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Many women who struggle with miscarriages look to progesterone to prevent them. Recently, a study by the Royal College of Obstetricians and Gynecologists suggested progesterone therapy could prevent 8,450 miscarriages every year ¹.

The evidence so far has been puzzlingly mixed, suggesting the story behind progesterone may be more nuanced than just blood progesterone levels.

In this article, part 1, we’re sharing the background information about progesterone, progesterone treatments, and factors linked to low progesterone.

In part 2, we will cover luteal phase defects, the current state of evidence, and treatment options, including natural approaches.

What is progesterone?

Progesterone is a sex steroid hormone produced mainly by the ovaries and the adrenal glands. In pregnancy, it’s also produced by the placenta. Progesterone helps to prepare the uterine lining for pregnancy and subsequently maintains the pregnancy.

The menstrual cycle is divided into follicular and luteal phases. During the follicular phase, the ovaries mostly produce estrogen, a hormone that stimulates follicular growth and egg development. Follicle-stimulating hormone (FSH) also stimulates egg development, and the developing eggs stimulate estrogen. Once estrogen is sufficiently high, it stimulates the pituitary to release a large amount of luteinizing hormone (LH) to trigger ovulation.

After ovulation, in the luteal phase, the egg becomes ready to fertilize. What is left of the follicle becomes the corpus luteum, which is a temporary organ made of cells surrounding the eggs in the follicle.

The corpus luteum then secretes progesterone in response to LH stimulation. The LH and rise of progesterone indicate a normal cycle with normal ovulation.

If pregnancy occurs, human chorionic gonadotropin (hCG) then keeps the corpus luteum producing the progesterone for another 10 weeks before the placenta takes over.

If a pregnancy does not occur and hCG does not increase, progesterone and estrogen levels drop. This allows the uterine lining cells to die, which presents as menstruation.

Normal blood progesterone levels

To evaluate infertility causes, your doctor may instruct you to get morning blood draw on the 21st day of your cycle, as it’s the typical day of progesterone peak.

When monitoring a pregnancy, your doctor may order a blood draw after the pregnancy becomes viable (around 5 gestational weeks) to check if the progesterone levels are rising as expected to indicate a healthy pregnancy.

If you’ve had a history of miscarriage, your doctor may continue to check your progesterone levels throughout the first trimester. After the first trimester, progesterone levels are usually only checked if cervical competence is an issue or if uterine contractions occur.

There is no need for any special preparation for any of these blood draws.

Different lab providers may use different reference ranges, and your progesterone levels tend to vary throughout the day. Therefore, you should strive to get a blood draw at the same time of day by the same lab provider each time. This way, if your progesterone gets measured a few times, your results will be comparable ².

If you’ve had a history of miscarriage, your doctor will usually check your progesterone levels in the first trimester. After that, in later stages of pregnancy, there is no need to check the levels of this hormone, and your OB/GYN will prescribe progesterone treatment based on clinical and ultrasound examination—for example, if there are signs of cervical incompetence or uterine contractions.

*Progesterone is typically not tested after the first trimester unless there is cervical incompetence or uterine contractions.

In addition to bood tests, you can use an at-home urine test like Proov to test PdG (Pregnanediol Glucuronide), the urine metabolite of progesterone.

How progesterone helps with fertility, pregnancy, and preventing miscarriage

1) Preparing the uterine lining for pregnancy

During the luteal phase, progesterone prepares the endometrium (uterine lining) so it’s ready for the embryo to implant after fertilization. If you have healthy levels of progesterone, your endometrium will be thick and rich in blood vessels, ready to accept the fertilized egg. These blood vessels are extremely important because they accept the fertilized eggs, nourish the growing embryo, and form the placenta.

2) Maintaining pregnancy

During pregnancy, progesterone helps grow the uterus and prevent premature contractions. It also makes changes to the mother’s circulatory system and prepares the breasts for breastfeeding.

Progesterone also keeps the mother’s immune system from rejecting the fetus, which is genetically different from her own ³. Normally, the body sees anything genetically different from itself as a threat and attacks it, but progesterone stops this from happening to the fetus. This is why low progesterone levels may contribute to miscarriage and why progesterone therapy may help.

According to a 2020 study by the Royal College of Obstetricians and Gynecologists, progesterone therapy could prevent almost 8,500 miscarriages every year ⁴. Many large clinical trials have found that progesterone therapy may improve low birth rates by 3-15% among women with recurrent miscarriage.

3) Preparing for labor

At full term, progesterone stimulates shortening of the cervix and prepares the uterus for contractions ⁵. However, overly high progesterone levels at this time may inhibit labor, so progesterone therapy is often stopped after 36 weeks of gestation.

4) Balancing estrogen functions

In many ways, progesterone counterbalances the effects of estrogen. Estrogen typically stimulates the increase in the number of estrogen-sensitive cells, such as the endometrial cells. Progesterone, on the other hand, inhibits the increase in number of endometrial cells, but instead stimulates the differentiation that creates specialized cells.

Conditions that involve excess estrogen function are partly caused by low progesterone function. This could be due to low progesterone levels or the cell’s inability to receive progesterone signals. These estrogen-dominant conditions tend to relate to excess cell growth, and include:

• Endometriosis
• Uterine fibroids
• Breast and uterine cancers

How progesterone affects your mental and physical health beyond fertility and pregnancy

• Maintaining bone mass ⁶
• Reducing anxiety and promoting relaxation ⁷
• Increasing body temperature by about 0.5° C after ovulation ⁸
• Body composition and weight control, although specific effects seem to be individual ^{9 10}
• Stimulating appetite ¹¹
• Slowing down gut movement, which may cause constipation for some women ¹²

These effects of progesterone may explain why many women experience fatigue right before their periods and during pregnancy. Also, some progesterone-like medications may have side effects related to these roles of progesterone.

How progesterone treatment may delay miscarriage and preterm birth ¹³

• Oxytocin is a vital hormone and neurotransmitter that triggers uterine contractions during childbirth. By blocking oxytocin receptors, progesterone inhibits uterine contractions.
• Corticotropin-releasing hormone controls the body’s “check and respond” system that detects threats to the fetus. This hormone serves as the “placental clock” that regulates the timing of labor onset. Progesterone interferes with this hormone’s production, meaning that in high enough concentrations, it can delay labor and birth.
• Progesterone increases phospholipase A₂, an enzyme vital for the production of prostaglandins that starts and promotes labor.
• Progesterone can inhibit fetal membrane cell death and, therefore, inhibits premature membrane rupture even in inflammation or infection settings.

Progesterone therapy for luteal phase defects and recurrent miscarriage

There is currently no universal consensus guideline for the optimal time to start and finish progesterone use ¹⁴. Progesterone is usually excluded from therapy after 36 gestational weeks because it may inhibit labor ^{15 16 17}.

When to start and stop progesterone for miscarriage

Progesterone shots are usually given from the beginning of pregnancy or gestation week (GW) 5-6 until GW 10-12, or as far as GW 20. Your doctor may also prescribe it if you experience any cramping or bleeding during pregnancy ¹⁸.

Your doctor will determine whether to prescribe progesterone and when to start and stop treatment. They may take into account these factors:

• Your pregnancy history
• Whether the pregnancy was natural or through IVF
• Route of administration
• Clinical findings based on cervical and uterine findings from physical and ultrasound exams
• Liver enzyme levels (in the case of oral intake)

In IVF pregnancies, it’s very common to start progesterone prior to the embryo transfer to prepare the uterine lining for implantation. Typically, the progesterone is continued for the first trimester. Some doctors may start the progesterone after the confirmation of pregnancy from weeks 5-6 and even until week 36.

In the case of placental hematoma (bleeding under one of the membranes surrounding the fetus), progesterone may be used until the clot resolves.

Routes of progesterone administration

• Vaginal suppositories or vaginalettes are best and most popular because they only have local effects and no side effects. Also, progesterone is better absorbed through the vaginal tissue.
• Oral pills and intramuscular progesterone shots can be difficult to tolerate because they tend to cause nausea, headaches, hot flushes, or mood swings. They may also cause liver lesions and raised liver enzyme levels, so your doctor may also do blood tests to check for this.
• Intramuscular injections or progesterone in oil (PIO) injections are typically reserved for cases of heavier bleeding or cramping. It is also the most common administration route for IVF. However, your doctor may start them if you have a history of repeated miscarriages and fetal death. The injections may be administered every second, third, or even fourth day at a dose of 250 mg. This is possible because the formula enables the progesterone to remain for longer in the bloodstream and act over several days.

Progesterone dosages for miscarriage and pregnancy complications

Your doctor may determine your progesterone dosage taking into account these factors:

• Cervix shortening and dilatation
• Presence of uterine contractions
• Parity, or whether it’s a twin pregnancy
• Experience from previous pregnancies

Most clinicians will start with 200 mg of progesterone to insert vaginally once or twice a day.

If 200 mg is not enough, they may increase the dosage to 2×2 vaginalettes daily. Some patients, especially those with recurrent vaginal infections, prefer to take progesterone orally.

If your doctor prescribes progesterone, it typically means they’re trying to stabilize the pregnancy. They may advise you avoid vaginal or anal sex, along with any movements that can impose stress on your cervix. At this time, avoid heavy exercise or housework, but you can continue with less physically-demanding work and movements. You can continue to take walks or perform light yoga.

Progesterone can mask miscarriages not caused by low progesterone, causing the miscarriage to be missed. Since it inhibits contractions, if the miscarriage is ongoing, progesterone can prolong the duration between embryo/fetal death and its expulsion from the body. If this happens, your doctor should stop the progesterone immediately so that the miscarriage can be treated.

What causes low progesterone and luteal phase defects?

The following conditions and factors are associated with low progesterone and luteal phase defects:

1) Miscarriage and ectopic pregnancy

Progesterone levels are lower in ectopic pregnancies and miscarriages, but it’s unclear whether the low progesterone is the cause or the sign of miscarriage ¹⁹. Miscarriages from other causes may also present with low progesterone levels.

2) PCOS and endometriosis

PCOS and endometriosis are linked to low progesterone. If you have one of those conditions, ask your OB/GYN about progesterone therapy and whether they think it can help.

3) Thyroid gland disorders (hypo/hyperthyroidism)

Healthy thyroid function is critical for other hormonal functions, uterine lining growth, and pregnancy ²⁰.

Consult a reproductive endocrinologist if you have trouble conceiving with normal cycle length or if you mainly have symptoms associated with thyroid gland disorders, such as:

• Rapid weight loss/gain
• Faster/slower heart rate
• Faster/slower digestion
• Excessive sweating
• Hearing loss
• Irregular cycle or shorter luteal phase

4) Hyperprolactinemia

Prolactin is a pituitary hormone normally secreted during breastfeeding. When its levels are too high at other times, it can shorten the luteal phase, leading to infertility and miscarriages ²¹.

5) Hormone disruptors

Some common hormone disruptors can reduce progesterone levels, such as bisphenol A (BPA, which is found in some plastics) and the flavonoid fisetin ^{22 23}. These substances can act like hormones or interfere with hormone functions. Studies on hormone disruptors are mostly in animals or cell models due to ethical concerns. However, the evidence is convincing that these hormone disruptors also disrupt steroid production, including progesterone in humans.

6) Stress

Stress can temporarily reduce fertility because of its effects on the nervous and hormonal systems ²⁴. Chronic stress increases the need for the stress hormone cortisol, which uses the same backbone as progesterone. Your body can convert progesterone into cortisol when needed, reducing progesterone’s availability for fertility purposes

In rhesus monkeys, short-term psychological stress for 12 days reduced progesterone levels by 51.6% during the follicular phase and 30% during the luteal phase. The animals also had a significant reduction in LH during the luteal phase, suggesting that the stress affected their hormones and menstrual cycles from the brain ²⁵.

7) Medications

Clomiphene, a medication often used to treat infertility, can cause a thin uterine lining ²⁶. Therefore, it is common for fertility doctors to prescribe progesterone along with clomiphene to help thicken and ready the uterine lining for pregnancy.

8) High volumes of exercise training

Exercise training and dieting can take a toll on the stress response axis, which involves the hypothalamus, pituitary, and adrenals. The pituitary hormone LH also controls progesterone.

A small clinical study compared athletic and sedentary women’s menstrual cycles. They found that athletic women had shorter luteal phases and less frequent LH secretion pulses. Women with athletic amenorrhea (no menstruation) had low levels of breakdown products of LH, progesterone, and estrogen, suggesting all of their reproductive hormones may be low ²⁷.

9) Aging and perimenopause

As a woman ages, her progesterone levels decline faster than her estrogen levels. Also, her menstrual cycles shorten. The LH pulses become less frequent, reducing overall progesterone levels ²⁸.

Aging is also associated with reduced egg quality, which is linked to progesterone production ²⁹.

10) Metabolic endotoxemia or leaky gut

Leaky gut (intestinal permeability) may allow gut bacteria toxins such as lipopolysaccharides (LPS) into the bloodstream. An overall unhealthy diet can cause a leaky gut.
The chronic low-grade inflammation from LPS may impair corpus luteum function, menstrual disturbance, and infertility. In animal studies, LPS interfered with progesterone production ³⁰.

In Part 2 of this 2-part article, we cover luteal phase defects more in-depth.

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