Monotherapy HRT: Estrogen, Progesterone, and Testosterone

Monotherapy HRT refers to the use of a single hormone, most commonly estrogen alone, to manage menopausal symptoms or hormonal deficiencies. For decades, the question of whether one hormone is enough has shaped prescribing decisions, clinical guidelines, and patient anxieties. The answer depends almost entirely on the person’s anatomy, medical history, and what symptoms they need treated. Estrogen-only therapy remains the most studied and most commonly discussed form of monotherapy HRT, but progesterone-only and testosterone-only regimens each have distinct roles that are gaining recognition.

Why Estrogen Alone Is the Default After Hysterectomy

The single biggest factor determining whether someone receives monotherapy or combination HRT is whether they still have a uterus. Estrogen is the primary hormone responsible for relieving hot flashes, night sweats, vaginal dryness, and the bone loss that accelerates after menopause. When given alone, it does these jobs well. In a dose-response trial, oral micronized estradiol at 1 mg and 2 mg doses produced rapid, significant reductions in moderate to severe hot flashes within four weeks compared to placebo.¹ The problem is what estrogen does to the uterine lining when no progestogen is around to keep it in check.

Unopposed estrogen stimulates the endometrium to grow. Over months and years, that unchecked growth raises the risk of endometrial cancer substantially. A meta-analysis found that women using unopposed estrogen had roughly 2.3 times the risk of endometrial cancer compared with nonusers, and that risk climbed steeply with duration, reaching about 9.5 times the risk after ten or more years of use.² The risk also persisted for years after stopping therapy. This is not a subtle statistical signal. It is the reason progestogen was added to HRT in the first place, transforming estrogen monotherapy into a regimen reserved almost exclusively for women who no longer have a uterus.

The historical arc here is straightforward. Estrogen prescriptions surged in the 1960s and early 1970s, then collapsed in 1975 when reports linked them to dramatically higher rates of endometrial cancer.³ By the mid-1980s, evidence showed that adding a progestogen reversed estrogen-induced endometrial changes in over 98% of cases, and combination therapy became the new standard for women with an intact uterus.⁴ Women who had undergone hysterectomy, however, had no endometrium to protect, making estrogen monotherapy both safe and simpler for them.

The Breast Cancer Paradox

One of the most counterintuitive findings in HRT research is that estrogen alone and estrogen combined with a progestogen appear to push breast cancer risk in opposite directions. The Women’s Health Initiative, the largest set of randomized HRT trials ever conducted, found that estrogen-only therapy in women with prior hysterectomy actually decreased both breast cancer incidence and breast cancer mortality over long-term follow-up.⁵ The combination arm, estrogen plus medroxyprogesterone acetate, did the opposite: it increased breast cancer incidence, delayed diagnosis, and increased breast cancer mortality.⁶

This divergence is striking and still not fully explained. It suggests that adding a progestogen does not simply cancel out estrogen’s effects but introduces its own biological activity that matters for breast tissue. For women who have had a hysterectomy and are weighing their options, the breast cancer data around estrogen monotherapy is genuinely reassuring. For women with an intact uterus, it creates an uncomfortable tension: the progestogen that protects the endometrium may simultaneously carry breast risk. This tradeoff is one reason researchers have pursued alternatives to traditional progestogens, a topic covered later in this article.

Bone Protection With Estrogen Monotherapy

Estrogen is the most thoroughly validated hormonal treatment for preventing the bone loss that follows menopause. It works on both sides of the bone remodeling process, slowing the cells that break bone down and supporting those that build it up.⁷ In practical terms, this translates into fewer fractures. A large observational study found that women currently using estrogen had about a 40% lower risk of all nonspinal fractures compared with never-users, and the benefit was even more pronounced for those who started within five years of menopause: about a 70% reduction in hip fracture risk and a similar reduction in wrist fractures.⁸

The results were similar whether women were using estrogen alone or estrogen plus a progestogen, meaning that estrogen monotherapy is not giving up bone protection by leaving out the second hormone. What matters more than the regimen is timing and continuation: benefits were strongest in current users and in those who started relatively soon after menopause. Once estrogen is stopped, bone loss resumes, and fracture protection fades. This is relevant for anyone considering monotherapy long-term, because the skeletal benefits are a meaningful argument for continuing therapy, balanced against the risks discussed elsewhere.

Cardiovascular Risk and the Timing Hypothesis

The cardiovascular story of HRT has gone through dramatic reversals. Early observational studies suggested heart protection; the WHI trials appeared to show harm; and subsequent analysis revealed that the answer depends heavily on when therapy begins. The timing hypothesis holds that HRT started in early menopause, while arteries are still relatively healthy, may have a beneficial effect on the heart, but the same therapy started a decade or more after menopause, when atherosclerosis may already be established, can cause harm.⁹

Subanalyses of the WHI data by age group, along with later randomized trials like KEEPS and ELITE, support this idea. The risk of adverse cardiovascular events on HRT is low for women under 60 or within ten years of menopause.¹⁰ This finding applies broadly to menopausal hormone therapy rather than specifically to monotherapy versus combination therapy, but it is crucial context for anyone considering estrogen alone. Starting early matters more than which regimen you choose, and route of delivery matters too.

Oral Versus Transdermal Estrogen Monotherapy

How estrogen enters the body changes its risk profile significantly. Oral estrogen passes through the liver before reaching the rest of the body, a process called first-pass metabolism. This liver pass triggers changes in clotting factors, inflammatory markers, and binding proteins that transdermal estrogen largely avoids.¹¹ The clinical consequence that gets the most attention is blood clot risk.

Transdermal estrogen, delivered through a patch or gel applied to the skin, does not increase the risk of venous blood clots in healthy postmenopausal women. This holds even in women at elevated risk: those with a history of prior clots, those with higher body weight, and those carrying genetic variants that predispose to clotting all showed minimal to no added risk when using transdermal estrogen.¹² For anyone using estrogen monotherapy who has even moderate clot risk factors, transdermal delivery is the clear choice.

The liver-related differences go beyond clotting. Oral estrogen produces more favorable shifts in cholesterol ratios but raises triglycerides, while transdermal estrogen has a better effect on triglycerides but a smaller cholesterol impact. Oral estrogen also boosts a liver protein called sex hormone-binding globulin, which binds up circulating testosterone. This can reduce sexual desire and energy, an effect that transdermal delivery largely sidesteps.¹³ For women on monotherapy who are already concerned about low libido, the route of estrogen delivery may matter as much as the dose.

Vaginal Estrogen as Localized Monotherapy

Not every woman who needs estrogen needs it circulating through her entire body. Vaginal dryness, painful sex, urinary symptoms, and tissue thinning in the genital area are among the most common and persistent problems after menopause, and they respond well to estrogen applied directly to the vaginal tissue. Low-dose vaginal estrogen products, including creams, tablets, and rings, treat these symptoms effectively with minimal systemic absorption. At the lowest doses, circulating estrogen levels either do not rise at all or rise so slightly that standard blood tests cannot detect the change.¹⁴

This matters enormously for women who cannot or do not want systemic estrogen, including breast cancer survivors, women at high clot risk, and those who simply prefer to keep hormonal exposure to a minimum. Vaginal rings delivering a very low daily dose and vaginal tablets at low twice-weekly doses produce no measurable increase in blood estrogen levels.¹⁵ In practice, many clinicians consider low-dose vaginal estrogen a separate category from systemic HRT entirely, with a much more favorable risk profile. It is, technically, estrogen monotherapy, but its safety considerations are different from taking an estrogen pill or wearing a patch.

Progesterone Monotherapy

Estrogen gets most of the attention in menopause treatment, but progesterone used alone has its own niche. A Phase III trial found that oral micronized progesterone, taken without any estrogen, significantly reduced night sweats and improved sleep quality compared with placebo in perimenopausal women.¹⁶ Micronized progesterone also improved daytime hot flash intensity in that trial, though the effect on hot flashes was less dramatic than its impact on night symptoms and sleep.

A narrative review of the broader evidence on progestogen monotherapy confirmed that various progestogens provide significant relief from vasomotor symptoms across oral, injectable, and transdermal forms. Micronized progesterone stood out for its sleep benefits, while synthetic progestins like medroxyprogesterone acetate and norethindrone acetate offered variable degrees of bone protection.¹⁷ This makes progestogen-only therapy a viable option for women who cannot take estrogen due to a personal history of breast cancer, blood clots, or other contraindications, or for perimenopausal women whose primary complaints are disrupted sleep and night sweats rather than the full constellation of estrogen-withdrawal symptoms.

Testosterone Monotherapy in Women

Testosterone is not just a male hormone. Women produce it too, and levels decline with age. When low testosterone causes distressing loss of sexual desire, a condition formally called hypoactive sexual desire disorder, testosterone therapy can help. In a trial of postmenopausal women who were not taking estrogen, a transdermal testosterone patch delivering 300 micrograms per day significantly increased the frequency of satisfying sexual episodes, raised desire scores, and reduced personal distress about low libido compared with placebo.¹⁸ The lower dose of 150 micrograms per day showed improvement in desire but did not reach statistical significance for satisfying sexual episodes.

Transdermal delivery is the preferred route for testosterone in women, because it avoids the liver’s first-pass metabolism, which can alter lipid profiles and binding proteins in unfavorable ways.¹⁹ It is worth noting that no testosterone product is currently approved by the FDA specifically for women, though testosterone is widely prescribed off-label by menopause specialists. Dosing must be careful, since women need far lower concentrations than men, and excess testosterone can cause acne, facial hair growth, and voice changes.

Testosterone Replacement in Men

For men with clinically confirmed low testosterone, replacement therapy is essentially always monotherapy: testosterone alone, without any second hormone as standard practice. The goals are different from menopausal HRT. Men typically receive testosterone to address fatigue, reduced muscle mass, low mood, decreased libido, and metabolic changes associated with hypogonadism. Evidence suggests testosterone improves blood sugar control, promotes vasodilation, has anti-obesity effects, and shortens a particular heart rhythm interval in favorable ways.²⁰

Cardiovascular safety has been a persistent concern. An individual-patient-data meta-analysis drawing from more than 3,000 men with hypogonadism across randomized placebo-controlled trials found that testosterone treatment was not associated with increased risk of cardiovascular events in the short to medium term. It did, however, raise hemoglobin and hematocrit levels, which need monitoring because excessively thick blood can increase clot risk.²¹ Regular blood work to check red blood cell counts is a standard part of testosterone therapy in men, and one of the reasons ongoing medical supervision matters.

Estrogen Monotherapy in Gender-Affirming Care

Transgender women and gender-diverse individuals assigned male at birth often use estrogen as the cornerstone of feminizing hormone therapy. In many cases, estrogen is combined with an antiandrogen to suppress testosterone more effectively. But injectable estradiol as monotherapy achieves testosterone suppression without any second medication in the majority of patients. A study found that injectable estradiol alone suppressed testosterone in about 83% of patients, a rate comparable to combination therapy using antiandrogens or progestogens.²²

This is a meaningful finding for patients who experience side effects from antiandrogens such as spironolactone, including dizziness, frequent urination, and potassium imbalances. If injectable estradiol alone can do the job, avoiding the second drug simplifies the regimen and removes a layer of side effects. The limitation is that roughly one in six patients will not achieve adequate suppression on estradiol monotherapy alone and may still need adjunctive therapy.²³

Premature Ovarian Insufficiency

Women who lose ovarian function before 40, a condition called premature ovarian insufficiency, face a different calculus than women going through menopause at the typical age. Their bodies are losing hormones decades earlier than expected, and the health consequences of that early loss, including accelerated bone thinning, cardiovascular risk, and cognitive changes, accumulate over a much longer period. For these women, hormone replacement is not optional in the way it can be for someone experiencing menopause at 50. It is considered essential to reducing long-term morbidity.

Guidelines recommend formulations that closely mimic what the ovary would normally produce and continuing therapy until at least the typical age of natural menopause, around 50.²⁴ Whether this is monotherapy or combination therapy depends on whether the woman still has a uterus, following the same logic as for older women. But the risk-benefit analysis tilts much more decisively toward treatment, because these women are replacing hormones their body should still be producing rather than supplementing hormones that have naturally declined.

Mood, Sleep, and Cognitive Effects

Beyond hot flashes and bone density, estrogen monotherapy has shown promise for perimenopausal depression. A review of clinical trials found that three of four trials demonstrated significant improvement in depressive symptoms with estrogen therapy. The one trial that did not find a direct antidepressant effect still showed that estrogen significantly improved sleep quality, which itself feeds back into mood regulation.²⁵ Transdermal estradiol at standard doses for four to twelve weeks appeared to be the most effective form for mood symptoms.

The cognitive picture is murkier. Estrogen has clear neuroprotective properties in laboratory settings, and some observational data suggest that early use of HRT may reduce dementia risk. But the effects vary with timing, the type of estrogen used, and the person’s genetic and cardiovascular profile.²⁶ The WHI’s Memory Study actually found increased dementia risk in older women starting combined HRT, which likely reflects the same timing issue seen in cardiovascular outcomes: starting too late may do more harm than good in the brain, just as in the arteries. For now, HRT should not be started for the purpose of preventing cognitive decline, but the timing-dependent neuroprotective effects remain an active area of research.

The Tissue-Selective Estrogen Complex Approach

One creative attempt to solve the progestogen problem involves pairing estrogen with a different kind of molecule rather than a traditional progestogen. A tissue-selective estrogen complex combines conjugated estrogens with bazedoxifene, a selective estrogen receptor modulator that blocks estrogen’s effects in the uterus while allowing them elsewhere. In clinical evaluation, this combination improved bone mineral density and relieved vasomotor and vaginal symptoms while maintaining endometrial safety, without using a progestogen at all.²⁷

This is not monotherapy in the strict sense, since two active compounds are involved. But it eliminates the progestogen component that drives concerns about breast cancer risk in combination HRT, and the clinical experience of taking one pill without cyclical bleeding has appeal for many women. The concept represents where the field has been heading for years: trying to capture the benefits of estrogen across multiple tissues while selectively blocking it where it causes harm.

Why Individual Responses Vary

One underappreciated reason that HRT experiences differ so much from person to person is genetic variation in estrogen receptors. A study of perimenopausal women identified four distinct patterns of menopausal symptom trajectories, and variations in estrogen receptor genes were significantly associated with which pattern a woman followed. These genetic differences also influenced how fluctuating estrogen levels translated into symptom severity.²⁸ In other words, two women with identical blood estrogen levels can have wildly different symptom experiences because their cells respond differently to the same hormone.

This has practical implications for monotherapy. If you start estrogen alone and find it less effective than expected, the explanation may not be an inadequate dose or the wrong product. It may be that your estrogen receptors are wired to respond differently. Pharmacogenomic testing for hormone therapy is still in early stages and not part of routine clinical practice, but the research suggests that eventually, the choice of monotherapy versus combination therapy, and the specific formulation used, could be guided by a person’s individual receptor genetics rather than by broad population-level guidelines.