Drug & supplement interaction

Progesterone + Estradiol, Norethindrone Acetate

Estradiol, Norethindrone Acetate brand name: Activella.

Moderate Interaction
Medically reviewed by · Updated September 2026
The bottom line Moderate

Progesterone has a moderate interaction with Estradiol, Norethindrone Acetate. Theoretically, using estrogen along with progesterone supplements or non-prescription bioidentical progesterone products might alter the effects of estrogen.

Read the full interaction report
SeverityModerate
LikelihoodPossible
EvidenceA
What do Severity, Likelihood & Evidence mean?
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Interaction report

Progesterone and Estradiol, Norethindrone Acetate

Here is the interaction we found between these two, with the evidence behind it.

Moderate

ESTROGENS

Why this applies to Estradiol, Norethindrone Acetate

Estradiol, Norethindrone Acetate falls under ESTROGENS — the group Progesterone interacts with.

Theoretically, using estrogen along with progesterone supplements or non-prescription bioidentical progesterone products might alter the effects of estrogen.
Concomitant use of estrogen with prescription progesterone products can cause breast tenderness. Also, use of conjugated equine estrogens with oral micronized progesterone in postmenopausal patients seems to blunt the beneficial effects of estrogen on the lipoprotein profile, although it might not affect estrogen-induced reduction in plasma lipoprotein (a). It is unclear if this interaction would be clinically significant with the doses found in oral or topical progesterone supplements or non-prescription bioidentical products.
Severity Moderate Likelihood Possible Evidence A

Interaction has been documented in animal or in lab research, or the interaction has been documented in humans but is limited to case reports or conflicting clinical research exists.

Dr. Brian Staiger, PharmD, BCPS
Dr. Brian Staiger explains PharmD, Clinical Pharmacist

Here is something worth knowing: your Activella already contains both an estrogen (estradiol) and a progestin (norethindrone acetate). So if you add an outside progesterone product, like a cream or capsule, you are essentially stacking a second progesterone-type hormone on top of one you are already taking. The most likely real-world result is more of the hormone-related effects you might already notice, such as breast tenderness, bloating, mood changes, or spotting.

There is also a theory that extra progesterone can soften some of estrogen's helpful effects on cholesterol, but this was studied with specific products, and we honestly don't know if it matters at the doses in over-the-counter creams. Please don't start, stop, or double up on anything on your own. Loop in your doctor or pharmacist first, since these are real hormones working together.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Greendale GA, Reboussin BA, Hogan P, et al. Symptom relief and side effects of postmenopausal hormones: results from the Postmenopausal Interventions Trial. Obstet Gynecol 1998;92:982-8.
  2. Chen FP, Lee N, Soong YK. Changes in the lipoprotein profile in postmenopausal women receiving hormone replacement therapy. Effects of natural and synthetic progesterone. J Reprod Med 1998;43:568-74.
  3. Espeland MA, Marcovina SM, Miller V, et al. Effect of postmenopausal hormone therapy on lipoprotein(a) concentration. Postmenopausal Estrogen/Progestin Interventions (PEPI) Investigators. Circulation 1998;97:979-86. DOI

What These Ratings Mean

Every interaction above is graded three ways — here’s the key to each label.

Severity how clinically significant the interaction is
Major

Clinically significant. Avoid the combination, or use only under close professional supervision.

Moderate

Usually worth avoiding or managing — may need monitoring, a dose change, or timing apart.

Minor

Generally not serious. Be aware of it and mention it to your pharmacist.

Likelihood how strong the evidence is that the interaction actually happens in people
  • LikelyWell-controlled human studies have demonstrated the likely existence of this interaction.
  • ProbableInteraction has not been documented in well-controlled studies, however, the interaction has been demonstrated in some small human studies or in controlled animal studies in conjunction with multiple case reports.
  • PossibleInteraction has been documented in animal or in lab research, or the interaction has been documented in humans but is limited to case reports or conflicting clinical research exists.
  • UnlikelyInteraction has been demonstrated in animal or in lab research but has been shown not to occur in humans.
Evidence the quality of the studies behind the rating (graded A–D)
  • AHigh-quality meta-analysis (quantitative systematic review).
  • BCase-control study.
  • CConsensus.
  • DAnecdotal evidence.

These ratings are for information only. Never start, stop, or otherwise change your therapy before speaking with your provider.

Keep it in perspective

Progesterone Also Interacts With Other Medications

Progesterone has 40 moderate, 1 minor known drug interactions in our database — the Estradiol, Norethindrone Acetate one above is one of them. If you take anything else, check it against the full list below.

Moderate 40 Minor 1 No known interaction 2,789 (incl. Estradiol, Norethindrone Acetate)
Taking anything else?

Check Another of Your Medications Against Progesterone

Covers the 2,830 medications we’ve checked against Progesterone. Pick one to open its full report.

From our Q&A

Questions About Progesterone or Estradiol, Norethindrone Acetate

These are real questions from readers, answered by the pharmacists at HelloPharmacist — written by a person, not generated from a database. Each one covers Progesterone or Estradiol, Norethindrone Acetate, not necessarily both, but if one is close to what you were about to ask it will usually go further than a database entry can:

Not quite your question? Ask our pharmacists directly — it is free, there is no account required, and answers usually come back within 24 hours.

Everything else you take

See Every Supplement That Interacts With Estradiol, Norethindrone Acetate

This page covers Progesterone only. If you take other supplements — a multivitamin, a sleep aid, something for joints — the Estradiol, Norethindrone Acetate page lists 212 supplements it has a documented interaction with, worst first, each one explained.

The most serious there right now: Activated Charcoal (major), Grapefruit (major), St. John's Wort (major), Acacia Rigidula (moderate) and Adrafinil (moderate).

By severity: 3 major · 171 moderate · 38 minor.

From our pharmacist’s overview on the Estradiol, Norethindrone Acetate page

“Activella pairs estradiol with norethindrone as hormone therapy, and because the treatment depends on steady hormone levels in the blood, supplements that raise or lower those levels warrant real scrutiny. Three of the 212 interacting ingredients rate major, and all three hit that weak point: St.”

Reviewed by 2 · Jul 18, 2026

Open the Estradiol, Norethindrone Acetate interaction page

One more smart check

Taking Progesterone as Part of a Dietary Supplement Product? Check It for Interactions

We hold 3 real supplement products containing Progesterone, each one broken down to its full ingredient list — and combination products often carry several ingredients besides Progesterone. Your product may carry other ingredients that interact with Estradiol, Norethindrone Acetate too, on top of Progesterone — and those would not show on this page. Find your product and we’ll check every ingredient on its label:

How much people look this up

Where Progesterone and Estradiol, Norethindrone Acetate Sit Against Everything Else

Out of every supplement and medication people look up on HelloPharmacist, here is where these two land this week — and which way each has been moving.

Supplement Progesterone
Top half

#557 of 1,452 supplements looked up here in the last 7 days

29 days ago today
Medication Estradiol, Norethindrone Acetate
Steady interest

#2,067 of 2,830 medications looked up here in the last 7 days

29 days ago today

Position among everything looked up on this site, not a measure of how commonly either one is used or how important it is. A supplement can climb this list because of a news story. It counts every request to the page, automated ones included, and nothing here identifies anyone.

Supplement

About Progesterone

What is Progesterone?

  • Hormone replacement therapy
  • Supporting fertility and early pregnancy (under medical care)
  • Irregular or absent menstrual periods
  • Menopause-related symptoms (with estrogen)
  • Symptoms some attribute to low progesterone

Progesterone is a natural hormone, and prescription forms are used for fertility support, menstrual problems, and hormone therapy. Over-the-counter "natural" progesterone creams are not well standardized and their benefits are unproven, so any use of progesterone should be guided by a doctor or pharmacist.

Read the full Progesterone monograph & all interactions
Keep checking

Other Drugs & Progesterone

Browse every other medication we’ve checked against Progesterone — both the ones with a known interaction and the ones without. Select any drug for the full detail.

0Major
40Moderate
1Minor
2,788No known interaction
40 Moderate 1 Minor 2,788 No interaction
Moderate

40 interactions

Minor

1 interaction

No interaction 2,788 drugs checked — show the list

We also checked Progesterone against these medications and found no known interaction in our sources. Open any page to confirm.

Showing the 60 most looked-up of 2,788 medications checked with no known interaction — see the full Progesterone list.

See the full Progesterone interactions page
See every supplement checked against Estradiol, Norethindrone Acetate, ranked by severity
Sources

Sources & How We Checked

Interaction details are evidence-graded and sourced from the Natural Medicines database. The medication overview comes from MedlinePlus.

Content is written and reviewed by licensed HelloPharmacist pharmacists. See our data sources and editorial standards for how this information is built and checked.

Parts of this content are provided by the Therapeutic Research Center, LLC.

DISCLAIMER: Currently this does not check for drug-drug interactions. This is not an all-inclusive comprehensive list of potential interactions and is for informational purposes only. Not all interactions are known or well-reported in the scientific literature, and new interactions are continually being reported. Input is needed from a qualified healthcare provider including a pharmacist before starting any therapy. Application of clinical judgment is necessary.

© 2021 Therapeutic Research Center, LLC

Keep exploring
Progesterone monograph › Uses, safety, and every drug interaction in one place Estradiol, Norethindrone Acetate supplement interactions › Every supplement checked against Estradiol, Norethindrone Acetate, ranked by severity Supplement interaction checker › Check any supplement or product against your medications Browse medications A–Z › Every drug we've checked against herbs & supplements Ask a pharmacist › Free, personal answer from our licensed team
Pharmacist Counseling Corner

Taking Progesterone and Estradiol, Norethindrone Acetate Together: Common Questions

Can you take Progesterone with Estradiol, Norethindrone Acetate?
There is a moderate interaction, so it may be acceptable with monitoring or timing changes — but check with your pharmacist first. Read the full details on this page and confirm with your pharmacist before combining them.
How serious is the Progesterone and Estradiol, Norethindrone Acetate interaction?
We rate it Moderate. This combination may require monitoring, a dose adjustment, or separating the times you take each one. Consult your pharmacist before using them together.

Written and reviewed by the HelloPharmacist editorial staff. Our editorial policy

Still Have a Question About Estradiol, Norethindrone Acetate and Progesterone?

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This information is for education only and is not a substitute for professional medical advice. Always check with your pharmacist or doctor before starting, stopping, or combining supplements and medications.