Progesterone is an important hormone in women’s health, regulating menstruation, and vital for pregnancy. Additionally, it is important for everyone, men and women, for brain health.
This article explains the science (and genetics) behind progesterone — from how the body produces it to what exactly it does inside the cell. We’ll wrap up with genetic variants that influence your response to progesterone (both natural and exogenous).
What does progesterone do in the body?
Progesterone is a hormone made by both men and women. It plays a greater role in women who are premenopausal, and while that will be the main focus here, the same mechanisms take place for men to a lesser degree.
As a hormone, progesterone can interact with different receptors in the nucleus of cells and turn on or of the production of other genes. Progesterone can also act directly on non-nuclear receptors in the ovaries.[ref]
In the brain, progesterone acts on the HPA axis (hypothalamus, pituitary, adrenals) and regulates the production of luteinizing hormone (LH) in women. This is a feedback loop between the ovarian production of progesterone and the control of LH from the hypothalamus.
Progesterone also affects mood and the way people feel and behave. In general, progesterone reduces sexual desire in women as well as decreasing aggression and anxiety. When it comes to PMS (irritability, anxiety, and aggression), there is a lower than normal level of progesterone.
In the brain, progesterone metabolizes into allopregnanolone, which is neuroprotective in brain trauma.[ref]
How is progesterone made?
Progesterone’s generation in the body occurs during a multistep process that starts with LDL cholesterol.
The LDL cholesterol is taken into cells via cholesterol receptors, where it is transferred into the mitochondria to be converted into pregnenolone.
Pregnenolone is release by the mitochondria and can take two paths, depending on the organ where it is created: [ref]
- In the adrenals, pregnenolone turns into DHEA, androstenediol, and 17-alpha hydroxypregnenolone. From here, it generally gets converted into glucocorticoids and androgens.
- In the female reproductive organs, pregnenolone becomes progesterone and 17-alpha hydroxypregnenolone. From here it can become androstenedione and then estrogens. Progesterone from the reproductive system can circulate in the bloodstream, where it can then act on the regions of the brain that are controlling the reproductive hormones.
Diagram of steroid hormone production[ref]:
Mechanism of action for progesterone:
Let’s get into the details on how progesterone is working to turn on and off genes.
Progesterone is a lipophilic hormone, so it can diffuse across the cell membranes. Within the nucleus of the cell, it attaches to progesterone receptors. These progesterone receptors come in a couple of different sizes and are denoted as PR-A and PR-B. The different flavors of receptors are active in different tissues. PR-A is important for ovulation in the ovaries, and PR-B is part of the development of mammary glands.[ref]
Once progesterone binds to the receptor, it will bind to certain spots on the DNA to recruit other proteins to the site. These regulatory proteins then activate or repress the transcription of certain genes.
It gets a little complex – but just think of it as progesterone causing other genes to get turned on (via the progesterone receptor). These other genes help prepare the uterus for pregnancy, like growth factors needed for regenerating the uterine lining.[ref]
Interestingly, other genes regulated by progesterone include a couple of important circadian rhythm genes.
Additionally, progesterone can act on specific membrane-associated progesterone receptors. These receptors affect cholesterol and steroid biosynthesis and metabolism, as well as balancing iron. [ref]
Balancing act: Estrogen vs. Progesterone
Progesterone plays a role in preparing the uterus for implantation of the fertilized egg, and then if pregnancy occurs, progesterone levels rise over the course of the pregnancy and are essential for maintaining the pregnancy.[ref]
In a sense, progesterone is balancing out some of the growth that estrogen is promoting. Estrogen is stimulating the endometrium and progesterone is coming along to regulate the gene expression of the fibroblast growth factors.[ref]
When not pregnant, menstruation occurs when progesterone levels drop at the end of the menstrual cycle. The black line in the image below shows how progesterone rises after ovulation (by 10 to 35-fold) and drops at the start of menstruation.[ref]
In the uterus, progesterone receptor expression is dependent on and responsive to the amount of estrogen. Additionally, estrogen receptor expression is inhibited by progesterone forming a feedback loop.[ref]
Metabolism of progesterone:
Like all hormones created in the body, progesterone needs to be broken down (metabolized) and eventually excreted or recycled.
The metabolites of progesterone can also play an active role in the body. For example, allopregnanolone is important in brain health.
The steroid enzyme 5α-reductase (5αR) acts on progesterone, converting it to 5α-dihydroprogesterone (DHP). 5αR also metabolizes testosterone and deoxycorticosterone.
DHP, the progesterone metabolite, is active in the brain as a neuroactive steroid which modulates the GABA-A receptors. (Read all about GABA here) Both progesterone and the DHP metabolite are important in the brain. Animal studies show that changing 5αR levels (via drugs such as finasteride) affects behavior and brain function.[ref]
Additionally, progesterone and synthetic progestin are metabolized through the CYP450 enzymes, a family of enzymes responsible for breaking down many substances made by the body as well as toxins and medications. CYP3A4 is the main route of metabolism[ref], and CYP2C19 also plays a role.
Progesterone pills and supplements:
Progesterone can be a part of birth control pills (estrogen + progesterone) or it can be given alone (e.g. Depo-Provera birth control shots).
There are four main ways of getting additional progesterone (synthetic progestins or bioidentical) into the body:[ref]
- Transdermal progesterone cream is generally not enough to raise the plasma concentration of progesterone significantly – at least not compared with other methods.
- Oral progesterone pills are absorbed in the intestines and then travel to the liver where it is mostly broken down. Thus, oral doses of progesterone must be really high to get any of it past the liver.
- Vaginal progesterone suppositories make it into the uterus and endometrium more readily.
- Progesterone shots work to increase progesterone levels, but there is poor compliance.
Normally, progesterone rises to high levels during pregnancy, and it is essential for maintaining pregnancy. Sometimes women with a high risk of miscarriage are given progesterone.
Blocking the progesterone receptor is a way to terminate a pregnancy during the first two months. Mifepristone, or RU-486, is the name of this drug.
Ella (ulipristal acetate) is another medication that acts on the progesterone receptor.[ref] Known as the morning-after pill, ella is sold as a prescription emergency contraceptive in the US.
Synthetic progesterone medications are known as progestins or progestogens. They are often used as birth control or for menopausal hormone therapy.
Etonogestrel, a synthetic progestin, can be implanted into the arm for 1-3 years of birth control. Some people carry an extra copy of the CYP3A7 gene. This gene codes for an enzyme needed for a baby’s development, but then usually switch off at birth. About 4% of the population carries an additional copy of the CYP3A7 gene (not covered by AncestryDNA or 23andMe data), and this affects the metabolism of progestins (progestogens) as well as other steroid hormones. It can also affect the efficacy of etonogestrel as a birth control method.[ref]
Genetic variants related to progesterone:
Genetics plays a role in how your body reacts to progesterone and how it breaks down and eliminates progesterone and synthetic progestins.
Note that several of the variants below have links to increased cancer risk. I wanted to make clear that this refers to an increase in the relative risk of cancer. Relative risk just means the increase on top of your normal risk. Example: If your lifetime risk of ovarian cancer is 1 in 100, a variant causing a 20% increase in relative risk would increase your lifetime risk to 1.2 in 100.
- C/C: typical
- A/C: increased PGR (progesterone receptor), increased relative risk of ovarian cancer, uterine fibroids, breast cancer, endometrial cancer
- A/A: increased PGR, increased relative risk of ovarian cancer, uterine fibroids, breast cancer, endometrial cancer[ref][ref][ref][ref] later age of onset for migraines[ref]
Members: Your genotype for rs1042838 is —.
Check your genetic data for rs471767 (23andMe v4, v5; AncestryDNA):
- A/A: typical
- A/G: linked to an increased risk of preterm birth (which can be due to lower progesterone during pregnancy)
- G/G: linked to an increased risk of preterm birth[ref]
Members: Your genotype for rs471767 is —.
- C/C: typical
- A/C: increased relative risk of breast cancer, endometrial cancer
- A/A: increased relative risk of breast cancer, endometrial cancer[ref][ref][ref]
Members: Your genotype for rs10895068 is —.
- A/A: typical
- A/G: decreased risk of ovarian cancer
- G/G: decreased risk of ovarian cancer[ref]
Members: Your genotype for rs1042839 is —.
Once progesterone has completed its function, the body breaks it down (metabolizes it) and then can excrete it. This is true for both progesterone created in the body and progesterone pills.
CYP3A4 gene: codes for a liver enzyme that is important in breaking down progesterone[ref] (and many other drugs)
- G/G: CYP3A4*17, decreased function of enzyme[ref][ref]
- A/G: carrier of one CYP3A4*17 allele
- A/A: typical
Members: Your genotype for rs4987161 is —.
Check your genetic data for rs4986909 (23andMe v4; AncestryDNA):
- A/A: CYP3A4*13, decreased function of the enzyme[ref]
- A/G: carrier of one CYP3A4*13 allele
- G/G: typical
Members: Your genotype for rs4986909 is —.
Check your genetic data for rs2740574 (23andMe v4,v5; AncestryDNA):
- C/C: CYP3A4*1B, decreased function of the enzyme[ref]
- C/T: carrier of one CYP3A4*1B allele
- T/T: typical
Members: Your genotype for rs2740574 is —.
Check your genetic data for rs4986910 (23andMe v4, v5 ):
- G/G: CYP3A4*3, decreased function
- A/G: carrier of one CYP3A4*3 allele
- A/A: typical
Members: Your genotype for rs4986910 is —.
Check your genetic data for rs4986907 (23andMe v4, v5):
- T/T: CYP3A4*15A, decreased function
- C/T: carrier of one CYP3A4*15A allele
- C/C: typical
Members: Your genotype for rs4986907 is —.
CYP2C19 is also important in metabolizing supplemental progesterone (oral, vaginal):
- A/A: non-functioning (CYP2C19*2), decreased progesterone metabolism[ref]
- A/G: poorer metabolizer
- G/G: typical[ref]
Members: Your genotype for rs4244285 is —.
Luteal progesterone levels in women:
The APOE E4 allele, which also increases the risk for Alzheimer’s disease, has links to higher levels of luteal phase progesterone.[ref] You can check your APOE status, if you want to know, by reading this article.
Progesterone cream: Many health food stores sell over-the-counter progesterone creams, and often recommended by naturopathic medicine practitioners as a way to balance estrogen dominance or as hormone replacement in menopause. This transdermal approach avoids the pitfall of oral progesterone being broken down immediately in the liver.[ref] Talk with your doctor to see if this approach is right for you.
Menopausal Hormone Therapy and Breast Cancer: A study from 2019 looked at over 100,000 women with breast cancer. The results showed that postmenopausal hormone replacement therapy (estrogen plus progestin) increased the risk of breast cancer in women of normal weight.[ref]
Medications that mess with progesterone:
Finasteride inhibits the enzyme (5α-reductase) which is responsible for converting both progesterone and testosterone into their metabolites. This can affect the neuroactive metabolites that interact with GABA receptors in the brain.[ref]
Metformin also interacts with progesterone. In women with PCOS, progesterone is often lower than average during the luteal phase. Metformin for 4 weeks increased luteal progesterone levels.
Related Articles and Genes:
Estrogen: How it is made and how we get rid of it
Estrogen is usually thought of as the female hormone. While it is true women produce more estrogen than men, this applies to all of us. Estrogen – from how much is made to how it is broken down – is dependent on both genetics and lifestyle factors affecting both men and women.
PMS, Genetics, and Solutions
A lot of women know the moodiness and brain fog that comes with premenstrual syndrome (PMS). The symptoms can range from simply feeling irritable and icky to being something that interferes with your normal lifestyle.