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Subclinical Hypothyroidism—What Is It? and Could It Affect Fertility?

Thyroid hormones have a direct effect on all aspects of reproduction so being hypothyroid may be linked to infertility but this interrelationship remains uncertain.

with Maria Del Pilar Brito, MD, and Spyridoula Maraka, MD

The challenges of infertility can leave a couple feeling frustrated, especially if there is no obvious reason for their ability to conceive. When reproductive considerations are examined, one possibility may be hypothyroidism.

Sometimes blood tests will reveal subclinical hypothyroidism, a state that suggests possible dysfunction of the thyroid which may increase the risk of infertility and problems with pregnancy.

Here’s a closer look at what it means to have subclinical hypothyroidism and how it may play a role in reproductive outcomes:

Subclinical hypothyroidism means a normal T4 and a higher than normal TSH. Understanding the changes in hormone levels help to see how thyroid function is involved in pregnancy outcomes and may too affect fertility issues. Photo: Olena Troshchak @ iStock

How Can Thyroid Hormones Affect Fertility?

First a Review of Key Thyroid Hormones involved in reproduction

The thyroid, a small butterfly-shaped gland that sits at the front of the throat, produces two essential hormones: thyroxine (T4) and triiodothyronine (T3). These thyroid hormones are released in response to two other hormones:

  • Thyroxine-stimulating hormone (TSH) which is released from the pituitary gland 
  • Thyroxine-releasing hormone (TRH) released from the hypothalamus.

When the thyroid gland is healthy, as circulating blood levels of T4 and T3 increase, the release of TSH and TRH will decrease in a negative feedback loop, meaning as T4 and T3 rise and fall as TSH and TRH drop and increase. In evaluating your thyroid status, your doctor will likely take a blood sample in order to check your hormone levels of circulating T4 and TSH as indicators of your thyroid function.

Role of Thyroid Hormones in Reproductive Health

Thyroid hormones, T4 and T3, are necessary for the proper functioning of the reproductive system, including ovaries, uterus and placenta.1 In the ovaries specifically, thyroxine plays a role in the maturation of the follicles (folliculogenesis), ovulation, and of the corpus luteum.

The corpus luteum is the mass of cells left behind after ovulation, which is responsible for releasing progesterone to signal the uterine lining to thicken in anticipation of the arrival of a fertilized egg, and helps sustain a pregnancy until the fertilized ovum implants into the uterine lining.

When a woman has hypothyroidism, the ovaries may produce fewer mature follicles, prompt ovulation less often, and delay maturation of the corpus luteum. If these issues are recognized and addressed, then pregnancy usually occurs normally.1 However, the issue of hypothyroidism can continue to influence pregnancy and fetal development.

As such, if you are experiencing infertilty issues and have been diagnosed with subclinical hypothyroidism, the key is to work closely with a reproductive endocrinologist and your obstetrician. Getting pregnant, though, is the first hurdle.

Could Subclinical Hypothyroidism Increase the Risk of Infertility?

By some estimates, subclinical hypothyroidism appears in 4-8% of women of reproductive age.2 Having a low normal thyroid function means that you have a free thyroxine (fT4) level that falls within the normal range but your TSH level is above normal.

Typically this means that your TSH is higher than 4.0 mIU/L; however, there is some disagreement about the precise limits for a normal range of TSH levels3 and knowing the best levels for TSH is further complicated by pregnancy.During the first trimester, human chorionic gonadotropin (hCG) levels peak and complete with T4 for some of the same receptors. This interaction may interfere with a reliable fT4 reading.1

In addition, Maria Brito, MD, co-director of the Thyroid Center at Mount Sinai at Union Square and assistant professor of medicine at the Icahn School of Medicine at Mount Sinai in New York City tells EndocrineWeb

“Demands for thyroxine are larger in the first trimester more so than during the second or third trimesters because it is not until that time that the baby has a working thyroid. Before that, the baby is completely dependent on the mother to produce thyroid hormones.” 

Thus, in pregnant women, the upper range for TSH during the first trimester is lowered to 2.5 mIU/L, and during the 2nd and 3rd trimesters, TSH guidelines recommend an increased level of 3.0 and 3.5 mIU/L.3 In cases of infertility, some experts have advocated for the use of pregnancy TSH guideline, so some fertility specialists may diagnose a woman with subclinical hypothyroidism informed by these lower pregnancy levels.  

Subclinical Hypothyroidism When Attempting Pregnancy 

Since there is disagreement regarding TSH limits, the available research on subclincal hypothyroidism and infertility is hard to evaluate. This is because TSH limits vary widely across studies and include only a small number of patients, making it improper to act on any reported conclusions.

However, one research team led by Dr. Meng Rao, from the First Affiliated Hospital of Kunming Medical University in China, did study a large population of women who were struggling with infertility to compare those with subclincal hypothyroidism and those with normal thyroid function.4

This trial was unprecedented because of its robust sample size, and resulted in measures of markers reflecting healthy ovarian function in 2,279 normal (euthyroid) women and 289 women with subclinical hypothyroidism, all seeking treatment for infertility. The median TSH level for the women with subclinical hypothyroidism was 5.13 mIU/L, with 50% of the values falling between 3.56 and 6.70 mIU/L.4

The data from this retrospective study was gathered from patient files for four ovarian markers which are used to measure ovarian reserve:

  • Follicle-stimulating hormone (FSH), which recruits small immature (antral) follicles to the ovary
  • Antral Follicle Count (AFC), which reflects the total number of small immature follicles present in each ovary
  • AntiMüllerian Hormone (AMH), which provides an estimation of remaining viable oocytes (eggs)
  • Number of aspirated oocytes, or the number of eggs harvested for an in vitro fertilization (IVF) procedure or intracytoplasmic sperm injection (ICSI)

In the study, the women with subclinical hypothyroidism had a lower follicle count, lower AntiMullerian hormone levels, and fewer aspirated oocytes than women with normal thyroid function, suggesting that those with lower thyroid hormone levels may have a reduced ovarian reserve.

The authors reported that women with subclinical hypothyroidism who were 35 years or older had even lower ovarian reserves.4 In addition, these women had higher levels of FSH and even fewer aspirated oocytes that younger women with subclinical hypothyroidism.

Of particular importance, the study authors report finding a significant relationship between TSH levels and measures of ovarian reserve—as TSH levels increased, the levels of FSH increased, AMH levels decreased, and follicle count decreased as did the number of aspirated oocytes.4 A lower rate of ovarian reserves,seemed to occur in women with higher TSH levels, which is a telltale marker for subclinical hypothyroidism.

Should Women with Subclinical Hypothyroidism Take Levothyroxine?

While the results reported by Rao et al are intriguing, both the American Society for Reproductive Medicine (ASRM) and the American Thyroid Association (ATA) agree that there is not sufficient evidence to conclude that subclinical hypothyroidism is associated with infertility and therefore too soon to suggest that treating these women with supplemental thyroid hormone (levothyroxine) would improve or otherwise raise the rates of pregnancy.3,5

In fact, in an earlier study conducted by this same team of Chinese researchers, they found that treatment with levothyroxine (LT4) did not increase pregnancy rates in women with subclincal hypothyroidism women undergoing in vitro fertilization but did reduce the rate of miscarriage.Thus, the benefits of treating women with subclinical hypothyroidism might be associated more with pregnancy but not infertility.

Spyridoula Maraka, MD, assistant professor of internal medicine in the Division of Endocrinology and Metabolism at the University of Arkansas for Medical Sciences in Little Rock, suggests this to EndocrineWeb for any woman with subclinical hypothyroidism:

“Pregnancy is essentially a stress test for the thyroid. Although starting on LT4 treatment may not increase the chances of a woman to get pregnant, it will increase her chance to maintain normal thyroid status should she get pregnant and potentially avoid pregnancy complications.”

This is the same advice recommended in the 2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum.5

When discussing your situation with your physician, Dr. Brito suggests this: “Bringing a TSH value from 4.0mIU/L down to 2.5 mIU/L has no real down side and it could be a benefit once pregnancy occurs. In other words, it is better to be safe than sorry.”

The authors report no competing financial conflicts with regard to their involvement in conducting or discussing this study.

 

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Hypothyroidism and Hyperthyroidism During Pregnancy
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