Progesterone: A Hormone Your Body Already Makes

Before we talk about how Progesterone medication works, it helps to understand what Progesterone does naturally. Progesterone is a steroid hormone produced mainly by the ovaries — specifically by a structure called the corpus luteum that forms after ovulation each month. The adrenal glands also produce small amounts, and during pregnancy, the placenta becomes a major source.

Progesterone is often called the "pregnancy hormone" because its primary job is to prepare and maintain the uterus for a fertilized egg. But it does much more than that — it affects the brain, bones, immune system, and mood. Understanding how it works helps explain why it's prescribed for so many different conditions, from menopausal hormone therapy to fertility support.

How Progesterone Works at the Cellular Level

Progesterone works by binding to specific proteins inside cells called progesterone receptors. Think of these receptors like locks, and Progesterone is the key. When Progesterone binds to a receptor, it triggers a chain of events inside the cell that changes how genes are expressed — essentially turning certain cellular functions on or off.

Here's a simplified breakdown:

1. Progesterone enters the cell — Because it's a steroid hormone, Progesterone can pass directly through cell membranes (unlike many other hormones that need to stay outside the cell).
2. It binds to progesterone receptors — These receptors are found mainly in the uterus, breasts, brain, and other reproductive tissues.
3. The receptor-hormone complex enters the nucleus — Once activated, the receptor moves to the cell's nucleus where DNA is stored.
4. Gene expression changes — The complex attaches to specific sections of DNA, turning genes on or off. This changes the proteins the cell produces and, ultimately, how the tissue behaves.

This process is called a "genomic" mechanism of action because it works at the gene level. But Progesterone also has rapid, "non-genomic" effects — like influencing brain receptors that affect mood and sedation — which is why oral Progesterone can make you feel drowsy within minutes.

What Does Progesterone Do in the Uterus?

The uterus is Progesterone's primary target. Here's what happens in each phase of the menstrual cycle:

The First Half: Estrogen Builds the Lining

During the first half of your cycle (the follicular phase), estrogen causes the uterine lining (endometrium) to thicken and grow. This is called the "proliferative" phase — cells are multiplying rapidly.

The Second Half: Progesterone Transforms It

After ovulation, the corpus luteum starts producing Progesterone. This transforms the endometrium from a proliferative state to a "secretory" state. In plain terms:

• The lining stops growing wildly and becomes organized
• Blood vessel development increases to nourish a potential embryo
• Glands in the lining start producing nutrients
• The lining becomes receptive to embryo implantation

This is why Progesterone is critical for fertility — without enough Progesterone, the uterine lining can't properly support a pregnancy. It's also why fertility specialists prescribe Progesterone during IVF and other assisted reproductive treatments.

Why This Matters for Menopause

In postmenopausal women taking estrogen for symptom relief, the estrogen causes the uterine lining to grow — just like in the first half of the menstrual cycle. Without Progesterone to counteract this, the lining can keep growing unchecked, which increases the risk of endometrial hyperplasia and eventually endometrial cancer.

That's why any woman with a uterus who takes estrogen for menopause must also take Progesterone. It's not optional — it's a safety requirement.

How Progesterone Affects the Brain

One of the most noticeable effects of Progesterone — especially the oral form — is drowsiness. This isn't just a side effect. It's a direct result of how Progesterone interacts with the brain.

When your body metabolizes oral Progesterone, it produces a compound called allopregnanolone. This metabolite acts on GABA-A receptors in the brain — the same receptors targeted by anti-anxiety medications like benzodiazepines and sleep aids. The result is a calming, sedative effect.

This explains several things:

• Why doctors tell you to take oral Progesterone at bedtime
• Why Progesterone can affect mood (for better or worse)
• Why the oral form causes more drowsiness than vaginal forms — vaginal Progesterone bypasses the liver and produces less allopregnanolone

For more about these effects, see our guide on Progesterone side effects.

How Progesterone Supports Pregnancy

During early pregnancy, Progesterone is essential for:

• Maintaining the uterine lining: Without continued Progesterone, the lining would shed (causing a period or miscarriage)
• Suppressing uterine contractions: Progesterone keeps the uterine muscle relaxed to prevent premature contractions
• Supporting immune tolerance: Progesterone helps the immune system tolerate the embryo, which is genetically "foreign" to the mother
• Developing blood supply: It promotes blood vessel growth in the uterus to support the growing placenta

In IVF cycles, the body often doesn't produce enough Progesterone on its own (because the egg retrieval process disrupts the corpus luteum). That's why vaginal Progesterone supplementation (Endometrin, Crinone) is standard in fertility treatment.

How Progesterone Differs From Synthetic Progestins

Not all progestins are the same. Progesterone (the bioidentical version) has a different profile than synthetic progestins like Medroxyprogesterone (Provera) or Norethindrone (Aygestin):

• Bioidentical Progesterone (Prometrium, generics): Chemically identical to what your body makes. Produces the calming metabolite allopregnanolone. Generally considered to have a more favorable safety profile for breast tissue.
• Synthetic progestins (Provera, Aygestin): Chemically different. They activate progesterone receptors but may also interact with other hormone receptors (androgen, glucocorticoid). They don't produce allopregnanolone and may have different effects on mood, breast tissue, and cardiovascular risk.

Some studies suggest bioidentical Progesterone may carry a lower risk of breast cancer compared to synthetic progestins when used in menopausal hormone therapy, though more research is needed. Your doctor can help you decide which is right for your situation. For more on alternatives, see our guide to Progesterone alternatives.

Why Does the Form of Progesterone Matter?

The way Progesterone enters your body changes how it works:

• Oral capsules: Absorbed through the gut and processed by the liver ("first-pass metabolism"). This produces high levels of allopregnanolone, causing more sedation but also potential mood benefits. Systemic levels are lower because the liver breaks down much of it.
• Vaginal gel/inserts: Delivered directly to the uterus with high local concentrations but lower systemic levels. Less sedation, fewer whole-body side effects. Preferred for fertility support.
• Intramuscular injection: Bypasses the liver and provides consistent systemic levels. Used when reliable blood levels are needed.

The Bottom Line

Progesterone works by binding to receptors in your cells and changing gene expression — primarily in the uterus, but also in the brain, breasts, and other tissues. Its job is to transform the uterine lining for pregnancy, counteract estrogen's growth effects, and provide calming effects on the brain.

Understanding how Progesterone works helps explain why it's essential for so many conditions and why different formulations are used for different purposes. If you've been prescribed Progesterone and are having trouble finding it due to the current shortage, MedFinder can help you locate it at a pharmacy near you.