thyroid function: female fertility & art
TRANSCRIPT
Thyroid function:
Female fertility &
ART
Aboubakr Elnashar
Benha university Hospital, EGYPT
ABOUBAKR ELNASHAR
A. Thyroid Function and
female fertility
ABOUBAKR ELNASHAR
I. Thyrotoxicosis
a. Hormonal changes. Estrogen levels: 2- to 3-fold higher
{SHBG changes or
increase in free estrogen levels}
ABOUBAKR ELNASHAR
b. Menstrual disturbances.
Hypomenorrhea earliest clinical changes
Amenorrhea, Oligomenorrhea, anovulation. {Biochemical and hormonal abnormalities nutritional disturbances emotional upheavals}
Less than early studies: 3 times more than in control {better medical care and public awareness, thyroid disturbances are diagnosed much earlier when the symptoms are still mild}
Related to: Total T4 levels not to total T3
ABOUBAKR ELNASHAR
c. Fertility Reduced fertility
although most thyrotoxic women remain
ovulatory (Sturgis et al,1952).
Infertility: 5.8% (Joshi et al., 1993)
ABOUBAKR ELNASHAR
d. R-I131 and reproduction. Hyperthyroidism:
10 mCi (370 MBq): negligible genetic risk: no
significant detrimental effect on gonads
Cancer:
10–20 times higher:
Avoid conception at least 6 months
ABOUBAKR ELNASHAR
II. Hypothyroidism Prevalence:
Increasing with advancing age.
Most cases •Chronic autoimmune thyroiditis (3.5/1000 women/y), followed by •Destructive TT for thyrotoxicosis (0.6/ 1000 women/y). Risk factors for progression from SCH to overt
hypothyroidism (OH): thyroid antibodies already elevated TSH.
ABOUBAKR ELNASHAR
Screening:
/5 yrs beginning at 35y
/2 yrs beginning at 60y, or
any symptoms suggesting hypothyroidism (Sperof et al, 2010)
ABOUBAKR ELNASHAR
a.Hormonal changes. Gn levels: normal.
However, blunted or delayed LH response to GnRH
PRL
± increased
{hypothalamic TRH increasing both TSH and PRL }:
±Galactorrhea
These disturbances disappear after T4 administration.
ABOUBAKR ELNASHAR
b. Menstrual disturbances. Oligomenorrhea: most common
amenorrhea, polymenorrhea, and menorrhagia {1. Estrogen breakthrough bleeding secondary to anovulation. 2. Defects in hemostasis factors e.g. decreased levels of factors VII, VIII, IX, and XI) that occur in hypothyroidism}
Not related to: thyroid antibodies lower in recent studies: 3 times greater than in the normal population. {delayed diagnosis in the earlier studies: more severe clinical picture}
ABOUBAKR ELNASHAR
c. Fertility in SCH Definition
TSH or
TRH test: TSH response above 15 mIU/liter.
ABOUBAKR ELNASHAR
SCH and infertility
TSH:
significantly higher compared with the
controls.
ABOUBAKR ELNASHAR
AITD
No significant difference between infertile women
and controls.
Screening:
No {low incidence} (Zollenar et al, 2001)
LT4 treatment
Of SCH: pregnancy success rate of 44%.
ABOUBAKR ELNASHAR
SCH and miscarriage
TSH: high
More frequent miscarriages, irrespective of
the presence of AITD.
Screening
in recurrent pregnancy loss. Am Ass of endocrinology, 2013
Up Todate, 2013
ABOUBAKR ELNASHAR
SCH and OD:
OD:
SCH: 6.3%
SCH
precocious ovarian failure: 40%
OD: 15% (Abalovich et al. 2007).
Screening
In OD (Lincoln et al.1999; Poppe et al, 2007).
ABOUBAKR ELNASHAR
SCH and fertilization failure Both Gn and T4 necessary to achieve maximum fertilization rates and blastocyst development (Cramer et al. 2003)
Serum TSH levels are a significant predictor of fertilization failure in women undergoing IVF.
ABOUBAKR ELNASHAR
c. Fertility in OH.
Infertile females
SCH: 4%
OH: 3.3% (Arojoki et al. ,2000)
Myxedema
Anovulation
inadequate corpus luteum (10%).
menstrual irregularities 70% (Goldsmith et al., 1952).
Myxedema: associated with hypothyroidism; the facial changes are distinctive, with
swollen lips and thickened nose. myxedematous
ABOUBAKR ELNASHAR
High frequency of infertility in hypothyroidism 1. Altered peripheral estrogen metabolism 2. Hyperprolactinemia 3. Defects in hemostasis 4. Disturbances in GnRH secretion: an abnormal
pulsatile release of LH
ABOUBAKR ELNASHAR
Treatment with LT4:
normalize PRL levels
normal LH responses to LHRH
reduce menstrual disturbances
increase the chances of spontaneous fertility
ABOUBAKR ELNASHAR
d. Thyroid autoimmunity and fertility.
AITD
Prevalence:
5 and 15%:
most common endocrine disorders in women of
reproductive age.
often undiagnosed
{No overt thyroid dysfunction for several years} (Poppe et al, 2007).
Formal names
Thyroid Peroxidase Antibody : TPO-Ab
Thyroglobulin Antibody: Tg-Ab
ABOUBAKR ELNASHAR
AITD and infertility
Most studies:
increased prevalence of AITD (Kaprara et al, 2007, Krassas et al, 2008).
Reference Control Infertility
Roussev etal.(1996)
7% 65%
Kaider et al (1999) 10% 81%
Reimand et al.(2001) 15% 41%
ABOUBAKR ELNASHAR
Some studies: no significant difference (Wilson et al.1975, Abalovich et al. ,2007)
Pooling together all the studies: Significantly increased incidence of AITD in female infertility.
ABOUBAKR ELNASHAR
Mechanisms Adequate levels of circulating TH are important for normal reproductive function. T3 modulates FSH and LH action on steroid biosynthesis, and multiple T3 binding sites have been identified in granulosa and stromal cells, and human oocytes (Cecconi et al, 1999)
Any impairment of T3 locally (as in AITD): disruption of reproductive function.
ABOUBAKR ELNASHAR
AITD and PCOS:
AITD in PCOS: 3-fold greater than controls. (Janssen et al. , 2004)
1. Thyroid Peroxidase Antibody
2. Thyroglobulin Antibody
3. US hypoechoic areas characteristic of AITD,
Control PCOS
8% 27% Elevated TPO-Ab1 and TG-Ab2
6.5% 42% US thyroid hypoechoic areas3
2% 11% Elevated serum TSH
ABOUBAKR ELNASHAR
AITD and Endometriosis: No association (Petta et al, 2007).
Increased prevalence of AITD in endometriosis (Poppe et al, 2002).
ABOUBAKR ELNASHAR
AITD and recurrent miscarriage: TPOAb measurement should be considered when
evaluating patients with recurren
miscarriage Grade A Am Ass of endocrinology, 2013
TSH and thyroid peroxidase antibodies Up To date, 2013
ABOUBAKR ELNASHAR
Screening
Over 35y:
1. Risk of progression to OH in women with SCH
2. Morbidity-associated hypercholesterolemia
frequently seen in such patients
3. Reversal of potentially unrecognized symptoms
associated with mild TH deficiency (Dancase et al,1997).
Endometriosis or OD is the cause of infertility
For thyroid dysfunction and autoimmunity (Poppe et al. 2008)
RPL
ABOUBAKR ELNASHAR
B. Thyroid Function and
ART
ABOUBAKR ELNASHAR
I. Background
E2 levels become very high
(1470–2203 pmol/liter or 4000–6000 ng/liter):
depends on the type and duration of COH.
: strain on the hypothalamic-pituitary-thyroid axis:
impair TH distribution and kinetics.
: increase in serum T4- binding globulin (TBG).
ABOUBAKR ELNASHAR
COH and OHSS:
marked increase of E2 and TBG: more
severe thyroid function changes than
observed with spontaneous pregnancy.
ABOUBAKR ELNASHAR
COH: Significant increase in TSH
compared with baseline values
{rapid 10-fold E2 increase after COH (3492 vs. 359
pmol/liter}
Reference After
COH
Before
COH
Poppe et al, 2004, 2005 3.3 1.8 TSH mIU/L
Muller et al., 2000 3.2 2.3
Poppe et al, 2004, 2005 13.2 12.4 FT4 ng/L
Muller et al., 2000 12.9 14.4
ABOUBAKR ELNASHAR
In hypothyroid-treated women:
Rapid increase (already after 4–6 wk gestation) in
T4 is required to maintain euthyroidism.
The timing of such increased requirement is
more rapid and pronounced when conception had
been achieved after ART
ABOUBAKR ELNASHAR
II. Clinical management Screening for thyroid disorders
1. Universal screening is not recommended for patients who
are planning pregnancy, including ART. Am Ass of endocrinology, 2013
2. Endometriosis and OD {increased prevalence of
AITD which is risk factor for the development of
hypothyroidism}.
3. Menstrual irregularities, hyperprolactinemia {LT4
therapy has beneficial effect}.
4. Before COH {severe changes in serum TSH and
FT4 may occur} (Poope et al, 2008).
ABOUBAKR ELNASHAR
ART could be postponed When hypothyroidism is treated and normal menses
restored {avoiding medical and psychological burden of ART}
(Poppe et al, 2007).
LT4 administration on ART: no beneficial impact (Negro et al, 2005).
ABOUBAKR ELNASHAR
Treatment with L-thyroxine
in women with normal serum TSH levels when they
are planning a pregnancy, including ART in the
immediate future, if they have
1. Positive TPOAb, particularly when there is a
history of miscarriage or past history of
hypothyroidism.
2. TSH is greater than 2.5 mIU/L Am Ass of endocrinology, 2013, Grade B
ABOUBAKR ELNASHAR
LT4 dosage should be increased
To obtain TSH < 2.5 mIU/liter before COH
{latter procedure increases TH demands}.
AITD treated with LT4 who underwent COH
developed OHSS
{E2 increase sharply and markedly:
severe hypothyroidism (TSH, 42 mIU/liter)
{association between OHSS and AITD}.
:increase daily LT4 dosage 4 wk before starting the
COH (Poppe et al, 2008)
ABOUBAKR ELNASHAR
Spontanous pregnancy:
by 30%
Pregnancy after COH treatment with Gn
stimulation or oral medications:
by 32% (Davis et al., 2007)
ABOUBAKR ELNASHAR
Thank you
ABOUBAKR ELNASHAR