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Endometrial Effects of Progesterone: A Review​

By: Yayoi Kumata

Director’s Note: In 2010, Young and Lessey published an article titled, “Progesterone Function in Human Endometrium: Clinical Perspectives.” [1] The authors note progesterone’s vital role in maintaining pregnancy and emphasize the need to distinguish between insufficient progesterone concentration versus an inadequate response to the hormone. Among other consequences, changes in the response to progesterone may have significant implications for pregnancy outcomes. Young and Lessey’s article was summarized by FACTS elective student, Yayoi Kumata, who highlights its relevance for couples undergoing evaluation for infertility and hopes research continues to explore the role of progesterone levels as diagnostic criteria.

Introduction

Progesterone is a steroid hormone produced mainly in the corpus luteum in non-pregnant women. It is essential for successful implantation of the early human embryo and maintenance of pregnancy. Both estrogen and progesterone act on the endometrium, and a normal balance of these hormones is essential to support a normal menstrual cycle and pregnancy. Specifically, a poor response to progesterone or deficient progesterone levels may contribute to infertility and pregnancy loss.

“Both estrogen and progesterone act on the endometrium, and a normal balance of these hormones is essential to support a normal menstrual cycle and pregnancy.”

Historically, progesterone levels have been difficult to quantify as normal due to their fluctuating levels in accordance with the phases of the menstrual cycle. Furthermore, no reliable markers of endometrial function have been available to determine whether progesterone is causing an adequate response on the endometrium when progesterone levels seem adequate. Newer advances in medicine, such as molecular microarray, have identified candidate markers for endometrial function.

Progesterone & Endometrial Proteins

Estrogen primes the endometrium by increasing the number of progesterone receptors, and progesterone can counter estrogen by reducing the number of estrogen receptors and inducing estrogen degradation. In the absence of conception, withdrawal of progesterone induces degradation of the endometrium, leading to menstruation. Advances in research have identified endometrial proteins responsible for mediating some of progesterone’s effects on the endometrium. These proteins include insulin-like growth factor-binding protein 1 (IGFBP-1), glycodelin, complement proteins, and toll-like receptors; some of their relevant functions are summarized below.

• IGFBP-1 has been shown to be a major secretory progesterone and is implicated in embryo attachment and invasion.
• Glycodelin is produced in response to progesterone; although its mechanism of action is not fully understood, it likely prevents late fertilization.
• The complement system normally plays a role in immunity, and progesterone has been shown to increase both complement proteins and other proteins that limit complement system activation. A balanced increase in both likely has muted effects on the embryo; yet, conditions with increased complement expression, such as endometriosis, have been associated with pregnancy loss.
• Toll-like receptors (TLR) also play a role in immunity. Specifically, TLR3 has maximum expression during phases of the menstrual cycle corresponding to increased progesterone, and these receptors appear to be associated with implantation in animal studies.

“Estrogen primes the endometrium by increasing the number of progesterone receptors, and progesterone can counter estrogen by reducing the number of estrogen receptors and inducing estrogen degradation.”

Progesterone & Uterine Receptivity

Estrogen and progesterone are both necessary for a successful pregnancy: through their complementary actions, the endometrium becomes receptive to an embryo. Progesterone prepares the endometrium for implantation, a process mediated by cell adhesion molecules (CAM) and integrins. Progesterone increases CAM levels, which facilitates the “epithelialization” of the endometrium and embryo-endometrial interactions in preparation for invasion and implantation. Progesterone also induces the enzyme (17-beta-hydroxysteroid dehydrogenase type 2) which catalyzes the conversion of estradiol to estrone. This conversion to a less active form of estrogen causes decreased local effects of estrogen, a critical step toward endometrial receptivity. In patients with polycystic ovary syndrome (PCOS) or endometriosis, increased estrogen levels and decreased activity of 17-beta-hydroxysteroid dehydrogenase type 2 may cause an inadequate decrease in local estrogen effects and contribute to progesterone resistance.

Clinical Applications of Progesterone

The importance of progesterone for successful pregnancy has been well established but the lower limit of progesterone level required for pregnancy is not well studied. The current “normal” ranges for progesterone are based on population studies and do not adequately provide information on the amount of progesterone needed to successfully support a pregnancy. Luteal phase defect (LPD) is a disorder characterized by insufficient progesterone. Traditionally, the criteria to diagnose LPD has relied on microscopic assessment of an endometrial sample to establish whether the endometrium is responding appropriately to progesterone. However, this diagnostic approach is neither sensitive nor specific for fertility. Also, LPD assumes inadequate progesterone production but lab measurements vary, since progesterone is normally released in pulses and can be cleared quickly from the body. Furthermore, even if a woman has adequate progesterone levels, she may not be mounting an adequate response to the total progesterone circulating in her body.

Studies have shown women may respond differently to the same progesterone level. In a study of infertile and fertile women with artificial hormonally controlled cycles, the women with infertility benefited from progesterone supplementation. Since both groups had artificial hormonally controlled cycles, their progesterone levels at steady state were comparable. This finding suggests that a difference in progesterone response rather than progesterone levels may be contributing to infertility in women with LPD.

Studies have shown women may respond differently to the same progesterone level … [and studies also suggest] a difference in progesterone response rather than progesterone levels may be contributing to infertility in women with LPD.

Biomarkers of Progesterone Action

Given that differences in progesterone response rather than absolute concentrations of progesterone may be contributing to infertility in women with LPD, measurements of progesterone response would be useful in the accurate diagnosis of LPD. Although no consensus existed on biomarkers of progesterone response at the time of Young and Lessey’s article, modern advances in immunohistochemistry, monoclonal and polyclonal antibodies, and microarray technology continue to change this. Candidates for biomarkers of progesterone action include integrins, CAMs, selectins, cadherins, and certain growth factors. These molecules help mediate progesterone’s effects on the endometrium through various mechanisms and could be studied further as potential biomarkers of progesterone action.

Conclusion

In couples with infertility, the diagnosis and evaluation can be emotionally heavy and, at times, a devastating process. With progesterone levels commonly drawn during the work up, it is necessary to be mindful of their diagnostic role. Progesterone levels can vary widely due to the pulsatile nature of the hormone’s release and its rapid clearance from the body. Having “normal” progesterone levels based on population studies does not necessarily mean the patient will have an adequate progesterone response. More studies are needed to identify reliable biomarkers of progesterone action to accurately diagnose causes of infertility such as LPD.

References

[1] Young SL, Lessey BA. Progesterone function in human endometrium: clinical perspectives. Semin Reprod Med. 2010 Jan;28(1):5-16. doi: 10.1055/s-0029-1242988. Epub 2010 Jan 26. PMID: 20104424.

ABOUT THE AUTHOR

Yayoi Kumata

Yayoi Kumata is a fourth-year medical student at Philadelphia College of Osteopathic Medicine in Philadelphia, PA. She completed her undergraduate education at Rutgers University College of Nursing in New Brunswick, NJ. She plans to pursue residency in neurology. Kumata enrolled in the FACTS elective to expand her knowledge of natural family planning methods to which she had little exposure prior to the course. She hopes to one day share these methods with her patients.