Evidence Based
4.4 /5
10

Progesterone Function, Uses, Side Effects & Symptoms (if low)

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:

SelfHacked has the strictest sourcing guidelines in the health industry and we almost exclusively link to medically peer-reviewed studies, usually on PubMed. We believe that the most accurate information is found directly in the scientific source.

We are dedicated to providing the most scientifically valid, unbiased, and comprehensive information on any given topic.

Our team comprises of trained MDs, PhDs, pharmacists, qualified scientists, and certified health and wellness specialists.

All of our content is written by scientists and people with a strong science background.

Our science team is put through the strictest vetting process in the health industry and we often reject applicants who have written articles for many of the largest health websites that are deemed trustworthy. Our science team must pass long technical science tests, difficult logical reasoning and reading comprehension tests. They are continually monitored by our internal peer-review process and if we see anyone making material science errors, we don't let them write for us again.

Our goal is to not have a single piece of inaccurate information on this website. If you feel that any of our content is inaccurate, out-of-date, or otherwise questionable, please leave a comment or contact us at [email protected]

Note that each number in parentheses [1, 2, 3, etc.] is a clickable link to peer-reviewed scientific studies. A plus sign next to the number “[1+, 2+, etc...]” means that the information is found within the full scientific study rather than the abstract.

Woman
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. Read on to find out, along with its health effects and information about the progesterone blood test.

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.

What is Progesterone?

Post Breakdown

This post will cover everything you need to know about progesterone, including:

  • Why natural progesterone production is important and how it works
  • 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
  • The progesterone test and how to interpret results
  • Complementary approaches that may help balance progesterone levels

Definition

Progesterone is a sex hormone mainly produced by the ovaries, and less so by the placenta and adrenal glands. Also known as the pregnancy hormone, it prepares women for pregnancy and is essential to maintain it. In fact, that’s how progesterone got its name, which translates to “for pregnancy” from Latin (pro gestatio) [1+].

Progesterone is thought to be a female sex hormone. Aside from sustaining fertility and enabling a healthy pregnancy, it also prepares milk-producing glands for breastfeeding. In non-pregnant women, progesterone balances the menstrual cycle [2+, 1+].

But men also produce this hormone, although in smaller quantities and without cyclical variations. Women face changing progesterone levels every month with each phase of the menstrual cycle [2+].

Function

Progesterone is not just a sex hormone. It’s one of the curious signals the body uses to achieve wide-ranging effects beyond reproduction. Scientists think that naturally-released progesterone protects brain cells from injury, increases their myelin insulation, and aids the activity of neurotransmitters [2+].

In the fetus, progesterone seems to reduce oxidative stress and immune overactivity. Some studies suggest that progesterone helps create new brain cells and some of the first neuronal connections and branches in the developing fetal brain [2+].

For these reasons, progesterone can rather be considered a “neurosteroid” and is being investigated for reducing brain damage after stroke and traumatic injuries (TBIs). Clinical studies have yet to investigate these uses [2+].

Production

Cholesterol is the starting point for making all steroid hormones, including progesterone.

Cholesterol carried through the blood as LDL cholesterol is released in its free form into tissues, such as the ovaries. At this point, an important hormone-balancing cascade takes place:

  • Cholesterol is converted to pregnenolone (in the mitochondria)
  • Pregnenolone is released and transformed into progesterone
  • Both pregnenolone and progesterone can also be converted to glucocorticoids like cortisol, estrogen, DHA, or male sex hormones (androgens)

All sex hormones are produced using this versatile pathway, regardless of the location in the body. The main difference is what hormones will be produced in larger quantities, and that’s where the ovaries, testes, adrenals, brain, and placenta differ [1+].

Organs that produce steroid hormones normally work in synchrony to maintain health. But many factors–from diet and stress to aging and abnormal levels of a certain hormone–can shift the focus of this pathway and trigger hormonal imbalances.

In women, progesterone in the blood mostly originates from the ovaries, while progesterone in the adrenals is usually turned into cortisol [1+].

Progesterone doesn’t stay in the blood for long. It is bound to proteins and quickly reaches the liver to be metabolized (into sulfates and glucuronides). Its breakdown products are then removed from the body by urine [1+].

In Ovaries (Menstrual Cycle Phases)

The ovaries are unique in their cyclical activity, unlike the testes that stay more or less constant all the time.

Hormones produced by the ovaries, including progesterone, will vary based on the phase of the menstrual cycle. The release of pituitary hormones FSH and LH that orchestrate the activity of progesterone and estrogen is also in sync with these cycles [3].

The most important stages of the menstrual cycle flow in the following order [3]:

  1. On the first day of the menstrual cycle (first day of menstruation) estrogen and progesterone release from the ovaries is low. As a result, FSH starts to slowly increase.
  2. During the first phase of the cycle, estrogen production in the ovaries starts to increase but progesterone stays low.
  3. LH and estrogen peak during ovulation while progesterone only mildly rises. Ovulation typically marks the middle of the menstrual cycle.
  4. The second phase of the menstrual cycle, which follows after ovulation, is dominated by progesterone. If the mature egg (follicle) released during ovulation is not fertilized, it is remodeled to form the corpus luteum or “yellow body”.
  5. During the last phase of the cycle, the yellow body starts to break down, and both progesterone and estrogen decline.
  6. The drop in progesterone and estrogen triggers another rise in FSH secretion and a new cycle begins all over again.

After menopause and as ovulation ceases, progesterone levels drop. This is because the main source of progesterone, the yellow body, is no longer being formed in the ovaries. In postmenopausal women, progesterone continues to be produced only in the adrenals in much smaller amounts.

womens-health-issues-767837

Fertility and Pregnancy

The female body undergoes a fascinating and complex coordination of hormonal events to establish and maintain pregnancy [4].

Healthy progesterone levels are essential for maintaining fertility in women, along with other hormones.

The Implantation Phase

Progesterone’s role is to make the tubes better prepared to carry the fertilized egg and the uterus better prepared for its implantation [4].

During the so-called “implantation window,” which is open for about 5 days around ovulation, progesterone makes the uterus more receptive to attaching a fertilized egg [4].

The tubes and uterus might not be receptive to transporting and attaching a fertilized egg if progesterone levels are out of balance.

Early Pregnancy

After the implantation phase, progesterone helps maintain pregnancy and prevents unwanted ovulation.

One of its crucial roles is to shift the production of progesterone to the placenta, which happens 6 – 7 weeks into pregnancy. Remember, shortly before pregnancy, progesterone was being produced in the yellow body that’s no longer needed [4].

Progesterone alone can maintain pregnancy at the beginning. Given to women who can’t produce it (due to surgical removal) during the first trimester, progesterone maintains a pregnancy that would otherwise cause miscarriages [4].

Women with abnormal progesterone levels may be more likely to experience recurrent miscarriages [4].

Late Pregnancy

After the first trimester, the placenta takes on full responsibility for making progesterone.

As pregnancy progresses, progesterone and estrogen levels continue to rise, spiking in the last trimester [4].

Together, these two hormones stimulate the growth of breast tissue and milk glands, preparing the body for lactation. Estrogen also increases the number of progesterone receptors in breast tissue, making the breasts more sensitive to its effects [4].

In late pregnancy, high progesterone and estrogen trigger the release of prolactin from the pituitary. Prolactin is the main hormone that enables milk production (pro= increasing lactin=milk) [4].

Throughout pregnancy, progesterone relaxes the uterus and prevents contractions.

Shortly before and during labor, progesterone activity drops while estrogen increases, triggering contractions. For example, substances that oppose the effects of progesterone (progesterone receptor antagonists) can induce labor in the third trimester [4].

Abnormal progesterone levels during late pregnancy can affect breast tissue, milk glands, and the uterus.

Progesterone in Men

Much less is known about the function of progesterone in men than in women. Nonetheless, women in the first phase of the menstrual cycle have very similar progesterone levels to men [5].

We know that in men, progesterone is produced in the adrenal cortex and in the testes in small amounts. It serves to balance testosterone and estrogen, impacting the production of both sperm and testosterone in the testes [5, 2+].

Very low progesterone blood levels in men have been linked to obesity, a higher BMI and waist circumference [6].

Low levels of the male sex hormone DHEA-S were also linked to low progesterone in one study. Researchers have suggested that, in obese men, low progesterone may be a result of an underactive adrenal cortex. This theory hasn’t been properly verified, though [6].

On the other hand, high progesterone or an increased number of progesterone receptors in men seem to be detrimental.

In tissue samples from over 500 men, prostate cancer cells had more progesterone receptors. The density of these receptors was linked to poorer prostate cancer outcomes in limited studies [7, 5].

Scientists proposed that progesterone receptors have the potential to be used in diagnosing benign vs. malignant prostate cancers – but further clinical work is needed [7, 5].

Interestingly, animal research suggests that progesterone may play a role in making men more hostile toward their children. This hasn’t yet been proven in humans.

In mice, progesterone worsened aggression toward infants. Mice that can’t produce progesterone completely lack aggression and become more active caretakers of their infants [2]!

However, many other factors can affect aggression in men, especially during the parenting phase. Simply lowering progesterone levels is unlikely going to make men better and more caring fathers.

Progesterone as a Medication

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

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 [8, 9]:

  • 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 [9, 8].

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 [8].

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) [8].

Once synthesized, progesterone can be forwarded to manufacturers or compounding pharmacies that often prepare various formulations of bioidentical hormones [8].

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 [8, 9].

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 [9].

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 [10].

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 [11].

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 [11].

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 [11].

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 [12].

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 [13, 12].

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 [13].

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 [13].

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) [9].

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 [14].

An interesting finding from this study was that natural, oral progesterone may act differently than its synthetic cousins [15].

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 [15].

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) [16].

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 [17].

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 [18, 19].

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 [20].

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 [21].

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 [22].

New studies using the cream are desperately needed to determine its effectiveness and safety compared to the pills [8].

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 [1+].

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 [23].

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 [24]
  • 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 [24]

Insufficient Evidence

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 [22].

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 [25].

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 [25].

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 [25].

The combination of synthetic progestin (medroxyprogesterone acetate) and estrogen lowered blood pressure in 12 postmenopausal women [26].

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 [27].

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 [25].

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 [25].

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) [28].

In another study, synthetic progestins with estrogens (medroxyprogesterone acetate + estradiol valerate) increased muscle strength in postmenopausal women [29].

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 [30].

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 [31].

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 [31, 32].

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

Lacking Evidence (Animal Research)

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 [1+].

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 [1+].

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 [33, 1+].

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 [34].

On the other hand, studies suggest that synthetic progestins found in birth control pills might contribute to low mood and libido [35].

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 [36].

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) [36].
  • Reduce the activity of genes that trigger inflammation and hinder the healing of damaged brain tissue (NF-κB and MAPK) [36].
  • 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 [1+].
  • Increase the production of the insulating myelin in brain cells via its metabolite (allopregnanolone)[1+].

On the other hand, synthetic progestins (like medroxyprogesterone acetate) sometimes used in hormonal therapy do not appear to have neuroprotective properties [5, 2+, 5].

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 [37].

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% [38].

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 [38].

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) [39].

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 [39].

Progesterone increased serotonin activity in the brain in animals, which hypothetically helps improve mood [39].

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 [39].

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 [39].

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 [6, 14].

In hamsters, the combination of progesterone and estrogen (17 beta-estradiol) lowered their fat stores and increased weight loss [40].

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 [41, 42].

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 [43].

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 [2+].

In one study, a combination of transdermal progesterone (along with conventional therapy) increased bone density in women with osteoporosis [2+].

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 [43].

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 [43].

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 [44].

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 [45].

Women with polycystic ovary syndrome are especially prone to progesterone and insulin resistance [45].

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 [46]:

  • 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 [47].

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 [15].

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 [9].

In studies of one million women, synthetic progesterone combined with estrogens increased breast cancer risk [48, 49].

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 [50, 9, 8].

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 [51].

Forms

Natural Progesterone is available in various forms [21]:

  • 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 [22].

Progesterone Levels & Blood Test

Progesterone Test

This test measures the amount of progesterone in the blood and is most commonly used to help monitor a woman’s health during pregnancy, diagnose pregnancy complications, determine the cause of infertility, or determine the cause of abnormal uterine bleeding [52].

If you are a woman, you need to know at what point you are of your menstrual cycle (period) or pregnancy to accurately interpret your results. Progesterone levels normal rise and fall over the course of your cycle. If they are not following this pattern, then you may not be ovulating or have regular periods, which may cause infertility [53, 54].

During pregnancy, progesterone levels also normally rise. If they do not, you may have an abnormal or unsuccessful pregnancy, or there may be problems with the fetus [53, 54].

In men, progesterone is produced at a much lower level than in women. Most men do not normally get their progesterone levels tested unless they are suspected to have an adrenal disease, such as congenital adrenal hyperplasia (CAH). CAH is a group of disorders that limit hormone production in the adrenal glands [5].

Normal Levels

Lab results are commonly shown as a set of values known as a “reference range”, which is sometimes referred to as a “normal range”. A reference range includes the upper and lower limits of a lab test based on a group of otherwise healthy people.

Your healthcare provider will compare your lab test results with reference values to see if any of your results fall outside the range of expected values. By doing so, you and your healthcare provider can gain clues to help identify possible conditions or diseases.

Depending on the menstrual cycle phase:

  • First half: 0.02 – 1 ng/mL
  • Ovulation-2nd half: 2 – 30 ng/mL

Progesterone levels during pregnancy can widely range. The following are not strict ranges, the normal range will vary between labs and other factors. As a rough guide, during pregnancy progesterone levels can vary between [55, 56, 57]:

  • 8 – 48 ng/mL in the first trimester
  • 29 – 50 ng/mL in the second trimester
  • 99 – 342 in the third trimester

In postmenopausal women and in men, the normal range is : 0 – 1 ng/mL

Some lab-to-lab variability occurs due to differences in equipment, techniques, and chemicals used. Don’t panic if your result is slightly out of range in the app – as long as it’s in the normal range based on the laboratory that did the testing, your value is normal.

However, it’s important to remember that a normal test doesn’t mean a particular medical condition is absent. Your doctor will interpret your results in conjunction with your medical history and other test results.

Have in mind that a single test isn’t enough to make a diagnosis. Your doctor will interpret this test, taking into account your medical history and other tests, such as X, Y, Z. A result that is slightly low/high may not be of medical significance, as this test often varies from day to day and from person to person.

High Levels

Having a high progesterone level does not always indicate health problems [58]. Progesterone levels increase during pregnancy and are even higher in pregnancies that involve multiples (twins, triplets, quadruplets, etc.) [4].

Very high progesterone can damage the fetus [59].

Causes

Causes and symptoms shown here are commonly associated with high progesterone. Work with your doctor or other health care professional for an accurate diagnosis.

High progesterone may be caused by:

High progesterone symptoms

  • Feeling stressed [60]
  • Low sex drive [64]
  • Depression [65]
  • Heavy menstrual bleeding [51]

Factors that lower Progesterone

Most importantly, work with your doctor to treat any underlying conditions causing your high progesterone levels.

You may try the additional strategies listed below if you and your doctor determine that they could be appropriate. None of these strategies should ever be done in place of what your doctor recommends or prescribes.

  • Eat more fiber: Fiber intake might decrease progesterone levels [66, 67]
  • Exercise may also help reduce progesterone [68]
  • Stop smoking [62]
  • Reduce your caffeine intake [61]
  • Increase natural sun exposure or consider Vitamin D supplements [69]
  • Reduce stress

Low Progesterone

In women, progesterone levels can increase and decrease throughout the menstrual cycle, so you should make sure that the levels correlate with your current menstrual cycle phase.

Low progesterone can potentially cause ovulation and fertility problems. Low progesterone may cause:

  • Ectopic pregnancy [70]
  • Miscarriage [71]
  • Toxemia (blood toxicity and high blood pressure) in late pregnancy [72]

Causes and symptoms shown here are commonly associated with this low progesterone. Work with your doctor or other health care professional for an accurate diagnosis.

Symptoms of low progesterone

  • Headaches [73]
  • Bloating [73]
  • Mood swings [73, 74]
  • Insomnia [75]
  • Irregular menstrual cycle [73]
  • Depression [73, 74]
  • Infertility [76]

Causes

Low progesterone may be caused by:

  • Exercise [68]
  • Obesity [77, 6]
  • Menopause [78]

Factors that Increase Progesterone

Most importantly, work with your doctor to treat any underlying conditions causing your low progesterone levels.

You may try the additional strategies listed below if you and your doctor determine that they could be appropriate. None of these strategies should ever be done in place of what your doctor recommends or prescribes.

Maintain a healthy body weight: Obesity and excess weight can cause low progesterone; losing weight can help prevent your progesterone levels from becoming low [14].

The following supplements may also help:

However, supplements have not been approved by the FDA for medical use. Supplements generally lack solid clinical research. Regulations set manufacturing standards for them but don’t guarantee that they’re safe or effective. Speak with your doctor before supplementing.

What about the “pregnenolone steal” and estrogen dominance?

Unlike some sources claim, stress does not “steal” progesterone. On the contrary, studies suggest that progesterone increases together with the stress hormone cortisol [60].

But, based on the existing evidence, chronic stress that can lead to chronic fatigue syndrome reduces cortisol. Progesterone may decrease or stay within the normal range [83, 84].

The “pregnenolone steal” theory claims that high levels of stress steal pregnenolone to produce more cortisol, reducing the amount available to produce progesterone. All of this is usually explained within the scientifically-unvalidated theory of adrenal fatigue.

Others talk about “estrogen dominance (ED),” a theory that can be traced to the late John M. Lee, MD.

Dr. Lee’s popular books claimed that everything from breast cancer to PMS and osteoporosis is caused by “estrogen dominance secondary to relative insufficiency of progesterone.” The truth is that this is another overly-hyped theory. Estrogen dominance is talked about a lot but it has been researched very little [8, 85].

An increased number of estrogen receptors, exposure to estrogen-like environmental toxins, and more rarely, high estrogen levels have been linked to poor health in some studies. Excessive estrogen increases the risk of cancer of the uterine lining and may contribute to obesity. But no studies support that estrogen can simply steal pregnenolone from progesterone [86, 87, 14].

Sex hormones undergo complex changes, especially in women who experience cyclical changes each month. It’s quite unlikely that these biochemical pathways can be deduced to an exclusive theory like estrogen dominance [8, 85].

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 symptoms with your doctor. He or she will recommend safe and approved therapies for your condition.

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.

Click here to subscribe

RATE THIS ARTICLE

1 Star2 Stars3 Stars4 Stars5 Stars
(14 votes, average: 4.43 out of 5)
Loading...

Leave a Reply

Your email address will not be published. Required fields are marked *

This site uses Akismet to reduce spam. Learn how your comment data is processed.