Stress and Implantation Failure

  • Jeffrey L. Deaton
  • Bonnie Patel
  • Erika Johnston-MacAnanny
  • Jie Yu
  • Shannon D. Whirledge
  • Alexandra Wilson
  • J. David Wininger
  • Yimin Shu
  • Robert N. Taylor
  • Sarah L. BergaEmail author


The cornerstone of female reproduction is the hypothalamic-pituitary-ovarian (HPO) axis. This term is incomplete in that it omits reference to the uterus and endometrium, which are clearly critical to the most important step in reproduction, namely, implantation. Implantation requires that the endometrium become receptive to a healthy blastocyst. Thus, folliculogenesis must result not only in ovulation but also in the secretion of estradiol and progesterone in a pattern that prepares the endometrium for implantation. While implantation failure can be defined as absent hCG production after ovulation that is signaled by menstrual bleeding, the definition also encompasses transient hCG production that is not sustained, which is often called “chemical” pregnancy.

Stress has been implicated as a cause of implantation failure. Putative mechanisms by which stress could impair endometrial development and implantation include:
  1. 1.

    Alteration of the HPO axis resulting in inappropriate temporal or quantitative exposure of the endometrium to estradiol and progesterone;

  2. 2.

    Exposure of the endometrium to the myriad of endocrine signals that accompany stress including elevated glucocorticoids, reduced thyroxine, and alterations in other metabolic factors;

  3. 3.

    Stress-induced obesity that results in inappropriate exposure to metabolic factors such as glucose and insulin that alter both embryo health and endometrial development;

  4. 4.

    Exposure of embryos to laboratory stressors that alter embryogenesis and trophectoderm development We review these mechanisms in greater detail in the following sections.



Epigenetics Endometrial receptivity Functional hypothalamic hypogonadism Gametogenesis Glucocorticoids GnRH Kisspeptin Methylation 



Adrenocorticotropic hormone


Assisted reproductive technology


Body mass index


Cognitive behavior therapy


Central nervous system


Corticotropin-releasing hormone


DNA methyltransferase


Functional hypothalamic amenorrhea


Follicle-stimulating hormone


Gamma-aminobutyric acid


Growth hormone


Gonadotropin-inhibitory hormone


Human chorionic gonadotropin

HPA axis

Hypothalamic-pituitary-adrenal axis

HPO axis

Hypothalamic-pituitary-ovarian axis




In vitro fertilization


In vitro fertilization-embryo transfer

KNDy neurons

Kisspeptin-neurokinin B-dynorphin neurons




Neuropeptide Y


Oxidative stress

POMC-related peptides

Pro-opiomelanocortin-related peptides




Randomized controlled trial


RF-amide-related peptide-3


Reactive oxygen species


Tumor necrosis factor


Thyroid peroxidase antibody


Thyroid-stimulating hormone


Volatile organic compound


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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Jeffrey L. Deaton
    • 1
  • Bonnie Patel
    • 1
  • Erika Johnston-MacAnanny
    • 1
  • Jie Yu
    • 1
  • Shannon D. Whirledge
    • 2
  • Alexandra Wilson
    • 1
  • J. David Wininger
    • 1
  • Yimin Shu
    • 1
  • Robert N. Taylor
    • 1
  • Sarah L. Berga
    • 1
    Email author
  1. 1.Department of Obstetrics and GynecologyWake Forest School of MedicineWinston-SalemUSA
  2. 2.Department of Obstetrics, Gynecology and Reproductive SciencesYale University School of MedicineNew HavenUSA

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