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The relationship between subclinical hypothyroidism and female infertility.

INTRODUCTION

Subclinical hypothyroidism is a common disorder with a prevalence of about 7% to 8% in women. It is characterized by elevated serum TSH in the presence of normal concentrations of serum thyroxin [1].

Systematic screening for thyroid disorders remains controversial in infertile women [2]. Subclinical hypothyroidism as well as disorders of prolactin secretion may play a role in infertility [3]. Subclinical hypothyroidism constitutes a frequent cause of infertility [4]. It may be associated with ovulatory dysfunction [5]. Also [6], stated that thyroid disorders may not only be the cause of infertility but also increases the incidence of miscarriages and the morbidity of the pregnancies.

Prolactin is a 198 amino acid polypeptide hormone, its principal physiological action is to initiate and sustain lactation. It is produced by lactotrophic cells of the anterior pituitary. Hyperprolactinemia has been often observed in some autoimmune diseases such as Graves disease, Hashimotos thyroiditis and multiple sclerosis [7]. But there is still considerable controversy concerning the immunomodulatroy role of PRL [8].

Hyperprolactinemia is the most prevalent endocrine disorder in hypothalamic--pituitary axis that can result from a number of causes including medications, hypothyroidism. Prolactin secretion is controlled by prolactin inhibitor factor that is secreted from hypothalamus, other factors like thyroid releasing hormone (TRH) lead to increase prolactin secretion [9].

Subclinical hypothyroidism can cause anovulation directly or by causing elevation in prolactin .Many infertile women with hypothyroidism had associated hyperprolactinemia due to increased production of thyrotropin releasing hormone in ovulatory dysfunction [10] and [11].

Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are both glycoproteins of molecular weight approximately 30kDa consisting of two subunits: the B subunits are unique to each hormone but the [alpha]-subunit is the same in each. The synthesis and release of both hormones are stimulated by the hypothalamic decapeptide gonadotrophin-releasing hormones (GnRH) [12].

The thyroid gland and gonadal axes interact continuously before and during pregnancy. Hypothyroidism influences ovarian function by decreasing levels of sex hormone binding globulin and increasing secretion of prolactin. Prevalence of thyroid autoimmunity is significantly higher among infertile women than among fertile women [2].

Thyroid autoimmune testing may or may not be included in the basic fertility workup because the presence of thyroid antibodies doubles the risk of recurrent miscarriages in women with normal thyroid function. A slight increase in TSH levels with normal T3 and T4 indicates subclinical hypothyroidism [13]. The aim of the present study is to assess the relationship between subclinical hypothyroidism and female infertility.

MATERIALS AND METHODS

This study was carried out on 78 subjects, classified into two groups according to the following scheme: Group I (G I), included 48 healthy subjects (48 females aged 22--40 years) with normal thyroid function, regular cycles and no history of infertility as controls. Group II (G II), included 30 patients (30 females, aged 21--40 years) diagnosed as subclinical hypothyroidism patients.

All subjects in this study were recruited from Cleopatra Hospital, Heliopolis, Cairo, Egypt and subjected to clinical screening based on history, physical examination and biochemical analysis. Diagnosis of subclinical hypothyroidism was based on high TSH values (> 3.52 uIU/ml) [14]. SHypo patients have normal values of total thyroxin levels. This study was conducted after taking informed, written consent of the participants.

Ten millimeter of venous blood samples were taken from all subjects at the 3rd day of menstrual cycle (follicular phase), then serum was separated and subjected to the following analysis.

Total T4 was quantitatively determined using competitive, chemiluminescent enzyme immunoassay) [15] using kits supplied from Siemens Diagnostic, Los Angeles, USA. TSH was quantitatively determined by chemiluminescent immunometric assay kit, catalogue number, [L.sub.2][KRT.sub.2] according to the method of [16] (Siemens Diagnostic, Los Angeles, USA). FSH and LH were quantitatively determined using competitive, chemiluminescent enzyme immunoassay [17] using kits supplied from Siemens Diagnostic, Los Angeles, USA. Oestradiol was quantitatively determined by chemiluminescent immunometric assay kit, catalogue number, L2KE22 according to the method of [18] (Siemens Diagnostic, Los Angeles, USA). Prolactin was quantitatively determined by chemiluminescent immunometric assay kit, catalogue number, L2KPR2 according to the method of [19] (Siemens Diagnostic, Los Angeles, USA) and an Immulite 2000 instrument (Roche, Mannheim, Germany). Antimicrosomal antibodies and antithyroglobulin antibodies were determined by enzyme linked immunoassay (ELISA) according to the methods of [20] and [21] respectively.

Results were analyzed statistically according to student's-test and Mann-Whiteny sum test using statistical package for social sciences (Sigma Stat) software. The results were expressed as mean [+ or -] standard error. Statistical significance was considered at p<0.05.

Results:

There was no significant difference between the mean age value of controls and SHypo patients (Table1). A highly significant increase (p< 0.001) of serum TSH was observed in SHypo patients as compared to controls (Fig.1). Serum total thyroxine (TT4) levels showed non significant changes when compared to normal controls (Table 1 and Fig 1). There was no significant difference in FSH and oestradiol levels when we compared SHypo patients with controls (Table 1, Fig 2 and Fig.3). Prolactin levels in SHypo group revealed a significant increase (p<0.001) with respect to controls (Table 1 and Fig 2). Serum levels of LH were shown in Table (1) and Fig (2), their levels were significantly lower (p< 0.01) than the levels of normal controls.

Antimicrosomal and antithyroglobulin antibodies were measured in 37 cases (22 controls and 15 SHypo). There was a significant increase in antimicrosomal antibodies in SHypo patients (66 % SHypo vs. 0.0 % controls, p<0.001) (Fig 4). Also SHypo patients showed a significant increase in antithyroglobulin antibodies (66% SHypo vs. 0.0 % controls, p< 0.001) (Fig 4).

[FIGURE 1 OMITTED]

[FIGURE 2 OMITTED]

[FIGURE 3 OMITTED]

Discussion:

Subclinical hypothyroidism as well as disorders of prolactin secretion may play a role in fertility [3]. Thyroid hormones are essential both for the physiological course of pregnancy and for the optimal differentiation of embryonic tissues and fetal brain development. Overt and subclinical hypothyroidism constitutes a frequent cause of infertility, it carries along an increased risk of spontaneous abortion and premature birth, and it may lead to an impaired fetal brain development [4].

In the present study, there was a non significant difference in FSH levels in female SHypo patients when compared to female controls (Table 1). This was in contrast to [22] who stated that the decrease in FSH levels in SHypo patients was significant. This difference might be attributed to variation in sample size.

The current results showed a highly significant difference between the sera levels of LH compared to controls (Table 1, Fig 2), This decrease in LH levels might be due to pituitary failure and was in agreement with [22].

Estradiol secretion by the ovaries is stimulated by FSH in the first part of the menstrual cycle. As oestrogen concentration in blood rise, FSH secretion decline .Slowely rising of sustained high concentration of estradiol inhibits pituitary gonadotropin secretion by negative feedback [12]. In the present study, there was a non significant difference between the sera levels of estradiol in SHypo patients when compared to controls (Table 1).

The impact of increased prolactin secretion observed in subclinical hypothyroidiusm, on gonadal function and infertility has yet to be clarified [23]. Hypothyroidism influences ovarian function by increasing the secretion of prolactin [2]. [24] Stated that in subclinical hypothyroidism, prolactin regulation is altered with elevated basal prolactin. Hypothyroidism is associated with increased production of TRH which stimulates pituitary to secrete TSH and prolactin. Hyperprolactinemia adversely affects fertility potential by impairing gonadotropin releasing hormone (GNRH) pulsatility and thereby ovarian function [25].

In the current study, there was a significant increase in prolactin levels in patients with Shypo when compared to controls which were in agreement with [24].

Autoimmune diseases result from failure of self-tolerance. A balance between positive and negative regulatory factors, both of genetic and environmental in origin, may control the susceptibility to these diseases and their progression [26].

Antithyroglobulin (Anti-TG) and antimicrosomal (anti-TPO) are indicators of thyroid inflammation and detection of these autoantibodies is a very specific means of diagnosing autoimmune thyroid diseases. Subjects with autoantibodies positivity have high prolactin levels. This might indicate an association between hyperprolactinemia (HPRL) and severe thyroid inflammation in patients with Shypo [8].

In the current study, there was a significant increase in antimicrosomal and antithyroglobulin levels in patients with Shypo when compared to controls which were in agreement with [2] who stated that prevalence of thyroid autoimmunity is significantly higher among infertile women than fertile.

Conclusion:

Shypo may be associated with increased prolactin, antimicrosomal and antithyroglobulin antibodies levels while LH levels were decreased. It is recommended to screen for TSH, prolactin, LH, antimicrosomal and antithyroglobulin levels to avoid any complications result from subclinical hypothyroidism.

ACKNOWLEDGMENTS

The authors are grateful to clinical stuff of Cleopatra hospital for their valuable assistance in this research.

REFERENCES

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[5] Trokoudes, K.M., N. Skordis and M.K. Picolos, 2006. Infertility and thyroid disorders. Curr. Opin. Obstet. Gynecol., 18(4): 446-451.

[6] Cartner, R., 2009. Thyroid disorders during pregnancy. Dtsch. Med. Wochenschr., 134(3): 83-86.

[7] Azar, S. and B. Yamout, 1999. Prolactin secretion is increased in patients with multiple sclerosis. Endocr. Res., 25(2): 207-214.

[8] Eda, D., S. Fatma, S. Muhammed, E. Reyhan and C. Bekir, 2014. Thyroid autoimmunity in patients with hyperprolactinemia. Arq Bras Endocrinol Metab., 58(1): 1-8.

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[10] Raber, W., A. Gessl, P. Nowo and H. Vierhapper, 2003. Hyperprolactinemia in hypothyroidism; Clinical significance and impact of TSH Normalization. Clin Endocrinol., 58: 185-191.

[11] Oliver, A., L. Chaffkin, R. Kates, T. Allan, P. Beller and N. Graham, 2003. Is it necessary to obtain serum levels of thyroid stimulating hormone and prolactin in asymptomatic women with infertility? Conn Med., 67: 393-405.

[12] Marshall, W. and S. Bangert, 2004. Clinical Chemistry, 5th ed. Mosby., 123,124,183.

[13] Indu, V., S. Renuka, J. Sunil and K. Satinder, 2012. Prevalence of hypothyroidism in infertile women and evaluation of response of treatment of hypothyroidism on fertility.Int J. Appl Basic Med Res., 2(1): 17-19.

[14] Iqbal, A., R. Jorde and Y. Figenschau, 2006. Serum lipid levels in relation to serum thyroid stimulating hormone and the effect of thyroxine treatment on the serum lipid levels in subjects with subclinical hypothyroidism: the Tromso Study. J. Intern. Med., 260: 53-61.

[15] Refetoff, S., 1979. Thyroid function tests. In De Groot L. J .editor .Endocrinology, Philadelphia: Grune and Stratton., 1: 387-428.

[16] Chen, I. and L. Heminger, 1984. Thyroid--stimulating hormone. In: Clinical Chemistry. L. A. Kaplan. A. J. Pesce edd. St Louis: C.V. Mosby., 1160-1164.

[17] Davidsohn, I. and J. Henery, 1974. Clinical diagnosis by laboratory methods. 15th ed.Phildelphia :W. B. Saunders., pp.704.

[18] Batzer, F.,1980. Hormonal evaluation of early pregnancy. Fertil. Steril., 34: 1-13.

[19] Cowden, E.A., W.A. Ratcliffe, G.H. Beastall and J.G. Ratcliffe, 1979. Laboratory assessment of prolactin status.Ann.Clin.Biochem., 16: 113-21.

[20] Roitt, I.M. and D. Doniach, 1958. Human Auto-Immune Thyroiditis: Serological Studies. Lancet, 11: 1027-1033.

[21] Ericson, M.B., S.B. Christensen and J.A. Thorell, 1985. High prevalence of thyroglobulin autoantibodies in adults with and without thyroid disease as measured with sensitive solid phase immunosorbent assay. Clin. Immunol. Immunopathol., 37: 154-162.

[22] Neema, A., A. Sourya, S. Samarth, S. Inamdar, M. Khatri, S. Mahajan, 2011. Gonadotropin levels in hypothyroid women of reproductive age group. J. Obstet Gynaecol India, 61(5): 550-553.

[23] Staub, J.J., B.U. Althaus, H. Engler, A.S. Ryff, P. Trabucco, K. Marquardt, D. Burckhardt, J. Girard and B.D. Weintraub, 1992. Spectrum of subclinical and overt hypothyroidism: effect on thyrotropin, prolactin, and thyroid reserve, and metabolic impact on peripheral target tissues. Am. J. Med., 92(6): 631-642.

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(1) Amin A.I. and (2) Samir H. Haggag

(1) Biochemistry Department, Faculty of science, Cairo University, P. O.12613 Giza, Egypt

(2) Therapeutic chemistry Department, National Research Center, El-Tahrir St., Dokki, P.O. 12622 Cairo, Egypt.

ARTICLE INFO

Article history:

Received 23 June 2015

Accepted 28 July 2015

Available online 5 August 2015

Corresponding Author: Samir H. Haggag, Therapeutic chemistry Department, National Research Center, El- Tahrir St., P.O. 12622 Dokki, Cairo, Egypt. E-mail: samirhih@yahoo.com
Table 1: Serum levels of TSH, TT4, FSH, LH, oestradiol and
prolactin in different studied groups.

                        Control group            SHypo group

Number                       48                       30

Age(years)
Range                       22-40                 21.0-40.0
Mean [+ or -] S.E.   31.15 [+ or -] 0.6     30.27 [+ or -] 1.0 NS
TSH(uIU/ml )
Range                     1.31-3.90                 4.1-6
Mean [+ or -] S.E     2.7 [+ or -] 0.1      4.6 [+ or -] 0.08 ***
TT4(ug/dl)
Range                      4.24-12                  5.7-12
Mean [+ or -] S.E     8.7 [+ or -] 0.23    8.72 [+ or -] 0.31 (NS)
FSH(mIU/ml)
Range                      2.1-37                   2.1-37
Mean [+ or -] S.E    10.25 [+ or -] 1.37    8.91 [+ or -] 1.5 (NS)
LH(mIU/ml )
Range                      2.2-37                   2.1-27
Mean [+ or -] S.E    11.83 [+ or -] 1.2       7.15 [+ or -] 1 **
Oestradiol(pg/ml)
Range                       10-86                   10-86
Mean [+ or -] S.E    34.96 [+ or -] 2.48   38.77 [+ or -] 3.78 (ns)
Prolactin (ng/ml)
Range                      3.7-17                   18-33
Mean [+ or -] S.E    9.27 [+ or -] 0.61    27.13 [+ or -] 0.64 ***

Data are expressed as mean [+ or -] S.E.

* P < 0.5, ** p < 0.01, *** p < .001as compared to control group

NS=Non significant

Fig. 4: Percentage of increased Antimicrosoma antibodies (IU/ml)
and antithyroglobulin IU/ml levels in SHypo patients compared to
controls.

Antimicrosomal and antithyroglobulin
antibodies (llU/ml) percent

                               G1      G2

Antimicrosomal antibodies      0.00%   66%
Antithyroglobulin antibodies   0.00%   66%

Note: Table made from bar graph.
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Author:A.I., Amin; Haggag, Samir H.
Publication:Advances in Environmental Biology
Article Type:Report
Date:Jul 1, 2015
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