https://imcjms.com Ibrahim Medical College Journal of Medical Science https://imcjms.com/registration/journal_full_text/67 Tue, 02 Aug 2016 11:59:22 +0000 Subclinical hypothyroidism (SCH) may be of greater clinical importance in women with “unexplained” infertility, especially when the luteal phase is inadequate, and such patients should be investigated for thyroid dysfunction in detail. To date, studies investigating the association between SCH and infertility are still based on the high serum thyroid stimulating hormone (TSH) levels while some older studies are based on the presence of an abnormal serum TSH after a thyrotropin releasing hormone (TRH) stimulation test. The recommendation in the current guidelines to treat subclinical hypothyroidism is based on minimal evidence and it is thought that with treatment the potential benefits outweigh the potential risks. Thyroxine-replacement therapy should be started in patients with SCH caused by conditions which are at high risk of progression to overt hypothyroidism. Introduction   Infertility is defined as inability to conceive after one year of regular normal sexual activity without any contraceptive measures.8 This definition was based on a study conducted on 5574 women during the period between 1946 and 1956 who had unprotected intercourse and  ultimately conceived. Among these women 85% conceived within 12 months, 72% within first 6 months, and 50% within first 3 months. Two more recent prospective population-based studies showed that 50% of healthy women having unprotected intercourse become clinically pregnant during the first two cycles, and 80–90% during the first 6 months.9,10 Though these studies may not represent the general population globally, but these indicate that under appropriate circumstances, most females are likely to conceive  early.11 The prevalence of infertility has been found stable over the recent decades.12 Causes of female infertility comprise endometriosis, tubal damage and ovulatory dysfunctions. Excepting tubal disorders which is more prevalent in Africa due to infections, all other causes of infertility have similar worldwide prevalence.15 Endometriosis is only considered as a cause of infertility when the disease exceeds stage I (as defined by the American Society for Reproductive Medicine).16 The cause of ovulatory dysfunction is further divided according to criteria established by  World Health Organization (WHO) into: hypogonadotrophic - with low level of endogenous gonadotophins (Group -I), normogonadotrophic - with lnormal endogenous gonadotophins (Group -II) and hypergonadotrophic defective ovulation (Group -III).17 Age and smoking habit of woman also constitute important prognostic factors.18-21   In a Consensus Development Conference held in September, 2002 the American Association of Clinical Endocrinologists(AACE), American Thyroid Association (ATA) and The Endocrine Society (TES) have defined SCH as a disorder with high serum thyroid-stimulating hormone (TSH) level above upper limit of the reference range with normal serum free thyroxine (FT4) level.25 The third National Health and Nutrition Examination Survey (NHANES III)26 screened 13,344 disease-free, euthyroid participants who were thyroid antibody negative. In this population, the median TSH concentration was1.39 mIU/L [95% CI: 0.45-4.12 mIU/L]. This was accepted as normal by the above mentioned consensus conference on sub clinical thyroid diseases25 and Surks et al.27  agreed with this reference range. In contrast, the National Academy of Clinical Biochemistry28 suggested 0.4–2.5 mIU/L as the normal range, while Wartofsky and Dickey29 and the AACE suggested  0.3–3.0 mIU/L  as normal.30 According to United States Preventive Services Task Force (USPSTF) Guidelines defined SCH to have high serum TSH  2.5-10 mIU/L with a normal FT4 concentration.   Evidence based literatures strongly suggest that reference range for TSH is lower throughout pregnancy,  both the lower and upper normal limit of serum TSH are decreased by about 0.1-0.2 mIU/L and 1 mIU/L respectively, compared with the customary TSH reference interval of 0.4–4.0 mIU/L in non-pregnant women. The largest decrease in serum TSH is observed during the first trimester which is transient, apparently related to hCG levels. (Table 1) Table-1: Trimester-Specific Serum TSH Reference Intervals   Sub clinical hypothyroidism (SCH) has recently been challenged. Variations of FT4 within the reference range in individual is less than that observed  in a population. These data might reflect an abnormally low FT4 value for patients who present with a mildly increased serum TSH.40,41 Many authors have proposed serum TSH 2·5 mIU/L as upper normal limit. However, there is no general agreement among the endocrinologists about the most appropriate normal (i.e. physiologically relevant) upper limit serum TSH.42 Sub clinical hypothyroidism (SCH) and infertility     Recently, Raber et al. Investigated prospectively a group of 283 women with infertility.49 All patients underwent a TRH stimulation test (SCH was defined as a serum TSH >15 mU/L). Women with a diagnosis of SCH were treated with thyroxine and followed prospectively over a 5-year period. Among these women 34% had SCH, an unusually high prevalence reflecting the specific referral pattern. Among the women who became pregnant during the follow-up period, over 25% still had SCH. Furthermore, the women who never achieved a basal serum TSH<2·5 mU/L or a TRH-stimulated TSH<20 mU/L became pregnant less frequently than those who could achieve. More frequent abortions were also observed in the women with a higher basal serum TSH (independent of the presence of autoimmunity). Arojoki et al found elevated serum TSH levels (>5·5 mU/L) in 4% women presenting with infertility for the first time.50 The prevalence of having an increased serum TSH was highest in the group with ovulatory dysfunction (6·3%). Prior to infertility examinations, 10 of 299 women were already receiving L-thyroxine for primary hypothyroidism. The incidental finding of an elevated serum TSH value in patients with infertility was therefore reduced to four among 299 women (1·3%), and this was in the range of the prevalence of SCH in the general population in Finland (2–3%). The prevalence of SCH was considerably higher in the studies based on a TRH stimulation test to detect SCH compared with the studies that were based only on the upper limit of basal serum TSH. This difference might indicate that in older studies, using less sensitive measurements of serum TSH, the actual TSH reference levels are perhaps slightly  higher in the setting of infertility. In a study, basal and TRH-stimulated TSH concentrations were measured in 834 infertile women, and 20% had abnormal results.51 Postcoital tests and spontaneous conceptions were significantly poorer in women with SCH than in controls. Staub et al.52 suggested that secondary hyperprolactinemia could be a cause of infertility in SCH women. In contrast, menstrual function in SCH patients and controls was similar, such as luteinizing hormone pulse patterns, 24-h mean serum luteinizing hormone, TSH, and prolactin concentrations.53 Lincoln et al. reported a 2.3% prevalence of elevated serum TSH concentrations in 704 women with infertility for at least 1 year. Eleven out of sixteen hypothyroid patients’ had ovulatory dysfunction. TSH values were not determined in the control group.54 Treatment interventions and guideline for subclinical/clinical hypothyroidism Two cohort studies reported on pregnancy complications for women with clinical or sub clinical hypothyroidism who were adequately, and who were not adequately treated.56,57 Not adequately treated hypothyroid women had higher TSH and a lower than normal thyroxine level, despite treatment. In the case of subclinical hypothyroidism, a TSH higher than the reference interval despite treatment was defined as not adequately treated. The first study showed no significant difference in the prevalence of gestational hypertension in 68 women not adequately treated for subclinical or clinical hypothyroidism compared with 38 women who remain still hypothyroid despite treatment (RR: 0.14, CI: 0.01–2.20: P ¼ 0.16) for clinical hypothyroidism, (RR: 0.41, CI:0.11–1.62:P¼0.21) for subclinical hypothyroidism.56 The second study reported no significant difference in Neonatal Intensive Care Unit (NICU) admissions             (RR:0.31, CI:0.08–1.2: P¼0.09). A significant difference was found in low birth weight (RR:0.31, CI: 0.11–0.92: P¼ 0.04) for 127 women with subclinical hypothyroidism with normal TSH level with levothyroxine treatment compared with 40 women with abnormal TSH levels in the first trimester despite levothyroxine treatment, while Caesarean section rates were almost similar in the two groups, respectively 27.5% and 29.1%.57 One case control study on 38 women with hypothyroidism treated with levothyroxine during pregnancy reported no significant difference in the IQ level, verbal performance or cognitive performance between the 19 children of subclinically hypothyroid mothers despite treatment and 19 children of mothers who were euthyroid with treatment.58   Severe hypothyroidism is commonly associated with failure of ovulation. Ovulation followed by pregnancy can occur in case of mild hypothyroidism. However, these pregnancies are often associated with abortions, stillbirths, or pre-maturity. 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