TSH Levels and Unexplained Infertility: A Review of Research​

By: Rafael Victorio, Jr, DO

Director’s Note: The relationship between thyroid dysfunction and infertility is well established in the literature. Yet, this research specifically investigated TSH levels among women with unexplained infertility and their impact in that unique population. Former FACTS elective student, Dr. Rafael Victorio, Jr, summarized the study titled, “Higher TSH Levels within the Normal Range are Associated with Unexplained Infertility.” [1] In particular, the authors explored the link between subclinical hypothyroidism and unexplained infertility. Among women and couples struggling with infertility, charting with fertility awareness-based methods (FABMs) provides objective data that enables medical professionals to conduct targeted evaluations that facilitate diagnosis and treatment. Please visit the FACTS website to learn more about this evidence-based, modern approach.

Introduction

Infertility affects 7-15% of reproductive aged women in the U.S. It is defined as an inability to conceive after 12 months of regular unprotected intercourse. Among women with infertility, 10-30% have unexplained infertility (UI); they are unable to conceive even though they have regular ovulation, tubal patency, and a normal uterine cavity, and their partners have normal semen analysis. Many of these couples choose in vitro fertilization (IVF), which is the most expensive form of treatment.

“Among women with infertility, 10-30% have unexplained infertility; they are unable to conceive even though they have regular ovulation, tubal patency, and a normal uterine cavity, and their partners have normal semen analysis.”

Although hyperprolactinemia and thyroid dysfunction are known causes of infertility, normal range thyroid function and prolactin levels have not been implicated in increased risk of infertility. There is no consensus on the definition of subclinical hypothyroidism in nonpregnant women who are trying to conceive. Subclinical hypothyroidism is defined as an elevated TSH in the setting of normal thyroid hormone levels, but the upper limit remains controversial. A TSH level ≥ 2.5 has been suggested based on data showing that 95% of people without thyroid autoimmunity and with no personal or family history of thyroid disease have a TSH at or below this level, while levels higher than this lead to poor obstetrical outcomes. According to the authors of this 2018 publication, existing guidelines established a TSH level of 4 as the upper limit of normal in first trimester women. [1] The 2017 guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and the postpartum period provide a thorough review of this topic. [2]

The authors hypothesized women with unexplained infertility would have higher TSH and prolactin levels compared to a control group of women who had a normal infertility evaluation and partners who were azoospermic or severely oligospermic.

Methodology

The authors chose data on female patients from the Research Patient Data Registry of Partners HealthCare system between the ages of 18 and 39 without menstrual disorders who presented for infertility. Inclusion criteria included those who were infertile with appropriate exposure to sperm, inadequate exposure to sperm due to male azoospermia or severe oligospermia. Women also had normal uterine cavity examination, menstrual cycle day 3 FSH ≤ 10 alongside estradiol level ≤ 80, TSH ≤ 5 (normal range), and prolactin ≤ 20. Women were excluded who had a history of hypothyroidism or hyperthyroidism, high prolactin, low BMI (< 18.5), pregnancy loss, endocrine disorder or abnormalities associated with reproduction. Labs were drawn and statistical analysis was then performed.

Results

Median TSH levels were significantly greater in the UI group than in the severe male factor group (control). The median TSH for the UI group was 1.95 and that for the severe male factor group was 1.66. When controlled for BMI and age, variables associated with TSH in previous studies, TSH levels remained significantly higher in the UI group. Smoking is associated with lower TSH levels but there was no significant difference between the smoking habits in the two groups, and TSH levels in the UI group remained significantly higher compared to the male factor group. Nearly twice the percentage of women who had TSH ≥ 2.5 were part of the UI group compared to the severe male factor group (26.9% vs. 13.5%; P < 0.05). Prolactin levels were similar between the two groups (10.4 vs. 11, UI vs. control).

“Median TSH levels were significantly greater in the unexplained infertility group.”

 Discussion

In this study, women who had unexplained infertility had significantly higher TSH levels than the control group of women who had a normal fertility evaluation except for severe male factors affecting fertility. Nearly twice the number of women with UI compared to the control group had TSH levels ≥ 2.5. These numbers were all within the normal range, which suggests even mild variations in thyroid function impact fertility in women who have no known cause for their infertility. Given that proof of fecundity was not required in the severe male factor group, there was likely bias toward the null hypothesis, as some of the women in that group may have been classified as having UI if their male partners had normal semen profiles. This strengthens the findings because there was still a significant difference in TSH levels between the two groups.

“These numbers were all within the normal range, which suggests even mild variations in thyroid function impact fertility in women who have no known cause for their infertility.”

Multiple variables affect prolactin levels. Thus, it is possible there was a difference in prolactin between the two groups, but they may have been unable to control enough of these variables to detect a difference. A question remains of whether treating subclinical hypothyroidism would be an appropriate first step in the treatment algorithm of unexplained infertility.

References

[1] Orouji Jokar T, Fourman LT, Lee H, Mentzinger K, Fazeli PK. Higher TSH Levels within the Normal Range are Associated with Unexplained Infertility. J Clin Endocrinol Metab. 2018;103(2):632-639. doi:10.1210/jc.2017-02120.
[2] Alexander EK, Pearce EN, Brent GA, et al. 2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum [published correction appears in Thyroid. 2017 Sep;27(9):1212]. Thyroid. 2017;27(3):315-389. doi:10.1089/thy.2016.0457.

ABOUT THE AUTHOR

Rafael Victorio, Jr, DO

Rafael Victorio, Jr, DO is a PGY-1 anesthesiology resident and recent graduate of Arizona College of Osteopathic Medicine (COM) in Glendale, AZ. He completed his undergraduate and graduate degrees in biochemistry at the University of California, Riverside. He was president of the Medical Students for Choice club at Arizona COM and a board member of a family planning non-profit while in medical school.