Natural selection of human embryos: impaired decidualization of endometrium disables embryo-maternal interactions and causes recurrent pregnancy loss.
BACKGROUND
Recurrent pregnancy loss (RPL), defined as 3 or more consecutive miscarriages, is widely attributed either to repeated chromosomal instability in the conceptus or to uterine factors that are poorly defined. We tested the hypothesis that abnormal cyclic differentiation of endometrial stromal cells (ESCs) into specialized decidual cells predisposes to RPL, based on the observation that this process may not only be indispensable for placenta formation in pregnancy but also for embryo recognition and selection at time of implantation.


RESULTS
Analysis of mid-secretory endometrial biopsies demonstrated that RPL is associated with decreased expression of the decidual marker prolactin (PRL) but increased levels of prokineticin-1 (PROK1), a cytokine that promotes implantation. These in vivo findings were entirely recapitulated when ESCs were purified from patients with and without a history of RPL and decidualized in culture. In addition to attenuated PRL production and prolonged and enhanced PROK1 expression, RPL was further associated with a complete dysregulation of both markers upon treatment of ESC cultures with human chorionic gonadotropin, a glycoprotein hormone abundantly expressed by the implanting embryo. We postulated that impaired embryo recognition and selection would clinically be associated with increased fecundity, defined by short time-to-pregnancy (TTP) intervals. Woman-based analysis of the mean and mode TTP in a cohort of 560 RPL patients showed that 40% can be considered "superfertile", defined by a mean TTP of 3 months or less.


CONCLUSIONS
Impaired cyclic decidualization of the endometrium facilitates implantation yet predisposes to subsequent pregnancy failure by disabling natural embryo selection and by disrupting the maternal responses to embryonic signals. These findings suggest a novel pathological pathway that unifies maternal and embryonic causes of RPL.
Salker
Madhuri
M
Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Hospital, London, United Kingdom.
Teklenburg
Gijs
G
Molokhia
Mariam
M
Lavery
Stuart
S
Trew
Geoffrey
G
Aojanepong
Tepchongchit
T
Mardon
Helen J
HJ
Lokugamage
Amali U
AU
Rai
Raj
R
Landles
Christian
C
Roelen
Bernard A J
BA
Quenby
Siobhan
S
Kuijk
Ewart W
EW
Kavelaars
Annemieke
A
Heijnen
Cobi J
CJ
Regan
Lesley
L
Macklon
Nick S
NS
Brosens
Jan J
JJ
D000026:Abortion, Habitual / Q000209:etiology*; D000328:Adult; D002454:Cell Differentiation; D003656:Decidua / Q000473:pathology*; D010064:Embryo Implantation; D004622:Embryo, Mammalian; D053595:Embryonic Stem Cells / Q000166:cytology; D004717:Endometrium / Q000473:pathology*; D005260:Female; D005298:Fertility; D005768:Gastrointestinal Hormones / Q000032:analysis; D006801:Humans; D008597:Menstrual Cycle; D011247:Pregnancy; D011388:Prolactin / Q000032:analysis; D012641:Selection, Genetic; D017154:Stromal Cells / Q000166:cytology; D042662:Vascular Endothelial Growth Factor, Endocrine-Gland-Derived / Q000032:analysis; D055815:Young Adult
D005768:Gastrointestinal Hormones; C467610:PROK1 protein, human; D042662:Vascular Endothelial Growth Factor, Endocrine-Gland-Derived; D011388:Prolactin