Subclinical hypothyroidism may play a role in some cases of unexplained infertility, a new study suggested.
Women with unexplained infertility had significantly higher median levels of thyroid-stimulating hormone (TSH) compared to a control group of women with infertility of a known cause (1.95 mIU/L versus 1.66 mIU/L; P=0.003), reported Pouneh Fazeli, MD, of Harvard Medical School in Boston, and colleagues.
Nearly twice as many women with unexplained infertility had TSH levels of 2.5 mIU/L or higher compared with the control group (26.9% versus 13.5%; P<0.05), Fazeli's group said online in the Journal of Clinical Endocrinology & Metabolism.
The findings remained significant after controlling for age, body-mass index (BMI), and smoking status. Fazeli and colleagues also examined levels of prolactin, but prolactin levels did not differ significantly between the two groups, they said.
“Importantly, all of the subjects in this study had TSH levels within the normal, pre-pregnancy reference range, suggesting that even mild variations of thyroid dysfunction within the normal range may be an important factor in fertility in women who have no known cause for their infertility,” Fazeli’s group wrote.
“Since we now know from our study that there is an association between TSH levels at the high end of the normal range and unexplained infertility, it is possible that a high-normal TSH level may negatively impact women who are trying to get pregnant,” Fazeli said in a statement. “This could open up new avenues for possible treatments. The next step will be to see if lowering TSH levels will help this group conceive.”
Approximately 10%-30% of infertile couples have unexplained or idiopathic infertility, which is defined as infertility in the setting of regular ovulation, tubal patency, a normal uterine cavity, and normal semen analysis. Unexplained infertility is associated with significant emotional and economic costs, Fazeli and colleagues said.
Previous studies have suggested that elevated TSH levels, a sign of an underactive thyroid, affect fertility. However, there is no consensus on the definition of subclinical hypothyroidism in non-pregnant women who are attempting to conceive. “Subclinical hypothyroidism is defined as an elevated TSH level in the setting of normal thyroid hormone levels, but what the upper limit of normal should be for TSH is controversial,” the study authors said.
One study, based on data from the National Health and Nutrition Examination Survey, suggested an upper limit of 6.10 mIU/L. Another study, based on data from the national Academy of Clinical Biochemistry, put the upper limit at 2.5 mIU/L. Current guidelines from the American Thyroid Association provide an upper limit of 4 mIU/L, the study authors said.
“Furthermore, current guidelines do not recommend treating women with subclinical hypothyroidism, who are attempting to conceive naturally, with thyroid hormone replacement for the purposes of improving the likelihood of conception,” they said.
The cross-sectional study included 187 women age 18-39 with unexplained infertility who were evaluated at Partners HealthCare Systems hospitals in Boston from 2000 to 2012. Only women with regular menstrual cycles, a normal fertility evaluation, and normal TSH levels were included. Women with a history of hypo- or hyperthyroidism were excluded. All diagnostic and laboratory testing was done as part of routine clinical care.
For a control group, the investigators chose 57 women with infertility of a known cause — male partners with low sperm counts. These women were not proven to be fertile on their own, the study authors noted. “It is possible that some of the women in the severe male factor group would have been classified as having unexplained infertility had they been with a partner with a normal semen profile. Therefore, we believe that the fact that we found a difference in TSH levels, despite this choice of control group, only adds to the strength of our findings,” they said.
The main limitation of the study was that it relied on medical records and therefore was limited to laboratory tests that were done for clinical purposes, the authors said. Thyroid hormone and thyroid antibody levels were not measured in most of the participants.
“In conclusion, TSH levels are significantly higher in a population of women without known thyroid dysfunction and with unexplained infertility as compared to a control group. The fact that nearly 27% of women with unexplained infertility have TSH levels ≥2.5 mIU/L as compared to 13.5% of women in the control group suggests that mild abnormalities in thyroid function may potentially contribute to some cases of unexplained infertility,” Fazeli and colleagues said.
“It also raises the question of whether treatment with thyroid hormone replacement for individuals with TSH levels ≥2.5 mIU/L may be an economical first step in treating unexplained infertility,” they added. “Especially for this population for whom early use of IVF [in-vitro fertilization]– a resource intensive treatment – has been shown to result in higher conception rates.”
The study was funded by the National Institutes of Health and the Claflin Distinguished Scholar Award.
No study authors disclosed financial relationships.