Progesterone Intolerance in Perimenopause

Progesterone is often described as the “calming” or “balancing” hormone. For many women, it supports sleep, steadies mood, and counterbalances estrogen. But for a significant minority, progesterone — or more commonly its synthetic counterparts — can trigger symptoms that feel very much like severe PMS.

If you’ve noticed bloating, breast tenderness, acne, headaches, anxiety, low mood, or a sense that you feel worse rather than better when taking hormonal contraception or hormone replacement therapy (HRT), you are not imagining it. You may be experiencing progesterone intolerance.

As a doctor working closely with women through perimenopause, I want to be very clear: progesterone intolerance is real, recognised, and common — and there are ways to manage it.

What is progesterone intolerance?

Progesterone intolerance (sometimes called progesterone sensitivity) refers to a pattern of physical, psychological, or metabolic symptoms that occur in response to progesterone exposure. This exposure may be:

• Endogenous (your own progesterone during the menstrual cycle), or

• Exogenous (progesterone or progestogens used in contraception or HRT).

It is estimated to affect around 10–20% of women [1].

Progesterone intolerance is distinct from progesterone hypersensitivity, which is a rare allergic condition involving reactions such as hives, swelling, or anaphylaxis. The vast majority of women experiencing intolerance are dealing with neurohormonal and receptor-mediated effects, not allergy [1–3].

Progesterone, progestogens, and why the distinction matters

There are two broad categories of progesterone-related hormones used in clinical practice.

Progesterone (body-identical progesterone)

This is chemically identical to the progesterone naturally produced by the ovaries after ovulation. It is derived from plant sources (such as yam or soy) and processed to match human progesterone exactly.

In New Zealand, the only regulated, prescribed body-identical progesterone is micronised progesterone (commonly known as Utrogestan).

Progestogens (synthetic progesterone-like hormones)

Progestogens (also called progestins) are synthetic compounds designed to act like progesterone but differ slightly in molecular structure. They are used in:

• The combined oral contraceptive pill

• The progestogen-only pill

• Contraceptive implants and injections

• Hormonal coils (IUS)

• Some forms of HRT

Because of their altered structure, synthetic progestogens can bind not only to progesterone receptors, but also to androgen (testosterone) and mineralocorticoid receptors. This explains why they are more likely to cause side effects such as acne, fluid retention, bloating, and mood changes [1,4].

Symptoms of intolerance are far more common with synthetic progestogens than with body-identical progesterone.

What does progesterone intolerance feel like?

Symptoms typically fall into three overlapping domains.

Psychological symptoms

• Anxiety or inner restlessness

• Low mood or depressive symptoms

• Irritability or emotional volatility

• Panic attacks

• Poor concentration and memory

• Heightened emotional sensitivity

Progesterone and progestogens act on receptors in the central nervous system, influencing neurotransmitters such as GABA and serotonin, which are central to mood regulation [1].

Physical symptoms

• Abdominal bloating or cramping

• Breast tenderness

• Fluid retention

• Headaches or dizziness

• Fatigue

• Greasy skin or acne

Metabolic effects

Some synthetic progestogens can adversely affect:

• Cholesterol profiles

• Blood pressure regulation

• Insulin sensitivity

Natural, body-identical progesterone does not usually have these metabolic effects [4].

Progesterone intolerance, PMS, and PMDD — an important clarification

Many women with progesterone intolerance notice that their symptoms worsen during the luteal phase of the menstrual cycle — the time after ovulation and before a period, when progesterone levels are highest.

This phase is commonly associated with premenstrual syndrome (PMS). It is important to be clear that PMS is not caused by progesterone alone. PMS arises from the interaction between fluctuating ovarian hormones (including estrogen and progesterone) and the brain’s sensitivity to these changes. Neurotransmitters such as serotonin and GABA play a key role in how these hormonal shifts are experienced.

That said, progesterone appears to be a key contributor for many women — particularly those who are sensitive to it or to synthetic progestogens. In women with progesterone intolerance, the rise in progesterone during the luteal phase can trigger low mood, anxiety, irritability, bloating, breast tenderness, and fatigue. When symptoms are severe and predominantly mood-related, this may meet criteria for premenstrual dysphoric disorder (PMDD).

This helps explain why women who struggled with PMS or PMDD earlier in life are often the same women who find certain progestogens difficult to tolerate during perimenopause or on HRT [1,2].

Why progesterone is still needed in HRT

If you have a uterus and take estrogen as HRT, progesterone (or a progesterone-like agent) is essential.

Estrogen stimulates the cells lining the uterus (the endometrium). Without progesterone to counterbalance this effect, the lining can become excessively thickened, increasing the risk of abnormal cell changes and, over time, endometrial cancer.

Progesterone’s role when using estrogen is to:

• Stabilise the uterine lining

• Prevent estrogen overstimulation

• Allow estrogen to be used safely

The challenge in progesterone intolerance is not whether progesterone is needed, but how to deliver uterine protection without causing distressing symptoms.

Why intolerance often emerges in perimenopause or on HRT

Perimenopause is characterised by hormonal volatility, not simply low hormone levels. Estrogen and progesterone fluctuate unpredictably, and the brain’s response to hormones also changes during this transition [5–7].

Many women notice:

• Feeling significantly worse during the progesterone phase of cyclical HRT

• New or worsening mood symptoms when switching to continuous progesterone

Progesterone intolerance is one of the most common reasons women discontinue HRT, even when estrogen is clearly helping symptoms such as hot flushes, sleep disturbance, joint pain, and brain fog [1].

Management options for progesterone intolerance

1. Micronised (body-identical) progesterone

Micronised progesterone (Utrogestan) is generally the best-tolerated option for women with progesterone intolerance [8,11].

Because it is structurally identical to endogenous progesterone, it binds selectively to progesterone receptors and is less likely to activate other hormonal pathways.

It is a systemic progesterone, meaning it circulates throughout the body and may:

• Support sleep

• Reduce inflammation

• Relax smooth muscle

• Improve mood and cognition

Some women still experience side effects when taken orally, as oral progesterone is metabolised in the liver into neuroactive metabolites that can influence sedation and mood [8]. 

For women who are sensitive to progesterone, small adjustments to Utrogestan can make a meaningful difference. In New Zealand, cyclical (sequential) progesterone regimens are usually used while a woman is still having periods, whereas continuous progesterone is typically introduced once periods have stopped.

Common cyclical options include 200 mg nightly for 12 days each month, or in some women, 100 mg taken nightly every day with a planned 5–7-day break each month to allow a withdrawal bleed. Some women find this lower-dose cyclical approach more tolerable than higher-dose short courses.

Once periods have ceased, a continuous regimen of 100 mg nightly every day is commonly used. Many progesterone-sensitive women feel better on a lower daily continuous dose rather than higher intermittent dosing.

Timing can also influence tolerability — taking Utrogestan at night often reduces side effects such as dizziness or grogginess and can support sleep. If symptoms persist, the route of administration may be adjusted, with vaginal use often improving mood and physical side effects for women with progesterone intolerance.

Any adjustments to dose, timing, or route should be made together with a clinician experienced in menopause care. This allows treatment to be tailored to you — ensuring the uterine lining remains safely protected while also prioritising symptom relief and quality of life. The amount of progesterone needed can also vary depending on the dose of estrogen being used.

2. Vaginal progesterone

Using micronised progesterone vaginally allows absorption directly into the bloodstream and uterus, bypassing liver metabolism.

This route often results in:

• Fewer systemic side effects

• Improved mood tolerance

Although off-label, vaginal progesterone is widely used, considered safe, and supported by evidence [5]. Progesterone pessaries such as Cyclogest or Lutigest (non-funded in NZ) may also be used.

Dosages are usually the same as oral for example:

• 200mg daily for 12–14 days per month (for cyclical use)
• 100mg daily continuously (for those not having periods).

3. Levonorgestrel intrauterine system (Mirena)

The Mirena coil releases a low, steady dose of synthetic progestogen directly into the uterus.

For many women, this provides excellent uterine protection with minimal systemic exposure. Some experience PMS-like symptoms for the first 3–6 months, which often settle. A minority continue to experience systemic effects and require removal.

4. Exploring alternative progestogen options

While many women with progesterone intolerance feel best on body-identical progesterone, responses are highly individual. Interestingly, some women find they tolerate older synthetic progestogens, such as medroxyprogesterone acetate (Provera) or norethisterone, better than newer formulations, despite these being traditionally associated with a higher side-effect burden.

Others may find improved stability with certain progesterone-only contraceptives, such as drospirenone (Slinda) or desogestrel (Cerazette), which can create a more consistent hormonal environment and reduce cyclical symptom fluctuations. These responses highlight that there is no single “right” progesterone — careful, individualised trialling under medical guidance can be key to finding the best fit for each woman.

5. Estrogen plus bazedoxifene (Duavive)

Duavive is an oral HRT option that combines:

• Conjugated estrogens (a synthetic, non–body-identical estrogen), and

• Bazedoxifene, a synthetic selective estrogen receptor modulator (SERM).

SERMs act like estrogen in some tissues and block estrogen in others. Bazedoxifene has a strong anti-estrogen effect on the uterus, meaning progesterone is not required for endometrial protection.

It is:

• Neutral in breast tissue

• Estrogenic in bone (supporting bone density)

Duavive can be a useful option for women who cannot tolerate progesterone at all, but as an oral estrogen therapy, cardiovascular and thrombotic risk must be carefully assessed [9,10,14].

6. Tibolone

Tibolone is a synthetic steroid that is metabolised into compounds with estrogen-like, progesterone-like, and testosterone-like effects.

It may improve:

• Vasomotor symptoms

• Libido

• Mood and energy

However, there are important safety considerations:

• Tibolone is associated with an increased risk of stroke, particularly in women over 60

• In women with a history of breast cancer, tibolone increases the risk of recurrence and is contraindicated

• Careful cardiovascular risk assessment is essential

For these reasons, tibolone is not a first-line therapy and should only be considered in carefully selected women [9,14].

7. Surgical options (last resort)

In rare cases, where symptoms are severe and all medical strategies have failed, hysterectomy (with or without oophorectomy) may be considered, allowing estrogen-only HRT. This is always a last-resort option.

Final thoughts

When it comes to progesterone, most women fall into one of three groups:

• Those who love it

• Those who hate it

• Those who barely notice it

If you are in the second group, you are not difficult, sensitive, or failing treatment. Your nervous system and hormone receptors are responding in a very real way — and with the right approach, most women can find a solution that protects their long-term health and restores quality of life.

If progesterone intolerance is affecting you, seek care from a clinician with a specific interest in menopause. This is nuanced medicine, and with the right individualised approach, most women can find a path that truly supports their wellbeing.

References

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2. MacLean J, Hayashi K. Progesterone actions and resistance in gynecological disorders. Cells. 2022;11:647.

3. Li RC, Buchheit KM, Bernstein JA. Progestogen hypersensitivity. Curr Allergy Asthma Rep. 2018;18:1.

4. Palacios S, Mejía A. Progestogen safety and tolerance in hormonal replacement therapy. Expert Opin Drug Saf. 2016;15(11):1515–1525.

5. IMS Menopause Live Case Report: A bad case of progestogen intolerance. International Menopause Society. 2020.

6. Santoro N. Perimenopause: From research to practice. J Women’s Health. 2016;25(4):332–339.

7. Davis SR et al. Menopause—biology, consequences, and therapeutic options. Cell. 2023;186:4038–4058.

8. Memi E et al. Diagnostic and therapeutic use of oral micronized progesterone. Rev Endocr Metab Disord. 2024;25(4):751–772.

9. Crandall CJ et al. Management of menopausal symptoms. JAMA. 2023;329(5):405–420.

10. Lumsden MA et al. European Society of Endocrinology guideline for menopause. Eur J Endocrinol. 2025;193:G49–G81.

11. Prior JC. Progesterone for treatment of symptomatic menopausal women. Climacteric. 2018;21(4):358–365.

12. BMJ Clinical Review. Management of perimenopausal and menopausal symptoms. 2023.

13. Palacios S et al. Safety of tibolone. Climacteric. 2019.

14. Duralde ER et al. Management of perimenopausal and menopausal symptoms. BMJ. 2023;382:e072612.