What is hypothyroidism?

The thyroid is a small gland located in the front of the neck that produces the thyroid gland hormones thyroxine (T4) and triiodothyronine (T3).ⁱ The thyroid hormones control the body's metabolism and act on virtually every cell in the body, particularly ones that produce proteins and that increase the oxygen usage of cells.ⁱⁱ They also have many downstream effects, including the following:

• Fertility  
• Hair and skin health
• Stimulating growth  
• Altering how calories are burned and food is digested 
• Regulating heart rateⁱⁱⁱ

Hypothyroidism is one of the many conditions that can affect the thyroid and causes the thyroid gland to produce less thyroid hormone than normal. This can be caused either by an issue with the thyroid gland itself (primary hypothyroidism) or with the part of the brain that makes the hormone that stimulates the thyroid gland (secondary hypothyroidism). The hormone released from the brain that stimulates the thyroid is called thyroid stimulating hormone (TSH). In primary hypothyroidism, which is most common, the TSH level is higher than normal. In the much rarer secondary hypothyroidism, the TSH level is lower than normal. In both cases, the levels of thyroid hormone T3 and T4 are lower than normal.^iv

In parts of the world where people consume sufficient iodine, approximately 0.3 to 1 percent of people have overt hypothyroidism, meaning low levels of the thyroid hormones T3 and T4.^v A larger percentage - 2 to 10 percent - have subclinical hypothyroidism or a condition where the TSH is high, but levels of T3 and T4 are normal.^vi

Certain people are more at risk for this condition. Hypothyroidism is more common in women (3 percent prevalence, 10x more common in women than in men), older individuals (5x greater odds of hypothyroidism in patients >80 years old), and in patients who have been treated for hyperthyroidism.^vii An iodine deficiency can increase a person's risk as well. Iodine is essential to the thyroid’s ability to create thyroid hormone, and insufficient iodine intake can cause birth defects in children and lead to growth retardation. Therefore, in the United States, Canada, and much of the rest of the world, salt is fortified with iodine to ensure there is enough iodine in people’s diets. In countries where iodine is not included in the diet, iodine deficiency is the most common cause of both hypo- and hyperthyroidism.^viii

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Hypothyroidism vs hyperthyroidism

While overt hypothyroidism results from insufficient thyroid hormone production, in hyperthyroidism too much thyroid hormone is produced.^ix The normal value for TSH is typically between 0.4 and 4 mIU/L (however, different laboratories may have slightly different reference ranges depending on the assay used for the test). A TSH higher than the upper limit of normal with a low free T4 indicates an underactive thyroid or primary overt hypothyroidism,^x while a TSH value of less than the lower limit of normal with a high free T4 indicates an overactive thyroid or hyperthyroidism.^xi

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What are the symptoms of hypothyroidism?

Since symptoms can mimic those of other conditions, only a health care provider can provide a definitive diagnosis. Patients with hypothyroidism may present with a variety of symptoms, including the following:  

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• Fatigue
• Weight gain despite no change in diet or activity 
• Body temperature issues, intolerance to cold  
• Constipation
• Muscle aches 
• Dry/flaky skin
• Swelling of the legs
• Swelling around the eyes
• Irregular menstrual cycles
• Thinning hair
• Heavy menstrual bleeding.^xii

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Because many patients have non-specific symptoms, a delayed diagnosis is not uncommon.

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What causes hypothyroidism?

When a person experiences reduced thyroid hormone production, it is generally caused by a problem within the thyroid gland itself.^xiii

In areas of the world such as the U.S. where iodine is sufficiently available in the diet, Hashimoto’s thyroiditis is the most common cause of not enough thyroid hormone. This is a chronic autoimmune disease, whereby the patient’s immune system develops antibodies that attack and destroy their own thyroid gland cells. This condition – as with many autoimmune diseases – is most common in women.^xiv

Another common cause of hypothyroidism is treatment for hyperthyroidism or thyroid cancer, which can include thyroid surgery, medications, radiation, or radioiodine therapy.^xv These treatments remove or shrink part of or the whole thyroid gland, thereby reducing the amount of thyroid hormone production. After this, patients typically require lifelong thyroid hormone supplementation. In addition, hypothyroidism can result from medications such as lithium (psychiatric), amiodarone (heart), and certain immune treatments for cancer.^xvi

Sometimes, inflammation of the thyroid gland can first cause hyperthyroidism and then over time may transition to hypothyroidism. This can occur in women immediately after pregnancy, as part of a condition called postpartum thyroiditis. Women with postpartum thyroiditis have hyperthyroidism for a period of time, after which the thyroid gland “burns out," and the patient develops hypothyroidism. In most cases, these changes are temporary and improve with time or resolve on their own.^xvii However, there is a high risk for this condition to recur following future pregnancies and these patients are more likely to develop hypothyroidism in the future. Because of this, it is recommended that patients with postpartum thyroiditis have TSH screened annually following their initial recovery.^xviii  While it is rare for hypothyroidism to stem from any other part of the body besides the thyroid, in <1 percent of patients with hypothyroidism, hypothyroidism can be caused by a problem in the part of the brain secreting the hormone that stimulates thyroid hormone production (secondary hypothyroidism). In this case, the brain does not produce enough TSH.^xix

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How is hypothyroidism diagnosed?

If patients have symptoms of hypothyroidism or are suffering from multiple miscarriages, their doctor may initiate a work-up. In general, hypothyroidism can be diagnosed by a simple blood test measuring the level of thyroid stimulatory hormone (TSH). In patients with primary hypothyroidism, the TSH value is typically high because the thyroid is not producing enough hormone; therefore, the brain is secreting more TSH to encourage the thyroid to produce more thyroid hormone.^xx When the TSH level is elevated, a free T4 must be measured. If the free T4 is low, this confirms the diagnosis of overt hypothyroidism. If the TSH is elevated and the free T4 is normal, this indicates subclinical hypothyroidism.

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What should the TSH level be if I am trying to conceive or considering assisted reproduction or IVF? 

Patients diagnosed with overt hypothyroidism should have their physician test and adjust as needed the dose of their thyroid hormone supplementation, to ensure that their TSH lab values return to the normal reference range. This often requires increasing or decreasing the medication being used. This is true for all non-pregnant patients, including those who are trying to conceive.  

For pregnant women, the TSH reference ranges decrease because the pregnancy hormone (hCG) can bind TSH receptors and lead to lower TSH levels while maintaining a normal level of thyroid hormone. This means that a normal TSH in pregnant patients is lower than a normal TSH in non-pregnant patients.  

For women with subclinical hypothyroidism who are trying to conceive, the cut-off TSH level for treatment is controversial. There is evidence that a TSH level above 4.0 mIU/L with a normal free T4 is associated with increased risk of miscarriage in infertile and non-infertile patients. Further, TSH values greater than 4.0 mIU/L have also been associated with decreased pregnancy rates after embryo transfer among infertile patients. Therefore, women with subclinical hypothyroidism defined as a TSH greater than 4.0 mIU/L should be treated when trying to conceive.^xxi

A more controversial topic is how to manage a TSH level between 2.5 to 4.0 mIU/L in women trying to conceive. There is insufficient evidence that a TSH level in this range is associated with infertility or miscarriage. However, some doctors recommend treating patients who are trying to conceive, especially if infertile, when the TSH is above 2.5 mIU/L. This is related to the fact the 2.5mIU/L is often used as the upper limit of normal in the first trimester once a woman achieves pregnancy. On the other hand, in most women, TSH is expected to decrease as hCG rises in pregnancy as described above so a TSH above 2.5 mIU/L may naturally fall below this threshold once a pregnancy is achieved.^xxii

In addition, many other endocrinologists, as well as the guidelines from the American Thyroid Association (ATA), do not support this cut-off value of 2.5mIU/L for those trying to conceive. A 2017 review notes that there is not enough evidence to routinely recommend treatment with levothyroxine for TSH levels 2.5 to 4.0 mIU/L.^xxiii The American Society for Reproductive Medicine states that due to the limited data for pre-conception TSH levels in this range, reasonable management options for a patient with a pre-conception TSH between 2.5 to 4.0 mIU/L includes either monitoring and treating if the level increases above 4.0 mIU/L or alternatively treating the patient to maintain a TSH less than 2.5 mIU/L.  In published studies, the evidence for an association of TSH with adverse fertility outcomes is observed at TSH levels above 4.0 mIU/L, and thus the ATA suggests that reference ranges for hypothyroidism in the general population should be applied.^xxiv

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Who should be tested for hypothyroidism?

Often, hypothyroidism develops slowly, and the typical symptoms of a problematic thyroid may not appear until severe hypothyroidism is evident. While those with actual symptoms of hypothyroidism should be tested, a physician may also recommend thyroid testing for women or couples struggling with recurrent pregnancy losses or women who do not ovulate or who have irregular or absent menstrual cycles.^xxv

A doctor may recommend TSH be tested as a standard screening test prior to starting attempts at conception even if there is no history of infertility. In particular, individuals with a family history of thyroid disease or mild hypothyroid signs or symptoms should have their TSH levels checked.^xxvi

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How does hypothyroidism impact fertility and pregnancy?

A woman with hypothyroidism can get pregnant and have a healthy pregnancy, but it may take medical intervention which may not always be successful. Maternal thyroid hormones are essential to the growth and maturation of the fetal brain because the fetal thyroid does not produce its own thyroid hormone until the 10^th week of pregnancy. Because of this, if the mother’s thyroid gland does not produce enough thyroid hormone, this can lead to spontaneous miscarriages or fetal birth defects.^xxvii Furthermore, hypothyroidism leads to changes in other hormones – such as estrogen, testosterone, prolactin, luteinizing hormone (LH), and gonadotropin releasing hormone (GnRH) - that support fertility and pregnancy. These hormonal changes may also affect fertility and maintenance of pregnancy.^xxviii

Additionally, thyroid issues can affect menstruation, as briefly noted above. For 16 percent of women with hypothyroidism, they may have light periods or the complete absence of menstruation, while 7 percent have heavy menstrual bleeding.^xxix

Underactive thyroid symptoms can also affect men. In men, hypothyroidism may affect testicular function, as the body does not produce hormones normally. As in females, hypothyroidism in males can change the levels of important hormones such as testosterone and prolactin. Hypothyroidism is also associated with low libido, erectile dysfunction, and delayed ejaculation, which can secondarily affect the ability to conceive.^xxx

Can IVF drugs cause thyroid problems?

While there is some evidence that fertility treatments may lead to an increase in TSH and asymptomatic (sub-clinical) hypothyroidism, these effects will typically resolve on their own and it is unclear what effect this has on the success of IVF.^xxxi There may be a small increased risk of thyroid cancer in women treated with clomiphene or progesterone for infertility.^xxxii

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What treatments exist and how successful are they?

Hypothyroidism is quite treatable, though not curable. Treatment involves supplementation with the thyroid hormone levothyroxine (ex. Synthroid (R), Levothroid (R), or Tirosint (R)). In terms of success rate, 15 percent of patients treated with levothyroxine do not achieve normal T3 and T4 despite TSH being in a normal range, and sometimes different dosages or formulations of medication are required. About 5 percent of patients have persistent symptoms of hypothyroidism despite normalization of thyroid hormone levels with treatment.^xxxiii

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What are the other hypothyroidism risks or complications?

Untreated hypothyroidism can lead to weight gain/obesity, shortness of breath or fatigue on exertion, or muscle weakness.^xxxiv A hypothyroid individual could also experience difficulty with memory/confusion, tingling in the extremities, constipation, changes in vision or taste, bleeding, changes in hair and skin, or kidney damage.^xxxv

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Conclusion

Hypothyroidism can take a toll on a woman’s overall health and affect their fertility and ability to sustain a pregnancy. Anyone who suspects that they are having thyroid issues should initiate a conversation with their physician in order to check thyroid levels and determine a course of treatment to alleviate both short and long-term repercussions of hypothyroidism.

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