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Uses of Progesterone Cream & Pills + Side Effects

Written by Ana Aleksic, MSc (Pharmacy) | Last updated:
Jonathan Ritter
Puya Yazdi
Medically reviewed by
Jonathan Ritter, PharmD, PhD (Pharmacology), Puya Yazdi, MD | Written by Ana Aleksic, MSc (Pharmacy) | Last updated:

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Progesterone has spurred a lot of attention. Despite a lack of evidence, some popular authors claimed it can balance hormones in women, reduce “estrogen dominance,” and delay aging. Few people know what natural progesterone is or how it differs from its synthetic cousins. Get a science-based breakdown in this post.

Disclaimer: Progesterone, as part of hormonal replacement therapy (HRT), is a prescription medication. We recommend against using progesterone cream that is sold as an over-the-counter product, as it is classified by the FDA as an unapproved new drug. Please discuss your medications with your doctor.

Progesterone as a Medication

Post Breakdown

This post will cover:

  • The differences between natural and synthetic progesterone
  • The benefits and risks of progesterone (either naturally produced or taken as a supplement/prescription)
  • Forms of progesterone (creams, pills) and where you can get them

Snapshot

Proponents

  • Approved by the FDA for certain indications
  • Treats the absence of periods before menopause
  • Approved for use as a part of infertility treatment in women.
  • Helps with menopausal symptoms, as part of HRT
  • May help reduce stress & anxiety in menopausal women
  • Claimed to improve energy and sleep

Skeptics

  • Should only be used with a doctor’s prescription
  • Evidence is lacking for unapproved uses
  • May cause dizziness, headaches, and painful/tender breasts
  • Synthetic progestins may increase the risk of breast cancer
  • Interacts with some medications

Synthetic vs. Natural Progesterone

The Main Differences to Watch Out For

We often hear about products with so-called “natural” progesterone vs. “synthetic” progesterone.

This can cause a lot of confusion, as additional phrases are thrown in such as “bioidentical progesterone” or “naturally-sourced progesterone.” And to make everything even more perplexing, you may sometimes also hear the term “progestins” being used.

The main difference between them is not that complex [1, 2]:

  • Natural progesterone is biochemically identical to progesterone produced by the body. It’s usually made from wild yams, which is why manufacturers say it’s “naturally sourced”
  • Synthetic progesterone is made by chemically modifying the naturally-occurring progesterone molecule. Some of these drugs are even made by modifying testosterone. Technically speaking, these new molecules are no longer progesterone but are instead called “synthetic progestins.” They mimic some of the effects of progesterone but also have some different actions.
  • Progestins is an umbrella term that covers both natural progesterone and synthetic progestins.

Commonly used synthetic progestins include:

  • Medroxyprogesterone acetate and Dydrogesterone (created by modifying progesterone)
  • Levonorgestrel and Drospirenone (created by modifying testosterone)

Synthetic progestins are often used in hormonal replacement therapy (HRT) and have spurred a lot of attention after studies pronounced that they may increase the risk of breast cancer.

A recent analysis of over 86k postmenopausal women found that natural progesterone combined with estrogen is linked to a lower breast cancer risk compared to synthetic progestin. Another observational study of 100k French women had similar results [2, 1].

Natural progesterone is the original progesterone molecule, which gave birth to the term “bioidentical” – chemically the same as what the human body makes. But are these products actually natural?

The truth is that even this form of progesterone is semi-synthetic. Plants don’t make progesterone but similar compounds that need to be converted into progesterone in the lab [1].

Natural progesterone is identical to progesterone produced by the human body. Synthetic forms are made by chemically modifying progesterone and are also called “synthetic progestins.”

How is natural progesterone made and is it safe?

The starting point for making bioidentical progesterone is either of the two plant compounds: diosgenin from an inedible Mexican yam (Dioscorea villosa) or stigmasterol from soybeans (Glycine max) [1].

Once synthesized, progesterone can be forwarded to manufacturers or compounding pharmacies that often prepare various formulations of bioidentical hormones [1].

Natural progesterone is micronized, which means that it’s made into a very fine powder. It can be filled into capsules (Prometrium) or formulated into creams, vaginal gels, and suppositories.

Despite a couple of studies indicating that natural progesterone may carry less risk than synthetic progestins, the research is sparse.

Most of the hype originates from a couple of avid doctors who promoted it and popular books on the subject. However, natural progesterone is no panacea but a hormone that needs to be thoroughly tested in clinical trials [1, 2].

Natural or bioidentical progesterone is usually mass-made either from soybeans or Mexican yams. It’s then micronized and filled into capsules, pills, creams, and other formulations.

Uses of Progesterone

Likely Effective for:

1) Hormonal Menopausal Therapy

Menopausal hormone replacement therapy (HRT) can effectively reduce symptoms of menopause. It consists of estrogen and progestins to compensate for their declining levels in women with an intact uterus [2].

HRT may help with hot flashes, mood swings, insomnia, night sweats, vaginal dryness, and restlessness. Various combinations of natural or synthetic estrogens or progestins have been used and researched, which are all linked to different health risks and benefits [3].

Micronized progesterone (Prometrium) is FDA-approved for this use with estrogen as a component of HRT.

2) Missed Periods (Amenorrhea)

Oral progesterone and progesterone vaginal gel treat amenorrhea or the absence of menstrual periods in premenopausal women [4].

The following formulations are FDA-approved for this use:

  • Micronized progesterone
  • Intravaginal progesterone gel (Crinone 4%).

3) Infertility

Intravaginal progesterone gel (Crinone 8%) is FDA-approved as part of infertility treatment in women.

According to clinical trials, both intravaginal and intramuscular progesterone achieve pregnancy rates comparable to oral progesterone in infertile women [4].

During in vitro fertilization (second/luteal phase of the menstrual cycle), intravaginal progesterone appears to promote ongoing pregnancy rates as well as human chorionic gonadotropin (HCG). Studies suggest that progesterone does not increase rates of ovarian hyperstimulation syndrome when used for this indication [4].

4) Birth Control in Older Women (the Minipill)

Also known as the “minipill”, progestin-only birth control is an option used by few women, more commonly in their late reproductive years (usually above 40). These pills are seen as a safer option for women at higher risk of vein problems (venous thromboembolism) due to a family history of the disease, diabetes, obesity, smoking, or other factors [5].

The minipill contains synthetic progestins in doses lower than those in the typical combination (estrogen + progestin) oral contraceptive pills. It should be taken continuously, without the 4 – 7 day breaks women taking combination birth control are advised to make. In a survey of 13k US women, only 0.4% used the minipill [6, 5].

Various synthetic progestins can be used in these pills, although studies didn’t find any specific derivatives more effective than others. All may cause side effects, such as irregular bleeding and irregular cycles [6].

The minipill works by thickening the cervical mucus and thinning the uterus lining, which prevents sperm from reaching the egg. It only partially suppresses ovulation, unlike typical birth control (combination) pills [6].

Possibly Effective for:

5) Uterine Lining Overgrowth

Before menopause, the uterus lining sheds with each menstruation. After menopause, the uterus stops receiving hormonal signals to shed.

Estrogen alone can trigger overgrowth in the uterus and lead to cancer without progesterone to balance its effects. Some evidence suggests that adding progesterone to HRT protects the uterus lining, thins it, and lowers the risk of cancer (endometrial) [2].

Scientists think this might also explain why women who had their uterus surgically removed probably won’t benefit from progesterone. It’s still possible that the combination of both may have other benefits for women without a uterus, but clinical studies haven’t confirmed it.

A link has also been suggested between obesity and progesterone levels. According to one study, obese women are more likely to be progesterone-deficient, which increases their risk of endometrial cancer. This hasn’t been confirmed in large enough studies, though [7].

An interesting finding from this study was that natural, oral progesterone may act differently than its synthetic cousins [8].

The authors suggested that it reduced cell overgrowth in the uterus (i.e. it’s antiproliferative) while synthetic progestins didn’t. They say that vaginal natural progesterone also can’t par with the oral form. Both oral synthetic forms and the vaginal natural form seem to only trigger secretory changes in the uterus [8].

How progesterone cream impacts endometrial cancer risk, on the other hand, is unclear.

More clinical research is needed.

6) Breast Pain (Mastalgia)

Some evidence suggests that vaginal progesterone cream (Crinone) may reduce breast pain and tenderness in women with non-cancerous breast pain (mastalgia) [9].

7) Preterm Birth

According to most studies, vaginal progesterone gel or inserts delay labor and reduce the risk of premature birth in some women at high risk [10].

However, some studies have had mixed results. Additionally, the safety and effectiveness of progesterone in women with twin pregnancies at risk of premature birth is unclear [11, 12].

8) Menopausal Symptoms

Natural Progesterone Cream

Unlike pills, creams with natural progesterone usually don’t require a prescription and some women prefer them.

Progesterone cream is still considered an “alternative” to the pills, as fewer studies have confirmed its effects and the ones that have been carried out had somewhat inconsistent results [13].

Applied on the skin, progesterone should be absorbed and have similar effects as the oral form. It has been tested for hot flashes, with one study finding a positive effect and another no effect. In one study of 54 women, a cream with natural progesterone and estrogen did relieve menopausal symptoms. But progesterone blood levels remained lower than expected [14].

The cream is also promoted to treat and prevent osteoporosis and as a general health tonic. The FDA has issued several warnings to manufacturers making these claims.

For, most of these claims are unsubstantiated as they rely on studies with progesterone pills.

Progesterone cream sold as an over-the-counter product is classified by the FDA as an unapproved new drug since it is not generally recognized as safe and effective for the labeled uses among experts [15].

New studies using the cream are desperately needed to determine its effectiveness and safety compared to the pills [1].

Possibly Ineffective for:

PMS and Spotting

Some studies suggest that women who experience intense PMS symptoms may be deficient in progesterone during this phase of the menstrual cycle. In healthy women, low progesterone worsens PMS mood symptoms such as aggressive behavior and fatigue [16+].

However, taking progesterone pills likely doesn’t help during PMS. In a review of studies including almost 300 women, progesterone had no effect on PMS symptoms [17].

Experts point out that having balanced progesterone levels throughout the different menstrual cycle phases maintains healthy, regular cycles.

Research has associated high progesterone and other hormonal changes with certain symptoms:

  • High progesterone was linked to heavier menstrual bleeding [18]
  • Higher estrogen and LH levels around ovulation and high estrogen and progesterone in the second phase (after ovulation) are common in women who experience spotting midway through their cycle [18]

Insufficient Evidence for:

The following purported uses are only supported by limited, low-quality clinical studies.

There is insufficient evidence to support the use of progesterone for any of the below-listed uses.

Remember that progesterone is a prescription medication approved only for hormonal replacement therapy, along with estrogen. It should be prescribed by a doctor.

Progesterone cream sold as an over-the-counter product is classified by the FDA as an unapproved new drug since it is not generally recognized as safe and effective for the labeled uses among experts [15].

High Blood Pressure After Menopause

Women often experience high blood pressure after menopause, but the difference to men becomes more apparent only decades after. Women over 65 years of age experience much faster and greater increases in blood pressure than men [19].

According to studies of over 40k Italian women, the chances of high blood pressure increase 2-fold after menopause, a risk that may be reduced with hormone therapy. Race may also affect it, as being postmenopausal didn’t increase the risk of high blood pressure in a study of 22k Japanese women [19].

In a study of 270 women, both natural (200 mg/day) and synthetic progesterone lowered blood pressure given to women shortly after the menopause. Neither combination had beneficial effects if given later after the start of menopause, so early interventions may be key. Larger trials are required [19].

The combination of synthetic progestin (medroxyprogesterone acetate) and estrogen lowered blood pressure in 12 postmenopausal women [20].

One Australian survey study found the opposite. According to a survey of 43k postmenopausal women, those who used hormone therapy were much more likely to have high blood pressure, the risk increasing with the duration of use. One big flaw in this study was not making any distinction between natural and synthetic progesterone or various other factors that can play in [21].

Scientists think that estrogen appears to have a stronger blood-pressure-lowering effect than progesterone. Studies suggest that naturally-produced progesterone seems to both relax and narrow blood vessels and doesn’t have beneficial effects on blood pressure in postmenopausal women without estrogen [19].

Even when combined with estrogen, it’s still unclear if hormonal therapy is beneficial for reducing the risk of high blood pressure or if it can even increase it. Rigorous clinical trials are warranted [19].

Muscle Mass After Menopause

In a study of 12 postmenopausal women, progesterone increased muscle mass, unlike estrogen. Progesterone also increased the activity of genes that help build muscles (MYOD1) [22].

In another study, synthetic progestins with estrogens (medroxyprogesterone acetate + estradiol valerate) increased muscle strength in postmenopausal women [23].

More research is needed.

Skin Aging

There’s not enough evidence to rate the effects of progesterone on skin aging.

In one study on 40 women (menopausal and postmenopausal), 2% progesterone cream reduced wrinkles and increased skin elasticity and firmness. The authors claimed that progesterone facial creams may help slow down skin aging in women after the onset of menopause – but their findings have yet to be replicated [24].

Autoimmune Progesterone Dermatitis

Autoimmune progesterone dermatitis is a very rare condition that affects young women, mostly in their 30s. Women with this condition experience an allergic reaction to normally raised progesterone in the second phase of the menstrual cycle [25].

The symptoms range from eczema and skin redness to very severe allergic reactions. Given that only a handful of cases have been documented so far, dermatologists and gynecologists are rarely aware of it. A progesterone skin test is needed to diagnose it. In one case, this condition went away with oral contraceptives [25, 26].

However, we can’t draw any conclusions from a single case. Proper studies are needed.

Lacking Evidence for:

No clinical evidence supports the use of progesterone for any of the conditions listed in this section.

Below is a summary of the existing animal and cell-based research, which should guide further investigational efforts. However, the studies listed below should not be interpreted as supportive of any health benefit.

Aggression and Anxiety

Given its large impact on the brain and behavior, it’s no wonder that scientists say progesterone is a “neurosteroid.”

According to one hypothesis, progesterone may increase caretaking behavior and relaxation. Increased levels of this hormone after giving birth may explain why breastfeeding female mice become less aggressive. This hasn’t been proven in humans, though [16+].

Scientists are investigating whether progesterone can activate GABA receptors–the brain’s “calmness sensors.” It’s being researched for reducing aggression in people with psychiatric disorders, depression, and anxiety [16+].

Although one small study of 43 women with PMS didn’t find any link between progesterone levels and anxiety, larger studies may be needed. Larger drops in progesterone may shed light on why some women become more “hostile” during PMS even if they don’t experience typical anxiety symptoms [27, 16+].

Some researchers believe that progesterone levels in the amygdala, a region of the brain that registers fearful stimuli, may be one key to this mystery. Rats given progesterone directly into the amygdala experienced less anxiety, fear, and pain [28].

On the other hand, studies suggest that synthetic progestins found in birth control pills might contribute to low mood and libido [29].

More research is needed.

Brain Inflammation

Once scientists observed that female animals seem to improve better than males after brain injuries, they started wondering how female sex hormones might play a role in brain protection. We still don’t have any conclusive answers [30].

Cell-based and animal studies are investigating whether progesterone can:

  • Reduced key inflammatory markers in brain cells exposed to LPS (NF-kB, TNF-alpha, COX-2, iNOS) [30].
  • Reduce the activity of genes that trigger inflammation and hinder the healing of damaged brain tissue (NF-κB and MAPK) [30].
  • Enhance the integrity of the blood-brain barrier. Some researchers think it should be further studies in animals with a damaged, “leaky” blood-brain barrier [16+].
  • Increase the production of the insulating myelin in brain cells via its metabolite (allopregnanolone)[16+].

On the other hand, synthetic progestins (like medroxyprogesterone acetate) sometimes used in hormonal therapy do not appear to have neuroprotective properties [31, 32+, 31].

Human studies are needed.

Sleep and OSA

One study states that progesterone may help with sleep onset, sleep quality, and normal breathing during sleep. It has been linked to improved symptoms of obstructive sleep apnea (OSA) in men and menopausal women with obesity [33].

In another trial of 8 postmenopausal women, progesterone (300 mg/day) restored normal sleep in those who suffered from sleep disturbances. Progesterone increased restorative, deep, slow-wave sleep by 50% [34].

In this trial, progesterone didn’t sedate women who were already sleeping well, so the authors suggested that it’s not a sedative but rather a balancing hormone. This is still unproven [34].

However, there’s insufficient evidence to draw any conclusions. Larger trials are needed.

Mood, Cognition, and SSRI Response

Science suggests that progesterone and other sex hormones shape the brain and increase its plasticity throughout our lifetime.

Progesterone is thought to be especially important for mental health in women. Receptors for this hormone are located all along the areas of the brain involved in cognition, memory, and emotional processing (hippocampus, hypothalamus, and amygdala) [35].

In women, both estrogen and progesterone balance are crucial for brain cells to make new connections, branch out, and maintain their myelin insulation – key processes for cognition and brain health [35].

Progesterone increased serotonin activity in the brain in animals, which hypothetically helps improve mood [35].

Genetics and age may impact the effects of progesterone on mood and the response to common antidepressants (like SSRIs). This has yet to be determined in proper, large trials. In one small study, premenopausal women with more active serotonin transporter genes (5-HTTLPR) were more likely to benefit from antidepressants [35].

Some scientists believe that higher sex hormone levels may be needed for antidepressants to achieve the desired effect in women. This experimental hypothesis claims that due to drops in estrogen and progesterone, menopausal women might gain less benefit from antidepressants – but this is a preliminary finding that needs to be confirmed in large studies [35].

Weight Loss

The effects of progesterone on weight loss are still unknown.

Limited data suggest that men with progesterone levels in the higher end of the normal range are less obese, have lower BMI and smaller waist circumference. Obese women also seem to be more likely to have very low progesterone levels, according to another small study. Larger human studies are needed [36, 7].

In hamsters, the combination of progesterone and estrogen (17 beta-estradiol) lowered their fat stores and increased weight loss [37].

Bone Protection

After menopause, women are at a greater risk of osteoporosis. For a long while, it was thought the blame should fall on declining estrogen. Conventional treatment with vitamin D, calcium, and estrogen can only delay but not reverse osteoporosis. Doctors and scientists turned to progesterone in search of the missing link, though they are still on the hunt for answers [38, 39].

Some say progesterone’s role is to be estrogen’s side partner is maintaining bone health. It seems to collaborate with estrogen to increase slow, long-term (3 – 4 months) activity of bone-building cells [40].

The effect of synthetic progesterone on bone mineral density is limited and carries the risk of adverse effects. Although natural progesterone creams are thought to protect the bones “relatively free from adverse effects,” data are lacking to determine their effectiveness and safety [32+].

In one study, a combination of transdermal progesterone (along with conventional therapy) increased bone density in women with osteoporosis [32+].

Experts say that, in premenopausal women, it’s important to pay attention to various factors that can reduce progesterone and predispose to osteoporosis later on in life [40].

Low progesterone levels can be triggered by many factors, including everyday stress, poor diet, emotional, social and financial insecurity, and illness. Also, low levels are more common in teens and in women shortly before menopause [40].

Unwanted Hair Growth

In a skin-tissue study, natural progesterone blocked the enzyme that causes a buildup of male sex hormones and contributes to unwanted hair growth in women (5-alpha reductase). Blocking this enzyme can lower high testosterone levels. A commonly used synthetic progestin (medroxyprogesterone acetate) had no effect on this enzyme [41].

Insulin resistance

High estrogen and progesterone levels in women during the second phase of the menstrual cycle and during normal pregnancy are linked to reduced insulin sensitivity. Tissues can become insensitive to progesterone, triggering progesterone resistance that worsens insulin resistance [42].

Women with polycystic ovary syndrome are especially prone to progesterone and insulin resistance [42].

No studies show that natural progesterone will worsen or improve insulin sensitivity in postmenopausal women.

Progesterone Side Effects & Formulations

This list does not cover all possible side effects. Remember to contact your doctor or pharmacist if you notice any other side effects.

Call your doctor for medical advice about side effects. In the US, you may report side effects to the FDA at 1-800-FDA-1088 or at www.fda.gov/medwatch. In Canada, you may report side effects to Health Canada at 1-866-234-2345.

Prometrium

Progesterone (Prometrium) pills can cause the following side effects [43]:

  • Breast tenderness
  • Headaches
  • Fluid retention
  • Fatigue
  • Dizziness and drowsiness
  • Depression
  • Hot flashes
  • Bloating or stomach cramps
  • Increased risk for viral infections
  • Coughing

Synthetic Progesterone

Heart Disease Risk

Synthetic progestins have been associated with congestive heart failure [44].

Breast Cancer Risk

Most of the claims about the increased risk of breast cancer span from misinterpreting cellular, animal, and human studies on premenopausal women. Additional misinterpretation spans from assuming synthetic and natural are the same [8].

Synthetic estrogens (conjugated equine estrogens) and synthetic progestins (medroxyprogesterone acetate) have been associated with an increased risk of breast cancer, especially when compared only to synthetic estrogens [2].

In studies of one million women, synthetic progesterone combined with estrogens increased breast cancer risk [45, 46].

By contrast, natural progesterone and estrogen did not increase breast cancer risk in large observational studies. These were carried out in France and included over 100k women who were followed up for 6 – 9 years [47, 2, 1].

Heavy Bleeding or Spotting

High progesterone levels can cause heavy menstrual bleeding or spotting. Synthetic progestins used in the minipill also cause spotting more often than combination birth control pills [48].

Pills, Cream, Shots, and Other Forms

Natural Progesterone is available in various forms [14]:

  • Tablets
  • Cream
  • Suppositories
  • Vaginal gel
  • Progesterone shots/injections, sometimes given during pregnancy to prevent early labor

Both natural progesterone and synthetic progestins are combined with estrogen as part of hormonal replacement therapy, available with a doctor’s prescription.

Progesterone cream sold as an over-the-counter product is classified by the FDA as an unapproved new drug since it is not generally recognized as safe and effective for the labeled uses among experts [15].

Further Reading

Takeaway

Natural progesterone or bioidentical progesterone is completely identical to progesterone created by the human body. It’s mass-produced from hormone-like plant compounds and ground into a fine powder, creating micronized progesterone that’s formulated into capsules, pills, and creams.

On the other hand, synthetic forms are made by chemically modifying progesterone and are also called “synthetic progestins.” They are often used as part of hormonal replacement therapy (HRT), which reduces symptoms of menopause.

Progesterone can also be used as a vaginal gel (for infertility), breast gel (for breast pain) and as oral birth control (the minipill) in women over 40.

Natural forms of progesterone have been linked to a lower breast cancer risk compared to synthetic progestins in some studies, but the research is still sparse.

Progesterone cream has become an increasingly popular alternative to progesterone pills. It allegedly has fewer side effects, but we’re still lacking solid data to say whether it’s safe and effective.

About the Author

Ana Aleksic

Ana Aleksic

MSc (Pharmacy)
Ana received her MS in Pharmacy from the University of Belgrade.
Ana has many years of experience in clinical research and health advising. She loves communicating science and empowering people to achieve their optimal health. Ana spent years working with patients who suffer from various mental health issues and chronic health problems. She is a strong advocate of integrating scientific knowledge and holistic medicine.

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