HRT and incretin-based therapies (GLP-1 & GIP RAs)

This advice applies to Incretin-based therapies including glucagon-like peptide-1 receptor agonists (GLP-1RAs) such as semaglutide, and the dual glucagon-like peptide-1 and glucose-dependent insulinotropic peptide agonist tirzepatide.

Summary of key information: –

• Incretin-based therapies could reduce exposure to oral progestogens used as part of HRT, and thus compromise the essential endometrial protection the progestogen confers.
• Non-oral progestogens are unlikely to be affected.
• Exposure to oral estrogen could also be reduced; this could cause unwelcome recurrence of menopausal symptoms or some unscheduled bleeding, but not clinical harm.
• Note that effectiveness of oral contraceptives could also be affected by incretin-based therapies (please consult FSRH guidance for more information).

Summary of recommendations:-

• All prescribers of incretin-based therapies should inform HRT users about this potential effect and ensure that HRT is reviewed if an oral HRT progestogen is being used.
• All HRT users should be advised at HRT initiation and at every HRT review about this potential effect.
• All HRT users taking their HRT progestogen orally and also using an incretin-based therapy should be advised either:-
  • To switch to an appropriate non-oral HRT progestogen, or if this is not acceptable
  • To increase the oral progestogen dose for the duration of the incretin-based therapy (see Table 1 for suggested doses).
  • Please inform the user that there is not study evidence to inform whether the suggested increased oral progestogen doses provide adequate endometrial protection during use of incretin-based therapies.
• Anyone with unscheduled bleeding on HRT that contains an oral progestogen should be asked about use of incretin-based therapies.
• Anyone using an oral HRT progestogen and an incretin-based therapy who has unscheduled bleeding should:-

1. Be assessed as usual for unscheduled bleeding on HRT (check adherence to correct HRT use, check for use of any drug that could interact with HRT hormones, check STI and pregnancy risk, check smear status and examine the cervix, consider referral for endometrial investigation) AND

2. Be advised to switch to a non-oral HRT progestogen (or increase the progestogen dose as per Table 1 if non-oral progestogen is not acceptable). If unscheduled bleeding persists 3 months after this switch of progestogen, refer for endometrial investigation.

What is the concern?

It is possible that use of incretin-based therapies could reduce exposure to oral progestogens used as part of HRT and compromise the endometrial protection that they confer.

Background information

Incretin-based therapies delay gastric emptying.  Studies indicate that as a result they alter exposure to exogenous hormones given orally for contraception. The evidence is limited, but Faculty of Sexual and Reproductive Healthcare (FSRH) guidance recommends additional contraceptive precautions for 4 weeks after initiation of the incretin-based therapy and for 4 weeks after any dose increase. It is not clear by what mechanism absorption is expected to recover after 4 weeks. There is not an expected pharmacodynamic interaction.

Direct evidence is lacking to inform the effect of incretin-based therapies on absorption of oral HRT hormones. It is, however, possible that exposure to oral estrogen and oral progestogens could be reduced. HRT hormones administered by non-oral routes are not expected to be affected, although there is not robust evidence to support this.

Incretin-based therapies and the estrogen component of HRT

It is generally prudent to use transdermal (rather than oral) estradiol for individuals with higher BMI because both high BMI and oral estradiol increase thrombotic risk. Thus, many people commencing incretin-based therapies will already be using transdermal estradiol, and exposure to the transdermal estrogen is unlikely to be affected.

If someone is using HRT containing oral estradiol they might potentially experience a change in control of menopausal symptoms and/or bleeding when they start or increase dose of the incretin-based therapy. These effects would be unwelcome for the patient but there would not be clinical harm. They may wish to switch to transdermal estrogen to avoid this potential problem.

 Incretin-based therapies and the progestogen component of HRT

The progestogen component of HRT is essential for anyone using estrogen replacement who has a uterus and/or endometriosis. The role of the progestogen is to prevent endometrial hyperplasia and endometrial cancer. It is possible that exposure to oral progestogens could be reduced when incretin therapies are initiated or have their dose increased. There is not, unfortunately, evidence to inform the magnitude or duration of this effect, nor whether endometrial protection is significantly compromised. Extrapolating from the guidance given for oral contraception, it may be that the effect on progestogen exposure could be short-lived for a few weeks after initiation or dose increase, but there is not robust evidence to inform this.

In line with British Menopause Society guidance, it is expected that exposure to transdermal progestogen, intrauterine progestogen and vaginal progestogen would not be affected.

Progestogen options unlikely to be affected by incretin-based therapies include:-

• Transdermal norethisterone (as part of a combined transdermal patch like Evorel Sequi®/Conti)
• Transdermal levonorgestrel (as part of a combined transdermal patch like Femseven Conti®)
• Intrauterine levonorgestrel (a 52mg LNG-IUD like Mirena®, Levosert® or Benilexa® – effective for 5 years after insertion)
• Off label vaginal use of oral micronised progesterone – used at the same dose and in the same pattern as when used orally.

What does this mean in practice?

It is the responsibility of the prescriber of an incretin-based therapy to advise the user about interactions with other medications, including HRT. It is recommended, however, that HRT prescribers advise all users at the time that HRT is initiated and at each annual HRT review that they should seek early review if they start an incretin-based therapy, as it could affect the safety of their HRT. All HRT users should routinely be advised to seek review if they have unscheduled bleeding.

At the time of each annual HRT review, HRT users should be asked specifically about use of incretin-based therapies. If it is identified at any time that an HRT user is using one of these therapies and is using an oral progestogen, they should be offered a switch to a non-oral progestogen as above. If this is not acceptable, it is suggested that they increase the dose of the oral progestogen for the duration of use of the incretin-based therapy (see Table 1 below). They should be advised that we do not know what dose of progestogen would be required to achieve effective endometrial protection and that a switch to non-oral progestogen is recommended.

If any HRT user has unscheduled bleeding, check adherence to correct HRT use, pregnancy risk, STI risk, smear status, examine the cervix, and ask about use of any drugs that could interact with the HRT hormones – this would include incretin-based therapies.  The requirement for endometrial investigation should always be assessed. If they are using an incretin-based therapy and an oral HRT progestogen they should be switched to a non-oral HRT progestogen. If this is not acceptable the dose of oral progestogen could be increased as per Table 1, with a switch to a non-oral progestogen and referral for endometrial investigation if the bleeding persists after 3 months at the higher progestogen dose.

Table 1: Suggested dose of oral progestogen by estradiol dose and use of incretin-based therapy (note that there is not study evidence to inform whether the doses in the shaded rows provide adequate endometrial protection)

Estrogen dose?*	Incretin-based therapy use?	Daily dose of oral medroxyprogesterone acetate		Daily dose of oral Utrogestan (taken at night)
		Sequential	Continuous	Sequential	Continuous
High	No	10mg	5mg	300mg	200mg
	Yes	20mg	10mg	400mg	300mg
Medium-high	No	10mg	5mg	200mg	100mg
	Yes	20mg	10mg	300mg	200mg
Standard	No	10mg	5mg	200mg	100mg
	Yes	20mg	10mg	300mg	200mg
Low	No	10mg	5mg	200mg	100mg
	Yes	20mg	10mg	300mg	200mg

SH & CM 23/06/25