Thyroid dysfunction is a well documented, but often overlooked, factor in both male and female infertility. It can also have severe consequences during pregnancy, leading to miscarriages, premature birth, fetal death, low birth weight, gestational hypertension and developmental problems for offspring.
It makes good clinical sense to make thyroid function screening a standard practice during preconception planning and prenatal care.
Thyroid disorders are common in the general US population, with a 2010 review finding the prevalence of thyroid disorders as follows: Hypothyroidism 4.6%, Hyperthyroidism 1.6% and Autoimmune Thyroiditis (AITD) 5.13% (Golden S, et al. J Clin Endocrinol Metab. 2009; 94(6): 1853-1878). However, hypothyroidism, in particular, remains highly under-diagnosed.
The standard reference range for thyroid stimulating hormone (TSH) varies among labs but is generally considered to be 0.5-4.0mIU/L, despite the recommendations in 2002 by the American Association of Clinical Endocrinologists (AACE) to narrow the range to a more optimal 0.3-3.0 mIU/L (AACE Medical Guidelines. Endoc Prac 2002; 8(6): 457-467). This newer reference range has particular consequence in fertility studies and for treatment guidelines during pregnancy.
The American Endocrine Society and other major international thyroid organizations have endorsed international guidelines recommending screening of pregnant women. The impact of hyper- and hypothyroid states during pregnancy is well documented in a recent paper by Alex Stagnaro-Green, MD, and colleagues (Stagnaro-Green A, et al. Thyroid 2011; 21(10): 1081-1125).
However, undiagnosed and untreated hypothyroid conditions have serious consequences for women in general. For one, subclinical hypothyroidism is a risk factor for atherosclerosis and myocardial infarction comparable to other major CVD risk factors (Hak AE, et al. Ann Intern Med 2000; 132:270-278). Regardless of pregnancy status, thorough screening for thyroid dysfunction and carefully tailored treatment can prevent a multitude of sequelae.
Hypothyroidism & Infertility
In women, a low functioning thyroid can lead to ovulatory dysfunction, especially if it is severe enough to cause a delayed response of LH to GnRH. This leads to corpus luteum inadequacy. Prolactin may be increased in these cases, due to TRH stimulation of both TSH and PRL. For this reason, women most commonly present with oligomenorrhea and amenorrhea, but some have polymenorrhea, and menorrhagia.
These menstrual irregularities are three times more common in hypothyroid women than in the general population. They are usually due to high levels of estrogen with relatively low levels of progesterone, causing breakthrough bleeding with anovulatory cycles. Some of these women also have low levels of clotting factors, which contribute to bleeding irregularities (Krassas et al.Endocr Review. 2010; (5):702-55).
Elevated TSH has been observed in 4.6% of cases of female infertility (Grassi G, et al. Gynecol Endocrinol 2001; 15:389-396). Thyroid autoimmunity also contributes to thyroid related infertility, even in the absence of elevated TSH, which logically increases the known risk. In a review of several studies, AITD was significantly more prevalent in infertile versus fertile women (Krassas et al. 2010).
Thyroid Assessment in Infertile Women
Primary hypothyroidism is characterized by low levels of available thyroid hormones (T3 and T4). This causes the TSH level to rise. Many health practitioners test thyroid function using a stand-alone TSH test, but particularly in cases of infertility it is vital to look at a more complete panel that includes TSH, FFT, and the anti-Tg and anti-TPO antibodies.
Hashimoto's (autoimmune) thyroiditis is the most common cause of hypothyroidism in the US, where iodine deficiency is uncommon. Consider testing for anti-thyroglobulin antibodies (anti-Tg) and anti-thyroid peroxidase antibodies (anti-TPO), when evaluating for hypothyroidism, especially if a patient presents with clinical symptoms but appears “euthyroid” (using the older reference ranges) on the initial TSH test. This is even more reason for adopting the newer, narrower TSH reference range: it may help to identify many at-risk women.
Hypothyroidism with ART
Infertile couples frequently resort to assisted reproductive technology (ART), usually after having had no success with other methods such as ovulation induction, endoscopic alleviation of tubal obstruction or endometriosis, and intrauterine insemination (Krassas et al. 2010). ART involves controlled ovarian hyperstimulation (COH), which downregulates the pituitary-gonadal axis and utilizes recombinant FSH to promote growth of multiple oocytes. This is followed by a high dose of hCG to cause ovulation.
The principle is to induce a high level of E2, similar to that seen in the second trimester of pregnancy, but this can have significant consequences for the thyroid. The estrogen surge increases T4-binding globulin (TBG), which increases the demand for thyroid hormone and can raise TSH levels significantly (Muller AF, et al. J Clin Endocrinol Metab. 2000; 85: 545-548). This can be problematic in women who already have AITD.
A 2004 study by Poppe et al., which followed TSH and T4 levels into the first trimester, showed that women with AITD have a markedly greater increase in TSH and a greater drop in T4 after COH, compared to those without AITD (Poppe K, et al. J Clin Endocrinol Metab. 2004; 89:3808-3812). This is an important factor to consider in ART treatment failure. High TSH levels are associated with greater rates of miscarriage and fetal death (Benhadi N, et al. Eur J Endocrinol 2009; 160: 985-991). Whether COH-related hypothyroidism remits after pregnancy ends or it propels patients into lifelong hypothyroidism is a good subject for future long-term studies.
During pregnancy, it is even more essential for a woman to have adequate thyroid hormone, as low levels can affect not only the outcome of the pregnancy, but also the health of the developing fetus. Yet subclinical hypothyroidism or “euthyroid” autoimmune thyroid disorders in pregnancy are even more easily missed, because of the normal suppression of TSH by hCG. Slight TSH increases due to thyroid dysfunction may seem within normal range unless narrower reference ranges are utilized.
Children born to women with low T4 or high TSH have shown developmental delays and significantly lower IQ (Mitchell ML and Klein RZ Eur J Endocrinol2004; 151:U45-U48). Iodine deficiency may underlie this phenomenon, since iodine requirements increase during pregnancy (Krassas et al. 2010). This disorder is being assessed further to better understand the value of screening tests throughout pregnancy. Because hypothyroid states have such potentially dire consequences on the child, it makes sense to consider testing for T4 at intervals throughout pregnancy.
It is also important to test for autoimmune antibodies, even in euthyroid patients. The presence of either TPOAb or TgAb doubles the prevalence of preterm birth in euthyroid women (Stagnaro-Green et al. 2011). Pregnancy-induced hypertension (PIH) is also associated with low thyroid function, especially if the TSH level remains elevated throughout the pregnancy (Leung AS et al Obstet Gynecol 1993; 81: 349-353).
Keep in mind that during pregnancy, autoantibody titers may be reduced even while thyroid function is decreased. This can be a confounding factor in studies of AITD in pregnancy. Reduced antibody output during pregnancy often has detrimental effects postpartum, as suppressed auto-antibodies may rebound and cause a postpartum thyroiditis.
Postpartum thyroiditis (PPTD) is one of the most common endocrine disorders in women, with prevalence between 5-9% in the general female population. Additionally, 30-50% of women with PPTD develop permanent primary hypothyroidism within 10 years (Krassas et al. 2010). One reason is that the autoimmune disease greatly reduces thyroid reserves, and the body is unable to compensate for the increased thyroid hormone requirement during pregnancy. After the immune tolerance of pregnancy, the autoantibody titers dramatically increase, creating an unexpected hypothyroid state.
PPTD can be transient or permanent, but occurs within the first year postpartum. It may also occur after a loss of pregnancy of 5 to 20 weeks’ gestation. PPTD is very easy to miss, because many of the symptoms are considered to be “expected” or “normal” postpartum manifestations. These include fatigue, palpitations, weight loss, heat intolerance, irritability and depression, all of which are easily attributed to the lack of sleep and the stress of caring for a newborn. There may be an association between PPTD and postpartum depression (Muller A, et al. Endoc Rev 2001 Oct; 22(5): 605-630), though there is not currently sufficient evidence to prove this definitively.
The role of the thyroid in reproductive function is very a broad topic, with significant clinical implications. We clearly need more research in this field, as the rates of thyroid disease in the US seem to be increasing. Better detection and treatment of thyroid problems may be a key to restoring fertility for many couples struggling to conceive, and it could potentially reduce a large number of serious complications of pregnancy.
Rhesa Napoli is a naturopathic medical student at National College of Natural Medicine, Portland, OR, with a focus on chronic diseases, especially those associated with the endocrine system. She is currently developing models to increase accessibility to affordable naturopathic healthcare.