Progesterone-Gut Microbiome Axis

Dr Carly Polland ND in hormones Progesterone 21 Feb 2025 • 3 min read

Author Bio

Dr Carly Polland ND | Clinical Lead at Biomesight

Dr. Carly Polland is an integrative physician focused on the intersection of endocrinology and immunology with the microbiome. Early in her clinical practice, she focused on hormonal imbalances, but she quickly realized these patients also had digestive issues and autoimmune disease. She dug into the research and realized the microbiome was connecting these symptoms. Standard stool testing was not useful in decoding the microbiome so she upgraded to microbiome testing like Biomesight. She has used this technology for over 6 years to help her patients modulate their microbiomes and improve their symptoms.

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Progesterone is an important steroid hormone produced by gonads (ovaries and testes) and adrenals. It plays an important role in reproductive health, mood, sleep, and more. And it turns out, the microbiome and progesterone interact.

Progesterone Basics

In patients without ovaries or who are postmenopausal, progesterone levels are very low all the time. In individuals with ovaries, progesterone levels fluctuate throughout the menstrual cycle. During the first phase of the menstrual cycle, a follicle will mature and release an egg at ovulation, the remains of the follicle will create what is called the corpus luteum, which produces lots of progesterone. Progesterone levels will peak about one week after ovulation. If pregnancy does not occur, progesterone levels will drop. Declining progesterone (and estrogen) levels will trigger a menses.

Progesterone’s Influence on the Microbiome

Preclinical studies and some human studies suggest that progesterone can modulate the microbiome.

• In the oral microbiome, progesterone may increase Bacteroides and Prevotella intermedium¹
• Progesterone may increase Lactobacillus reuteri¹
• Progesterone may increase Bifidobacterium²

Further studies are needed to fully explore how progesterone may modulate the microbiome.

Progesterone can also modulate how the gut interacts with the microbiome. For example, some studies found that serum lipopolysaccharide (LPS) levels inversely correlated with serum progesterone levels in pregnancy.³ LPS is an inflammatory microbial metabolite that is a loose marker of intestinal permeability. This suggests that progesterone may have an impact on intestinal permeability. In vitro studies showed that progesterone decreased intestinal permeability by increasing the tight-junction protein occluding.³ Progesterone also decreased the inflammatory impact of LPS on colon cells.³ However, this has not been studied directly in humans. It is always important to keep in mind that what happens in a test tube may not happen in human beings. 

The Microbiome’s Impact on Progesterone

The microbiome may be able to make progesterone metabolites. Some bacteria produce an enzyme called 21-dehydroxylase. When this acts on metabolized steroid hormones in the bile, it can create allopregnanolone, which is a progesterone metabolite.⁴ Research has identified Gordonibacter pamelaeae and Eggerthella lenta as bacteria that make this enzyme.⁴ It also turns out that hydrogen gas (produced by bacteria) can increase the activity of this enzyme.⁴ 

Allopregnanolone is an important progesterone metabolite that interacts with the nervous system, particularly GABA receptors. It can be helpful for insomnia, anxiety, and even postpartum depression. In premenstrual dysphoric disorder (PMDD), the GABA receptors may have an altered response to allopregnanolone.⁵ Addressing the microbiome as it relates to progesterone metabolites may be helpful for these hormone-related symptoms and conditions.

In vitro studies show that butyrate may increase progesterone production.⁶ This has not been corroborated yet in human studies, but it is a reasonable hypothesis. So maintaining healthy levels of butyrate producers and feeding them prebiotics so they can actually produce butyrate may enhance progesterone production during the luteal phase. It would be interesting to see if this would also be true for people without ovaries or people who are postmenopausal. 

Lastly, in vitro studies indicate that microbes can metabolize progesterone, including synthetic progesterone drugs.⁷ This has interesting applications for the use of progesterone medications. Progesterone medications are used to treat a variety of conditions such as menopausal symptoms, heavy periods, PCOS, amenorrhea, and more. Progesterone medications can be bio-identical or synthetic and can be delivered topically, orally, intramuscularly, and vaginally. For oral progesterone, which is a very common route of administration, the microbiome could influence clinical outcomes by interacting with oral progesterone. And addressing the microbiome could enhance the clinical outcomes of oral progesterone. This is an area of research yet to be studied but it could yield some interesting treatment options, particularly for menopausal symptoms.

References

1. Siddiqui R, Makhlouf Z, Alharbi AM, Alfahemi H, Khan NA. The Gut Microbiome and Female Health. Biology. 2022; 11(11):1683. https://doi.org/10.3390/biology11111683
2. Nuriel-Ohayon M, Neuman H, Ziv O, et al. Progesterone Increases Bifidobacterium Relative Abundance during Late Pregnancy. Cell Reports. 2019;27(3):730-736.e3. doi:10.1016/j.celrep.2019.03.075
3. Zhou, Z., Bian, C., Luo, Z. et al. Progesterone decreases gut permeability through upregulating occludin expression in primary human gut tissues and Caco-2 cells. Sci Rep 9, 8367 (2019). https://doi.org/10.1038/s41598-019-44448-0
4. McCurry MD, D’Agostino GD, Walsh JT, et al. Gut bacteria convert glucocorticoids into progestins in the presence of hydrogen gas. Cell. 2024;187(12):2952-2968.e13. doi:10.1016/j.cell.2024.05.005
5. Hantsoo L, Epperson CN. Allopregnanolone in premenstrual dysphoric disorder (PMDD): Evidence for dysregulated sensitivity to GABA-A receptor modulating neuroactive steroids across the menstrual cycle. Neurobiol Stress. 2020 Feb 4;12:100213. doi: 10.1016/j.ynstr.2020.100213. PMID: 32435664; PMCID: PMC7231988.
6. Lu N, Li M, Lei H, Jiang X, Tu W, Lu Y, Xia D. Butyric acid regulates progesterone and estradiol secretion via cAMP signaling pathway in porcine granulosa cells. J Steroid Biochem Mol Biol. 2017 Sep;172:89-97. doi: 10.1016/j.jsbmb.2017.06.004. Epub 2017 Jun 8. PMID: 28602959.
7. Coombes Z, Yadav V, E. McCoubrey L, et al. Progestogens Are Metabolized by the Gut Microbiota: Implications for Colonic Drug Delivery. Pharmaceutics. 2020;12(8):760. doi:10.3390/pharmaceutics12080760
8. Memi, E., Pavli, P., Papagianni, M. et al. Diagnostic and therapeutic use of oral micronized progesterone in endocrinology. Rev Endocr Metab Disord 25, 751–772 (2024). https://doi.org/10.1007/s11154-024-09882-0