DeMayo, F. J., & Lydon, J. P. (2020). 90 YEARS OF PROGESTERONE: New insights into progesterone receptor signaling in the endometrium required for embryo implantation. Journal of molecular endocrinology, 65(1), T1-T14. https://doi.org/10.1530/JME-19-0212
DeMayo FJ, Lydon JP. 90 YEARS OF PROGESTERONE: New insights into progesterone receptor signaling in the endometrium required for embryo implantation. Journal of molecular endocrinology. 2020;65(1):T1-T14. doi:10.1530/JME-19-0212
DeMayo, F. J., and J. P. Lydon. "90 YEARS OF PROGESTERONE: New insights into progesterone receptor signaling in the endometrium required for embryo implantation." Journal of molecular endocrinology, vol. 65, no. 1, 2020, pp. T1-T14.
Progesterone signaling makes the uterine lining ready for an embryo
A 2020 review of mostly mouse studies reports that progesterone, through its receptor, prepares the uterine lining for embryo implantation. The authors trace the signals involved. Many questions remain open.
Key Findings
In mice, progesterone turns on Indian hedgehog in the uterine lining. The review calls this signal essential for receptivity and decidualization, the change that makes stromal cells into decidual cells.
Female mice whose uterine epithelium lacks either Gata2 or Pgr show similar infertility: a block in uterine receptivity and decidualization. GATA2 is responsible for epithelial PGR expression.
One regulatory element 19kb from the Ihh gene carries binding sites for PGR, GATA2, FOXA2 and SOX17. The element is associated with over 700 uterine genes.
In human biopsies, glandular epithelial PGR is strongest in the proliferative phase and undetectable in the mid-secretory phase, when FOXO1 is strongly expressed.
The authors cite studies estimating a 30% chance of natural conception per cycle in healthy women. They attribute the low rate in large part to implantation failure.
Interpretation
The paper is a review by two authors that covers a select number of signals and reports no new data. The authors say most mechanistic understanding comes from the mouse uterus, including genetically engineered mice. They say mouse and human share the basic steps of receptivity, so many signals may be shared, and they report differences too. Human evidence comes from biopsies and cell culture. The review reports no patient outcomes or treatment results. The authors predict better diagnosis of conditions linked to abnormal progesterone responsiveness.
RRM Context
Progesterone comes from a corpus luteum that forms after ovulation. Restorative reproductive medicine asks why a cycle fell short. The review links abnormal progesterone responsiveness to common gynecologic conditions. The authors say the mechanisms are only now emerging.
Our editorial summary of this paper, not the article's abstract.
Abstract
Progesterone's ability to maintain pregnancy in eutherian mammals highlighted this steroid as the 'hormone of pregnancy'. It was the unique 'pro-gestational' bioactivity of progesterone that enabled eventual purification of this ovarian steroid to crystalline form by Willard Myron Allen in the early 1930s. While a functional connection between normal progesterone responses ('progestational proliferation') of the uterus with the maintenance of pregnancy was quickly appreciated, an understanding of progesterone's involvement in the early stages of pregnancy establishment was comparatively less well understood. With the aforementioned as historical backdrop, this review focuses on a selection of key advances in our understanding of the molecular mechanisms by which progesterone, through its nuclear receptor (the progesterone receptor), drives the development of endometrial receptivity, a transient uterine state that allows for embryo implantation and the establishment of pregnancy. Highlighted in this review are the significant contributions of advanced mouse engineering and genome-wide transcriptomic and cistromic analytics which reveal the pivotal molecular mediators and modifiers that are essential to progesterone-dependent endometrial receptivity and decidualization. With a clearer understanding of the molecular landscape that underpins uterine responsiveness to progesterone during the periimplantation period, we predict that common gynecologic morbidities due to abnormal progesterone responsiveness will be more effectively diagnosed and/or treated in the future.
042nb2s44