Hormone therapy: what's the difference between bioidentical and synthetic hormones?

When hormone therapy is considered to relieve the symptoms of perimenopause or menopause, several questions come up.

Are hormones safe? What does the term "bioidentical" mean? Are synthetic hormones riskier? Is the patch better than the tablet?

These questions matter, because not all hormone therapies are equivalent. Their effects and risks can vary depending on the molecule used, its dose, or its route of administration.

Understanding these differences helps in choosing a hormone therapy suited to each situation.

At a Glance

• Bioidentical hormones have a molecular structure identical to that of the hormones produced by the human body. 17β-estradiol and micronized progesterone are the main examples used in menopausal hormone therapy (MHT).
• The "bioidentical" label does not guarantee that a treatment is safer. The route of administration also plays an important role. Even though it is bioidentical, 17β-estradiol taken orally passes through the liver before reaching the general circulation and may increase the risk of thromboembolism.
• Transdermal 17β-estradiol, delivered as a patch or gel, avoids this first pass through the liver. It is therefore generally associated with a more favourable thromboembolic profile than oral estrogens.
• When protection of the endometrium is needed, micronized progesterone also offers certain advantages compared with synthetic progestins. However, it may not be suitable for every woman.

What is a bioidentical hormone?

A hormone is said to be bioidentical when its molecular structure is identical to that of the hormone naturally produced by the human body.

In menopausal hormone therapy, the two main bioidentical hormones are:

• 17β-estradiol: the main estrogen produced by the ovaries during the reproductive years.
• Micronized progesterone: progesterone whose structure is identical to the one naturally produced by the body after ovulation.

The term "micronized" means that the progesterone has been processed into very small particles to improve its absorption by the body.

A bioidentical hormone can be manufactured in a laboratory from plant-based raw materials. What makes it bioidentical is therefore not its origin, but rather its final molecular structure.

In Canada, there are approved bioidentical preparations, manufactured according to precise pharmaceutical standards and offered in standardized doses. Oral or transdermal 17β-estradiol and micronized progesterone are among the recognized systemic hormone therapy options.

Bioidentical does not necessarily mean custom-compounded

The term "bioidentical hormones" is sometimes associated with compounded preparations made to order by a pharmacy. Yet hormone therapy does not need to be custom-compounded in order to be bioidentical.

Regulated formulations of 17β-estradiol and micronized progesterone are already available by prescription. They have been evaluated for their quality, dosage, and manufacturing.

Compounded preparations may be indicated in certain specific circumstances, for example when a commercial formulation is not suitable. They are not, however, generally considered safer or more effective.

Unapproved preparations may show greater dosage variability and have less data on their efficacy and safety. Their routine use is therefore not recommended when a regulated, approved preparation meets the person's needs.

What do we mean by synthetic hormones?

The term "synthetic" is often used to describe hormones whose structure differs from that of human hormones, even if they produce some similar effects in the body.

Commonly encountered examples include certain synthetic progestins, such as:

• medroxyprogesterone acetate;
• norethindrone;
• levonorgestrel.

Ethinylestradiol is another type of hormone (an estrogen) that is not bioidentical.

The distinction between "bioidentical" and "synthetic" can therefore be useful, but it is not enough to determine a treatment's profile.

Other factors must also be considered:

• the route of administration;
• the dose;
• the specific type of estrogen;
• the type of progestogen (progesterone vs synthetic progestins);
• individual risk factors.

Why does the route of administration of estradiol matter?

17β-estradiol, a bioidentical estrogen, can be administered in different ways, including:

• orally, as a tablet;
• transdermally, as a patch or gel.

The molecule is the same, but its journey through the body is different.

Oral 17β-estradiol

When taken as a tablet, estradiol is absorbed by the digestive system, then passes through the liver before reaching the general circulation.

This process is called the first-pass effect (hepatic first pass).

Passing through the liver can alter the production of certain proteins, notably those involved in blood clotting.

For this reason, oral estrogens, whether bioidentical or not, can increase the risk of venous thromboembolism.

Venous thromboembolism can notably take the form of:

• a deep vein thrombosis;
• a pulmonary embolism.

In addition, oral 17β-estradiol is largely converted into estrone (E1), an estrogen naturally found in the female body, but with a less favourable anti-inflammatory profile than estradiol (E2).

Transdermal 17β-estradiol

When applied to the skin as a patch or gel, estradiol passes directly into the bloodstream.

It therefore avoids the first pass through the liver and has fewer effects on the proteins involved in clotting.

Studies generally indicate that transdermal estradiol is associated with a lower risk of venous thromboembolism than oral estrogens.

The transdermal route may also help reduce the risk of stroke compared with certain oral hormone therapies.

The main advantages of transdermal estradiol

Transdermal 17β-estradiol is often preferred when clinically appropriate, notably because it:

• avoids the hepatic first pass;
• influences clotting factors less than oral estrogens;
• generally presents a more favourable thromboembolic profile;
• allows the use of a hormone whose structure is identical to that of human estradiol;
• can be considered in the presence of certain risk factors.

The transdermal route may in particular be preferred in the presence of certain situations, such as:

• migraines;
• obesity;
• metabolic syndrome;
• smoking;
• hypertension;
• dyslipidemia;
• certain cardiovascular or thromboembolic risk factors.

However, this does not mean that transdermal estradiol is appropriate for every woman. An individualized assessment remains necessary to determine whether hormone therapy is appropriate and which formulation best matches the person's clinical profile.

Why is a progestogen often needed?

In a woman who still has her uterus, a systemic estrogen used alone can stimulate the endometrium, the lining of the inside of the uterus.

Prolonged exposure to an estrogen without adequate protection can lead to endometrial hyperplasia and increase the risk of endometrial cancer.

Progesterone or a synthetic progestin must therefore generally be added to protect this lining.

After a hysterectomy, although this protection is no longer necessary, many women may benefit from adding progesterone to their treatment plan.

Micronized progesterone or synthetic progestins?

Micronized progesterone is bioidentical. Its structure is identical to that of human progesterone.

Synthetic progestins, such as medroxyprogesterone acetate, also bind to progesterone receptors, but their structure and biological effects are not exactly the same.

Some progestins can also interact with other hormone receptors, which may contribute to differences in their metabolic or vascular effects.

The available data suggest that micronized progesterone may present a more favourable thromboembolic profile than certain synthetic progestins.

Conversely, some combinations including conjugated estrogens and synthetic progestins, such as medroxyprogesterone acetate, have been associated with an increased thromboembolic risk.

The possible advantages of micronized progesterone

When prescribed at an appropriate dose and according to an appropriate regimen, micronized progesterone offers several advantages.

It protects the endometrium

When combined with a systemic estrogen in a woman who has her uterus, an important role is to reduce stimulation of the endometrium and to prevent its excessive thickening.

This protection depends, however, on:

• the dose used;
• the duration of administration;
• the continuous or cyclic regimen;
• adherence to treatment.

Its thromboembolic profile appears more favourable

Studies suggest that micronized progesterone does not add the same thromboembolic risk as certain synthetic progestins.

In some studies, the combination of an estrogen and micronized progesterone did not appear to significantly increase the risk of venous thromboembolism compared with no hormone therapy.

It may present a different breast profile

Some studies have observed a lower risk of breast cancer with combinations including micronized progesterone than with several combinations containing synthetic progestins.

These results are reassuring, but they do not mean that hormone therapy including micronized progesterone carries no breast risk.

The risk also depends on:

• age;
• the type of estrogen used;
• personal and family history;
• the individual risk profile.

It may promote sleep in some women

Micronized progesterone has a calming effect that promotes sleep for many women and is generally taken at bedtime.

Some studies have observed improvements in sleep-related parameters, notably the time needed to fall asleep.

Progesterone can have a sedative effect through its action on the GABA (gamma-aminobutyric acid) pathways. This effect can be beneficial for some women, but it can also cause:

• drowsiness;
• dizziness;
• a feeling of fatigue;
• reduced alertness.

The response can vary from one person to another.

Some formulations may contain sunflower or peanut oil. It is important to check the ingredients in case of allergy.

Why don't older studies represent all current hormone therapies?

A large part of the concerns surrounding hormone therapy comes from the Women's Health Initiative, whose first results were published in 2002.

In the combined arm of this study, the hormone therapy evaluated included:

• conjugated equine estrogens (CEE) taken orally;
• medroxyprogesterone acetate (MPA), a synthetic progestin.

This combination is not equivalent to today's menopausal hormone therapy, which often includes transdermal 17β-estradiol and micronized progesterone.

The results obtained with a given formulation cannot therefore be applied automatically to all hormone therapies, all routes of administration, and all women. When we talk about hormones, it is important to ask the question: "Which hormone exactly are we talking about?"

This does not mean that the Women's Health Initiative data should be discarded. Among other things, they provided essential information about the risks of certain formulations and about the importance of considering age and the timing of when hormone therapy is started.

Hormone therapy: safe when tailored

Hormone therapy should not be seen as a one-size-fits-all formula.

It must be individualized and reassessed over time; the need to periodically adjust the treatment plan is entirely normal. Current recommendations emphasize shared decision-making that takes several factors into account.

Key Takeaways

Bioidentical hormones have a molecular structure identical to that of human hormones. 17β-estradiol and micronized progesterone are the main examples.

The term "bioidentical" is not enough, however, to predict the safety profile of a hormone therapy.

The route of administration plays a decisive role: oral 17β-estradiol passes through the liver and may increase thromboembolic risk, whereas the transdermal route avoids this first pass and generally presents a more favourable profile.

Micronized progesterone protects the endometrium when used appropriately and appears to be associated with a lower thromboembolic risk than certain synthetic progestins.

It may also promote sleep in some women.

The choice of a hormone therapy must always take the overall clinical profile into account.

Looking Ahead

The distinction between bioidentical and synthetic hormones is only one of the elements to consider in order to better understand menopausal hormone therapy. The type of hormone, its molecular structure, its route of administration, its dose, and the way it is combined with other hormones can all influence its efficacy and risk profile.

To explore the benefits, risks, and most common misconceptions about menopausal hormone therapy, see also our article “Hormone therapy: myths and facts”.

In an upcoming article, we'll discuss the different types of female sex hormones, their main characteristics, and their roles in the menopausal transition.

Disclaimer

This article presents general educational information. It does not replace a clinical assessment or the advice of a healthcare professional.

References and Further Reading

1. Canonico, M., Oger, E., Plu-Bureau, G., Conard, J., Meyer, G., Lévesque, H., Trillot, N., Barrellier, M. T., Wahl, D., Emmerich, J., Scarabin, P. Y., & Estrogen and Thromboembolism Risk (ESTHER) Study Group. (2007). Hormone therapy and venous thromboembolism among postmenopausal women: Impact of the route of estrogen administration and progestogens: The ESTHER study. Circulation, 115(7), 840–845. https://doi.org/10.1161/CIRCULATIONAHA.106.642280

2. Demers, S. (2026, May 28). Prescrire l'hormonothérapie féminine avec Art et Science [Webinar].

3. Fournier, A., Berrino, F., & Clavel-Chapelon, F. (2008). Unequal risks for breast cancer associated with different hormone replacement therapies: Results from the E3N cohort study. Breast Cancer Research and Treatment, 107(1), 103–111. https://doi.org/10.1007/s10549-007-9523-x

4. Institut national d'excellence en santé et en services sociaux (INESSS). (2024). Les bénéfices et les risques de l'hormonothérapie.

5. Institut national d'excellence en santé et en services sociaux (INESSS). (2024, revised 2026). Prise en charge des manifestations cliniques liées à la ménopause par l'hormonothérapie.

6. Lalitkumar, P. G. L., Lundström, E., Byström, B., Ujvari, D., Murkes, D., Tani, E., & Söderqvist, G. (2023). Effects of estradiol/micronized progesterone vs. conjugated equine estrogens/medroxyprogesterone acetate on breast cancer gene expression in healthy postmenopausal women. International Journal of Molecular Sciences, 24(4), 4123. https://doi.org/10.3390/ijms24044123

7. Manson, J. E., et al. (2013). The Women's Health Initiative hormone therapy trials: Update and overview of health outcomes during the intervention and post-stopping phases. JAMA, 310(13), 1353–1368.

8. Mohammed, K., Abu Dabrh, A. M., Benkhadra, K., Al Nofal, A., Carranza Leon, B. G., Prokop, L. J., Montori, V. M., Faubion, S. S., & Murad, M. H. (2015). Oral vs transdermal estrogen therapy and vascular events: A systematic review and meta-analysis. The Journal of Clinical Endocrinology and Metabolism, 100(11), 4012–4020. https://doi.org/10.1210/jc.2015-2237

9. Nolan, B. J., Liang, B., & Cheung, A. S. (2021). Efficacy of micronized progesterone for sleep: A systematic review and meta-analysis of randomized controlled trial data. The Journal of Clinical Endocrinology and Metabolism, 106(4), 942–951. https://doi.org/10.1210/clinem/dgaa873

10. North American Menopause Society. (2022). The 2022 hormone therapy position statement of The North American Menopause Society. Menopause, 29(7), 767–794.

11. Rossouw, J. E., et al. (2002). Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA, 288(3), 321–333.

12. Rowe, T. (2016). A word about bioidenticals. Journal of Obstetrics and Gynaecology Canada, 38(8), 697–699.

13. Women's Health Initiative Steering Committee. (2004). Effects of conjugated equine estrogen in postmenopausal women with hysterectomy. JAMA, 291(14), 1701–1712.