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INVITATION ARTICLES - Thyroid And Infertility - By Dr. Mandakini Parihar

Dr Mandakini Parihar MD, DGO
Director, Mandakini IVF Center, Mumbai
Chairperson, Family Welfare Committee, FOGSI(04-09)
Hon Associate Professor OBS.GYN
K.J. Somaiya Medical College & Hospital, Mumbai
Member, Governing Council, ICOG
Member, Managing Committee, ISAR
Jt. Treasurer, Indian Menopause Society

Address for correspondence:
Mandakini Fertility Clinic and IVF Centre
48, Swastik Park
Chembur
Mumbai 400071.

Fax: 91-22-25233672
Tel : 91-22-25224845 / 25227539
Email: mandakiniparihar@gmail.com

Thyroid and Infertility

“Real knowledge is to know the extent of one's ignorance” ~Confucius

INTRODUCTION

The thyroid gland is situated in the neck region and consists of two lateral lobes, one on each side of the trachea immediately below the larynx. Three hormones are produced and released into the blood, Tri-iodothyronine(T3), Thyroxine(T4), Calcitonin(CT). The T3 and T4 increase metabolic rate in most cells by stimulating oxidative process. Hormones are essential for normal physical growth, sexual maturation and mental development. Production and release of thyroid hormones are controlled by thyroid stimulating hormone (TSH) secreted by anterior pituitary.

The disturbances of thyroid function have diverse effects on male and female infertility. The chance of thyroid disease is 5-10 more in female than in male. As Thyroid dysfunction is known to reduce the likelihood of pregnancy and to adversely affect pregnancy outcome, estimation of thyroid function is an integral part of infertility works-up.

Both hypo-and hyperthyroidism can be readily treated and, if missed, is associated with an increased risk of miscarriage and possible long-term health consequences for the child.1 The difficulty is in identifying the sub-clinical hypothyroidism and treating it appropriately as it too can adversely affect ovulation and cause recurrent pregnancy loss as well.

HYPOTHYROIDISM AND INFERTILITY

Prevalence of hypothyroidism in the population of reproductive age, defined as abnormally elevated TSH (Thyroid stimulating Hormone) concentration is 2 to 4%.1,2

There is an alteration in metabolism of the reproductive steroids, mainly estradiol and testosterone. These cause inappropriate estrogen feedback and hence result in anovulation. One of the first signs of sub-clinical hypothyroidism is that there is a subtle increase in prolactin levels. Treatment with thyroid replacement normalizes prolactin levels too.

In males, it is the thyroid antibodies which cause disturbances of the semen with anatomical as well as functional parameters altered depending on the auto-immune response to the thyroid antibodies.

Table 1: Etiology of Thyroid disease (Hypo and hyperthyroid)

Table 2: Common Presentation in Thyroid dysfunction

HYPOTHYROIDISM
Possible Mechanisms for Infertility and Hypothyroidism:

Thyroid dysfunction is a common cause of infertility and easily managed by correcting the inappropriate levels of thyroid levels. TSH secretion is closely linked with reproductive function and is known to affect the menstrual cycle. The impact of hypothyroidism on the menstrual cycle has been known since 1950.3 Severe hypothyroidism is commonly associated with failure of ovulation, but ovulation and conception can occur in milder hypothyroidism. This impact on menstrual function and ovulation is related to numerous interactions of thyroid hormones with the female reproductive system.
 

Hypothyroidism causes:
• changes in cycle length and blood flow
• menorrhagia occurs in 60% of overt hypothyroid women.4

In women attending the infertility OPD, the incidence of Thyroid dysfunction was twice that of general population. The common cause was anovulation. These ovulatory disorders included evidence of galactorrhea, hirsuitism, amenorrhea and menorrhagia. In a study on Indian women, Joshi et al found 68.2% of menstrual abnormalities in hypothyroid women (15/22) compared with 12.2% of healthy controls (6/49).5

Many patients with raised TSH also had a raised prolactin and this is due to increased production of TRH. This raised prolactin then causes anovulation through the altered dopaminergic pathway. The resultant hyperprolactinemia is the cause of the ovulatory dysfunction and in 1–3% of cases, especially when associated with galactorrhea.6 An alternative hypothesis is that diminished synthesis and secretion of dopamine in the hypothalamus could account for loss of dopaminergic inhibitory influences on secretion of PRL, TSH and also to some extent on the LH.7 It has been recommended that in the presence of raised TSH along with raised PRL levels, the treatment should be first to correct the hypothyroidism before evaluating further causes of raised PRL.8 Another study in the Asian sub-continent also found a higher incidence of raised serum prolactin and serum TSH level in women with infertility. It also noted that the Prolactin level was high in more frequently in patients with primary infertility and TSH level was higher in patients with secondary infertility.9 Another presentation of infertility can be decreased sexual desire (libido) associated lethargy of hypothyroidism.

T3 modulates FSH and LH action on steroid biosynthesis and multiple T3 binding sites have been identified in mammalian granulosa and stromal cells and more recently in human oocytes. Any impairment in locally available T3 may therefore disrupt normal female reproductive function. 10
 

How does thyroid influence Ovulatory cycle?

Dysfunction of thyroid secretion results in inappropriate production of TRH. This interferes with normal physiological pulsatile GnRH secretion which is required for normal follicular development and maturation. Hypothyroidism in adult women often results in changes in cycle length and blood flow. In older series, menorrhagia (increased blood flow) was the most prevalent symptom and occurred in 60% of overt hypothyroid women.4
Hypothyroidism also results in altered peripheral estrogen metabolism. Decrease in SHBG and its binding activity, together with an altered peripheral metabolism of estrogen may result in abnormal feedback at the pituitary level.1 The anovulation or oligo-ovulation causes a short luteal phase because of delay in LH response and inadequate corpus luteal progesterone secretion . In adult women, more common ovulatory disorders including galactorrhea, hirsuitism, amenorrhea and menorrhagia have been reported. 4,,6,7,9

In the presence of anovulation, ovarian androgen production increases with higher biologically active androgens which are compounded by the low SHBG. These changes further contribute to anovulation and an increased incidence of hirsuitism. It is important to remember that independent of hormonal changes, menorrhagia can result from defects in hemostasis, involving decreased levels of factors VII, VIII,IX and XI and must also be evaluated and treated as well.11

DIAGNOSIS:
The diagnosis is very easy and consists of combination of clinical evaluation and serum hormonal assays of TSH, total or free T3 and T4. In cases of high suspicion, TSH levels and free T4 are the most important.

Sub-clinical Hypothyroidism:
Sub-clinical hypothyroidism is defined as elevated serum TSH in the presence of free thyroxin (fT4) concentrations within the normal reference range. After the introduction of third-generation assays for serum TSH, it is more often detected. Subclinical hypothyroidism results from the same causes as overt hypothyroidism and is an important cause of menstrual dysfunction. Considering the largest cohorts published the prevalence of sub-clinical hypothyroidism in infertility ranges from 1 to 4% and most cases are associated with ovarian dysfunction. However, these studies looking at the association of sub-clinical hypothyroidism and infertility are poorly controlled.

Recent data indicate that variations of free T4 in the individual are narrower than variations within the reference range for the population. These data may indicate that normal fT4 (for the population reference range) could reflect an abnormal fT4 for the individual patient with increased serum TSH.12
A study recommend performing TRH(thyroid releasing hormone) stimulation testing in women suffering from ovulation disorders who have normal basal TSH levels ,followed by repeat assessment of thyroid function to enable treatment with thyroxin in cases with abnormal results .13 Treatment with hormone in sub-clinical hypothyroidism is still debatable, there are two schools of thoughts one says give hormone only in documented deficiency while the other believes in thyroxin hormone treatment to improve the outcome.

Treatment of Hypothyroidism:
Hormone therapy with thyroxin extract (Levo thyroxin) is the choice of treatment in established hypothyroidism. It normalizes the menstrual cycle, prolactin level and improves the fertility rate.

THYROID AUTOIMMUNITY AND INFERTILITY

Autoimmune abnormalities have been investigated for possible associations with reproductive failure. The tests for thyroid autoimmunity (AITD) include testing for 1. Anti-TPO and 2 Anti-thyroglobulin antibodies

AITD is the most common autoimmune disorder in the female population, affecting 5–10% of women of childbearing age and secondly it is the most frequent cause of thyroid failure including both sub-clinical as well as overt hyperthyroidism.14,15,16

AITD can also be present without thyroid dysfunction and will be undiagnosed. In patients with clinical suspicion of thyroid dysfunction and infertility should have the tests done. Many cases of unexplained infertility may have the AITD positive. It was noted that in infertile women thyroid autoimmunity features are significantly more frequent than in healthy fertile controls. In patients with unexplained infertility and with endometriosis subgroup, the Thyroid Peroxidise antibody (TPO-Ab) tests are positive more frequently than in fertile women.17 In a Spanish prospective study higher prevalence of thyroid autoimmunity (Anti TPO antibodies) were found in unexplained infertility and implantation failure than in the control group.18
 

In severe cases of autoimmune disorders like Graves disease and Hashimoto’s thyroditis which is caused by proteins and white cells in the blood can also attach the same proteins in the ovaries. This leads to shriveling of the ovary, failure to ovulate and in some cases there is a total ovarian failure causing, premature menopause and infertility. Treatment options for thyroid autoimmunity are low dose heparin, aspirin and IV immunoglobulin.

HYPERTHYROIDISM AND INFERTILITY

The prevalence in the general population is around 1.5%19,20 A suppressed serum TSH and increased FT4, FT3 or both characterize hyperthyroidism along with the clinical signs and symptoms as tabled above.

Possible Mechanism for Infertility:
The exact impact of hyperthyroidism on fertility remains ill-defined. Menstrual disturbances in hyperthyroidism have been described by Von Basedow in 1840 and confirmed by other groups.4 Joshi et al found menstrual irregularities in 64.7% of hyperthyroid women, compared with 17.2% of healthy controls in a study in india. The incidence of menstrual abnormalities was two-and-a-half times higher than in the controls.5

Krassas et al observed irregular cycles in only 46 of 214 hyperthyroid women (21.5%). Twenty-four women had hypomenorrhea, 15 polymenorrhea, 5 oligomenorrhea, 2 hypermenorrhea and none had amenorrhea. The prevalence of similar abnormalities in the control population was 8.4%.19 but surprisingly most women with hyperthyroidism maintain ovulatory function as seen on follicular studies and the incidence of spontaneous pregnancies. This has also been confirmed by endometrial biopsies.1

In contrast to the hypothyroid state, SHBG production is increased. Therefore the estrogen metabolism is altered and conversion of androgens to estrogens increased. Hyperthyroidism also augments gonadotropin response to GnRH and baseline gonadotropin concentrations are frequently elevated. The decrease in menstrual flow may also relate to effects on haemostatic factors, including the synthesis of factorVIII.1,20

As for hypothyroidism, most studies on the prevalence of hyperthyroidism in infertility are derived from uncontrolled, retrospective cohort studies. An Indian study by Joshi et al showed that out of 53 hyperthyroid patients, 5.8% had primary and secondary infertility.5 Usually, treatment corrects cycle changes observed with hyperthyroidism. The exact impact of hyperthyroidism on fertility remains ill-defined.

Diagnosis
Diagnosis is made with clinical findings and serum TSH, T3, T4 assays. Low TSH levels with raised T3 and T4, either one or both clinch the diagnosis. However, to know the cause of hyperthyroidism, other investigations like ultrasonography, radioactive iodine uptake and antithyroid antibodies would need to be carried out.

Treatment:
Treatment of overt hyperthyroidism normalizes menstrual pattern. Data on the impact of treatment of subclinical hyperthyroidism are not available. The mainstay of treatment is anti-thyroid drugs. Radio-iodine therapy may be needed in some cases. And surgery may also be suggested depending on the cause.

ANTITHYROID DRUGS
Carbimazole(10-20mg 8hrly), Methimazole(10-15mg 8hrly), propylthiouracil(100-200mg 8hrly) are the drugs available for treatment, dosages depend on severity. For symptomatic relief beta blocker like Propanolol (40-60mg 6-8hrly) can be given. Propylthiouracil can be used safely in patients undergoing infertility treatment and continued during pregnancy under supervision.
 

Surgery should be considered in the following cases:

1. In presence of large goiter/ multinodular goiter
2. In patients with poor compliance to drugs
3. In patients with persistent side effects with drugs.

Irradiation with I-131(radioactive iodine) can be used to destroy thyroid gland in certain cases. Krassas et al reviewed the impact of radioiodine in the management of hyperthyroidism in patients of reproductive age. It was observed that fertility is not disturbed in the long term and I131 is not contra-indicated in hyperthyroid patients because of the risk of infertility.1

Assisted Reproduction and the THYROID

ART Procedure impact on thyroid function
A study of impact of COH (Controlled ovarian hyperstimulation) on thyroid hormone profile shows, significant increase in serum TSH and fT4 levels compared with baseline values. The ovarian stimulation during Assisted Reproduction induces high estradiol level and thus might therefore additionally impair thyroid function even before pregnancy is established. Altered thyroid levels can affect the quality of the oocytes and hence adversely affect the ART outcome. After this initial peak serum TSH and Ft4 levels decreased comparable with pretreatment values.21

Thyroid Dysfunction Impact on ART Procedure

There are some studies which say that women with positive TPO-Ab before the first ART cycle have significantly increased risk of miscarriage and there is increased prevalence of thyroid antibodies in euthyroid women with a history of recurrent in vitro fertilization failure. Thyroid antibodies might be independent markers for reproductive failure in IVF-ET programme but larger studies needed.22,23

Summary

Women presenting with infertility should be screened for thyroid function. Earlier guidelines mention it is unnecessary in asymptomatic patients but evidence today is clear that all patients with infertility should be screened. A retrospective analysis of the results of routine thyroid function screening showed that occult thyroid dysfunction was seen in 5.1% of the population studied. So the assessment of thyroid in infertility is recommended. A clinical challenge is to identify cases of sub-clinical hypothyroidism and improve clinical outcomes. There may be a role of anti-thyroid antibodies in cases of repeated IVF failures, which needs more studies. The take home message is to routinely screen for thyroid dysfunction and if present treat it effectively to improve pregnancy rates.

Female Infertility

REFRENCES:

1. Krassas GE. Thyroid disease and female reproduction Fertility & Sterility 2000; 74: 1063–1070
2. Wang C, and Capro C M. The epidemiology of thyroid diseases and its implications for screening Endocrinology and Metabolism clinics of North america1997,26:189-218.
3. Benson RC & Dailey ME. The menstrual pattern in hyperthyroidism and subsequent post-therapy hypothyroidism Surgical Gynecology and Obstetrics 1955; 100: 19–26
4. Goldsmith RE, Sturgis SH, Lerman J & Standburg JB. The menstrual pattern in thyroid disease. Journal of Clinical Endocrinology and Metabolism 1952; 12: 846–855
5. Joshi JV, Bhandarkar SD, Chadha M, et al. Menstrual irregularities and lactation failure may precede thyroid dysfunction or goiter. Journal of Postgraduate Medicine 1993; 39: 137–141
6. Longcope C, Abend S, Braverman LE & Emerson CH. Androstenedione and estrone dynamics in hypothyroid women. Journal of Clinical Endocrinology and Metabolism 1990; 70: 903–907
7. Scanlon MF, Chan V, Heath M, et al. Dopaminergic control of thyrotropin, alpha-subunit, thyrotropin beta-subunit, and prolactin in euthyroidism and hypothyroidism: dissociated responses to dopamine receptor blockade with metoclopramide in hypothyroid subjects. Journal of Clinical Endocrinology and Metabolism, 1981; 53: 360–365.
8. Thomas R & Reid RL. Thyroid disease and reproductive dysfunction: a review. Obstetrics and Gynecology 1987; 70: 789–798
9.N Akhter and SA Hassan. Subclinical hypothyroidism and hyperprolactinemia in infertile women: Bangladesh perspective after universal salt iodination. Journal of endocrinology 2009 volume 5 No.1
10.Wakim AN ,Polizotto SL, Bulfo MJ. Thyroid hormones in human follicular fluid and thyroid hormone receptor in human granulose cells Fertil Steril 1993;59:1187-90
11. Ansell JE. The blood in the hypothyroidism In Braverman L & Utiger R (eds) Werner and Ingbar’s the Thyroid, a Fundamental and Clinical Text, seventh edn. Philadelphia: Lippincott Raven, 1996, pp 821–825.
12. Andersen S, Pedersen KM, Bruun NH & Laurberg P. Narrow individual variations in serum T(4) and T(3)in normal subjects: a clue to the understanding of subclinical thyroid disease. Journal Clinical Endocrinology of Metabolism 2002; 87: 1068–1072.
13.Eldar-Gevat T,Shoham M, Roster A, Margalioth EJ, Livne, Meirown. Gynaecol Endocrinol 2007, June23 (6):332-7subclinical hypothyroidism in infertile women; the importance of continuous monitoring and the role of thyrotropin releasing hormone
14. Wang C & Crapo LM. The epidemiology of thyroid disease and implications for screening Endocrinology and Metabolism Clinics of North America 1997; 26: 189–218
15. Bjoro T, Holmen J, Kruger O, et al. Prevalence of thyroid disease, thyroid dysfunction and thyroid peroxidase antibodies in a large, unselected population. The Health Study of Nord-Trondelag (HUNT) European Journal of Endocrinology 2000; 143: 639–647.
16. Hollowell JG, Staehling NW, Flanders WD, et al. serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). Journal of Clinical Endocrinology and Metabolism 2002; 87: 489–499.
17. Poppe K, Glinoer D, Van Steirteghem A, Tournaye H, Devroey P, Schiettecatte J, Velkeniers B. Thyroid dysfunction and autoimmunity in infertile women. Thyroid: official journal of the American Thyroid Association, of2002,12(11);997-1001
18. Beliver J, Sores SR; Alvarez C, Pellicer A. Human reproduction 2008,23(2)278-284,ISSN: 1460-2350
19. Krassas GE, Pontikides N, Kaltsas T, et al. Menstrual disturbances in thyrotoxicosis. Clinical Endocrinology1994; 40: 641–644.
20. Tanaka T, Tamai H, et al. Kuma K.Gonadotropin response to luteinizing hormone releasing hormone in hyperthyroid patients with menstrual disturbances. Metabolism 1981; 30: 323–326
21. The thyroid and autoimmunity; Merck European Thyroid Symposium, Noordwijk, By Wilmar Wiersinga.
22. The Journal of clinical endocrinology metabolism, vol 88,no 9 4149-4152.2003,Assisted reproduction and Thyroid autoimmunity an unfortunate combination
23.Gillian A, Strafford, Jullian H, Barth Anthony J,Rutherford and Adem H, Balen, Human Fertility 2000,vol 13 no3,pages 203-206

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