Hormones in Contraceptives and Menopause Hormone Therapy Explained

Have you noticed how quickly we went from “we fear hormones” to “we love hormones”? When you look at social media, the conversation is polarized. Some influencers are telling us that hormonal contraception is bad, and others are telling us that every woman should be taking menopause hormone therapy.

The reality (as usually is in medicine) is more nuanced, but also more practical: not all hormones are created equal. Exogenous hormone therapies, including hormonal contraception and menopause hormone therapy (MHT), differ in their clinical purpose, formulations, dosing strategies, and physiological effects.

In this two-part series, we’ll unpack the difference between the exogenous hormones used in contraception and those used in menopause therapy, with a specific focus on formulations - what is actually in each product, how it is designed, and why those details matter. These distinctions go a long way in explaining the different experiences women report.

Note: Here are a few key terms before we dive in:

• Bioavailability: How much of a hormone actually reaches your bloodstream in an active form after you take it. Lower bioavailability doesn’t mean a hormone “doesn’t work,” but it often means higher oral doses are required, the liver is more involved in processing it, and side effects can look different depending on the method the hormone is delivered (pill vs patch, for example).

• Receptor affinity: How tightly a hormone binds to its receptor - essentially, how strongly it “fits” and activates the hormone receptor. Different hormone formulations bind to receptors with different strengths. For example, Ethinyl estradiol (EE) has a much higher binding affinity compared to estradiol (E2), which is why the dosages of EE are much lower compared to E2. 

• Potency: How much of a hormone is needed to produce a biological effect. Potency is directly correlated with receptor affinity and bioavailability. Potency in and of itself is not a real pharmacological property, since it is more of a summation of other pharmacological properties, like receptor affinity and bioavailability. When a hormone is ‘more potent’ than another, it means that it can achieve the same effect at a lower dose. This is why some synthetic estrogens work in micrograms, while bioidentical hormones are often dosed in milligrams.

• Half-life: The time it takes for the level of a hormone in the blood to drop by 50% after it peaks. It influences how often a hormone needs to be taken, how steady hormone levels are throughout the day, and how quickly effects, and side effects, appear or wear off.

• First-pass metabolism: When a hormone is taken orally, it passes through the gut and then the liver before entering the bloodstream. The liver can break down a large portion of the hormone and also responds by making other proteins. Hormones that bypass this process (methods like patches or gels) behave quite differently from those taken as pills.

Contraception

Historical evolution of hormone formulations in contraceptives: From high-dose to low-dose estrogen forms 

Hormonal contraception was originally designed with one primary goal in mind: reliable suppression of ovulation. From the beginning, that job belonged to the progestin part of hormonal contraceptive methods. In fact, the earliest oral contraceptives developed in the late 1950s were intended to be progestin-only formulations. An estrogenic compound (mestranol) was initially present as a manufacturing byproduct, but researchers soon realized that its inclusion improved bleeding patterns and cycle predictability. Rather than being added to drive contraception, estrogen was retained to improve tolerability.

As oral contraceptives evolved through the 1960s and beyond, combined formulations became standard. Over subsequent decades, studies showed that these benefits could be maintained with progressively lower estrogen doses, driving the shift from early formulations containing 50 micrograms of ethinyl estradiol to today’s low-dose pills (modern standard of 10–35 micrograms).

At the same time, progestin doses also declined, reflecting improved understanding of potency, receptor activity, and pharmacokinetics. Modern combined oral contraceptives achieve reliable ovulation suppression with lower total hormone exposure than their predecessors, using progestins that are more selective and effective at smaller doses.

What is becoming increasingly clear, through pharmacokinetic, pharmacogenetic, and real-world data, is that women do not all react to hormonal contraception the same way (1). The same “low-dose” pill may fully suppress ovulation in one person and help manage their symptoms, while it might be insufficient or produce side effects in someone else who metabolizes the hormones more slowly. This variability might explain why some women experience breakthrough bleeding, severe side effects, and intolerance.

Estrogens in Contraception

Why ethinyl estradiol became the estrogen of choice in contraception

Ethinyl estradiol (EE) became the dominant estrogen in hormonal contraception for a very practical reason: it works reliably when taken by mouth (orally). Unlike endogenous estradiol (the estrogen the ovaries naturally produce), which is rapidly broken down during first-pass metabolism in the liver, EE has a small chemical modification (an ethinyl group) that makes the molecule much more resistant to degradation (2). The ethinyl group dramatically increases its metabolic stability and functional potency, allowing consistent estrogenic signaling at very low doses. In simple terms, EE is structurally “built to last” when swallowed.

This design gives EE two key properties that early contraceptive development needed: high potency and predictability. Even though only about 40–45% of an oral EE dose reaches the bloodstream, the estrogen signal it produces is strong and consistent. That made it particularly useful for stabilizing the endometrium and reducing unscheduled bleeding with once-daily oral dosing - something native estradiol could not reliably achieve in early formulations.

As pharmacology advanced, it became increasingly clear that effective contraception did not require high estrogen exposure, only predictable estrogen signaling and support alongside progestin-driven ovulation suppression. This understanding allowed estrogen doses to fall substantially over time, while progestins continued to provide reliable inhibition of ovulation.

There is, however, a trade-off built into this design. Because EE strongly engages the liver (a consequence of its resistance to first-pass metabolism), it has more pronounced hepatic effects than estradiol. Clinically, this explains why EE behaves differently from the estrogens used in MHT and why there has been growing interest in using alternative estrogens for contraceptives that more closely resemble endogenous estradiol (3-4).

So is EE our only option for estrogen when it comes to contraception? 

No. Over the last two decades, alternative estrogens have been explored with the aim of moving closer to endogenous hormone physiology, while still maintaining reliable cycle control. One of the best-studied examples is estradiol valerate (E2V).

Estradiol valerate: Bringing contraception closer to endogenous estrogen

Estradiol valerate (E2V) is a prodrug of 17β-estradiol—chemically modified for oral use, then converted back to estradiol after absorption. Because it ultimately becomes estradiol (the same core estrogen the ovaries produce), its signaling profile is often described as more “physiologic” than ethinyl estradiol (EE). Because EE is designed to resist breakdown in the liver, it produces a stronger hepatic estrogen signal, which is one of the mechanisms thought to contribute to blood clot risk in susceptible individuals.3 Estradiol-based regimens may produce a different hepatic signal, which is one reason they’ve been explored as alternatives in contraception.

Where E2V gets interesting is the formulation strategy around it. Earlier attempts to build combined pills around estradiol or estradiol valerate ran into a practical problem: bleeding predictability. In response, the E2V/dienogest product was developed and approved with a dynamic (four-phasic) dosing regimen intended to support cycle control while using an estradiol-based estrogen. 

From a formulation perspective, E2V is a proof of concept: you can build effective contraception using an estrogen that converts to estradiol. It's more limited real-world uptake likely reflects practical factors: brand-only availability in many markets, the unfamiliar multi-phase pack, and user preference, rather than a lack of contraceptive efficacy.

These lessons have directly informed the development of newer estrogen options in contraception, including estetrol, which aims to further refine this balance between physiologic signaling and practical usability.

Estetrol (E4): a newer estrogen with more selective signalling

Estetrol (E4) represents the newest attempt to refine estrogen formulation in contraception. It is a naturally occurring estrogen produced by the human fetal liver during pregnancy, and until recently, it had never been used therapeutically. Today, it is included in a single FDA-approved combined oral contraceptive paired with drospirenone (Nextstellis®).

What makes E4 different from both ethinyl estradiol and estradiol valerate is how it interacts with estrogen receptors and the liver. E4 binds more weakly to estrogen receptors and appears to activate a narrower set of estrogen pathways, particularly those involved in gene transcription, while exerting less influence on vascular, metabolic, and coagulation signalling. This more selective estrogen activity is the reason E4 has attracted interest as a potentially “gentler” oral estrogen.

From a pharmacologic standpoint, E4 is also unusual. It has high oral bioavailability and a relatively long half-life, meaning stable estrogen levels can be achieved with once-daily dosing. Unlike EE, it has limited stimulation of hepatic protein synthesis, which helps explain why laboratory studies consistently show smaller shifts in liver-derived markers associated with coagulation and binding proteins. Importantly, these findings reflect biochemical signals rather than clinical outcomes, and large head-to-head trials powered for rare events such as blood clots do not yet exist.

One of the historical challenges in lowering estrogen exposure in contraception has been bleeding control. When estrogen doses fall too low, the progestin’s effects on the endometrium can dominate, leading to unscheduled bleeding or absent withdrawal bleeds. In clinical trials, E4-containing pills appear to offer bleeding patterns broadly comparable to low-dose ethinyl estradiol (EE) pills, without the high rates of irregular bleeding seen in some ultra-low-estrogen (10 mcg) formulations. However, differences in study design make direct comparisons difficult, and longer real-world data are still emerging. Taken together, estetrol can be viewed as a natural estrogen: not designed to eliminate risk, but to more precisely balance oral usability, cycle control, and physiologic signaling. Whether this translates into meaningful long-term clinical advantages over existing formulations remains an active area of study.

Conclusion

Understanding which estrogen is used in a given contraceptive can help explain differences in bleeding patterns, side effects, and overall tolerability.

A useful mental model: Ethinyl estradiol (EE) was engineered for reliability, estradiol valerate (E2V) for physiologic similarity, and estetrol (E4) for signaling selectivity.

Tools like the Dama Rx Checker, which allows you to look up contraceptive brands and see which estrogen they contain, can make these formulation differences easier to identify and compare in practice.

In Part 2 of this three-part series, we’ll shift focus to progestins in contraception and explore how differences in progestin design drive effectiveness, tolerability, and individual response as well.

Authors: Dr Paulina Cecula, Namrata Ashok. Reviewed and edited by: Dr Aaron Lazorwitz, Elena Rueda

References:

1. Nuzzo M, Erickson EN, Groth SW, Yu Y, Koleck T, Li H, et al. Genetic variation associated with side effects of hormonal contraception exposure: a narrative review. Frontiers in Reproductive Health. 2025 Nov 14;7.

2. Frank S. Ethinyl estradiol and 17β-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment. Contraception [Internet]. 2013 Jun 1 [cited 2021 Apr 28];87(6):706–27. Available from: https://www.sciencedirect.com/science/article/pii/S0010782412010797#bb0420

3. Laing A, Hillard T. Oestrogen-based therapies for menopausal symptoms. Best Practice & Research Clinical Endocrinology & Metabolism [Internet]. 2023 Jun 12 [cited 2023 Nov 3];101789. Available from: https://www.sciencedirect.com/science/article/pii/S1521690X23000635

4. Practice Committee of the American Society for Reproductive Medicine. Combined hormonal contraception and the risk of venous thromboembolism: a guideline. Fertility and Sterility [Internet]. 2017 Jan 1;107(1):43–51. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27793376