Reproductive Hormone and Thyroid Hormone Profile in Polycystic Ovarian Syndrome

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1 Article ID: WMC ISSN Reproductive Hormone and Thyroid Hormone Profile in Polycystic Ovarian Syndrome Corresponding Author: Dr. Kiran Dahiya, Associate Professor, Department of Biochemistry, Pt. B.D. Sharma PGIMS. - India Submitting Author: Dr. Kiran Dahiya, Associate Professor, Department of Biochemistry, Pt. B.D. Sharma PGIMS. - India Article ID: WMC Article Type: Research articles Submitted on:05-jun-2012, 03:59:28 AM GMT Article URL: Subject Categories:ENDOCRINOLOGY Published on: 05-Jun-2012, 01:43:41 PM GMT Keywords:Polycystic ovary syndrome, Reproductive hormones, Thyroid profile How to cite the article:dahiya K, Sachdeva A, Singh V, Dahiya P, Singh R, Dhankhar R, Ghalaut P, Malik I. Reproductive Hormone and Thyroid Hormone Profile in Polycystic Ovarian Syndrome. WebmedCentral ENDOCRINOLOGY 2012;3(6):WMC Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License(CC-BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Source(s) of Funding: None Competing Interests: None Webmedcentral > Research articles Page 1 of 11

2 Reproductive Hormone and Thyroid Hormone Profile in Polycystic Ovarian Syndrome Author(s): Dahiya K, Sachdeva A, Singh V, Dahiya P, Singh R, Dhankhar R, Ghalaut P, Malik I Abstract Polycystic ovarian syndrome (PCOS) is associated with a derangement in reproductive hormones and its clinical features resemble those with thyroid insufficiency. Therefore, this study was conducted on 50 newly diagnosed patients of PCOS and their serum samples were analysed for follicle stimulating hormone (FSH), leutinizing hormone (LH), estradiol, progesterone, testosterone, thyroid stimulating hormone (TSH), free and total T 3 and T 4. The patients of PCOS were found to be suffering form hypothyroidism as was evident by increased TSH and decsreased free and tolal T 3 and T 4 levels. Thus, thyroid profile analysis may help in providing a better insight into symptomatology and treatment of PCOS. Introduction Polycystic ovarian syndrome (PCOS) is a disorder characterized by oligomenorrhoea or amenorrhea with clinical or laboratory evidence of hyperandrogenemia (1). Polycystic ovaries are defined as the presence of twelve or more follicles in each ovary measuring 2-9 mm and /or increased ovarian volume greater than 10 ml. Most cycles fail to lead to the emergence of dominant follicle that releases an oocyte on a monthly basis. Although follicle development occasionally proceeds to ovulation in affected patients, development of the follicle to only its initial growth stage is common. The hyperandrogenemic state is believed to be a cause of incomplete follicular development (2). PCOS is a common endocrinopathy in reproductive age group and is commonly associated with obesity, menstrual irregularity, insulin resistance and infertility (3). Various therapeutic modalities for PCOS include lifestyle modification, combined oral contraceptive pills, androgen receptor antagonists and insulin-lowering medications (4,5). Thyroid gland dysfunction leading to hypothyroidism is a common disorder affecting women more often than men. The clinical features of hypothyroidism also include weight gain, menstual irregularities and infertility (6). An association has been reported between PCOS and hypothyroidism. Most of the times hypothyroidism is subclinical and diagnosed first time during evaluation of PCOS (7,8). Tri-iodothyronine (T 3 ) and thyroxine (T 4 ) circulate in blood bound to carrier proteins which are T 4 binding globulin (TBG), T 4 binding prealbumin (TBPA) and albumin. Approximately 99.97% of T 4 and 99.7 % of T 3 is in bound form and only a small fraction of these hormones circulate unbound and is free for biological activity (9). Thus, to reach the actual diagnosis and to assess the thyroid function, free fraction of these hormones is essential. Therefore, this study was planned to estimate total and free T 3 and T 4 and thyroid stimulating hormone (TSH) in patients of PCOS. Methods This study was conducted on 50 newly diagnosed patients of PCOS according to Rotterdam consensus diagnostic criteria before starting any treatment. Only infertile patients in an age group of years and presenting with other features of PCOS were enrolled for the study. Patients presenting with two or more of the following features were selected: 1. Oligomenorrhoea and/ or anovulation 2. Clinical and/ or biochemical signs of hyperandrogenism 3. Polycystic ovaries Patients of any other chronic illness or thyroid disorders or on any hormonal medication were excluded. Fifty age matched healthy females were taken as controls. The selected patients were subjected to detailed clinical history including menstrual history and thorough clinical examination. After obtaining the informed consent, venous blood samples of these patients were collected on the second day of menstrual cycle under all aseptic conditions. Serum was separated and analysed for leutinising hormone (LH), follicle stimulating hormone (FSH), Testosterone, estradiol, progesterone, free T4 (FT4), free T3 (FT3) and TSH on chemiluminometer (Advia Centaur CP, Siemens) and total T3 and T4 using radioimmunoassay technique. Body mass index (body weight in Kg/ height in meter squared) was also calculated for all the subjects. The results were statistically compared using SPSS version 17.0 and expressed as mean ±standard deviation. Webmedcentral > Research articles Page 2 of 11

3 Results Out of 50 patients, 20 patients were in the age group of years, 20 patients were in years, 10 were in the age group of years. The mean age of PCOS patients was 27.48±4.22 years and that for controls was 28.28±3.55 years. The serum levels of various hormones and BMI are shown in table1. Discussion The present study shows a state of hypothyroidism in the patients of PCOS which is obvious by raised levels of TSH and decreased levels of total and free T3 and T4 as compared to healthy females (p<0.001). PCOS patients were found to have increased levels of LH, FSH, estradiol and testosterone though the increase in the levels of FSH was not statistically significant (p>0.05). The levels of progesterone were significantly decreased in these patients (p<0.001) Exposure of ovaries to high LH concentration during the phase of follicular growth is deleterious to the developing oocyte. LH penetrates the follicle and causes premature completion of the oocyte maturation and reduces its chances of fertilization and implantation. Estimation of FSH is also a direct method to assess ovarian reserve which is an indicator of reproductive potential (10,11). TSH is the most sensitive indicator of hypothyroidism. The prevalence of hypothyroidism in reproductive age group is upto 4 % and it is associated with a broad spectrum of reproductive disorders ranging from menstrual irregularities to infertilty and abortions (12). Thyroid responsivity by the ovaries could be explained by the presence of the thyroid hormone receptors on human oocytes. TSH also affects estrogen metabolism and decreases production of sex hormone binding globulin (8,9,13). Serum testosterone levels were found to be increased in PCOS patients with hypothyroidism. This may be explained as hypothyroidism reduces sex hormone binding globulin and increases free testosterone. This free testosterone is responsible for most of the features of PCOS like hirsutism, infertility, polycystic ovaries, acne etc (14,15). PCOS patients were found to have increased estrogen levels as compared to controls. This increased estrogen dominance may increase the levels of TBG and may mask the activity of free thyroid hormones. Thus, there may be associated clinical features of hypothyroidism which generally overlap with features of PCOS (16). Levels of progesterone were found to be decreased in patients of PCOS. Low progesterone levels produce a stimulatory effect of estrogen on the immune system (16). The hypothyroidism associated with PCOS is generally found to be due to Hashimoto s thyroiditis, an autoimune disease of the thyroid gland (7). Conclusion(s) Thus, a variety of disturbance in reproductive hormone profile is found to be associated with a state of hypothyroidism. As the features of both PCOS and hypothyroidism are overlapping and an association between these two disease states is not uncommon, therefore, thyroid profile should be analysed along with the reproductive hormonal profile which may help in better understanding of the etiology and management of PCOS. References 1. Lindholm A, Andersson L, Eliasson M, Bixo M, Sundstrom-Poromaa I. Prevalence of symptoms associated with polycystic ovary syndrome. Int J Gynaecol Obstet 2008; 102: Yildiz BO, Azziz R. The adrenal and polycystic ovary syndrome. Rev Endocr Metab Disord 2007; 8: Frank S. Polycystic ovary syndrome. N Engl J Med 1995; 333: Badawy et al. Treatment options for polycystic ovary syndrome. International Journal of Women s Health 2011:3; David H Geller etal. State of the Art Review: Emerging Therapies: The Use of Insulin Sensitizers in the Treatment of Adolescents with Polycystic Ovary Syndrome (PCOS). Int J Pediatr Endocrinol 2011; 2011(1):9. 6. Arojoki M, Jokimaa AM, Juuti A, Koshiken P, Irjala K, Antilla L. Hypothyroidism among infertlile women in Finland. Gynecol Endocrinol 2000; 14: Janssen OE, Mehlmauer N, Hahn S et al. High prevalence of autoimmune thyroiditis in patients with polycystic ovary syndrome. Eur J Endocrinol 2004; 150: Poppe K, Velkeniers B, Glinoer D. Thyroid disease and female reproduction. Clin Endocrinol 2007; 66: Krassas GE. Thyroid disease and female reproduction. Fertil Steril 2000; 74 (6): Homburg R. Adverse effects of leutinizing hormone on fertility: fact or fantasy. Baillieres Clin Obstet Gynaecol 1998; 12 (4): Webmedcentral > Research articles Page 3 of 11

4 11. Levi AJ, Raynault MF, Bergh PA, Drews MR, Miller BT, Scott RT Jr. Reproductive outcome in patients with diminished ovarian reserve. Fertil Steril 2001; 76 (4): Poppe K, Glinoer D. Thyroid autoimmunity and hypothyroidism before and during pregnancy. Hum Reprod update 2003; 9: Thomas R, Reid RL. Thyroid disease and reproductive dysfunction: a review. Obst Gynae 1987; 70 (5): Azziz R, Carmina E, Dewailly D, Diamanti- Kandarakis E, Escobar- Morreale HF et al. Positions statement: Criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: An androgen excess society guideline. J Clin Endocrinol Metab 2006; 91: Schuring AN, Schulte N, Sonntag B, Kiesel L. Androgens and Insulin- Two key players in Polycystic Ovary Syndrome. Gyn?kol Geburtshilfliche Rundsch 2008; 48: Yildiz BO, Azziz R. The adrenal and polycystic ovary syndrome. Rev Endocr Metab Disord 2007; 8: Webmedcentral > Research articles Page 4 of 11

5 Illustrations Illustration 1 Table 1 BMI and serum levels of reproductive and thyroid hormones (mean±sd) Controls PCOS patients p Value Number BMI (Kg/m 2 ) 22.89± ±3.24 <0.001 LH (miu/ml) 5.64± ±3.76 <0.001 FSH (miu/ml) 6.34± ±2.34 >0.05 Testosterone (ng/dl) 34.12± ±6.98 <0.001 Estradiol (pg/ml) 113± ±12.34 <0.001 Progesterone (ng/ml) 0.94± ±0.012 <0.001 FT 3 (pg/ml) 3.02± ±0.06 <0.001 FT 4 (ng/dl) 0.97± ±0.03 <0.001 Total T 3 (ng/dl) ± ±6.54 <0.001 Total T 4 (μg/dl) 8.56± ±0.76 <0.001 TSH (μiu/ml) 2.76± ±2.16 <0.001 Webmedcentral > Research articles Page 5 of 11

6 Reviews Review 1 Review Title: Reproductive Hormone and Thyroid Hormone Profile in Polycystic Ovarian Syndrome Posted by Lead Faculty Dr. Daniel B Williams on 19 Jun :24:15 PM GMT What are the main claims of the paper and how important are they?: The paper claims that thyroid hormone levels as well as female gonadal steroid levels are irregular in polycystic ovarian syndrome. These hormones are in addition to the already established androgen and insulin concentrations abnormalities. The claim of abnormal gonadal steroids is not novel; the thyroid hormone abnormality is more novel. The hypothesis of the paper is weak; the author did not predict in which way the levels would be abnormal (high or low) which I do believe he could have done from his introduction. I thought jumping from PCOS symptomology to hypothyroidism was a bit of a stretch. There was no string written link there. It does not mean that link does not exist; it was not put into the introduction, The evidence and numbers are strong and clear, but the sample number is low. In addition I assume all his subjects were from the same ethnic (genetic) background. If a protocol is provided, for example for a randomized controlled trial, are there any important deviations from it? If so, have the authors explained adequately why the deviations occurred? There were no deviations. The methods used commercially available kits, and proper statistics so the methods look valid. The subjects were controlled well. The sample number is small. Needs to be replicated in larger population and in different ethnic groups. Needs to be replicated in larger population and in different ethnic groups. Rating: 5 Comment: NA Competing interests: No. Invited by the author to make a review on this article? : No Have you previously published on this or a similar topic?: No Experience and credentials in the specific area of science: Experience in the actions of hormones. Taught classes in endocrinology. How to cite: Williams D.Reproductive Hormone and Thyroid Hormone Profile in Polycystic Ovarian Syndrome[Review of the article 'Reproductive Hormone and Thyroid Hormone Profile in Polycystic Ovarian Syndrome ' by ].WebmedCentral 1970;3(6):WMCRW Webmedcentral > Research articles Page 6 of 11

7 Review 2 Review Title: Verification of the relationship among the reproductive hormones and thyroid dysfunction in polycystic ovarian syndrome. Posted by Faculty Dr. Pradip K Sarkar on 09 Jun :43:06 AM GMT What are the main claims of the paper and how important are they?: This manuscript addresses an important issue of the relationship of the reproductive hormones and associated thyroid dysfunction in polycystic ovarian syndrome. The findings described in the manuscript are interesting and possess publication for the better understanding of the etiology and management of polycystic ovarian syndrome. This paper validates previously published paper in this area. Relationship among reproductive hormones and thyroid dysfunction with polycystic ovarian syndrome has been described elsewhere in literature as evidenced by PubMed search. However, addressing the following minor comments with corrections will benefit towards the betterment of the scientific approach of the manuscript and its readability to the relevant scientific community. This claim is not novel. It validates previously publsihed papers by other authors. Ref: (1) doi: /2012/492803; (2) Eur J Endocrinol Mar;150(3): Previously published literature are not well compared and discussed with the context of present problem. Results supports and validates previously published papers by other authors. If a protocol is provided, for example for a randomized controlled trial, are there any important deviations from it? If so, have the authors explained adequately why the deviations occurred? No deviation is noticed. Experimental methodolgy and analyses are not described in detail so that other investigators can reproduce it. Additional experiemnts to assay thyroixine binding proteins would have been beneficial to interprete the results better, but it is not needed to draw conclusion in the present paper. Additional experiemnts to assay thyroixine binding proteins would have been beneficial to interprete the results better, but it is not needed to draw conclusion in the present paper. Rating: 5 Comment: Title: The title appropriately reflects the research performed. Abstract: The abstract is nicely written. However, the following minor comments are provided below: Paragraph 1, line 7: leutinizing should be spelled correctly as luteinizing. Paragraph 1, line 10: form should be corrected as from Introduction: Paragraph 1, line 4: Authors are defining polycystic ovaries and mentioning measurement of ovaries as 2 mm. Is this 2 mm size describing the diameter or the radius of the size of the ovaries? It is not clear. Inclusion of this information would be beneficial to understand it better. Paragraph 1, line 7: Webmedcentral > Research articles Page 7 of 11

8 Methods: Authors mentions about the cycle. It is understood that it is reproductive cycle. However, mentioning this would clarify this in a better manner to the readers. Along with TBG, TBPA, and albumin thyroid hormones are also bound to transthyretin in blood. Plasma concentrations of transthyretin are actually higher than TBG or TBPA. This additional information would be helpful to the readers. According to the goal of this article inclusion of some background information about the reproductive hormones also would enrich this section. It is only emphasizing about thyroid hormones. At the end of the introduction section this intends to study thyroid hormone profiles. However, intention of this article to measure also the reproductive hormones and indeed reproductive hormones were measured and tabulated as data. Hence, the authors should also mention about the assay of reproductive hormones along with thyroid hormones. This information in this section is lacking. Paragraph 2, line 11: Correctly check the spelling for the word leutinising. Results: Results of the hormone levels are shown in table 1. However changes in the levels of the hormones have not been described in the results section and should have been described in detail in this section. Some data for the reproductive hormone levels are not in consistent with previously published data by other authors. This inconsistency has not been discussed in this manuscript (ref: doi: /2012/492803). Discussion: Paragraph 1 describes the results of the levels of hormones. This portion should preferably be included in the result section. This section is expected to discuss the results obtained with relevant references and explain. Data on BMI is shown and described in the result section and in table 1. However, this data has not been discussed. Paragraph 2, line 3 is describing the mechanism of LH. It writes, LH penetrates the follicle.. LH is a peptide hormone and it has transmembrane receptors localized in the plasma membrane of the cells. It does not penetrate the cell. This information should be corrected. Paragraph 2: Incorporation of a brief explanation of why high TSH levels could lead to underactive thyroid gland producing low T3 and T4 would be important. A discussion about autoimmune thyroiditis is important in this context. Discussion is also needed for possible effect of low levels of progesterone. This has not been discussed in the manuscript. Competing interests: No Invited by the author to make a review on this article? : No Have you previously published on this or a similar topic?: No Experience and credentials in the specific area of science: Thyroid Endocrinology How to cite: Sarkar P.Verification of the relationship among the reproductive hormones and thyroid dysfunction in polycystic ovarian syndrome. [Review of the article 'Reproductive Hormone and Thyroid Hormone Profile in Polycystic Ovarian Syndrome ' by ].WebmedCentral 1970;3(6):WMCRW Webmedcentral > Research articles Page 8 of 11

9 Review 3 Review Title: Hypothyroidism in patients with PCOS Posted by Faculty Dr. Sarosh A Khan on 08 Jun :42:37 PM GMT What are the main claims of the paper and how important are they?: The opening statement that the symptoms of PCOS and Hypothyroidism resemble each other is incorrect. Hypothyroid patients do not have acne, anemia, oligomenorrhea (rather they have menorrhagia more often). They also have cold intolerance, decreased sweating, slow response, hoarse voice, constipation and hung up reflexes in advanced cases. Agreed both are overweight or obese but the disorders are different. No. NA The authors claim that the patients of PCOS were found to be suffering form hypothyroidism as was evident by increased TSH and decreased free and total T3 and T4 levels. However the Results are not in detail at all. How many patients had subclinical hypothyroidism, and how many had hypothyroidism is not shown in the only table shown. The Abstract says patients of PCOS were found to be suffering form hypothyroidism The statement presumes that all fifty patients having PCOS had hypothyroidism! Demonstrating that more patients who had PCOS had hypothyroidism than the controls would be better data than showing the mean of FT3, FT4 and TSH. If a protocol is provided, for example for a randomized controlled trial, are there any important deviations from it? If so, have the authors explained adequately why the deviations occurred? NA No. The only chart is incomplete in the data provided. Many details are missing. Yes. The details about the cases studied would enhance the paper's credibility and the results would be worth appreciating. The authors would have the details and a couple of more tables would have done the trick. Yes. The details about the cases studied would enhance the paper's credibility and the results would be worth appreciating. The authors would have the details and a couple of more tables would have done the trick. Rating: 4 Comment: The Conclusion that.may help in better understanding of the etiology and management of PCOS is misleading. Instead the more appropriate recommendation would be that since the two diseases coexist more often than by chance, all patients having PCOS should be subjected to analysis of thyroid profile so that this common treatable disorder is not missed and treated in time. Otherwise even after treatment of PCOS, many patients may not conceive and the underlying reason may be hypothyroidism as it itself is a common cause of infertility. Competing interests: None Invited by the author to make a review on this article? : No Have you previously published on this or a similar topic?: No Experience and credentials in the specific area of science: Hypothyroidism is very common in the iodine deficient state of Kashmir and we see many cases of this disease on a daily basis. Also I am a life member of the Indian Thyroid Society. How to cite: Khan S.Hypothyroidism in patients with PCOS[Review of the article 'Reproductive Hormone and Webmedcentral > Research articles Page 9 of 11

10 Thyroid Hormone Profile in Polycystic Ovarian Syndrome ' by ].WebmedCentral 1970;3(6):WMCRW Webmedcentral > Research articles Page 10 of 11

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