Study of Thyroid Dysfunction in Association with Infertility

Aims: To evaluate the relation of female infertility to thyroid dysfunction. Study Design: This is a descriptive, hospital-based study. Place and Duration of Study: The present study Methodology: The study group included 60 cases among which 48 women were having primary infertility & 12 women had secondary infertility, while control group included 40 fertile euthyroid women. Serum T3, T4 and TSH estimation was done by Enzyme linked fluorescent assay on mini VIDAS. Results: hyperthyroid level hypothyroid euthyroid Habbu and Shaikh; IJBCRR, 11(2): 1-6, 2016; significant), 4.17±0.80 pmol/L, when compared with control. FT 4 level was 52.7±4.52 pmol/L in hyperthyroid (p value ˂ 0.001. i.e. highly significant), while in hypothyroid 9.80±5.5 pmol/L, and in euthyroid 13.82±3.48 pmol/L (P value ˃ 0.05, i.e. not significant), 14.63±2.85 pmol/L, when compared with control. Serum TSH level in hyperthyroid was 0.22±0.10 µIU/ml, in hypothyroid 21.98±19.86 µIU/ml (P value ˂ 0.001, i.e. significant), 2.61±1.24 µIU/ml in euthyroid (P value ˃ 0.05, i.e. not significant); 2.72±1.51 µIU/ml when compared with control. Conclusion: Thyroid hormones play an important role in normal reproductive function, both through direct effects on the ovaries and also indirectly by multiple interactions with other sex hormones. Therefore, thyroid dysfunction can lead to menstrual irregularities and, thus, finally to infertility.


INTRODUCTION
Infertility is the failure of couple to conceive a pregnancy after trying to do so for at least one year. Infertility has increased as a problem over the last 30 year. Infertility although, is not lethal but the desire to reproduce is a basic human instinct & deprivation of fertility may lead to guilt & depression. Approximately one tenth of marriages are barren & 10% have fewer than desired number of children. If female fails to achieve pregnancy after one year of unprotected & regular sexual intercourse, it is an indication to investigate the couple. Although consative factor (33%), female is as fault in the predominant number of case. It should be remembered that infertility is not a disease & the couple generally is otherwise healthy, they should be encouraged to be active in their evolution & in determining their course of therapy [1][2][3].
Endocrine system is the second key regulator of organ system function after nervous system. Hormones are the messengers in endocrine signaling. Thyroid gland controlling brain & somatic development in infants & metabolic activities in adults upon stimulation by thyroid gland secretes thyroid hormones; triiodthyronine (T 3 ) & thyroxin (T 4 ). Thyroid hormones have a role in controlling basal metabolism rate, growth as well as the development & differentiation of many cells in the body [3,4].
Fertility in female is maintained by prevailing hormonal milieu, which is delicately balanced by hypothalamic pituitary thyroid adrenogonadal axis. Infertility is common accompaniment of disorders of thyroid function. Abnormalities of thyroid function hypo as well as hyperthyroidism are associated with variety of changes in reproductive system, including delayed onset of puberty, menstrual irregularities & recurrent fetal wastages. Anovulation is more commonly noted in association with hyperthyroidism. Significant interrelations have been found between thyroid disorders & gonadal functions by various laboratory & clinical studies [3,4] Therefore the present study has aim to evaluate thyroid status in the infertile women. For this certain biochemical parameters were done. These included T3, T4 and TSH by using Enzyme Linked Fluorescent Assays technique.

Study Design
This study was carried out on 100 women selected from outpatient & inpatient department of obstetrics and gynecology, Ashwini Rural Medical College, Hospital & Research center, Solapur, Maharashtra. Over the period of 6 month after taking consent from the subjects. Ethical clearance was obtained from the institution. The sample size calculate from hospital based gynae and obst department population.
Women with diagnosed or medications likely to affect thyroid function were excluded.
The study has been carried out in biochemistry department for thyroid profile evaluation, study group included 60 cases among which 48 women were having primary infertility & 12 women had secondary infertility, while control group included 40 fertile euthyroid women.

Assay of Thyroid Function
Thyroid function test panel (T 3 , T 4 and TSH) were assayed by Mini Vidas technique using standard kit. T 3 and T 4 were assayed by competitive enzyme immunoassay method with final fluorescent detection (ELFA). The Solid Phase Receptacle (SPR) serves as solid phase as well as the pipetting device for the assay. Reagents for the assay are ready to use and pre dispensed in the sealed reagent strips.
All of the assay steps are performed automatically by the instruments. The reaction medium is cycled in and out of the SPR several times. The sample is collected & transferred into the well containing an Alkaline Phosphatase labeled anti T 3 & anti T 4 antibody (conjugate).
The antigen present in the sample and the T 3 , T 4 antigen coated on the interior of the SPR compete for the available sites on the specific T 3 , T 4 antibody conjugates to alkaline phosphatase.
During the final detection step, the substrate (4 methyl-umbelliferyl phosphate) is cycled in & out of the SPR. The conjugate enzymes catalyze the hydrolysis of this substrate into fluorescent product (4 methyl-umbelliferone). The fluorescence of which is measure of at 450 nm. The intensity of the fluorescence is inversely proportional to the concentration of antigen present in the sample. At the end of the assay result are automatically calculated by the instrument in relation to the calibration curve stored in memory, & then printed out.
The TSH was assayed by one-step enzyme immunoassay sandwich method with final fluorescent detection (ELFA). When the sample is transferred into the well containing anti TSH antibody labeled with alkaline phosphatase. The sample conjugate mixture is cycled in & out of SPR. The antigen binds to antibodies coated on SPR & conjugate forming a " sandwich " unbound component are eliminated during the washing steps, during the final detection step the substrate is cycled in & out by the SPR. the conjugate enzymes catalyzes the hydrolysis of this substrate into a fluorescent product which measure of 450 nm.
All the three parameters were estimated by following the same standard protocol provided by the manufacture (M/S Biomerieux) [5][6][7]. The normal ranges of FT3 is 2.15 to 8.65 pmol/L, FT4 is 9 to 22 pmol/L, and TSH is 0.25 to 5 µIU/ml for our laboratory. The cutoff level for hyperthyroidism is TSH ˃ 0.25 µIU/ml and for hypothyroidism TSH ˂ 5 µIU/ml.

Criteria of Thyroid Dysfunction
Thyroid function is considered normal (Euthyroid) when subjects were presented with normal T 3

Statistical Analysis
Data were represented as percentage frequency, mean & standard deviation student "t" test and SPSS 17 software. The difference in mean values of various parameters was calculated and express in terms of P value.

RESULTS
The present study on "thyroid dysfunction in association with infertility", was conducted to correlate the role of T3, T4 and TSH as causative agent for infertility among females. The patients were divided as follows; study group included 60 patients of primary and secondary infertility. The control group contains 40 healthy fertile women of reproductive age group.
All the patients taken for study were in reproductive age group. Out of 60 patients in study group, 48 cases (80%) were having primary infertility and 12 cases (20%) secondary infertility [ Table 1].

DISCUSSION
The common endocrine disorders which result in infertility are hypothyroidism, hyperthyroidism, polycystic ovary syndrome diabetes mellitus, adrenogenital syndrome, Cushing's syndrome etc. Among these thyroid disorders are very important. Most of the studies available in literature have been done to find out infertility in cases of thyroid disorder, not the association of infertility with thyroid dysfunction, only few studies have been done so far [8,9].
In present study, there is statistically significant increase in mean serum T3 and T4 and decrease in TSH levels in infertile women when compared to controls. Hypothyroidism (40%) was more prevalent than hyperthyroidism (3.3%).
The prevalence of thyroid dysfunction in infertile women was found to be 33.3% in a study by Rahman et al. [10] and 23% by Sharma et al. [9] in our study, hypothyroidism was present in 40 % and hyperthyroidism in 3.3% of infertile women. It is concluded that fertility of female reproductive system is altered by thyroid hormone levels.
Majority of the patients were in euthyroid state which may be due to other cause of infertility.
The prevalence of hypothyroidism in the infertile women is abnormally elevated TSH concentration ranges from 2-4% which found to be 6.7% by Rahman et al. [10], 8% by Goswami et al. [11], and 20% by Sharma et al. [9] while in our study this prevalence was 40%.
The abnormal hypothyroidisms disturb the ovulation and menstrual patterns. It is related to numerous interactions of thyroid hormones with the female reproductive system, and finally leading to infertility. In hypothyroidism, abnormally elevated TRH production leads to hyperprolactinaemia and altered GnRH pulsatile secretion. The hyperprolactinaemia is due to abnormal thyroid hormone secretion lead to delay in luteinizing hormone response and inadequate corpus luteum. The sensitivity of ovaries to thyroid hormones could be explained by the presence of hormone receptors in human oocytes. Thyroid hormones can act in conjunction with FSH-mediated LH/hCG receptors to stimulate granulose cells leading to the secretion of progesterone and abnormal TSH levels have been reported. In women who produced oocytes that could not been fertilized among patient undergoing in vitro fertilization. Hypothyroidism can also impact on fertility by changing the peripheral metabolism of estrogen and by reducing steroid hormone binding globulin secretion [12][13][14][15].
Thyroid dysfunction is a one of the common cause of infertility in women, which can be easily managed by appropriate thyroid hormones levels. In our data there are variations in TSH levels in the narrower range but it should not be ignored in infertile women who are otherwise asymptomatic for clinical hyperthyroidism. For better management of infertility case, we should plan further studies.

CONCLUSION
Infertility is a complex disorder that in a quarter of the couples is due to a female cause. Thyroid hormones play an important role in normal reproductive function, both through direct effects on the ovaries and also indirectly by multiple interactions with other sex hormones. Therefore, thyroid dysfunction can lead to menstrual irregularities and, thus, finally to infertility.