In This article

• The menopausal transition has been associated with the worsening of mood symptoms, therefore maintaining therapeutic levels of lamotrigine is critical for women with bipolar disorder.
• Estrogen increases the activity of the liver enzyme UGT1A4, accelerating lamotrigine clearance and lowering serum drug levels in the body.
• This metabolic relationship is well established in birth control: oral estrogen has the clearest evidence for reducing lamotrigine levels, cutting blood levels of lamotrigine by 50%; transdermal patches and low-dose vaginal options have less systemic absorption, but evidence is currently insufficient to rule out interactions.
• Menopausal hormone therapy (MHT) uses lower estrogen doses and different formulations (such as estradiol or conjugated estrogens), leading to a less pronounced reduction of approximately 17–30%.
• Estrogen exposure reduces lamotrigine concentrations, but lamotrigine does not meaningfully compromise the effectiveness of MHT.
• Starting MHT should not prompt automatic, large dosage changes. Clinicians should establish baseline serum levels, monitor for mood symptom recurrence, and make tailored dose adjustments only if clinically indicated.

For women taking lamotrigine (Lamictal), the decision to start menopausal hormone therapy (MHT) raises an important but often overlooked question: Can estrogen-containing hormone therapy change lamotrigine levels?

We have known for many years that estrogen-containing oral contraceptives can substantially lower blood levels of lamotrigine. More recently, evidence has emerged suggesting that estrogen-containing MHT may also reduce lamotrigine concentrations. The magnitude of this interaction appears to be smaller but is much less well characterized than the interaction between lamotrigine and oral contraceptives.

This issue is becoming increasingly relevant as more women seek treatment for bothersome menopausal symptoms and consider MHT during the perimenopause and menopause. Because the menopausal transition has been associated with the worsening of mood symptoms, maintaining therapeutic levels of lamotrigine is particularly important in women with bipolar disorder. Fluctuating hormone levels, and accompanying sleep disturbance, may increase vulnerability to relapse; while MHT may have benefits in terms of decreasing the symptoms related to hormonal shifts, it is important to understand how estrogen affects the metabolism of mood stabilizers, specifically lamotrigine.

Why does estrogen affect lamotrigine?

Lamotrigine is primarily metabolized in the liver through a process called glucuronidation. One of the enzymes involved in this process is UDP-glucuronosyltransferase 1A4 (UGT1A4).

Estrogen can increase the activity of UGT1A4. When this happens, lamotrigine is metabolized more rapidly, resulting in lower concentrations of the medication in the bloodstream. Experimental research has demonstrated that 17beta-estradiol can increase expression of UGT1A4, providing a biologically plausible explanation for the interaction between estrogen and lamotrigine.

This interaction is particularly well established with combined oral contraceptives containing ethinyl estradiol. Studies have found that estrogen-containing oral contraceptives can reduce lamotrigine concentrations by approximately 50%, with studies reporting reductions ranging from 41% to 64%.

The interaction can occur rapidly. In one controlled study, stopping an estrogen-containing oral contraceptive resulted in an approximately 84% increase in lamotrigine concentrations, with most of the change occurring within the first week.

For women taking lamotrigine for bipolar disorder, a substantial reduction in lamotrigine exposure could potentially result in loss of antidepressant or mood-stabilizing benefit.

What about menopausal hormone therapy?

MHT generally contains much lower doses of estrogen than combined oral contraceptives, and the estrogen preparations used for MHT are usually estradiol or conjugated estrogens rather than ethinyl estradiol.

For this reason, it might be tempting to assume that MHT would have little or no effect on lamotrigine. Unfortunately, the available evidence does not allow us to make that assumption.

The most important study addressing this question was published by Reimers in 2017. Investigators examined therapeutic drug-monitoring data from 79 women taking lamotrigine and estrogen-containing HRT and compared them with 158 age- and dose-matched women who were not taking estrogen therapy.

The women taking HRT had significantly lower lamotrigine concentrations and lower lamotrigine concentration-to-dose ratios than the matched controls. Mean serum lamotrigine concentrations were approximately 10.6 µmol/L in the HRT group compared with 12.6 µmol/L in controls—a difference of about 17%.

Importantly, this study included a variety of HRT preparations, including estradiol, estriol, and combinations of estradiol with norethisterone. Most women were taking estradiol. The investigators concluded that estrogen-containing HRT may reduce lamotrigine concentrations, but they also emphasized that the study was retrospective and that prospective studies are needed to determine the magnitude and clinical significance of the interaction.

An earlier randomized trial of hormone therapy in postmenopausal women with epilepsy provides additional evidence. Two women taking lamotrigine experienced a 25–30% decrease in lamotrigine concentrations while taking conjugated equine estrogen plus medroxyprogesterone acetate.

Thus, the available evidence suggests that estrogen-containing MHT can lower lamotrigine concentrations, but the data are limited and it is difficult to predict how much an individual woman’s lamotrigine level will change if MHT is initiated.

Does the route of estrogen administration matter?

The strongest evidence for an interaction with MHT comes from women taking oral estrogen preparations. The Reimers study included women taking oral estradiol, estradiol combined with norethisterone, and estriol. Although the estrogen doses used in MHT are lower than those used in most combined oral contraceptives, the estrogen contained in these preparations is sufficient to potentially increase lamotrigine metabolism.

Therefore, women taking lamotrigine who start oral estrogen-containing MHT should be monitored for changes in their response to lamotrigine.  It is important, however, not to assume that the lamotrigine dose will need to be increased by a particular percentage. There are currently insufficient data to recommend a standard dose adjustment.

Transdermal estrogen

Transdermal estradiol is widely used for MHT and has become an increasingly popular option because it avoids first-pass hepatic metabolism and has a different pharmacokinetic profile than oral estrogen.

Could this make transdermal estrogen less likely to interact with lamotrigine? We don’t know.

The Reimers study included women using both oral and transdermal HRT, but only one woman in the study was identified as using a transdermal estradiol patch. Consequently, the study cannot tell us whether transdermal estrogen has a smaller effect on lamotrigine than oral estrogen.

Because transdermal estradiol is systemically absorbed, an interaction remains biologically plausible, but the available evidence is insufficient to determine the magnitude of the effect.

Thus, transdermal estrogen should not currently be considered completely free of interaction with lamotrigine.

Vaginal estrogen

Even less is known about vaginal estrogen.  Low-dose vaginal estrogen is commonly used for genitourinary symptoms of menopause, including vaginal dryness and discomfort with sexual activity. Because these preparations are administered locally, systemic estrogen exposure is generally lower than with systemic MHT.

However, systemic absorption does occur, and the degree of absorption varies according to the formulation and dose.

There are currently no good clinical studies evaluating whether low-dose vaginal estrogen changes lamotrigine concentrations. The available literature therefore does not allow us to conclude that vaginal estrogen has no interaction with lamotrigine.

What should women taking lamotrigine do if they want to start MHT?

The possibility of an interaction should not automatically prevent a woman from using MHT if she has an appropriate indication for treatment.

Instead, the goal is to anticipate the possibility of a change in lamotrigine exposure and monitor accordingly.

For a woman who is stable on lamotrigine and is considering MHT, it may be useful to:

• Obtain a lamotrigine level prior to starting MHT.  If the patient is not clinically stable, was there a lamotrigine level previously obtained during a period of clinical stability.

• Monitor for recurrence of depressive symptoms, mood instability, or other symptoms that previously responded to lamotrigine.
• If clinically indicated, obtain a follow-up lamotrigine level after estrogen therapy has reached a steady state.
• If there is evidence of loss of clinical response or a substantial decline in lamotrigine concentration, consider whether a dose adjustment is warranted.
• Avoid making large changes in lamotrigine dosage solely because MHT has been initiated. Changes in dose should reflect changes in the clinical picture.

When lamotrigine is used for the treatment of mood disorders, there is not a well-established therapeutic range, as exists for lithium.  Nonetheless, therapeutic drug monitoring can be useful in monitoring changes associated with MHT and may be particularly useful when a woman has previously had a well-documented relationship between her lamotrigine concentration and clinical response.

What happens if a woman is already taking MHT and starts lamotrigine?

If a woman is already taking estrogen-containing MHT and then begins lamotrigine, her lamotrigine dose should be titrated in the usual manner. There is not enough evidence to recommend a special higher starting dose simply because she is taking MHT.

Once an effective maintenance dose has been established, however, clinicians should be aware that the woman’s lamotrigine requirement may be different from that of a woman who is not receiving estrogen.

If MHT is subsequently discontinued, estrogen-mediated induction of lamotrigine metabolism may diminish. Lamotrigine concentrations could therefore rise.

Does lamotrigine reduce the effectiveness of MHT?

The available evidence suggests that lamotrigine does not meaningfully reduce estrogen levels.

This is an important distinction. The primary interaction is in the direction of estrogen reducing lamotrigine concentrations, rather than lamotrigine reducing the effectiveness of estrogen therapy.

Data from women taking combined oral contraceptives show that lamotrigine does not significantly alter the pharmacokinetics of ethinyl estradiol. Lamotrigine has been associated with modest reductions in levels of the progestin levonorgestrel, but these changes have not been shown to compromise contraceptive efficacy.

There is less data regarding MHT specifically, but there is currently no evidence that lamotrigine reduces the effectiveness of menopausal hormone therapy.

Thus, when a woman takes both medications, the primary concern is maintaining adequate lamotrigine exposure, rather than inadequate estrogen exposure.

The Bottom Line

Estrogen-containing MHT may reduce blood levels of lamotrigine, but the magnitude of this interaction is much less certain than the well-established interaction between lamotrigine and estrogen-containing oral contraceptives.

The available evidence suggests:

• Estrogen increases the activity of UGT1A4, the enzyme responsible for much of lamotrigine’s metabolism.
• Combined oral contraceptives containing ethinyl estradiol can reduce lamotrigine concentrations by approximately 50% or more.
• MHT preparations containing lower doses of estrogen may also affect lamotrigine levels; however, the magnitude of the effect is not well-established.
• We do not yet know whether oral and transdermal MHT have different effects on lamotrigine.
• There are very limited data regarding low-dose vaginal estrogen and lamotrigine.
• Starting or stopping estrogen therapy may warrant closer monitoring of clinical response and, when appropriate, lamotrigine blood levels.
• Lamotrigine does not appear to substantially reduce the effectiveness of estrogen therapy.

For women who are doing well on lamotrigine and considering MHT, the presence of this potential interaction does not mean that MHT should be avoided. Rather, clinicians should recognize that estrogen may alter lamotrigine exposure and should monitor for changes in mood or other clinical symptoms when MHT is started, changed, or discontinued.

More research is needed to determine whether the route, dose, and formulation of MHT influence the magnitude of this interaction. Until those data are available, an individualized approach—with attention to clinical response and, when useful, therapeutic drug monitoring—is reasonable.

—Ruta Nonacs, MD PhD