THYROID AND INFERTILITY

PROF. DR. BHARATI MISRA

MD (O&G) FICOG
FELLOW IN IVF ET,BOSTON (USA)
ENDOSCOPIST
DEPARTMENT OF OBST & GYNAECOLOGY
MKCG MCH
INTRODUCTION
• Infertility is defined as the inability to conceive after one year of regular
intercourse without contraception. The prevalence of infertility is estimated
between 12 and 14% and remains stable in recent years. It thus represents a
common condition, with important medical, economic and psychological
implications. According to a standard protocol infertility evaluation usually
identifies different causes, including, male infertility (30%), female infertility
(35%), the combination of both (20%), and finally unexplained or "idiopathic"
infertility (15%). Female causes of infertility comprise endometriosis, tubal
damage and ovulatory dysfunction (OD). Thyroid dysfunction is a condition
known to reduce the likelihood of pregnancy and to adversely affect
pregnancy outcome.
INTRODUCTION CONTD…….

• 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 the secretion of prolactin. In
women of reproductive age, hypothyroidism can be reversed by thyroxine
therapy to improve fertility and avoid the need for use of assisted
reproduction technologies.
• Thyroid hormones have profound effects on reproduction and pregnancy.
There is a known association of hyper- and hypothyroidism with menstrual
disturbances and decreased fecundity. Women with reproductive failure also
have an increased prevalence of organ specific autoimmunity compared to
fertile women.
• Female fertility is a cumulative process of ovarian function, oocyte
development, endometrial receptivity, and male factors. This chapter
examines the relationship between thyroid dysfunction and female
reproductive potential. Hypothyroidism is associated with changes in
menstrual patterns, including decreased menstrual cycle frequency and
increased volume of menses. Thyroid hormone, thyroid hormone
transporters, and nuclear thyroid hormone receptors have been found in
ovarian follicles and in oocytes. Thyroid hormone receptors are also found at
the surface of the endometrium and are thought to be involved in the
interaction between the endometrium and the blastocyst at the time of
implantation.
EPIDEMIOLOGY

• Female > Male 8:1

• Fortunately hypothyroidism is very rare in males with a occurrence of only
0.1% in general population
• Prevalence of hypothyroidism is 2% -4% in female of reproductive age group
• 90% of cases are primary hypothyroidism
HYPERTHYROIDISM
HYPOTHYROIDISM
CLINICAL SCENARIOS

• Clinical overt hypothyroidism (3.3%) – Elevated serum TSH and low FT4
(Symptomatic)
• Sub clinical hypothyroidism (0.7% – 43%)- Elevated serum TSH and normal
FT4( Biochemical thyroid hormone deficiency)
• Autoimmune thyroid disease (5%-20%)-Presence of antibodies to some
structures of thyroid gland such as thyroglobulin (TG) , Thyroid peroxidase
(TPO) and thyroid microsomale(TM)
 MECHANISM OF HYPOTHYROIDISM AND
INFERTILITY
1. Increased TRH production
2. Hyper prolactinemia
3. Altered GnRH pulsatile secretion
4. Leading to delay in LH response
5. Inadequate corpus luteum
6. Leads to failure of sex steroids by
disrupting the functioning of HPO axis
MECHANISM OF HYPERTHYROIDISM ON
INFERTILITY

• Exact impact of hyperthyroidism on fertility remains ill defined.

• Moreover studies are limited , uncontrolled and small in size
• Prevalence is 0.9% - 5.8%
• Menstrual irregularities
• Sex hormone binging globulin(SHBG) is increased
• Peripheral conversion of androgen to estrogen in increased
• Androstenedione and testosterone is increased
• Increased estradiol and estrone
MECHANISM OF INFERTILITY IN AUTO
IMMUNE THYROID DISORDER

• Abnormal immune response

• Release of cytokines
• Prevents successful implantation by altering profile of endometrial T cells
• Increase Anti thyroglobulin antibody(ATA) correlates with endometriosis
• ATA Positive associated with PCOD
• ATA Positive with POF (Premature ovarian failure)
IMPACT OF THYROID HORMONES

• 1/3 rd of sub fertile patients have thyroid disease.

• Over 50%-70% hypothyroid patients have menstrual irregularities
• 46% of infertile patients with hypothyroidism have hyper prolactinemia
• 10% of inadequate corpus luteum and luteal phase defects
EFFECT OF THYROID DISORDER ON MALE
FERTILTIY
• Thyroid failure in prepubertal period is associated with testicular enlargement and
alteration in sexual hormones.
• Decreased libido .
• There is macro orchidism without virilization.
• Greater longer the hypothyroidism persist greater is the degree of damage to the
testis.
• Hypothyroidism affects the motility of the sperm while hypothyroidism affects the
morphology of the sperm ( low sperm count with sperm motility effect).
• Thyroid auto antibodies interfere with spermatogenesis.
WHOM TO SCREEN
• It is recommended to screen women with signs and symptoms of hypothyroidism,
elevated levels of cholesterol, menstrual irregularities, and infertility. However, it is
preferred to screen all infertile women for thyroid disorders even though it is
controversial.
• ATA 2017 guidelines recommend screening for all infertile women but not so by
ASRM (2015). The SOGC committee opinion (2020) suggests that the clinicians who
check thyroid stimulating hormone (TSH) in all infertile women with minor
elevations of TSH (4–10 mIU/L) should have repeat test at least 4 weeks later
because minor elevations in TSH will normalize.
• The recent European Thyroid association (ETA 2021) recommend that all women
seeking medical advice for subfertility should be screened for serum TSH and
TPOAb. Since overt thyroid dysfunction can negatively affect fertility and pregnancy
outcomes, this approach has gained support.
CONTD…..

• Thyroid evaluation should be done

1. Any woman who wants to get pregnant with family history of thyroid
problem
2. having irregular menstrual cycle
3. had more than 2 miscarriages
4. Unable to conceive even after 1 year of unprotected intercourse
WHAT TESTS TO ORDER

• TSH alone if hypothyroidism is suspected.

• TSH and FT4 if hypothyroidism is suspected or for routine evaluation.
• FT3 if T3 toxicosis is suspected.
• For follow up of treatment only TSH
• Total T3 and Total T4 does not carry any significant value.
• Radio immune assay(RIA) should not be done in pregnancy and lactation.
• RIA – Third or fourth generation is best.
• Chemiluminescence immune assay is gold stand for FT4 but expensive and
less widely available.
TREATMENT

• Treating infertility caused by thyroid disease or in which a thyroid problem is a

contributing factor is, for the most part, a matter of using medication to bring
thyroid hormone levels within a normal range. For men, this may help
improve sperm quality and quantity.
• For women, normalizing thyroid hormone levels can help correct menstrual or
ovarian problems that may be causing infertility. Ideal thyroid hormone levels
also are necessary for conception to take place, for infertility treatments such
as IVF to be successful, and for a pregnancy to remain viable.
TREATMENT CONTD…..

• In the case of hypothyroidism, this means hormone replacement therapy.20

The medication most often prescribed is levothyroxine—a synthetic form of
T4 available under several brand names including Synthroid, Levothroid,
Levoxyl, and Tirosint. Sometimes synthetic triiodothyronine is included in
treatment for thyroid disease, but this is not recommended during pregnancy
because T3 does not cross the placenta.
• Treatment for hyperthyroidism is an antithyroid drug, which works by causing
the thyroid to make less thyroid hormones.21 Typically, Tapazole
(methimazole) is the preferred antithyroid medication for treating
hyperthyroidism; however, this drug is associated with birth defects when
taken during the first trimester of pregnancy. The alternative, propylthiouracil,
is usually the preferred antithyroid medication for women who have
hyperthyroidism of Graves' disease and are trying to conceive. However, it can
cause severe liver damage in adults and children.
• Oral levothyroxine is FDA approved for the treatment of primary, secondary,
and tertiary hypothyroidism. Primary hypothyroidism is due to the problem in
the thyroid gland, with the most common cause being an autoimmune
condition (Hashimoto thyroiditis) and iatrogenic hypothyroidism (after
thyroidectomy). Secondary hypothyroidism is when the problem is in the
pituitary gland (from adenomas to post-surgical intervention), and there is a
decrease in the production of thyroid-stimulating hormone(TSH). Tertiary
hypothyroidism is rare, and the problem is in the hypothalamus with decrease
production of a thyroid-releasing hormone(TRH).

• Additionally, levothyroxine has FDA approval for pituitary thyrotropin

suppression as an adjunct to surgery and radioiodine therapy to manage
thyrotropin-dependent well-differentiated thyroid cancer. Injectable
levothyroxine is FDA approved for the treatment of myxedema coma or
severe hypothyroidism.
 MECHANISM OF ACTION OF LEVO
THYROXINE
• Levothyroxine(T4) is a synthetic version of the body’s natural thyroid hormone:
thyroxine(T4). Normally, the hypothalamus secretes thyrotropin-releasing hormone(TRH),
which then stimulates the anterior pituitary to secrete thyroid-stimulating hormone(TSH),
which subsequently stimulates the thyroid to secrete 80% thyroxine (T4) and 20% L-
triiodothyronine(T3). 50% of thyroxine (T4) then gets converted to its active metabolite L-
triiodothyronine (T3). The thyroid hormones then work by binding to thyroid receptor
proteins contained within the cell nucleus.[7]

• Once inside the nucleus, thyroid hormones work by directly influencing DNA transcription
to increase body metabolism by increasing gluconeogenesis, protein synthesis, the
mobilization of glycogen stores, and other functions.[8] In scenarios where this process is
interrupted (as seen in primary, secondary, or tertiary hypothyroidism), levothyroxine(LT4)
can mimic the body’s endogenous T4 production by the thyroid
DOSING
• For the treatment of hypothyroidism (oral): Adults who are healthy and
diagnosed with hypothyroidism for a few months should receive an initial
dose of 1.6 mcg/kg/day with a 12.5 to 25 mcg/day dose adjustment every 6
to 8 weeks as needed.
• Adults with cardiac disease or elderly over 65 years old and hypothyroidism
should receive an initial dose of 25 mcg/day with a dose adjustment of 12.5 to
25 mcg every 4 to 6 weeks as needed.
• If a patient has a diagnosis of hypothyroidism before pregnancy, adjust the
dose of levothyroxine as needed. After pregnancy, the dose of levothyroxine
should decrease to 1.6 mcg/kg/day.
ADVERSE EFFECTS

• Generally, adverse events resulting from incorrect dosing (excessive dosing)

often form a hyperthyroid-like picture or an allergic reaction to the excipient
of the levothyroxine tablets. Levothyroxine 50 mcg tablets don't contain
allergic excipients, so there is a decreased risk for immune reactions
CARDIOVASCULAR ADVERSE DRUG
REACTION

• Angina pectoris
• Tachycardia
• Palpitations
• Arrhythmia
• Myocardial infarction
• Atrial fibrillation
NEUROPSHYCHIATRIC ADVERSE
REACTION

• Anxiety
• Insomnia(advise the patient to take levothyroxine in the morning)
GASTRO INTESTINAL DRUG EFFECTS

• Weight loss
• Fatigue
• Diarrhoea
• Emesis
• Dermatological Adverse Drug Reactions
ENDOCRINE ADVERSE DRUG REACTIONS

• Goiter
• Menstrual irregularities
• Heat intolerance
• Decreased bone mineral density (a result of TSH suppression)
CONTRAINDICATION

• Acute myocardial infarction

• Uncorrected adrenal insufficiency
• Acute myocarditis, pancarditis
• Active cardiac arrhythmias
• Thyrotoxicosis
• Hyperthyroidism
MONITORING
• In adults, monitor TSH levels approximately 6 to 8 weeks after initiating
treatment with levothyroxine. Upon achieving the correct dosing of
levothyroxine, monitor TSH levels after 4 to 6 months and then every 12
months. Patients should receive education about the symptoms of
hyperthyroidism and contact their clinician for medication dose decrease if
those symptoms were to appear. It is important to consider that the TSH is
unreliable in patients with secondary or tertiary hypothyroidism, and the best
indicator to adjust dosing will be the free T4 or total T4.

• The clinician should counsel the patient to use the same levothyroxine brand
because of the narrow therapeutic index.
ATA & AACR (2017) RECOMMENDS

• Administration of L –thyroxine may be considered in sub clinically hypothyroid

, women are attempting natural conception.
• With a presumption to prevent progression to more significant
hypothyroidism once pregnancy is achieved.
• Further low dose LT4 therapy ( 25 to 50 microgram) carries minimal risk.
ATA 2017 RECOMMENDS

• Sub clinically hypothyroid women undergoing IVF or ICSI should be treated

with LT4 to improve IVF-ICSI results
• Goal of treatment is to achieve a TSH < 2.5 mU/L
TREATMENT STRATEGIES

• Intravenous immunoglobulins
• Treatment with L thyroxine
• Steroids not to be used
• ICSI to avoid fertilization failure
HOW THE PATIENT IMPROVES

• Feels better in 2-3 weeks .

• Reduction in weight is the first improvement.
• Facial puffiness then starts coming down .
• Skin changes , hair changes take long time to regress.
• TSH starts showing decrements from the high value.
COPING
• There's no doubt that infertility is one of the most challenging medical problems an
individual or a couple faces.22 Even when the cause or causes of infertility are discovered,
the stress and continued uncertainty can be overwhelming for those wishing to have a
child.

• That said, when it turns out that thyroid disease is involved in infertility it should be
heartening to know that, whether the man or woman is affected, it generally can be
successfully dealt with via medication to get thyroid levels back within a normal range.
During this time, it's important for both partners to be open and supportive of one another
during treatment. Once thyroid levels are normalized, the chances of conception should be
greatly increased provided both partners are otherwise healthy .