How to reduce the side effects of natural progesterone
November 13, 2025 2025-12-08 22:00How to reduce the side effects of natural progesterone
How to Reduce the Side Effects of Natural Progesterone
Introduction
Natural progesterone side effects can be influenced by metabolism, genetics and the body’s response to hormonal pathways
It is one of the most physiologically aligned options used in menopause hormone replacement therapy (HRT). When combined with oestrogen, it helps protect the endometrium and is generally well tolerated. Yet some women still experience unwanted side-effects — such as dizziness, bloating, breast tenderness or mood changes.
These reactions are rarely caused by the hormone itself, but by individual differences in absorption, metabolism, receptor sensitivity and genetic background. Understanding these mechanisms is the key to improving tolerance and reducing side-effects safely.
When and why progesterone is needed
If you’re using oestrogen as part of menopause hormone therapy (MHT) and still have your uterus, you also need progesterone. It protects the endometrium (the uterine lining) from overgrowth and reduces the risk of hyperplasia and cancer.
Micronised (body-identical) progesterone — known commercially as Utrogestan®, Prometrium®, Progeffik®, or Susten® depending on the country — is considered the most physiologic and evidence-based option for women using MHT.
However, even this natural form can cause side effects in some women — often for reasons that have little to do with the drug itself.
Some women also notice improvements in sleep or mood, as natural progesterone is metabolised into calming neuroactive compounds — although these effects vary between individuals and are not the primary indication for its use.
For detailed guidance on endometrial protection, see the British Menopause Society’s “Progestogens and Endometrial Protection
Why your body can react differently to progesterone
Not every woman processes oral micronised progesterone (capsules) in the same way. Even when using the same dose, same formulation, and the same timing, two women can have completely different experiences. This does not mean the hormone is unsafe or unsuitable — it simply reflects natural biological variation.
Here are the three key mechanisms behind these differences:
Pharmacokinetics — how your body absorbs and clears progesterone
Pharmacodynamics — how sensitive your receptors are to progesterone
Pharmacogenetics — how your genes influence progesterone tolerance
Together, these three mechanisms create a unique response in every woman.
Understanding them allows for small, safe adjustments that often reduce unwanted side effects without needing to stop treatment
Pharmacokinetics: how your body absorbs and clears progesterone
Pharmacokinetics describes what the body does to a hormone once you take it — how it is absorbed, distributed, metabolised, and eventually cleared. With oral micronised progesterone, these steps can vary significantly from woman to woman, which explains why the same dose can feel completely different.
Some women absorb progesterone quickly and reach higher blood levels within hours. This can lead to temporary dizziness, breast tenderness, bloating, or a stronger sedative sensation. Others absorb it more slowly, with a gradual rise in levels and far fewer side-effects.
Absorption can also change depending on food intake. Because progesterone is lipophilic (fat-soluble), taking the capsule together with a high-fat meal — for example, meals containing avocado, olive oil, nuts, or oily fish — can increase absorption and produce stronger effects. Taking the capsule on an empty stomach, or with a low-fat meal, often leads to slower and more predictable absorption.
Metabolism also differs between women. Progesterone is processed by the liver through specific enzymes, and some women metabolise it faster or slower due to age, genetics, liver enzyme activity or interactions with other medications. For example:
some antidepressants (e.g., certain SSRIs) may slow the activity of enzymes that break down progesterone,
while some anti-epileptic medications may increase enzyme activity, making progesterone metabolise more quickly.
(We expand on these genetic and enzyme-related differences below, in the Pharmacogenetics section.)
Thyroid function and other health factors can also influence how progesterone is metabolised, especially in women with pre-existing thyroid conditions
Understanding your own absorption and metabolism patterns — including meal timing, liver enzyme activity, and individual variability — helps determine the best timing, dose adjustments, and formulation, often reducing side-effects without needing to stop treatment
Pharmacodynamics: how your receptor responds to progesterone
Pharmacodynamics describes what progesterone does to the body — in other words, how your cells and receptors respond to it. Not all women have the same receptor sensitivity, and this strongly influences how progesterone feels.
Some women have highly responsive progesterone receptors, so even a standard dose can produce a strong calming or sedative effect. Others have less responsive receptors and may feel almost nothing at all, even at a higher dose.
Sensitivity can also vary across different tissues in the same woman.
For example, the brain may respond more strongly (due to higher conversion into allopregnanolone), while the endometrium or breast may respond more mildly. This explains why some women notice pronounced mood or sleep effects but very few physical effects, or vice versa.
Receptor responsiveness can also fluctuate over time.
Factors such as stress, sleep quality, thyroid function, inflammation, and the natural hormone shifts of perimenopause can all change how strongly progesterone is felt from one week to the next. This is why a dose that felt “perfect” last month may suddenly feel too strong or too weak.
Recognising this natural variation helps your doctor adjust timing, dose, and formulation so progesterone becomes more predictable and easier to tolerate.
Pharmacogenetics: how your genes influence progesterone tolerance
Pharmacogenetics is one of the key reasons why two women taking the same dose of natural progesterone can have completely different experiences.
The reason lies in the genes that control how progesterone is metabolised, converted into its active metabolites such as allopregnanolone, and eventually cleared from the body.
Progesterone is processed through several enzymes. The most relevant for progesterone metabolism include CYP3A4 and CYP3A5, and 5-alpha-reductase and 3-alpha-HSD (which convert progesterone into allopregnanolone).
These enzymes vary from woman to woman due to normal genetic differences. As a result, metabolism can be unusually fast, unusually slow, or somewhere in between — leading to very different effects.
Two clear examples of how this affects your symptoms
Fast metabolisers
Some women carry genetic variants that make them convert progesterone into its metabolites more quickly than average.
What this means in practice:
• progesterone levels rise and fall rapidly,
• allopregnanolone can be produced in a quick, sharp peak,
• this sudden rise may cause drowsiness, dizziness, heavy sedation, mood swings or a “drugged” feeling shortly after taking the capsule.
These reactions are not a sign of intolerance, nor that “the hormone is too strong”. They simply reflect a faster metabolic pattern, which can usually be corrected safely by adjusting timing, dose or formulation.
Slow metabolisers
Other women naturally process progesterone more slowly.
What this means in practice:
Progesterone remains in the body for longer, so levels rise gradually.
The calming or sedative effects may feel very mild, delayed, or inconsistent.
Some slow metabolisers notice bloating or breast tenderness, because progesterone stays active in the tissues for more time before being cleared.
These reactions come from a slower metabolic pathway, not from taking “too much” progesterone.
Why this matters to you
Most unwanted effects from natural progesterone are not caused by the hormone itself. They usually reflect individual differences in absorption, metabolism, receptor sensitivity, and genetic background.
Understanding your own hormonal “response pattern” explains why:
one woman sleeps beautifully on 100 mg
another feels dizzy, bloated, or overly sedated
another feels almost nothing
the same dose can feel different from month to month
These variations are normal. They happen because women differ in:
absorption (affected by timing, food, gut factors)
metabolism (faster or slower liver enzymes)
receptor sensitivity (how the brain, breast, womb, and other tissues react)
genetic variants in the enzymes that convert progesterone into active metabolites
With this understanding, your doctor can make simple, safe, personalised adjustments—for example:
changing timing
modifying the dose
switching the formulation (capsule vs vaginal route)
These small changes often reduce side effects dramatically while allowing women to continue benefiting from natural progesterone’s protective role.
If deeper evaluation is ever useful, your clinician can guide you toward clinically appropriate pharmacogenetic testing, always after a full consultation and full medical assessment.
If you would like personalised medical guidance or wish to review your symptoms in depth, you can book an online consultation with Dr. María Zalazar
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Frequently Asked Questions
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Dr María Zalazar
Founder & Medical Director, MZ Medical
