The endocrinology of the pregnancy - Gyllenbergs · The endocrinology of the pregnancy Cornelis B....
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The endocrinology of
the pregnancy
Cornelis B. Lambalk
VU University Medical Center
Amsterdam, The Netherlands
The XXV Signe and Ane Gyllenberg Symposium. Childbearing,
parenthood and outcomes of children-an interplay between
psychogical and biological factors, Espoo, Finland, September
21st-23rd, 2017
“Endocrinology of pregnancy”
• Endocrinology of Normal Pregnancy
• Endocrinology of Implantation
• Endocrinology of Early Pregnancy Loss
• Endocrinology of Ectopic Pregnancy
• Endocrinology of Preterm Labour
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‘Fetal origin of development in later life’
‘The womb may be more important than the home’
Introduction
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The reproductive endocrinology of
the (PCOS & Twin) pregnancy
Cornelis B. Lambalk
VU University Medical Center
Amsterdam, The Netherlands
The XXV Signe and Ane Gyllenberg Symposium. Childbearing,
parenthood and outcomes of children-an interplay between psychogical
and biological factors, Espoo, Finland, September 21st-23rd, 2017
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Outline
• Introduction
• Background
• Polycystic ovarian syndrome and endocrinology of pregnancy
• Conclusions
• The endocrinology of the twin pregnancy
• Conclusions
8Cohen-Bendahan et al Neurosc Biobehav Rev 2005
0 6 10 14 18 22 26 30 34 38 42
0
17.5
15
12.5
10
7.5
5
2.5
Estrogens [ng/mL]
Estradiol
Estriol
Estrone
250
200
150
100
50
0
0 6 10 14 18 22 26 30 34 38 42
Progesterone [ ng/L]
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Sex differences in prenatal hormone levels
Van de Beek et al Arch Sex Behav 2009
12Kuijper et al RBM Online 2013
13Kuijper et al RBM Online 2013
14Kuijper et al RBM Online 2013
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Cord blood hormones and human development
Hollier et al Front Endocrinol 2014
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PCOS
Polycystic ovary syndrome (PCOS)
Criteria:
• clinical and/or biochemical signs of hyperandrogenism
• polycystic ovaries on ultrasound
• oligo- or anovulation
• 5-10 % of women
• Heredity 80 %
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Androgens in girls with PCOS mothers
Is there fetal hyperandrogenism in the PCOS pregnancy?
Does prenatal exposure to androgens cause PCOS?
Origin of fetal androgens in PCOS women?
• Maternal origin placental passage during gestation
• Fetal origin inherited trait apparent during/after
puberty
PCOS
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PCOS
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PCOS
Abbott et al, 1998. Trends Endocrinol Metab 9:62-67
Kent et al, 2008. J Clin Endocrinol Metab 93:1662–1669
Lummaa et al, 2007. Proc Natl Acad Sci USA 104:10915-10920
20Palomba et al Clin Endocrinol 2012
PCOS
mothers
Control mothers
P
Boys
0.87 +/- 0.21
(n = 17)
0.80 +/- 0.16
(n = 21)
n.s.
Girls
0.53 +/- 0.12
(n = 13)
0.36 +/- 0.10
(n = 12)
0.019
Free testosterone (pmol/l) in amniotic fluid
22Palomba et al Clin Endocrinol 2012
Autistic Quotient
23Kosidou et al Mol Psych 2016
Autistic Spectrum Disorder ASD
25Wu et al Hum Reprod 2017
26Homburg et al 2017, Reproductive Biology and Endocrinology
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PCOS
However,
Medland et al, 2008. Twin Res Hum Genet 11:481-487
Kuijper et al, 2009. J Clin Endocrinol Metab, 94:1987-1990
Heritability of PCOS in a Dutch Twin-family study
Vink et al, 2006. J Clin Endocrinol Metab, 91:2100-2104
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Aim of our study:
Compare androgen (and estrogen) levels during
gestation and in umbilical cord blood from
children born from PCOS mothers and controls
Caanen et al Eur J Endocrinol 2016
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Subjects
- Prospective, large cohort study, 523 mothers
- Hormones throughout pregnancy
- Natural pregnancy – assisted reproduction
Methods
Caanen et al Eur J Endocrinol 2016
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Subjects
Cases: PCOS defined by Rotterdam criteria (N=20)
Controls (N=83):
• regular cycle (<35 days)
• no acne or hirsutism
• natural conception
Inclusion:
• age > 18
• singleton pregnancies
Exclusion:
• multiple gestation
• delivery < 32 weeks
• assisted reproduction
Methods
Caanen et al Eur J Endocrinol 2016
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Time points
Maternal blood samples:• 20 weeks of gestation• delivery
Neonatal blood samples:• cord blood
Hormones measured*
Estrogens:• estrone (E1)• estradiol (E2)• estriol (E3)
Androgens:• testosterone (T)• androstenedione (ADION)• dehydroepiandrosterone sulfate (DHEAS)
*using LCMS technology (Salt Lake City)
Methods
Caanen et al Eur J Endocrinol 2016
Regression analyses
Maternal serum levels (means) - 20 weeks
PCOS mothers pregnant with a girl:
significantly higher ADION and T levels
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Girls Boys
PCOS Non-PCOS P-value PCOS Non-PCOS P-value
ADION (ng/ml) 2.13 1.08 0.034 2.60 1.24 0.084
T (ng/ml) 1.04 0.507 0.019 1.15 0.56 0.113
DHEAS (ng/ml) 3.12 2.76 0.788 4.18 2.58 0.654
E1 (pg/ml) 3889.3 4469.4 0.928 5433.3 3128.7 0.061
E2 (pg/ml) 6441.4 6942.2 0.559 7250.0 6074.4 0.300
E3 (pg/ml) 2213.6 2106.2 0.815 2345.0 1972.9 0.139
Results
Caanen et al Eur J Endocrinol 2016
Regression analyses
Maternal serum levels (means) - delivery
PCOS mothers pregnant with a girl:
significantly higher ADION and T levels
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Girls Boys
PCOS Non-PCOS P-value PCOS Non-PCOS P-value
ADION (ng/ml) 4.22 1.62 0.009 4.48 2.04 0.537
T (ng/ml) 2.79 0.91 0.004 2.57 1.1 0.675
DHEAS (ng/ml) 9.11 6.85 0.360 5.16 6.09 0.940
E1 (pg/ml) 9786.7 8845.3 0.690 13625 7454.5 0.015
E2 (pg/ml) 8184.8 9882.3 0.979 13850 9460.0 0.208
E3 (pg/ml) 2342.3 4392.9 0.461 19922.3 7843.4 0.341
Results
Caanen et al Eur J Endocrinol 2016
Regression analyses
Cord blood (means)
Girls from PCOS mothers: no elevated androgens
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Girls Boys
PCOS Non-PCOS P-value PCOS Non-PCOS P-value
ADION (ng/ml) 0.45 0.84 0.094 0.49 0.54 0.834
T (ng/ml) 0.12 0.15 0.959 0.178 0.20 0.676
DHEAS (ng/ml) 4.9 5.65 0.577 2.98 2.90 0.162
E1 (pg/ml) 10511.1 22025.7 0.007 14734.5 21123.9 0.718
E2 (ng/ml) 5426.1 8919.2 0.052 9601.5 9196.4 0.520
E3 (ng/ml) 57412.1 52729.2 0.836 51568 55135.1 0.378
Results
Caanen et al Eur J Endocrinol 2016
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• There are no indications of increased fetal androgen levels of
PCOS mothers in their offspring, despite consequently maternal
elevated levels throughout the pregnancy
• Apparently placental aromatase sufficiently protects
Conclusions (1)
Caanen et al Eur J Endocrinol 2016
• There is a significant reduction of E1 levels - E2 and ADION
tend to be reduced, only in the girls
• These gender specific differences may suggest a fetal gonadal
origin of altered sex-steroidogenesis
• It remains to be determined if this altered setting is intrinsic to
the female fetus of a PCOS mother, or still of maternal origin
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Conclusions (2)
Caanen et al Eur J Endocrinol 2016
Alterations in cord blood parameters of female
offspring of women with polycystyc ovary
syndrome: a systematic review
Schouten et al RBM Online submitted 39
Systematic review 2017
41Schouten et al
Methods
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Study Type of study Inclusion period Place
Cord
blood
Hormone
analyzing
method
Definition
PCOS
PCOS
n =
Control
n =
Anderson
2010
Prospective case-
control study
Not reported Chicago, USA Mixed LC-MS NIH 17 14
Barry
2010
Case-control Not reported University College
Hospital and Royal Free
Hospital, London
Venous IA (ECI) Rotterdam 10 20
Caanen
2016
Prospective
cohort study
2004-2009 Multicentre,
the Netherlands
Mixed LC-MS/MS Rotterdam 20 83
Daan
2016
Cross-sectional
case-control
study
PCOS: 2008-2010
Control: 2011-2014
Multicentre,
the Netherlands
Mixed LC-MS/MS Rotterdam 61 82
Maliqueo
2013
Case-control Not reported Santiago, Chile Mixed IA (RIA) Rotterdam* 20 30
Vanky
2012
Substudy of
PREGMET study
(prospective,
randomized,
double-blind
multicenter trial)
Not reported Trondheim, Norway Arterial
Venous
IA (ELISA) Rotterdam 68 -
Schouten et al RBM Online submitted
Results
43Schouten et al
Results
44Schouten et al RBM Online submitted
Results: overview
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Results: overview
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Conclusions (3)
• No clear indication of elevated androgen levels
• Different concentrations of steroids, E1 and E 2 lower
• Different reproductive endocrinology in female PCOS offspring
at time of birth
• Focus on placental enzyme activity
• IPD meta-analysis is on its way
48Schouten et al RBM Online submitted
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Outline
• Introduction
• Background
• Polycystic ovarian syndrome and endocrinology of pregnancy
• Conclusions
• The endocrinology of the twin pregnancy
• Conclusions
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Estrogens
Fetal
Maternal
DZ MZ Singleton
Endocrine assumptions in twins
Kuijper et al Fertil Steril 2015
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Androgens
DZ ♀♀ ♀♂
Maternal
Fetal
Endocrine assumptions; opposite sex twin girls
Kuijper et al Fertil Steril 2015
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Singleton mothers mid-gestation
N=248
Singleton mothers at delivery
N=178
Neonatal samples at delivery
N=178
♀N=89 ♂N=88
NC
N=54
Included after GA 20 weeks: 3
Blood sample not taken at delivery: 73
ART
N=35
NC
N=48
ART
N=40Kuijper et al Fertil Steril 2015
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Twin mothers mid-gestation N=204
Twin mothers at delivery N=174
Neonatal samples of the twins at delivery
N=156 (sample from both children) and N=12 (sample
from only one child)*
NC N=14
ART N=1
NC N=12
ART N=16
? N=2
MZ pairs N=14
N=1*
MZ pairsN=15
N=1*
DZ pairs N=29
N=1*
DZ pairsN=33
N=4*
♂♀♂♂♀♀
DZ pairs N=65
N=5*
NC N=11
ART N=2
? N=3
NC N=10
ART N=24
? N=3
NC N=25
ART N= 41
? N= 4
Included after GA 20 weeks: 24
Blood sample not taken at delivery: 54
Kuijper et al Fertil Steril 2015
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0
1
2
3
4
31 33 35 37 39 41 43
gestational age (weeks)
MZ
DZ
Singleton
Kuijper et al Fertil Steril 2015
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Twin vs singleton Estrogen & Progesterone
Kuijper et al Fertil Steril 2015
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Twin vs Singleton Androgens
Kuijper et al Fertil Steril 2015
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MZ versus DZ
• Overall no differences
• No differences between MZ boys and DZ boys
• DZ girls versus MZ girls• Higher Estriol • Lower FSH
Kuijper et al Fertil Steril 2015
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Same sex twin boys vs opposite sex twin boys
Kuijper et al Fertil Steril 2015
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No indications for androgen over exposure
Same sex twin girls vs opposite sex twin girls
Androgens
DZ ♀♀ ♀♂
Maternal
Fetal
Kuijper et al Fertil Steril 2015
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Endocrine facts in twins
Estrogens
Fetal
Maternal
DZ MZ Singleton
Kuijper et al Fertil Steril 2015
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• Estrogen and progesterone concentrations are higher in mothers of
twins compared to singletons
• In contrast to what is generally assumed opposite-sex twin babies
are in utero not overexposed to sex steroid hormones at time of
birth
• In opposite-sex twins we found no distinct androgenic effects of
boys on their female co-twin
• DZ girls experience a higher estrogenic milieu compared to MZ
girls
• The hypothalamic-pituitary-gonadal axis in male newborns with a
female co-twin is partially suppressed since these boys have lower
LH and inhibin B levels compared to same sex dizygotic twin boys
Conclusions (4)