Ethinyl Estradiol; Norgestimate

What it is

This is a combined oral contraceptive pill containing two synthetic hormones taken together in one tablet: ethinyl estradiol, an estrogen, and norgestimate, a progestin. It is sold under brand and generic names including Ortho Tri-Cyclen, Ortho-Cyclen, Sprintec, and Estarylla, and is taken daily in a cyclic (21/7 or similar) regimen.

What the research says

The evidence strongly supports that this combination prevents pregnancy when taken as directed, and one brand (Ortho Tri-Cyclen) has trial evidence supporting an approved use for moderate acne. It is not free of risk: it carries an FDA boxed warning for cardiovascular events in smokers over 35, and cohort studies quantify increased (though still numerically low in absolute terms) risks of venous thromboembolism, stroke, myocardial infarction, and a small increase in breast cancer risk with use, which is a different and more complete picture than 'the pill is just birth control.'

Evidence grade: Well established.

How it works

Drug class: Combined hormonal (estrogen-progestin) oral contraceptive: ethinyl estradiol (synthetic estrogen) plus norgestimate (a third-generation progestin, active mainly via its metabolite norelgestromin/levonorgestrel-like activity)

The combination works mainly by suppressing ovulation: it interferes with the hormonal signals from the brain (gonadotropins) that would otherwise trigger release of an egg each month. It also thickens cervical mucus, which makes it harder for sperm to reach an egg, and alters the uterine lining. The estrogen (ethinyl estradiol) and progestin (norgestimate) act together on the hypothalamic-pituitary-ovarian axis; norgestimate itself is largely converted in the body to active metabolites, primarily norelgestromin, which behaves similarly to levonorgestrel. (Source 1)

Boxed warning

WARNING: CIGARETTE SMOKING and SERIOUS CARDIOVASCULAR EVENTS Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, COCs are contraindicated in women who are over 35 years of age and smoke [see Contraindications (4)].

(Source 2)

What it is used for

• Combined oral contraceptives are established as highly effective in preventing pregnancy through ovulation suppression; this research focused on the drug's harms and less-known evidence per the group's brief rather than re-deriving contraceptive efficacy, which is well established in the literature and not disputed. Evidence: established. (Source 1)
• In two double-blind, placebo-controlled, six-month multicenter trials submitted to FDA, Ortho Tri-Cyclen produced significantly greater reductions in inflammatory and total lesion counts than placebo (mean inflammatory lesion reduction 56.6% vs 36.6% for placebo), supporting its approved acne indication. Evidence: established. (Source 3)
• This is an off-label use in most jurisdictions (COCs are not FDA-approved specifically 'for PCOS'). This research located systematic reviews evaluating combined oral contraceptives for PCOS but could not retrieve their verbatim findings in this session because the primary sources returned only bot-verification pages; a reviewer should re-pull the Cochrane/CEN systematic reviews on this question directly. Evidence: limited.

Interactions

• St John's wort (clinical trial): St John's wort strongly induces CYP3A4, the enzyme pathway that clears these contraceptive hormones, and is associated with breakthrough bleeding and signals of breakthrough ovulation across several studies, raising concern that it could reduce contraceptive effectiveness; the FDA label itself lists products containing St John's wort among substances that may decrease hormonal contraceptive effectiveness. (Source 4)
• Rifampin, and anticonvulsants (phenytoin, carbamazepine, oxcarbazepine, topiramate, barbiturates) and other enzyme-inducing drugs (label): These drugs induce CYP3A4 and can lower blood levels of the contraceptive hormones, potentially reducing effectiveness or causing breakthrough bleeding; the label lists this class explicitly. (Source 1)
• Cigarette smoking (tobacco, not a supplement but tracked here because it drives the boxed warning) (label): Smoking combined with this drug class sharply raises the risk of serious cardiovascular events, especially in women over 35 and with heavier smoking, which is why the FDA requires this as the product's boxed warning and contraindicates use in women over 35 who smoke. (Source 2)

Stopping it

• The elevated clotting (thromboembolic) risk from combined oral contraceptives is understood to fade after stopping rather than persist, per the label. Separately, a pooled analysis of prospective pregnancy-planning cohorts (nearly 18,000 women) found a short-term delay in return of fertility after stopping oral contraceptives and the vaginal ring specifically (about three menstrual cycles) compared with barrier methods, though the large majority of women still conceived within a year: about 56% within six cycles and 77% within twelve cycles across the pooled group. (Source 1)
• Regarding the specific delay after stopping oral contraceptives before fertility returns to baseline. (Source 5)

What goes wrong

The ASRM guideline's position is that combined hormonal contraceptives as a class raise the absolute risk of venous clots above the risk in non-users, though the absolute numbers are small and smaller than the risk in pregnancy. (Source 6)

• Official position, Moderate certainty.
• Size: Guideline synthesis of multiple cohort/case-control studies.
• Who: Reproductive-age women, non-pregnant.
• How long: Per woman-year of use.
• Result: VTE about 3-15 per 10,000 woman-years in users vs about 1-5 per 10,000 woman-years in non-users; the guideline states this risk is still smaller than the risk in pregnancy and appears to decline over time.
• Funding: Professional society guideline (ASRM Practice Committee), underlying studies independently funded/mixed.

Limit of this finding: These are class-level figures for combined hormonal contraceptives. This passage of the guideline does not break the numbers down by progestin, so it says nothing specific about norgestimate.

combined hormonal contraceptives (CHCs) are associated with an increased risk of VTE compared with non-use (3–15/10,000 woman-years in users vs. 1–5/10,000 risk in non-users)

In a large Danish cohort, combined oral contraceptives containing 30-40 mcg ethinyl estradiol roughly doubled the relative risk of thrombotic stroke and myocardial infarction versus non-use, with the estimated absolute risk still numerically low; this cohort's progestin breakdown reported norethindrone, levonorgestrel, desogestrel, and gestodene, not norgestimate specifically. (Source 7)

• Cohort study, Moderate certainty.
• Size: 1,626,158 women, 14,251,063 person-years.
• Who: Danish nonpregnant women aged 15-49.
• How long: 15-year historical cohort.
• Result: 3311 thrombotic strokes (21.4/100,000 person-years) and 1725 MIs (10.1/100,000 person-years) overall; relative risks with 30-40 µg ethinyl estradiol combinations ranged roughly 1.7-2.3 depending on progestin, versus non-use.
• Funding: not stated in this secondary source.

3311 thrombotic strokes (21.4 per 100,000 person-years) and 1725 myocardial infarctions (10.1 per 100,000 person-years) occurred

Current or recent use of hormonal contraception (including combined oral contraceptives) is associated with a small increase in relative and absolute breast cancer risk, which rises with longer duration of use. (Source 8)

• Cohort study, Moderate certainty.
• Size: 1.8 million women, 19.6 million person-years, 11,517 breast cancer cases.
• Who: Danish women of reproductive age using any hormonal contraceptive method.
• How long: Average follow-up 10.9 years.
• Result: RR 1.20 (95% CI 1.14-1.26) overall; RR rose from 1.09 (<1 year use) to 1.38 (>10 years use); absolute increase of 13 (95% CI 10-16) extra breast cancers per 100,000 person-years.
• Funding: not stated in this secondary source (Danish national registry study)

the relative risk of breast cancer among all current and recent users of hormonal contraception was 1.20 (95% confidence interval [CI], 1.14 to 1.26)

St John's wort induces the enzyme that metabolizes combined oral contraceptive hormones and is linked to increased breakthrough bleeding, raising concern for reduced contraceptive efficacy. (Source 4)

• Systematic review, Low certainty.
• Size: Systematic review of multiple small pharmacokinetic/clinical studies (three specifically on breakthrough bleeding)
• Who: Women using combined hormonal contraceptives who also took St John's wort.
• How long: Varies by included study.
• Result: Increased risk of breakthrough bleeding and ovulation signals in three studies; no quantified pregnancy-rate increase established, but concern raised for reduced efficacy.
• Funding: not stated in this secondary source.

Three studies demonstrated an increased risk of breakthrough bleeding with COCs and SJW.

What the evidence supports

Ortho Tri-Cyclen significantly reduces inflammatory and total acne lesion counts compared with placebo over six months. (Source 3)

• Randomized trial, Moderate certainty.
• Size: 163 (Ortho Tri-Cyclen) vs 161 (placebo)
• Who: Women with moderate facial acne vulgaris.
• How long: Six months.
• Result: Mean inflammatory lesion reduction 56.6% (drug) vs 36.6% (placebo); mean total lesion reduction 49.6% vs 30.3%.
• Funding: Manufacturer-sponsored (submitted as pivotal trials to FDA)

Inflammatory Lesions Mean Percent Reduction 56.6

What the evidence does not support

Across combined hormonal contraceptives generally (pills and patches, mixed progestins; not specific to ethinyl estradiol/norgestimate), placebo-controlled trials did not show that these methods caused weight change, and most head-to-head comparisons between different combined contraceptives showed no substantial weight difference. (Source 9)

• Systematic review, Low certainty.
• Size: 49 trials (52 treatment-pair comparisons); 4 of these trials included a placebo or no-hormonal-method comparison group.
• Who: Women enrolled in randomized trials of combined hormonal contraceptive pills or patches, across mixed progestin types; this Cochrane review is class-level evidence and does not isolate norgestimate-containing products specifically.
• How long: Included trials required at least three treatment cycles; literature search current to November 2013.
• Result: The four placebo/no-method trials did not show that pills or patches led to weight change; most comparisons of different combined contraceptives showed no large weight difference; discontinuation because of weight change did not differ between groups; evidence rated not strong enough to fully rule out some effect, but no major effect on weight was found.
• Funding: not stated in this plain-language summary.

The four trials with a dummy or no method group did not show that these pills or patches led to weight change.

Where the evidence is mixed

Norgestimate- and desogestrel-containing oral contraceptives carry a nonfatal VTE risk that is statistically similar to (not higher than) levonorgestrel-containing ones; a separate professional society guideline notes that norgestimate's activity works mainly through a levonorgestrel-like metabolite, which distinguishes it from some other third-generation progestins that the same guideline associates with a slightly higher VTE risk than norethindrone or levonorgestrel. (Source 10)

• Case-control study, Moderate certainty.
• Size: 281 VTE cases, 1,055 controls.
• Who: Women using combined oral contraceptives, nested case-control design.
• How long: Not specified in this secondary source.
• Result: Adjusted odds ratio for nonfatal VTE, norgestimate/desogestrel vs levonorgestrel: 1.1 (95% CI 0.8-1.6) - i.e., not significantly different from levonorgestrel.
• Funding: not stated in this secondary source.

adjusted ORs for nonfatal VTE comparing norgestimate- or desogestrel-containing OC users to users of levonorgestrel-containing OCs were 1.1 [95% confidence interval (CI), 0.8–1.6]

The ASRM guideline reports that third-generation progestins carry an increased VTE risk, and names norgestimate as an exception whose risk it describes as similar to levonorgestrel. (Source 11)

• Official position, Moderate certainty.
• Size: Guideline synthesis of cohort and case-control studies (its Table 1)
• Who: Reproductive-age women using combined oral contraceptives.
• How long: Not stated; per study.
• Result: The guideline states the increased VTE risk with third-generation progestins persists even when potential confounders are taken into account, with norgestimate excepted as having a risk similar to levonorgestrel; it gives no effect size for norgestimate in this passage.
• Funding: Professional society guideline (ASRM Practice Committee); underlying studies mixed/independent.

Limit of this finding: This is a comparison between progestin types, not a comparison with not using contraception. Norgestimate is not exempt from the raised clot risk: the same guideline puts venous clots at about 3-15 per 10,000 woman-years in users of combined hormonal contraceptives against about 1-5 per 10,000 in non-users. What the guideline says is that norgestimate does not appear to add risk on top of levonorgestrel, the way it says other third-generation progestins do. The guideline gives no number for norgestimate here.

However, additional studies have shown an increased risk of VTE with third-generation progestins (with the exception of norgestimate, which has been found to have a risk similar to levonorgestrel) even when potential confounders are taken into account

How much

• Reference intake: Dosing (which pill, how many days active vs placebo) is set by the prescriber based on the specific product; the FDA label states the approved regimen as the manufacturer's position, current as of the August 2017 boxed-warning label revision reviewed here. (Source 2)
• Upper limit: Not applicable in the usual sense of a nutrient upper limit; the label instead defines the fixed daily hormone doses per tablet in the approved regimen and contraindicates use in specific high-risk groups (e.g., smokers over 35), which is the label's position rather than a dose ceiling for a member to adjust. (Source 2)
• Studied: Acne trials: Ortho Tri-Cyclen tablets taken daily in the standard triphasic regimen for six months. (Source 3)
• Studied: VTE and stroke/MI cohort studies: standard combined oral contraceptive regimens as marketed, categorized by estrogen dose (20 vs 30-40 µg ethinyl estradiol) and progestin type. (Source 7)

A common belief, and what the research shows

The belief: A common belief is that birth control pills cause lasting infertility or make it hard to get pregnant once you stop.

What the research shows: Pooled prospective data on nearly 18,000 women planning pregnancy found only a short-term delay (about three cycles) in return of fertility after stopping oral contraceptives or the vaginal ring, not a lasting effect; the large majority of women conceived within a year of trying, similar to the general population.

Questions and answers

What is it?

This is a combined oral contraceptive pill that contains two synthetic hormones in every active tablet: ethinyl estradiol (an estrogen) and norgestimate (a progestin). It is sold under brand names such as Ortho Tri-Cyclen, Ortho-Cyclen, Sprintec, and Estarylla, taken once daily on a fixed cycle. (Source 1)

What does it do in the body?

It mainly prevents pregnancy by stopping the ovaries from releasing an egg each month, and also thickens cervical mucus and changes the uterine lining as backup mechanisms. One version, Ortho Tri-Cyclen, is also FDA-approved to treat moderate acne, where placebo-controlled trials showed significantly greater reduction in inflammatory lesions with the drug than with placebo. (Source 3)

Is it good or bad for you?

For most healthy, non-smoking women it is effective and generally well tolerated, but it is not without measurable risk: it carries an FDA boxed warning that smoking sharply raises cardiovascular risk on this drug, especially over age 35, and the evidence shows combined hormonal contraceptives raise the absolute risk of venous clots (about 3-15 per 10,000 woman-years in users versus about 1-5 in non-users), as well as stroke and heart attack risk and a small increase in breast cancer risk that grows with years of use. On clot risk specifically, a professional society guideline names norgestimate as an exception among third-generation progestins, with a risk it describes as similar to levonorgestrel. That is a comparison between progestin types, not an exemption: norgestimate still sits inside the raised class-level clot risk that all combined hormonal contraceptives carry compared with not using them. (Source 6)

How do you get more of it?

This does not apply the way it would to a nutrient; this is a prescription medicine obtained only through a prescriber, taken in the fixed daily regimen the specific product's label sets out, not something to seek out in food or supplements or to increase on one's own. (Source 1)

We searched: This is a synthetic pharmaceutical; there is no 'getting more of it' framework in the literature searched.

If it is harmful, what reduces it?

For the clotting risk specifically, the label states this risk fades after the drug is stopped rather than persisting. For acute serious harms (such as a blood clot, stroke, or heart attack while on the drug), the standard approach documented in the safety literature is to stop the drug and treat the event medically; this research did not find a specific 'reversal' therapy beyond discontinuation and treating the complication itself. (Source 1)

Why might someone be low in it or missing it?

This question does not apply in a deficiency sense; nobody is naturally missing ethinyl estradiol/norgestimate since it is a manufactured drug combination. The relevant question is why a person would or wouldn't take it, which depends on a prescriber's assessment of contraceptive need, acne severity, cardiovascular risk factors (like smoking or age over 35), and personal risk tolerance for the harms above. (Source 2)

We searched: Searched label and guideline literature for a deficiency framing; none exists for this synthetic combination drug.

Which whole foods contain it or feed it?

No whole food contains or substitutes for ethinyl estradiol or norgestimate; both are synthetic pharmaceuticals. This research also could not confirm, with a source it could fully verify in this session, a specific grapefruit-ethinyl estradiol interaction, so none is reported here; the label instead flags herbal products like St John's wort as reducing effectiveness via enzyme induction, the opposite direction from a food that might raise levels. (Source 1)

What happens if you do not have it?

If someone does not take this medicine, the specific effects it produces (ovulation suppression and its contraceptive effect, and for Ortho Tri-Cyclen, its acne-reducing effect) simply do not occur; there is no deficiency state from not taking a contraceptive. For the acne indication specifically, the placebo group in the pivotal trials still improved somewhat on its own (36.6% mean lesion reduction) but significantly less than the treatment group (56.6%). (Source 3)

How can you test for it?

There is no routine blood test for 'ethinyl estradiol/norgestimate levels' used in ordinary care; monitoring instead focuses on blood pressure checks and screening for risk factors (such as smoking status and personal/family clotting history) before and during use, and prompt evaluation of warning symptoms (leg swelling, chest pain, severe headache) rather than a lab test of the drug itself. This research did not find a validated drug-level test relevant to a member. (Source 1)

We searched: Searched label and clinical literature for a drug-level monitoring test; none is standard for this combined oral contraceptive.

References

1. DailyMed (NIH/NLM). Norgestimate and Ethinyl Estradiol kit - full prescribing information. 2023. Read the source
2. FDA (accessdata.fda.gov), NDA 019653/019697. Norgestimate and Ethinyl Estradiol Tablets - full prescribing information (boxed warning). 2017. Read the source
3. FDA (accessdata.fda.gov), NDA 021690. ORTHO TRI-CYCLEN Tablets / ORTHO-CYCLEN Tablets - full prescribing information (acne clinical studies). 2005. Read the source
4. Contraception journal (hosted copy, CDC stacks). Co-administration of St. John's wort and hormonal contraceptives: a systematic review. 2016. Read the source
5. Boston University School of Public Health. When Does Fertility Return After Stopping Contraceptive Use? (reporting a pooled analysis of prospective pregnancy-planning cohorts). 2020. Read the source
6. Fertility and Sterility / American Society for Reproductive Medicine (ASRM Practice Committee). Combined hormonal contraception and the risk of venous thromboembolism: a guideline - BACKGROUND. 2016. Read the source
7. New England Journal of Medicine. Thrombotic Stroke and Myocardial Infarction with Hormonal Contraception. 2012. PMID 22693997. Read the source
8. New England Journal of Medicine. Contemporary Hormonal Contraception and the Risk of Breast Cancer. 2017. PMID 29211679. Read the source
9. Cochrane Database of Systematic Reviews (plain-language summary, cochrane.org). Combination contraceptives: effects on weight (Cochrane Plain Language Summary, not the full review abstract). 2014. DOI 10.1002/14651858.CD003987.pub5. Read the source
10. Contraception (Elsevier/ScienceDirect). Risk of nonfatal venous thromboembolism with oral contraceptives containing norgestimate or desogestrel compared with oral contraceptives containing levonorgestrel. 2007. PMID 16730485. Read the source
11. Fertility and Sterility / American Society for Reproductive Medicine (ASRM Practice Committee). Combined hormonal contraception and the risk of venous thromboembolism: a guideline - section 'Does Type of Progestin Contribute to VTE Risk?'. 2016. Read the source