Micronised Progesterone vs Synthetic Progestins: What Is the Difference for Perimenopause?
Micronised progesterone and synthetic progestins both protect the uterus during HRT but have different safety profiles. Here is what the evidence says.
Why Progesterone Matters in HRT
For women who still have a uterus and are taking estrogen as part of hormone replacement therapy, a progestogen must be included to protect the uterine lining. Estrogen taken alone without progestogen stimulates the endometrium and raises the risk of endometrial hyperplasia and endometrial cancer. The progestogen component counteracts this stimulation, keeping the lining safe. For decades, synthetic progestogens (also called progestins) were the standard option used alongside estrogen in HRT. More recently, micronised progesterone (a bioidentical form of progesterone) has become widely available and is now preferred by many menopause specialists based on emerging evidence about its safety profile compared to synthetic alternatives.
What Is Micronised Progesterone?
Micronised progesterone is progesterone in a form that has been processed into tiny particles to improve absorption. Chemically, it is identical to the progesterone produced naturally by the ovaries. In the UK, it is available as Utrogestan, a soft gel capsule that can be taken orally or inserted vaginally. The micronisation process improves bioavailability significantly compared to older oral progesterone preparations. Because it is structurally identical to natural progesterone, it binds to progesterone receptors in the same way the body's own progesterone does, without the off-target effects that some synthetic progestins have on other hormone receptors.
What Are Synthetic Progestins?
Synthetic progestins are compounds developed to mimic the uterine-protective action of progesterone but with a different chemical structure. Common examples include medroxyprogesterone acetate (MPA), norethisterone (NET), and levonorgestrel. These are used not only in HRT but also in the contraceptive pill, hormonal coils, and contraceptive injections. Synthetic progestins were developed partly because early forms of progesterone were poorly absorbed orally, making them impractical for daily use. They are effective at protecting the endometrium but their structural differences from natural progesterone mean they interact with other hormone receptors in ways that can produce different side effects and health outcomes.
Breast Cancer Risk: The Critical Difference
One of the most important differences between micronised progesterone and synthetic progestins relates to breast cancer risk. The landmark French E3N cohort study, which followed a large group of postmenopausal women over many years, found that HRT using estrogen combined with synthetic progestins was associated with an increased breast cancer risk, while HRT using estrogen combined with micronised progesterone was not associated with a significant increase. The Women's Health Initiative study, which used MPA as the progestogen, found increased breast cancer risk with combined HRT. These findings have shifted prescribing guidance in many countries, with micronised progesterone now recommended as the preferred progestogen in updated UK NICE guidance and by leading menopause organisations.
Cardiovascular and Mood Effects
Synthetic progestins, particularly those derived from testosterone such as norethisterone, can have androgenic (testosterone-like) effects. These can negatively affect cholesterol profiles, potentially countering some of the cardiovascular benefits of estrogen. Micronised progesterone has a more neutral or potentially beneficial effect on lipid profiles. Mood is another area where differences have been observed. Some women report mood-related side effects including depression or irritability with certain synthetic progestins, whereas micronised progesterone has a calming, mildly sedative effect due to its conversion to allopregnanolone in the brain, a neurosteroid that acts on GABA receptors. Taking micronised progesterone at night can support sleep, an additional benefit during perimenopause when sleep disruption is common.
Practical Prescribing Differences
Micronised progesterone is available in the UK as Utrogestan, prescribed as a 100 mg or 200 mg capsule. It can be taken orally, typically at night, or used vaginally for women who experience side effects orally. It is available on NHS prescription. Synthetic progestins are used in various combined HRT preparations including combined patches (such as Evorel Conti and Evorel Sequi), which deliver both estrogen and progestogen through the skin. Some women find combined patches convenient as they simplify the regimen. However, the progestogen in most combined patches is a synthetic progestogen rather than micronised progesterone. Women who prefer micronised progesterone alongside transdermal estrogen use estrogen patches or gel with Utrogestan taken separately.
Which Should You Ask About?
Based on current evidence, micronised progesterone is the preferred progestogen for most women starting HRT. Its safety profile regarding breast cancer is more favourable, its mood effects are generally better tolerated, and its cardiovascular impact is neutral to positive. This does not mean synthetic progestins are unsafe for everyone. Women who have been on a particular HRT regimen for years and are doing well may not need to change. And for women using the Mirena hormonal coil as their progestogen component, a very low dose of levonorgestrel acts locally in the uterus with minimal systemic absorption, which carries a low risk profile. Discussing your current HRT regimen with your GP or menopause specialist and asking specifically about micronised progesterone is a reasonable step for any woman reviewing her options.
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