http://informahealthcare.com/gye ISSN: 0951-3590 (print), 1473-0766 (electronic) Gynecol Endocrinol, 2015; 31(2): 116–118 ! 2014 Informa UK Ltd. DOI: 10.3109/09513590.2014.964200
INFERTILITY AND FT3
The role of free triiodothyronine in pathogenesis of infertility in levothyroxine-treated women with thyroid autoimmunity – a preliminary observational study
Gynecol Endocrinol Downloaded from informahealthcare.com by Yale Dermatologic Surgery on 02/04/15 For personal use only.
Jerzy Sowin´ski1, Nadia Sawicka-Gutaj1, Paweł Gutaj2, and Marek Ruchała1 1
Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, Poznan, Poland and Department of Obstetrics and Women’s Diseases, Poznan University of Medical Sciences, Poznan, Poland
2
Abstract
Keywords
Introduction: The aim of this study was to analyze the possible role of free triiodothyronine (FT3) in infertility and in levothyroxine-treated (LT4) euthyroid women with Hashimoto thyroiditis (HT). Methods: It is an observational retrospective case control study. Twenty one euthyroid women with HT on LT4 replacement therapy and a medical history of idiopathic infertility were included into the study. To achieve higher FT3 level, the dose of LT4 was increased in every patient. Fifteen fertile women with HT on LT4 replacement therapy served as a control group. Results: At baseline in the study group mean thyroid stimulating hormone (TSH) level was 1.96 mU/ml ± 0.84 mU/ml and mean FT3 was 4.07 pmol/l ± 0.78 pmol/l. The mean TSH level after the increase of LT4 was 0.60 mU/ml ± 0.45 mU/ml (p50.0001), and the mean FT3 was 5.12 pmol/l ± 0.77 pmol/l (p ¼ 0.0001). Baseline TSH in the study group was higher than in controls (p50.0001) and baseline FT3 in the study group was lower than in controls (p ¼ 0.0003). Conclusions: Relatively low levels of FT3 in women with HT on LT4 replacement therapy may contribute to higher infertility rates.
Female infertility, Hashimoto disease, hypothyroidism, thyroxine
Introduction Data concerning the influence of thyroid autoimmunity (TAI) on the pregnancy rate are conflicting. Some authors suggest that the prevalence of infertility, understood as ‘‘a disease of the reproductive system defined by the failure to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse’’, is significantly higher among women with TAI [1–5]. In contrast, many studies have not found the significant association between TAI and infertility, despite a trend for higher TAI prevalence in infertile women, which is frequently associated with polycystic ovarian syndrome (PCOS) and endometriosis [6–8]. In addition, according to several clinical observations, the risk of early miscarriage is increased in women with TAI [9–11]. Higher rate of hypothyroidism including its subclinical phase is one of the potential mechanisms directly contributing to infertility in women with TAI [8]. The higher pregnancy achievement was observed in infertile women with subclinical hypothyroidism (SH) with levothyroxine (LT4) treatment as compared with infertile women with SH without LT4 [1,8,11]. In the second hypothesis, TAI is suggested to reflect general immune imbalance responsible for higher infertility and
Address for correspondence: Jerzy Sowin´ski, Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, Poznan, Poland. Tel: +48618691330. Fax: +48 61 869 16 82. E-mail: [email protected]
History Received 30 March 2014 Accepted 8 September 2014 Published online 30 September 2014
miscarriage rate despite adequate thyroid hormone production. Women with TAI are also older as compared with fertile controls, and advanced maternal age is a well known risk factor for infertility and pregnancy loss [12]. Since several metabolic changes lead to increase requirement of thyroid hormone production in pregnant women, significant efforts to find the normal range for thyroid stimulating hormone (TSH) levels in pregnancy have been implemented [13–15]. The rates of female patients diagnosed with TAI and treated with LT4 are increasing. The aim of this study was to analyze the possible role of free triiodothyronine (FT3) in infertility, in LT4-treated euthyroid women with HT.
Methods It is an observational case control study. A retrospective analysis was undertaken in twenty one LT4-treated infertile women (mean age ± SD 31 ± 4 years; range 25–39 years) with chronic autoimmune thyroiditis. All subjects underwent careful evaluation and other causes of infertility such as a male factor, ovulatory disorders, endometriosis, pelvic or tubal abnormalities and hyperprolactinemia were excluded in order to diagnose idiopathic infertility. The study group was diagnosed with hypothyroidism and treated with LT4 for at least 12 months. Therapy monitoring was based on regular physical examination and TSH monitoring in every female. However, despite having TSH levels within the norm range, all of the infertile women had relatively low serum
The role of free triiodothyronine in infertility
Gynecol Endocrinol Downloaded from informahealthcare.com by Yale Dermatologic Surgery on 02/04/15 For personal use only.
DOI: 10.3109/09513590.2014.964200
FT3 levels, in some patients even below the norm range. To achieve higher level of FT3 a dose of LT4 was increased in every patient. TSH and FT3 levels were tested in every female before and 6–8 weeks after the increase of LT4 dose. Titers of antithyroperoxidase antibodies (TPOAbs) were measured before the increase of LT4 dose. All women conceived within three months and delivered at term (mean birth weight ± SD 3454 g ± 524 g; median 1-minute Apgar score was 9 (min–max 7–10)). Fifteen randomly selected fertile women (mean age ± SD 30 ± 4 years; range 25–37 years) with HT on LT4 replacement therapy served as a control group. Their laboratory tests had been performed up to three months before they conceived. TSH and FT3 were measured using the electrochemiluminescence technique in Cobas E 601 (Warsaw, Poland) (norm ranges: TSH 0.27–4.2 mU/l; FT3 3.93–7.70 pmol/l). TPOAbs were measured by radioimmunoassay (norm range:534 IU/ml). Statistical analysis Comparison of initial and final results in the study group was performed by paired t test (when data follow normal distribution) or Wilcoxon test (when data did not follow normal distribution). Comparison of analyzed parameters between two groups was performed by independent samples t test (when data follow normal distribution) or Mann–Whitney test (when data did not follow normal distribution). Normality was analyzed by D’Agostino–Pearson test. P-value less than 0.05 indicated statistical significance. Statistical analyses were performed using MedCalc for Windows, version 12.1.3.0 (MedCalc Software, Mariakerke, Belgium). Results were presented as means and standard deviations (SD). Ethical approval The study was approved by the Poznan University of Medical Sciences Ethical Committee.
Results At baseline in the study group mean TSH level was 1.96 mU/ ml ± 0.84 mU/ml and mean FT3 was 4.07 pmol/l ± 0.78 pmol/l (Figures 1 and 2). These serum levels were achieved by the daily administration of 87 mg ± 41 mg of LT4. TPOAbs were elevated in every female. Mean TPOAbs titer was 149 IU/ml ± 58 IU/ml.
Figure 1. TSH levels at baseline (TSH_1) and after the increase of levothyroxine dose (TSH_2). The small dots are data points; SD error bars are shown.
117
The daily dose of LT4 was increased to 126 mg ± 40 mg (p50.0001). The mean TSH level after the increase of LT4 was 0.60 mU/ml ± 0.45 mU/ml, and the mean FT3 was 5.12 pmol/ l ± 0.77 pmol/l (Figures 1 and 2). There was extremely significant difference between the FT3 levels (p ¼ 0.0001) and TSH levels (p50.0001) before and after the increase of LT4 dose. In the control group mean TSH level was 0.52 mU/l ± 0.38 mU/l and mean FT3 level was 5.07 pmol/l ± 0.68 pmol/l. All women were positive for TPOAbs (mean ± SD 318 IU/ml ± 432 IU/ml). Controls were administered with mean LT4 dose of 124 mg ± 45 mg. The study and the control groups did not differ in age and in TPOAbs (p ¼ 0.2078 and p ¼ 0.0952, respectively). Baseline TSH in the study group was higher than in controls (p50.0001) and baseline FT3 in the study group was lower than in controls (p ¼ 0.0003). After the increase of LT4 dose, TSH and FT3 levels were similar in both groups (p ¼ 0.5638 and p ¼ 0.9106, respectively). Initial LT4 dose in the infertile group was lower than in controls (p ¼ 0.0144), after the correction it was similar to LT4 dose in fertile controls (p ¼ 0.9201).
Discussion This study presents a new data to the possible relationship between TAI, LT4-treated hypothyroidism and reproductive failure. Since adequate LT4 treatment in hypothyroid infertile women is always necessary, this study suggests that TSH monitoring may be insufficient to assess the efficacy of thyroid hormone replacement therapy. All infertile females had relatively low FT3 levels, despite having TSH indicating for adequate dose of LT4. The increase of daily dose of LT4 led to higher FT3 levels and they conceived. Moreover, we compared them with fertile women who were also treated with LT4. It is an observational retrospective study, but we made some interesting observations worth to be shared. Although an underlying pathogenic mechanism of the findings remains unclear, recent studies may provide an explanation. Thyroid hormone receptors (TRa1, TRb1 and TSHR) are expressed in endometrium [16]. Moreover, Aghajanova et al. found the highest level of expression of TH receptors in receptive endometrium and proved that thyroid hormones influence endometrial function [17]. Transcripts required for thyroid hormone synthesis and metabolism such as thyroid peroxidase, thyroglobulin, 5’ deiodinase type 2 (DIO2) were also identified in human endometrium suggesting possible TH production [16].
Figure 2. Free triiodothyronine levels at baseline (FT3_1) and after the increase of levothyroxine dose (FT3_2). The small dots are data points; SD error bars are shown.
Gynecol Endocrinol Downloaded from informahealthcare.com by Yale Dermatologic Surgery on 02/04/15 For personal use only.
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J. Sowin´ski et al.
Similarly, expression of TSH and thyroid hormone receptors was revealed in human oocytes, in physiological and nonphysiological (during in-vitro fertilization programme IVF) conditions indicating for direct TH action in human ovaries [17,18]. Moreover, DIO2 and 50 deiodinase type 3 (DIO3) transcripts were determined in granulosa cells suggesting their ability to control local hormone activity through deiodination of T4 to either T3 or, to lesser extent, to reverse T3 [17]. Zhang et al. have measured the concentration of FT3 and FT4 in follicular fluid from eight patients undergoing IVF. In three infertile women FT3 concentrations were below serum normal range. In remaining five infertile women FT3 concentrations were relatively low but still within normal range. In contrast, follicular total and free thyroxine concentrations were comparable with serum normal levels [18,19]. The clinical observations may be analyzed in a broader context of interplay of TSH and FT3 in patients under LT4 therapy. In a recently published paper, Hoermann et al. observed disparity between TSH and peripherally active FT3 concentration in LT4-treated subjects, querying diagnostic reliability of TSH measurement as a gold standard for assessment of euthyroidism restoration in this group of patients [20]. It must be emphasized here that the study has some limitations. Taken together, it has retrospective design with the small sample size. However, this clinical observation should prompt further investigations evaluating causal pathways for infertility in context of FT3 concentration in LT4 replacement therapy.
Conclusions In conclusion, available data suggest that FT3 influences ovarian follicle development and maturation. Since normal reproductive function does not exist without adequate circulating level of FT3, relatively low levels of FT3 could cause infertility. Furthermore, increase of FT3 could restore the normal female reproductive function. TSH monitoring may be insufficient in some LT4-treated patients, and assessment of FT3 might be considered in LT4-treated infertile woman.
Acknowledgements We would like to give special thanks to Chris Kerrigan for language revision of this article.
Declaration of interest The authors report no declaration of interest.
References 1. Gerhard I, Becker T, Eggert-Kruse W, et al. Thyroid and ovarian function in infertile women. Hum Reprod 1991;6:338–45.
Gynecol Endocrinol, 2015; 31(2): 116–118
2. Kaider AS, Kaider BD, Janowicz PB, Roussev RG. Immunodiagnostic evaluation in women with reproductive failure. Am J Reprod Immunol 1999;42:335–46. 3. Zegers-Hochschild F, Adamson GD, de Mouzon J, et al. International Committee for Monitoring Assisted Reproductive Technology (ICMART) and the World Health Organization (WHO) revised glossary of ART terminology. Fertil Steril 2009; 92:1520–4. 4. Krassas GE, Poppe K, Glinoer D. Thyroid function and human reproductive health. Endocr Rev 2010;31:702–55. 5. Evers AS. Paracrine interactions of thyroid hormones and thyroid stimulation hormone in the female reproductive tract have an impact on female fertility. Front Endocrinol (Lausanne) 2012;3:50. 6. Poppe K, Glinoer D, Van Steirteghem A, et al. Thyroid dysfunction and autoimmunity in infertile women. Thyroid 2002;12: 997–1001. 7. Petta CA, Arruda MS, Zantut-Wittmann DE, Benetti-Pinto CL. Thyroid autoimmunity and thyroid dysfunction in women with endometriosis. Hum Reprod 2007;22:2693–7. 8. Abalovich M, Mitelberg L, Allami C, et al. Subclinical hypothyroidism and thyroid autoimmunity in women with infertility. Gynecol Endocrinol 2007;235:279–83. 9. Poppe K, Glinoer D. Thyroid autoimmunity and hypothyroidism before and during pregnancy. Hum Reprod Update 2003,9:149–61. 10. Krassas GE. Thyroid disease and female reproduction. Fertil Steril 2000;74:1063–107. 11. Negro R, Mangieri T, Coppola L, et al. Levothyroxine treatment in thyroid peroxidase antibody-positive women undergoing assisted reproduction technologies: a prospective study. Hum Reprod 2005; 20:1529–33. 12. Heffner LJ. Advanced maternal age – how old is too old. N Engl J Med 2004;351:1927–9. 13. Hubalewska-Dydejczyk A, Bandurska-Stankiewicz E, Bar-Andziak E, et al. Management of thyroid diseases during pregnancy. Endokrynol Pol 2011;64:362–81. 14. De Groot L, Abalovich M, Alexander EK, et al. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2012; 97:2543–65. 15. Sowin´ski J, Czupryniak L, Milewicz A, et al. Recommendations of the Polish Society of Endocrinology and Polish Diabetes Association for the management of thyroid dysfunction in type 1 and type 2 diabetes. Endokrynol Pol 2013;64:73–7. 16. Catalano RD, Critchley HO, Heikinheimo O, et al. Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod 2007;13:641–54. 17. Aghajanova L, Stavreus-Evers A, Lindeberg M, et al. Thyroidstimulating hormone receptor and thyroid hormone receptors are involved in human endometrial physiology. Fertil Steril 2011;95: 230–7. 18. Zhang SS, Carrillo AJ, Darling DS. Expression of multiple thyroid hormone receptor mRNAs in human oocytes, cumulus cells and granulosa cells. Mol Hum Reprod 1997;3:555–62. 19. Wakim AN, Polizotto SL, Buffo MJ, et al. Thyroid hormones in human follicular fluid and thyroid hormone receptors in human granulosa cells. Fertil Steril 1993;59:1187–90. 20. Hoermann R, Midgley JE, Larisch R, Dietrich JW. Is pituitary TSH an adequate measure of thyroid hormone-controlled homoeostasis during thyroxine treatment? Eur J Endocrinol 2013;168:271–80.
INFERTILITY AND FT3
The role of free triiodothyronine in pathogenesis of infertility in levothyroxine-treated women with thyroid autoimmunity – a preliminary observational study
Gynecol Endocrinol Downloaded from informahealthcare.com by Yale Dermatologic Surgery on 02/04/15 For personal use only.
Jerzy Sowin´ski1, Nadia Sawicka-Gutaj1, Paweł Gutaj2, and Marek Ruchała1 1
Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, Poznan, Poland and Department of Obstetrics and Women’s Diseases, Poznan University of Medical Sciences, Poznan, Poland
2
Abstract
Keywords
Introduction: The aim of this study was to analyze the possible role of free triiodothyronine (FT3) in infertility and in levothyroxine-treated (LT4) euthyroid women with Hashimoto thyroiditis (HT). Methods: It is an observational retrospective case control study. Twenty one euthyroid women with HT on LT4 replacement therapy and a medical history of idiopathic infertility were included into the study. To achieve higher FT3 level, the dose of LT4 was increased in every patient. Fifteen fertile women with HT on LT4 replacement therapy served as a control group. Results: At baseline in the study group mean thyroid stimulating hormone (TSH) level was 1.96 mU/ml ± 0.84 mU/ml and mean FT3 was 4.07 pmol/l ± 0.78 pmol/l. The mean TSH level after the increase of LT4 was 0.60 mU/ml ± 0.45 mU/ml (p50.0001), and the mean FT3 was 5.12 pmol/l ± 0.77 pmol/l (p ¼ 0.0001). Baseline TSH in the study group was higher than in controls (p50.0001) and baseline FT3 in the study group was lower than in controls (p ¼ 0.0003). Conclusions: Relatively low levels of FT3 in women with HT on LT4 replacement therapy may contribute to higher infertility rates.
Female infertility, Hashimoto disease, hypothyroidism, thyroxine
Introduction Data concerning the influence of thyroid autoimmunity (TAI) on the pregnancy rate are conflicting. Some authors suggest that the prevalence of infertility, understood as ‘‘a disease of the reproductive system defined by the failure to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse’’, is significantly higher among women with TAI [1–5]. In contrast, many studies have not found the significant association between TAI and infertility, despite a trend for higher TAI prevalence in infertile women, which is frequently associated with polycystic ovarian syndrome (PCOS) and endometriosis [6–8]. In addition, according to several clinical observations, the risk of early miscarriage is increased in women with TAI [9–11]. Higher rate of hypothyroidism including its subclinical phase is one of the potential mechanisms directly contributing to infertility in women with TAI [8]. The higher pregnancy achievement was observed in infertile women with subclinical hypothyroidism (SH) with levothyroxine (LT4) treatment as compared with infertile women with SH without LT4 [1,8,11]. In the second hypothesis, TAI is suggested to reflect general immune imbalance responsible for higher infertility and
Address for correspondence: Jerzy Sowin´ski, Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, Poznan, Poland. Tel: +48618691330. Fax: +48 61 869 16 82. E-mail: [email protected]
History Received 30 March 2014 Accepted 8 September 2014 Published online 30 September 2014
miscarriage rate despite adequate thyroid hormone production. Women with TAI are also older as compared with fertile controls, and advanced maternal age is a well known risk factor for infertility and pregnancy loss [12]. Since several metabolic changes lead to increase requirement of thyroid hormone production in pregnant women, significant efforts to find the normal range for thyroid stimulating hormone (TSH) levels in pregnancy have been implemented [13–15]. The rates of female patients diagnosed with TAI and treated with LT4 are increasing. The aim of this study was to analyze the possible role of free triiodothyronine (FT3) in infertility, in LT4-treated euthyroid women with HT.
Methods It is an observational case control study. A retrospective analysis was undertaken in twenty one LT4-treated infertile women (mean age ± SD 31 ± 4 years; range 25–39 years) with chronic autoimmune thyroiditis. All subjects underwent careful evaluation and other causes of infertility such as a male factor, ovulatory disorders, endometriosis, pelvic or tubal abnormalities and hyperprolactinemia were excluded in order to diagnose idiopathic infertility. The study group was diagnosed with hypothyroidism and treated with LT4 for at least 12 months. Therapy monitoring was based on regular physical examination and TSH monitoring in every female. However, despite having TSH levels within the norm range, all of the infertile women had relatively low serum
The role of free triiodothyronine in infertility
Gynecol Endocrinol Downloaded from informahealthcare.com by Yale Dermatologic Surgery on 02/04/15 For personal use only.
DOI: 10.3109/09513590.2014.964200
FT3 levels, in some patients even below the norm range. To achieve higher level of FT3 a dose of LT4 was increased in every patient. TSH and FT3 levels were tested in every female before and 6–8 weeks after the increase of LT4 dose. Titers of antithyroperoxidase antibodies (TPOAbs) were measured before the increase of LT4 dose. All women conceived within three months and delivered at term (mean birth weight ± SD 3454 g ± 524 g; median 1-minute Apgar score was 9 (min–max 7–10)). Fifteen randomly selected fertile women (mean age ± SD 30 ± 4 years; range 25–37 years) with HT on LT4 replacement therapy served as a control group. Their laboratory tests had been performed up to three months before they conceived. TSH and FT3 were measured using the electrochemiluminescence technique in Cobas E 601 (Warsaw, Poland) (norm ranges: TSH 0.27–4.2 mU/l; FT3 3.93–7.70 pmol/l). TPOAbs were measured by radioimmunoassay (norm range:534 IU/ml). Statistical analysis Comparison of initial and final results in the study group was performed by paired t test (when data follow normal distribution) or Wilcoxon test (when data did not follow normal distribution). Comparison of analyzed parameters between two groups was performed by independent samples t test (when data follow normal distribution) or Mann–Whitney test (when data did not follow normal distribution). Normality was analyzed by D’Agostino–Pearson test. P-value less than 0.05 indicated statistical significance. Statistical analyses were performed using MedCalc for Windows, version 12.1.3.0 (MedCalc Software, Mariakerke, Belgium). Results were presented as means and standard deviations (SD). Ethical approval The study was approved by the Poznan University of Medical Sciences Ethical Committee.
Results At baseline in the study group mean TSH level was 1.96 mU/ ml ± 0.84 mU/ml and mean FT3 was 4.07 pmol/l ± 0.78 pmol/l (Figures 1 and 2). These serum levels were achieved by the daily administration of 87 mg ± 41 mg of LT4. TPOAbs were elevated in every female. Mean TPOAbs titer was 149 IU/ml ± 58 IU/ml.
Figure 1. TSH levels at baseline (TSH_1) and after the increase of levothyroxine dose (TSH_2). The small dots are data points; SD error bars are shown.
117
The daily dose of LT4 was increased to 126 mg ± 40 mg (p50.0001). The mean TSH level after the increase of LT4 was 0.60 mU/ml ± 0.45 mU/ml, and the mean FT3 was 5.12 pmol/ l ± 0.77 pmol/l (Figures 1 and 2). There was extremely significant difference between the FT3 levels (p ¼ 0.0001) and TSH levels (p50.0001) before and after the increase of LT4 dose. In the control group mean TSH level was 0.52 mU/l ± 0.38 mU/l and mean FT3 level was 5.07 pmol/l ± 0.68 pmol/l. All women were positive for TPOAbs (mean ± SD 318 IU/ml ± 432 IU/ml). Controls were administered with mean LT4 dose of 124 mg ± 45 mg. The study and the control groups did not differ in age and in TPOAbs (p ¼ 0.2078 and p ¼ 0.0952, respectively). Baseline TSH in the study group was higher than in controls (p50.0001) and baseline FT3 in the study group was lower than in controls (p ¼ 0.0003). After the increase of LT4 dose, TSH and FT3 levels were similar in both groups (p ¼ 0.5638 and p ¼ 0.9106, respectively). Initial LT4 dose in the infertile group was lower than in controls (p ¼ 0.0144), after the correction it was similar to LT4 dose in fertile controls (p ¼ 0.9201).
Discussion This study presents a new data to the possible relationship between TAI, LT4-treated hypothyroidism and reproductive failure. Since adequate LT4 treatment in hypothyroid infertile women is always necessary, this study suggests that TSH monitoring may be insufficient to assess the efficacy of thyroid hormone replacement therapy. All infertile females had relatively low FT3 levels, despite having TSH indicating for adequate dose of LT4. The increase of daily dose of LT4 led to higher FT3 levels and they conceived. Moreover, we compared them with fertile women who were also treated with LT4. It is an observational retrospective study, but we made some interesting observations worth to be shared. Although an underlying pathogenic mechanism of the findings remains unclear, recent studies may provide an explanation. Thyroid hormone receptors (TRa1, TRb1 and TSHR) are expressed in endometrium [16]. Moreover, Aghajanova et al. found the highest level of expression of TH receptors in receptive endometrium and proved that thyroid hormones influence endometrial function [17]. Transcripts required for thyroid hormone synthesis and metabolism such as thyroid peroxidase, thyroglobulin, 5’ deiodinase type 2 (DIO2) were also identified in human endometrium suggesting possible TH production [16].
Figure 2. Free triiodothyronine levels at baseline (FT3_1) and after the increase of levothyroxine dose (FT3_2). The small dots are data points; SD error bars are shown.
Gynecol Endocrinol Downloaded from informahealthcare.com by Yale Dermatologic Surgery on 02/04/15 For personal use only.
118
J. Sowin´ski et al.
Similarly, expression of TSH and thyroid hormone receptors was revealed in human oocytes, in physiological and nonphysiological (during in-vitro fertilization programme IVF) conditions indicating for direct TH action in human ovaries [17,18]. Moreover, DIO2 and 50 deiodinase type 3 (DIO3) transcripts were determined in granulosa cells suggesting their ability to control local hormone activity through deiodination of T4 to either T3 or, to lesser extent, to reverse T3 [17]. Zhang et al. have measured the concentration of FT3 and FT4 in follicular fluid from eight patients undergoing IVF. In three infertile women FT3 concentrations were below serum normal range. In remaining five infertile women FT3 concentrations were relatively low but still within normal range. In contrast, follicular total and free thyroxine concentrations were comparable with serum normal levels [18,19]. The clinical observations may be analyzed in a broader context of interplay of TSH and FT3 in patients under LT4 therapy. In a recently published paper, Hoermann et al. observed disparity between TSH and peripherally active FT3 concentration in LT4-treated subjects, querying diagnostic reliability of TSH measurement as a gold standard for assessment of euthyroidism restoration in this group of patients [20]. It must be emphasized here that the study has some limitations. Taken together, it has retrospective design with the small sample size. However, this clinical observation should prompt further investigations evaluating causal pathways for infertility in context of FT3 concentration in LT4 replacement therapy.
Conclusions In conclusion, available data suggest that FT3 influences ovarian follicle development and maturation. Since normal reproductive function does not exist without adequate circulating level of FT3, relatively low levels of FT3 could cause infertility. Furthermore, increase of FT3 could restore the normal female reproductive function. TSH monitoring may be insufficient in some LT4-treated patients, and assessment of FT3 might be considered in LT4-treated infertile woman.
Acknowledgements We would like to give special thanks to Chris Kerrigan for language revision of this article.
Declaration of interest The authors report no declaration of interest.
References 1. Gerhard I, Becker T, Eggert-Kruse W, et al. Thyroid and ovarian function in infertile women. Hum Reprod 1991;6:338–45.
Gynecol Endocrinol, 2015; 31(2): 116–118
2. Kaider AS, Kaider BD, Janowicz PB, Roussev RG. Immunodiagnostic evaluation in women with reproductive failure. Am J Reprod Immunol 1999;42:335–46. 3. Zegers-Hochschild F, Adamson GD, de Mouzon J, et al. International Committee for Monitoring Assisted Reproductive Technology (ICMART) and the World Health Organization (WHO) revised glossary of ART terminology. Fertil Steril 2009; 92:1520–4. 4. Krassas GE, Poppe K, Glinoer D. Thyroid function and human reproductive health. Endocr Rev 2010;31:702–55. 5. Evers AS. Paracrine interactions of thyroid hormones and thyroid stimulation hormone in the female reproductive tract have an impact on female fertility. Front Endocrinol (Lausanne) 2012;3:50. 6. Poppe K, Glinoer D, Van Steirteghem A, et al. Thyroid dysfunction and autoimmunity in infertile women. Thyroid 2002;12: 997–1001. 7. Petta CA, Arruda MS, Zantut-Wittmann DE, Benetti-Pinto CL. Thyroid autoimmunity and thyroid dysfunction in women with endometriosis. Hum Reprod 2007;22:2693–7. 8. Abalovich M, Mitelberg L, Allami C, et al. Subclinical hypothyroidism and thyroid autoimmunity in women with infertility. Gynecol Endocrinol 2007;235:279–83. 9. Poppe K, Glinoer D. Thyroid autoimmunity and hypothyroidism before and during pregnancy. Hum Reprod Update 2003,9:149–61. 10. Krassas GE. Thyroid disease and female reproduction. Fertil Steril 2000;74:1063–107. 11. Negro R, Mangieri T, Coppola L, et al. Levothyroxine treatment in thyroid peroxidase antibody-positive women undergoing assisted reproduction technologies: a prospective study. Hum Reprod 2005; 20:1529–33. 12. Heffner LJ. Advanced maternal age – how old is too old. N Engl J Med 2004;351:1927–9. 13. Hubalewska-Dydejczyk A, Bandurska-Stankiewicz E, Bar-Andziak E, et al. Management of thyroid diseases during pregnancy. Endokrynol Pol 2011;64:362–81. 14. De Groot L, Abalovich M, Alexander EK, et al. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2012; 97:2543–65. 15. Sowin´ski J, Czupryniak L, Milewicz A, et al. Recommendations of the Polish Society of Endocrinology and Polish Diabetes Association for the management of thyroid dysfunction in type 1 and type 2 diabetes. Endokrynol Pol 2013;64:73–7. 16. Catalano RD, Critchley HO, Heikinheimo O, et al. Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod 2007;13:641–54. 17. Aghajanova L, Stavreus-Evers A, Lindeberg M, et al. Thyroidstimulating hormone receptor and thyroid hormone receptors are involved in human endometrial physiology. Fertil Steril 2011;95: 230–7. 18. Zhang SS, Carrillo AJ, Darling DS. Expression of multiple thyroid hormone receptor mRNAs in human oocytes, cumulus cells and granulosa cells. Mol Hum Reprod 1997;3:555–62. 19. Wakim AN, Polizotto SL, Buffo MJ, et al. Thyroid hormones in human follicular fluid and thyroid hormone receptors in human granulosa cells. Fertil Steril 1993;59:1187–90. 20. Hoermann R, Midgley JE, Larisch R, Dietrich JW. Is pituitary TSH an adequate measure of thyroid hormone-controlled homoeostasis during thyroxine treatment? Eur J Endocrinol 2013;168:271–80.
