Thyroid and Pregnancy Loss Prof. Andrea R. Genazzani , MD, PhD, HcD, FRCOG, FACOG President of the International Society of Gynecological Endocrinology (ISGE) President of the European Society of Gynecology (ESG) General Secretary of the International Academy of Human Reproduction (IAHR) Chairman of the FIGO Working Group on Post Reproductive Health (FIGO) Department of Clinical and Experimental Medicine University of Pisa, Italy -
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Thyroid and Pregnancy Loss
Prof. Andrea R. Genazzani , MD, PhD, HcD, FRCOG, FACOG
President of the International Society of Gynecological Endocrinology (ISGE) President of the European Society of Gynecology (ESG) General Secretary of the International Academy of Human Reproduction (IAHR) Chairman of the FIGO Working Group on Post Reproductive Health (FIGO) Department of Clinical and Experimental Medicine University of Pisa, Italy -
Declaration for Conflict of Interest
Consultant and occasional presentations for : Abbott, Alfa-Sigma, Bionorica, Endoceutics, Exeltis, Grunenthal, Mithra, MSD, Se-Cure Pharma, Serelys Pharma,
The hypothalamic-pituitary-thyroid axis
The hypothalamic-pituitary-
thyroid axis follows the rules
similarly to all the other
endocrine axes.
TRH receptors are distributed
throughout the brain and
apparently in certain areas
TRH acts as a
neurotransmitter.
TRH is a potent stimulus to
TSH despite a half-life in
blood of less than 1 minute.
T3 and T4 modulates TSH
secretion.
TRH
TSH
T4 - T3
PRL
GnRH
LH - FSH
aromatase
gonadal steroids
SHBG
INTERACTION BETWEEN HYPOTHALAMIC-PITUITARY AXES
Thyroid and reproduction
Thyroid diseases, both hypo or hyper function, may lead to reproductive disturbances.
menstrual irregularities oligomenorrhea
amenorrhea menorrhagia
hyperandrogenism hyperestrinism
chronic anovulation PCOS
Estrogens and TSH secretion
Ramey JN et al., J Clin Endocrinol Metab , 1975
Such control seems to
be exerted mainly at
the hypothalamus-
pituitary levels.
Women taking oral
contraceptive have a
greater TSH response
to TRH, compared to
euthyroid control
women.
Gonadal steroids modulate the control of thyroid function.
•Infertile patients present a greater
prevalence of thyroid autoimmunity than
fertile patients
•Increasing evidence suggest that
spontaneous miscarriage is increased in
women positive for antithyroid antibodies,
regardless of their thyroid function status
Interactions between thyroid and ovary
•The presence of thyroid autoimmunity has
also been related to recurrent embryo
implantation failure and poor prognosis
undergoing assisted reproductive
techniques Poppe K et al., Thyroid 2002.
Stagnaro-Green A et al., JAMA 1990.
Prummel MF et al., Eur J Endocrinol 2004.
De Carolis C et al., Am J Reprod Immunol 2004.
A normal secretion of circulating thiroid
hormones is crucial for normal
reproductive function
Changes in fT3 cause
Gonadotropin altered secretion
Abnormal menstrual cyclicity and consequent
reduction of fertility
T4 promotes angiogenesis
in follicular vascularization in rats through an
up-regulation of mRNA expression of
major angiogenetic factors
Interactions between thyroid and ovary
Oocyte maturation needs normal levels of
thyroid hormones
Essential to obtain:
Good fertilization rates
Embryo development
and
Interactions between thyroid and ovary
Gonadotropin-induced increase in estradiol
during IVF cycles may cause thyroxin-
binding-globulin production to increase.
By consequence, the bioavailability of free
thyroxin decreases.
This would determine a subclinical
hypothyroidism, which in turn may play a role
in the failure of the embryo implantation
Physiopathology
Altered balance between free/bound T4
Altered balance
between free/bound
T and/or E2
“Thyroid Autoimmunity” means
the presence of circulating Auto-
antibodies directed against
thyroid, specifically of antibodies
anti-Tireoperoxidase
(anti-TPO) and/or anti-
Tireoglobulin (anti-TG), with or
without a clinical thyroid
dysfunction
Thyroid AutoImmunity
(TAI) is the more prevalent
autoimmune disease,
concerning about 5 - 20 % of
female population in
reproductive age (principal
cause of thyroid disease)
Many studies in literature have showed a connection
between thyroid autoimmunity (TAI) and infertility.
However, TAI can be present in complete absence of
clinically manifested disease.
Thyroid Autoimmunity
Indeed, active immunization of
mice with human Tg resulted in
the production of anti-Tg
autoantibodies and pregnancy
failure manifested by an
increased fetal resorption rate.
AUTOIMMUNITA’ ANTITIROIDEA Thyroid Autoimmunity:
Animal models
Matalon ST et al., Hum Reprod 2003;
Lee YL et al.,Fertil Steril 2009;
Recent experiments in animals
have shown that antithyroid
antibodies may interfere with
oocyte fertilization and embryo
development.
In a similar experimental
mouse model of
autoimmune thyroiditis,
anti-TPO antibody positivity
was associated with
reduced fertility and litter
size because of a higher
incidence of fetal loss.
Anti-TPO antibodies were
actually evidenced on the
embryo surface.
Thyroid Autoimmunity:
Animal models
Matalon ST et al., Hum Reprod 2003;
Lee YL et al.,Fertil Steril 2009;
Some researchers
studied the effects of
anti-TPO autoantibodies
on embryo development
before and during
implantation.
Antibodies bind embryo
early before
implantation, and they
might hamper embryo
development in early
division steps.
AUTOIMMUNITA’ ANTITIROIDEA Thyroid Autoimmunity
what about pregnancy?
• Thyroid dysfunction and thyroid autoimmunity are prevalent among
women at reproductive age and are associated with adverse
pregnancy outcomes.
• Subclinical hypothyroidism may be associated with ovulatory
dysfunction and adverse pregnancy outcome.
• Even minimal hypothyroidism can increase rates of miscarriage and
fetal death and may also have adverse effects on later cognitive
development of the offspring.
• Pregnancy affects thyroid economy with significant changes in iodine
metabolism, serum thyroid binding proteins, and the development of
maternal goiter, especially in iodine-deficient areas.
• The thyroid gland and gonadal axes interact continuously before and
during pregnancy.
• Autoimmune thyroid disease is present in 5-20% of unselected
pregnant women.
• Isolated hypothyroxinemia has been described in approximately 2% of
pregnancies, without serum TSH elevation and in the absence of
thyroid auto antibodies.
• There is an association of:
• Preeclampsia
• Anemia
• Low birth weigh
• Stillbirth
• Rarely, congestive heart failure can occur
• Miscarriage
• All antithyroid drugs cross the placenta and may potentially affect fetal
thyroid function.
Physiology of Thyroid: Iodine
need of iodine incerases 50%
Yarrington and Pearce, Clinic Obstet and Gynecol 2011