyroid function that falls within the normal range.
For the new study, the researchers, led by Tahereh Orouji Jokar, MD, a neuroendocrinologist at Massachusetts General Hospital and Harvard Medical School, both in Boston, assessed levels of thyroid-stimulating hormone (TSH) in 187 women with unexplained infertility, as well as 52 with no evidence cause of infertility other than having a partner with absent or poor sperm. The women were treated at Mass General between 2000 and 2012.
The researchers used a cut-off of TSH levels of at least 2.5 mIU/L as their definition of subclinical hypothyroidism.That threshold is somewhat lower than the upper limit of normal for most TSH assays, which ranges between 4.5 and 5 mIU/L, according to the researchers. However, some experts believe the true normal range tops out at the lower level.
“The problem with lowering the cut-off to 2.5 though is that we will dramatically increase the number of people diagnosed with an underactive thyroid and we don’t have data demonstrating negative consequences of a TSH greater than 2.5,” said Pouneh K. Fazeli, MD, a neuroendocrinologist at Harvard Medical School, and senior author of the study.
“The goal of this study was to figure out if high-normal TSH levels do potentially negatively impact women who are trying to conceive,” said Dr. Fazeli.
Levels of TSH were significantly higher in women with unexplained infertility than in women whose partners had severe male factor infertility (1.95 mIU/L vs. 1.66 mIU/L),1 according to the researchers. This pattern held after accounting for age, body mass index (BMI) and smoking status, they noted. The researchers also assessed levels of prolactin, which is linked to fertility, but found no difference between the two groups of patients.
However, the researchers acknowledged that their findings do not establish causality, or necessitate a change in recommendations for clinicians.
“Based on these data, we can not recommend thyroid hormone replacement at all as this was a cross-sectional study which showed an association between unexplained infertility and higher TSH levels,” Dr. Fazeli said, “Before treatment with thyroid supplementation can be recommended, further studies will need to be done to see if treatment with thyroid hormone replacement improves pregnancy outcomes.”
The Harvard research team hopes to conduct such a study in the future to see if treatment with thyroid hormone improves time to conception in this patient population.
Tamara Wexler, MD, PhD, clinical assistant professor at New York University School of Medicine in New York City, told EndocrineWeb, “I feel it is reasonable to test TSH and free T4 levels in women who are pursuing fertility, though currently, normal range results are not typically treated before pregnancy.”
Dr. Wexler said that her perspective is in line with recommendations from the Endocrine Society4 while other organizations including the American Congress of Obstetricians and Gynecologists (ACOG)5 and the U.S. Preventive Services Task Force discourage universal screening even during pregnancy.
“ACOG, in fact, recently strengthened its recommendation not to test all pregnant women, citing a lack of consistent and clear evidence linking subclinical hypothyroidism to adverse outcomes,” she said.
Dr. Wexler remains interested in the question of whether mild elevations in prolactin influence fertility.
“This was not addressed in the study by Jokar et al, as only women with normal prolactin levels [<20] were included in the analysis. However, there is good reason to investigate a link between infertility and mild elevations in prolactin, as well as TSH levels,” said Dr. Wexler, “That said, management decisions—whether to treat—cannot be based on association alone, and no causal link has been established.”