Progesterone, a reproductive hormone released during the luteal phase (second half) of the menstrual cycle, is critical for cycle health, pregnancy, and overall quality of life for women [1]. Restorative reproductive medicine (RRM) has historically emphasized the importance of measuring progesterone levels and understood low progesterone (often referred to as a luteal phase defect) to cause a host of issues. Progesterone supplementation, targeted to the luteal phase of the cycle, has long been a cornerstone of RRM treatment. But some women have normal progesterone levels and still have reproductive or other symptoms. For these women, progesterone resistance may be at play.
What does progesterone do in the female body?
Progesterone is responsible for relaxing the uterus, normalizing blood sugar, decreasing anxiety, and improving sleep and relaxation. It plays a major role in preparing the lining of the uterus for implantation of a newly conceived life, and is important for the success of early pregnancy. Progesterone also helps balance physiological processes like thyroid and glucose regulation.
Progesterone levels are connected to some health problems
Because of its major role in women’s reproductive health, issues with progesterone can lead to gynecologic and obstetric conditions. Low levels of progesterone are connected to premenstrual syndrome (PMS) or premenstrual dysphoric disorder (PMDD), irregular cycles, and infertility.
For women trying to conceive, progesterone is especially important, as it’s necessary for successful implantation and pregnancy. Low progesterone levels later in pregnancy are linked to preterm labor, pregnancy complications, and postpartum depression (PPD).
Even without a diagnosis, women may suspect they have issues with progesterone if they experience pre-period symptoms like breast tenderness, bloating, weight gain, carbohydrate cravings, headaches, fatigue, insomnia, irritability, tearfulness, or depression.
Progesterone resistance vs. progesterone deficiency
It’s well established that low levels of progesterone can cause reproductive health concerns. But is it always a lack of progesterone that’s truly causing the problem? Developing research suggests that these conditions may not be from too low progesterone levels but to a lack of response to the progesterone. The ovaries may be making normal amounts but the body isn’t responding to them normally.
This means it’s possible for a woman to have normal levels of progesterone, yet not receive the full health benefits, because her body is unable to utilize it. It is not only the level of progesterone that matters, but the ability of the body’s progesterone receptors to respond appropriately. This condition is called progesterone resistance [2].
What is progesterone resistance?
In a way that’s similar to insulin resistance (a condition in which the body becomes less and less sensitive to the impact of the hormone insulin on blood sugar regulation), progesterone resistance occurs when progesterone receptors become increasingly unable to respond to progesterone.
Research is still being done to identify precisely why this happens, but it may be connected to genetic preconditioning in utero and/or genetic expression that’s influenced by factors like chronic inflammation [3]. In the second scenario, this resistance is suspected to develop over time [2].
Without adequate effects of progesterone on the reproductive system, women with this resistance may develop additional reproductive concerns, like infertility or miscarriage, endometriosis, adenomyosis, uterine fibroids, polycystic ovary syndrome (PCOS), and endometrial hyperplasia (a precancerous condition) [2].
Progesterone resistance, implantation failure, and miscarriage
Insufficient progesterone is linked to implantation failure and early miscarriages. Without the necessary progesterone to prepare the lining of the uterus or, later, the developing placenta, there will be complications. This is not new information. The role of progesterone resistance, however, is only just beginning to be understood.
Women respond differently to the same levels of progesterone
Studies show that women with the exact same level of progesterone can have different physiological responses. This insight suggests that it is, in fact, “a difference in progesterone response, rather than progesterone levels [that may contribute] to infertility in women with luteal phase defect.” Another study showed women exhibiting normal physiological responses to even low levels of progesterone [4]. Based on this research, it seems likely that it is not only the level of progesterone, but the response to the progesterone present, that contributes to the success of implantation and early pregnancy [4].
Progesterone resistance and endometriosis
But progesterone resistance may affect more than pregnancy outcomes; it may negatively impact a woman’s ability to conceive at all, such as when it is paired with endometriosis.
Endometriosis is an inflammatory condition where cells like that of the uterine lining (that bleed and shed) are found outside of the uterus. Women with endometriosis often experience severe menstrual cramps, pelvic pain, and infertility.
Progesterone is anti-inflammatory in nature, and has the benefit of suppressing these cells and preventing unchecked estrogen activity (which further inflames endometriosis symptoms). Women with endometriosis who suffer from progesterone resistance don’t have this natural suppressant. The cells are more likely to become inflamed and spread, increasing the level and degree of endometriosis [3][5].
How do you treat progesterone resistance?
Understanding the role progesterone resistance plays in these reproductive conditions is critical for progress in diagnosis and treatment. At present, research on progesterone resistance is still in the very early stages. Continued research is needed on both causes and how to treat it. Once the causes are understood, treatment options can hopefully be developed to reduce the effect of progesterone resistance especially on infertility, miscarriage, endometriosis and more.
References:
[1] DeMayo FJ, Lydon JP. 90 YEARS OF PROGESTERONE: New insights into progesterone receptor signaling in the endometrium required for embryo implantation. J Mol Endocrinol. 2020 Jul;65(1):T1-T14. doi: 10.1530/JME-19-0212. PMID: 31809260; PMCID: PMC7261627 [2] MacLean JA 2nd, Hayashi K. Progesterone Actions and Resistance in Gynecological Disorders. Cells. 2022 Feb 13;11(4):647. doi: 10.3390/cells11040647. PMID: 35203298; PMCID: PMC8870180. [3] Patel, Bansari G et al. “Progesterone resistance in endometriosis: origins, consequences and interventions.” Acta obstetricia et gynecologica Scandinavica vol. 96,6 (2017): 623-632. doi:10.1111/aogs.13156 [4] Young, Steven L, and Bruce A Lessey. “Progesterone function in human endometrium: clinical perspectives.” Seminars in reproductive medicine vol. 28,1 (2010): 5-16. doi:10.1055/s-0029-1242988[5] Aghajanova, Lusine et al. “Altered gene expression profiling in endometrium: evidence for progesterone resistance.” Seminars in reproductive medicine vol. 28,1 (2010): 51-8. doi:10.1055/s-0029-1242994
