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1
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
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“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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3
‘Fetal origin of development in later life’
‘The womb may be more important than the home’
Introduction
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4
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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5
Outline
• Introduction
• Background
• Polycystic ovarian syndrome and endocrinology of pregnancy
• Conclusions
• The endocrinology of the twin pregnancy
• Conclusions
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8Cohen-Bendahan et al Neurosc Biobehav Rev 2005
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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
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250
200
150
100
50
0
0 6 10 14 18 22 26 30 34 38 42
Progesterone [ ng/L]
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11
Sex differences in prenatal hormone levels
Van de Beek et al Arch Sex Behav 2009
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12Kuijper et al RBM Online 2013
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13Kuijper et al RBM Online 2013
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14Kuijper et al RBM Online 2013
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15
Cord blood hormones and human development
Hollier et al Front Endocrinol 2014
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16
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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17
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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19
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
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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
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22Palomba et al Clin Endocrinol 2012
Autistic Quotient
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23Kosidou et al Mol Psych 2016
Autistic Spectrum Disorder ASD
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25Wu et al Hum Reprod 2017
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26Homburg et al 2017, Reproductive Biology and Endocrinology
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28
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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29
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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30
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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31
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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32
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
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Regression analyses
Maternal serum levels (means) - 20 weeks
PCOS mothers pregnant with a girl:
significantly higher ADION and T levels
34
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
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Regression analyses
Maternal serum levels (means) - delivery
PCOS mothers pregnant with a girl:
significantly higher ADION and T levels
35
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
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Regression analyses
Cord blood (means)
Girls from PCOS mothers: no elevated androgens
36
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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37
• 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
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• 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
38
Conclusions (2)
Caanen et al Eur J Endocrinol 2016
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Alterations in cord blood parameters of female
offspring of women with polycystyc ovary
syndrome: a systematic review
Schouten et al RBM Online submitted 39
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Systematic review 2017
41Schouten et al
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Methods
42
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
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Results
43Schouten et al
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Results
44Schouten et al RBM Online submitted
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Results: overview
46
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Results: overview
47
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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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49
Outline
• Introduction
• Background
• Polycystic ovarian syndrome and endocrinology of pregnancy
• Conclusions
• The endocrinology of the twin pregnancy
• Conclusions
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50
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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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53
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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54
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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57
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
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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
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Same sex twin boys vs opposite sex twin boys
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No indications for androgen over exposure
Same sex twin girls vs opposite sex twin girls
Androgens
DZ ♀♀ ♀♂
Maternal
Fetal
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Endocrine facts in twins
Estrogens
Fetal
Maternal
DZ MZ Singleton
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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)