The overlooked role of androgen signaling in vulvar and vestibular tissue 

Estrogen is essential to vaginal and vulvar health, but it is not the only steroid pathway operating in these tissues.

Both human vulvar and vaginal tissues express estrogen receptors and androgen receptors and possess intracrine steroid-metabolizing enzymes capable of converting DHEA into active androgens and estrogens.¹–³ Direct conversion of DHEA into testosterone and dihydrotestosterone, or DHT, has also been demonstrated in human vaginal smooth-muscle cells.²

Estrogen therapy can improve epithelial maturation, tissue thickness, glycogen availability, vaginal acidity, hydration, and comfort.⁴˒⁵ But estrogen does not activate the androgen receptor, and estradiol cannot be converted backward into testosterone or DHEA.

This means that estrogen can restore one part of the tissue’s hormonal environment without replacing the other.

The answer in brief

Estrogen is not enough to explain the full biology of vulvar, vestibular, and vaginal tissue because these tissues are both estrogen-responsive and androgen-responsive.

Estrogen and androgens have overlapping effects, but they are not interchangeable. Estrogen activates estrogen receptors. Testosterone and DHT activate androgen receptors. DHEA provides precursor material that local cells can convert into active sex steroids.

A tissue containing abundant androgen receptors and androgen-producing enzymes cannot be fully understood through an estrogen-only model.

This does not mean that vaginal estrogen is ineffective. It means that vaginal estrogen may not address every tissue pathway contributing to sensation, arousal, blood flow, smooth-muscle behavior, comfort, or sexual response.

Key points

• Estrogen supports vaginal epithelial maturation, glycogen production, tissue integrity, hydration, and acidity.

• Vulvar, vestibular, clitoral, urethral, and vaginal tissues also contain androgen receptors.

• Human postmenopausal vaginal tissue can convert DHEA into testosterone and DHT.

• Estrogen and androgen effects are partly overlapping but also biologically distinct.

• Estradiol cannot be converted backward into testosterone or DHEA.

• A partial response to estrogen may indicate that another tissue pathway remains limiting, but it does not prove androgen deficiency in an individual woman.

• The biological need for androgen signaling does not mean that every woman requires DHEA or testosterone treatment.

What pattern do some women describe?

Some women experience substantial relief with vaginal estrogen. Dryness improves, irritation decreases, examination findings normalize, and sexual activity becomes more comfortable.

Others describe a partial response:

• dryness improves, but sensation remains diminished;

• tissue looks healthier, but arousal response remains delayed;

• pain decreases, but the tissue still feels unresponsive;

• comfort improves, but sexual interest does not return;

• symptoms improve initially and then reach a plateau.

This pattern is sometimes attributed to an inadequate estrogen dose, age, psychological factors, relationship circumstances, or irreversible tissue change. Any of those explanations may be relevant in an individual case.

But there is another biological possibility:

Estrogen may have improved the estrogen-responsive dimensions of tissue function while a different pathway remained limiting.

A partial response does not prove that androgen signaling is the missing factor. It does show why a single-hormone explanation may be incomplete.

What does vaginal estrogen do?

Vaginal estrogen is a well-established treatment for genitourinary syndrome of menopause. It can improve symptoms such as dryness, irritation, burning, and pain with sexual activity.[1,2]

At the tissue level, estrogen supports:

• epithelial proliferation and maturation;

• increased epithelial thickness;

• glycogen availability;

• conditions that support vaginal Lactobacillus species;

• lower vaginal pH;

• mucosal integrity;

• collagen and connective-tissue maintenance;

• tissue hydration;

• aspects of vascular and neural function.

These effects are clinically meaningful. Vaginal estrogen should not be minimized simply because additional hormone pathways exist.

For many women, it is sufficient.

The scientific question is not whether estrogen works. It is whether estrogen alone accounts for every steroid-dependent function of the vulva, vestibule, and vagina.

The evidence indicates that it does not.

Why are androgens relevant to female genital tissue?

Androgens are often treated as though they are relevant primarily to male physiology. Female genital tissues do not support that assumption.

Androgen receptors have been identified in:

• the labia majora;

• the labia minora;

• the vulvar vestibule;

• the clitoris;

• the urethra;

• the vaginal epithelium;

• the vaginal lamina propria;

• vaginal smooth muscle;

• vascular endothelium within genital tissue.[3–6]

The distribution is biologically important. A receptor is the molecular structure through which a hormone signal acts. Estrogen cannot directly substitute for testosterone or DHT at the androgen receptor.

The vestibule is especially relevant because it is not simply external skin. It contains nonkeratinized or minimally keratinized tissue, glands, nerves, vessels, smooth muscle, and embryologically distinct structures with substantial androgen responsiveness.

The clitoris, vestibule, periurethral tissues, and distal vagina share developmental and functional relationships to the urogenital sinus and contain androgen-responsive structures.[3,6]

What did the human tissue research show?

In a 2021 study, Cellai and colleagues examined distal vaginal tissue obtained from postmenopausal women and isolated human vaginal smooth-muscle cells.[4]

The researchers found that:

• androgen-receptor messenger RNA was present throughout human vaginal tissue;

• androgen-receptor expression in whole vaginal tissue was lower than ERα but higher than ERβ, GPER1, and the progesterone receptor;

• in isolated vaginal smooth-muscle cells, the androgen receptor was the most highly expressed steroid receptor measured;

• vaginal tissue expressed enzymes required to convert DHEA into androstenedione, testosterone, and DHT;

• DHEA exposure produced testosterone and DHT in cultured human vaginal smooth-muscle cells;

• blocking the androgen receptor prevented several DHEA-induced gene responses.

This is direct human evidence that the vagina is both:

1. an androgen target tissue, because it expresses androgen receptors; and

2. an androgen-producing intracrine tissue, because it can convert DHEA into active androgens.

The study does not establish every function of androgen signaling in the vulva or vagina. It does establish that an estrogen-only description of the tissue is biologically incomplete.

What does estrogen do—and what do androgens do?

Estrogenic and androgenic functions overlap. The table below describes areas of relative emphasis, not absolute ownership.

Estrogen-associated functions	Androgen-associated or androgen-responsive functions
Vaginal epithelial maturation and thickness	Androgen-receptor signaling in the vestibule, clitoris, vagina, and urethra
Glycogen availability and vaginal acidity	Vaginal and genital smooth-muscle regulation
Support of Lactobacillus-dominant conditions	Nitric-oxide and cyclic-GMP signaling relevant to tissue relaxation
Mucosal integrity and hydration	Genital vascular responsiveness and arousal physiology
Collagen and connective-tissue maintenance	Clitoral and vestibular tissue responsiveness
Relief of dryness, irritation, and dyspareunia	Neural and sensory functions implicated in genital response
Estrogen-receptor-mediated transcription	Androgen-receptor-mediated transcription

Estrogen may also influence blood flow, nerves, collagen, inflammation, and smooth muscle. Androgens may also influence epithelial and connective-tissue biology.

The distinction is therefore not:

Estrogen affects structure, while androgens affect function.

The more accurate distinction is:

Estrogen and androgens produce partly overlapping but nonidentical signals through different receptors.

A tissue may require both signaling systems for its complete physiological range.

Why can’t more estrogen replenish the androgen pathway?

Because steroid conversion is directional.

A simplified pathway is:

DHEAS ↔ DHEA → androstenedione → testosterone → DHT

And, in tissues that express sufficient aromatase:

androstenedione → estrone

testosterone → estradiol

Estradiol cannot reverse this pathway and become testosterone. Testosterone cannot be converted backward into DHEA. The aromatase reaction that converts androgens into estrogens does not operate in reverse in human tissue.

Therefore:

• supplying estradiol supplies an estrogen-receptor ligand;

• it does not supply DHEA;

• it does not produce testosterone;

• it does not produce DHT;

• it does not directly activate the androgen receptor.

This is the central reason estrogen and DHEA are not biologically interchangeable.

DHEA is precursor substrate

DHEA is produced primarily by the adrenal glands and circulates as both DHEA and its sulfated storage form, DHEAS.

Peripheral tissues can use DHEA as precursor material for local production of androgens and estrogens. This local production is called intracrine steroidogenesis.

In the Cellai study, human vaginal tissue expressed very low levels of the enzymes required for the earliest steps of steroid production from cholesterol. The researchers concluded that the postmenopausal vagina did not appear able to synthesize meaningful DHEA de novo in their experimental model.[4]

It could, however, efficiently convert available DHEA into active androgens.

This creates an important distinction:

The tissue possesses conversion machinery, but that machinery still requires precursor substrate.

DHEA secretion declines substantially with age. Published estimates suggest that average DHEA secretion has fallen by approximately 60% from peak young-adult levels by the time of menopause, although concentrations and rates of decline vary considerably among women.[7,8]

The tissue may therefore retain the enzymes needed for intracrine conversion while receiving less precursor material to place into that pathway.

Is the vagina primarily estrogenic or androgenic?

Neither description is sufficient by itself.

In whole distal vaginal tissue, ERα was the most highly expressed receptor measured in the Cellai study. The androgen receptor was nevertheless abundant and exceeded several other steroid receptors.[4]

In isolated vaginal smooth-muscle cells, the androgen receptor was the most highly expressed steroid receptor measured.[4]

This difference matters because a tissue is composed of multiple compartments:

• epithelium;

• connective tissue;

• blood vessels;

• nerves;

• immune cells;

• smooth muscle;

• extracellular matrix.

Different compartments may express different receptors and perform different functions. A whole-tissue average can obscure strong receptor expression in a functionally important cell population.

The epithelium may be strongly estrogen-responsive while the smooth-muscle, vascular, sensory, clitoral, or vestibular compartments retain substantial androgen responsiveness.

This is why a treatment can improve one dimension of tissue biology without normalizing all of them.

What evidence links androgens to blood flow and arousal physiology?

Reviews of experimental and human-tissue evidence conclude that androgens contribute to genital tissue structure and function through effects that can be distinct from or complementary to estrogen.[5,6]

Potential androgen-associated functions include:

• smooth-muscle organization;

• nitric-oxide signaling;

• cyclic-GMP pathways;

• genital tissue relaxation;

• vascular responsiveness;

• clitoral physiology;

• sensory function;

• inflammatory regulation;

• connective-tissue maintenance.

In human vaginal smooth-muscle cells, DHEA and testosterone activated androgen-responsive genes involved in nitric-oxide signaling, and an androgen-receptor antagonist blocked those effects.[4]

Animal research also shows that testosterone can regulate nitric-oxide-mediated vaginal smooth-muscle relaxation and smooth-muscle organization independently of aromatization to estrogen.[9]

Animal findings cannot be treated as direct proof of clinical effects in women. They do, however, provide mechanistic support for the conclusion that androgen signaling contributes to aspects of genital arousal physiology that cannot be reduced to estrogen-receptor activity alone.

Why might comfort improve while responsiveness does not?

A partial response can occur when treatment improves one limiting process but not another.

For example:

• epithelial maturation may improve while sensory signaling remains altered;

• dryness may improve while vascular arousal remains delayed;

• pain may decrease while central sexual motivation remains low;

• tissue integrity may improve while pelvic-floor dysfunction persists;

• estrogen-receptor signaling may be restored while androgen-receptor signaling remains relatively reduced;

• hormonal signaling may be adequate while nerves, vessels, connective tissue, or inflammatory pathways remain impaired.

The observation that comfort improved while responsiveness did not is therefore meaningful—but not diagnostic.

It tells us that:

The functions that improved and the functions that remained impaired may not share exactly the same limiting biology.

It does not, on its own, identify which pathway is responsible.

The Tissue Response Model

The Tissue Response Model is a proposed framework describing vulvovaginal outcomes as the interaction of three inputs:

1. hormone-receptor signal;

2. precursor substrate;

3. tissue response capacity.

The model was developed by Laura Kelly, DAOM, to explain why women with apparently similar hormone states can experience different tissue symptoms and different responses to the same intervention.

Input	What it means	What happens when it is limiting
Hormone-receptor signal	Estrogenic and androgenic ligands reaching and activating their respective receptors	A receptor-specific pathway may remain underactivated even when another hormone pathway is adequately treated
Precursor substrate	DHEA or DHEAS available for local intracrine conversion	Local production of active androgens or estrogens may be constrained despite preserved conversion enzymes
Tissue response capacity	The ability of epithelium, vessels, nerves, smooth muscle, connective tissue, immune pathways, and metabolic systems to respond	Hormonal treatment may produce only a partial response because the downstream tissue cannot fully translate the signal

This can be expressed conceptually as:

Tissue outcome = receptor signal × precursor availability × response capacity

This is not a literal mathematical equation. It illustrates that a substantial limitation in one component may constrain the final tissue response even when the other components are relatively adequate.

What the model explains

The Tissue Response Model offers a possible explanation for why:

• two women prescribed the same estrogen dose can have different outcomes;

• examination findings can improve while subjective sensation remains altered;

• one symptom can resolve while another persists;

• hormone measurements may not correspond closely to local tissue function;

• escalating one hormone does not necessarily correct a limitation in another pathway;

• some women respond incompletely to otherwise appropriate therapy.

The model organizes the clinical question. It is not a validated diagnostic test and cannot determine treatment for an individual woman.

What do clinical trials tell us?

Clinical evidence supports vaginal estrogen as an effective treatment for many manifestations of GSM.[2,10]

Clinical trials of intravaginal prasterone—pharmaceutical DHEA—have also reported improvements in dyspareunia, vaginal tissue measures, and several domains of sexual function in selected postmenopausal women.[11]

However, DHEA can be converted locally into both androgenic and estrogenic metabolites. Prasterone studies therefore do not isolate how much of the observed effect came from androgen-receptor signaling, estrogen-receptor signaling, improved comfort, reduced pain, or interactions among these processes.

Similarly, evidence supporting systemic testosterone for hypoactive sexual desire disorder does not establish testosterone as a universal treatment for GSM or vulvar symptoms.[12]

The clinical evidence supports the biological relevance of multiple steroid pathways. It does not yet provide a validated method for determining which pathway is limiting in an individual woman.

What this article does—and does not—mean

It does mean:

• female genital tissue is not estrogen-only tissue;

• androgen receptors are present throughout the vulvovaginal and genitourinary system;

• the vestibule and clitoris are androgen-responsive structures;

• human vaginal cells can convert DHEA into testosterone and DHT;

• estrogen cannot directly activate the androgen receptor;

• estradiol cannot be converted backward into DHEA or testosterone;

• estrogen and androgen effects are distinct in some functions and complementary in others;

• an estrogen-only model cannot fully describe vulvar, vestibular, and vaginal physiology.

It does not mean:

• vaginal estrogen is ineffective;

• estrogen has no effect on blood flow, nerves, sensation, or sexual function;

• every persistent symptom is caused by inadequate androgen signaling;

• every woman requires testosterone or DHEA;

• a partial estrogen response proves an androgen deficiency;

• serum DHEA or testosterone directly measures intracrine tissue activity;

• evidence for one DHEA formulation or anatomical route applies automatically to another.

Frequently asked questions

Why is the article called “Why Estrogen Isn’t Enough”?

Because estrogen alone is not sufficient to explain the complete hormone biology of vulvar, vestibular, clitoral, urethral, and vaginal tissue.

The title does not mean estrogen therapy is ineffective. It means that female genital tissue also contains a substantial androgen-signaling system that estrogen cannot replace.

Should I stop using vaginal estrogen?

Nothing in this article argues for stopping vaginal estrogen. It is a well-studied treatment for GSM and provides substantial benefit for many women.[2,10]

Changes to prescribed therapy should be discussed with the clinician managing your care.

Does this mean I need DHEA or testosterone?

No.

The presence of androgen receptors establishes androgen responsiveness. It does not establish that every woman with symptoms needs androgen treatment.

DHEA and testosterone have different pharmacology, routes, evidence bases, risks, and clinical indications. Treatment decisions require individualized assessment.

Why did estrogen improve my dryness but not sensation?

Several explanations are possible.

The dryness may have been driven primarily by estrogen-responsive epithelial changes, while altered sensation may involve neural, vascular, inflammatory, pelvic-floor, androgen-responsive, or other processes.

A partial response identifies a difference between functions. It does not identify the cause by itself.

Why did estrogen improve comfort but not desire?

Comfort and desire are not the same biological function.

Improved tissue comfort may remove a barrier to sexual activity, but desire also depends on brain reward systems, attention, stress, relationship context, medications, sleep, health, and other factors.

Persistent low desire should not automatically be attributed to local androgen signaling.

Related reading: Why Does Desire Decline in Midlife?

Can estrogen become testosterone inside the tissue?

No.

Testosterone can be converted into estradiol by aromatase. Estradiol cannot undergo the reverse reaction and become testosterone. Estrogen therapy therefore does not replenish DHEA, testosterone, or DHT.

Can DHEA become estrogen as well as testosterone?

Yes.

DHEA can enter local pathways that produce androstenedione and testosterone. In tissues expressing sufficient aromatase, those androgens can then be converted into estrone and estradiol.

The products formed depend on the enzymes present in the particular cell or tissue.

Does a normal blood testosterone level prove that the tissue has enough androgen activity?

No.

Serum hormone concentrations do not directly measure receptor abundance, local enzyme activity, intracellular conversion, tissue metabolism, or androgen-receptor activation.

There is currently no validated routine clinical assay that measures intracrine androgen activity within vulvar or vaginal tissue.

Is a partial response to estrogen a treatment failure?

Not necessarily.

A partial response shows that some biological processes improved while others remained limiting. That information can help guide a more complete clinical evaluation.

Persistent symptoms may also reflect infection, inflammatory or dermatological disease, pelvic-floor dysfunction, neuropathic pain, medication effects, trauma, systemic illness, or other causes unrelated to hormone substrate.

What is established—and what remains uncertain?

Established

• Androgen receptors are present in the vulva, labia, vestibule, clitoris, urethra, and vagina.[3,5,6]

• Human postmenopausal vaginal tissue expresses enzymes capable of converting DHEA into testosterone and DHT.[4]

• Human vaginal smooth-muscle cells respond to DHEA through androgen-receptor-mediated pathways.[4]

• Estrogen and androgens can have distinct as well as complementary effects in genitourinary tissue.[5,6]

• Estradiol cannot be converted backward into testosterone or DHEA.

• DHEA availability declines substantially with age.[7,8]

• Vaginal estrogen effectively treats many manifestations of GSM.[2,10]

Supported but not fully established in women

• Androgen signaling contributes to genital vascular response, nitric-oxide signaling, smooth-muscle behavior, sensation, and arousal physiology.[4–6,9]

• Reduced DHEA availability may constrain local androgen production in some women.

• Different tissue compartments may respond differently to estrogenic and androgenic input.

Proposed or inferred

• A plateau after vaginal estrogen may sometimes reflect an unaddressed androgen-responsive pathway.

• Signal, substrate, and tissue response capacity may explain individual differences in treatment response.

• The Tissue Response Model may provide a useful framework for organizing persistent symptoms.

Not established

• That androgen insufficiency explains every incomplete response to estrogen.

• That a particular blood hormone level identifies the limiting tissue pathway.

• That every symptomatic woman benefits from DHEA or testosterone.

• That findings from vaginal prasterone trials can be applied directly to oral DHEA or external vulvar formulations.

• That the Tissue Response Model can presently be used as a validated diagnostic or treatment-selection instrument.

The central idea

Estrogen is essential. But essential does not mean sufficient.

The vulva, vestibule, clitoris, urethra, and vagina contain androgen receptors as well as estrogen receptors. Human vaginal tissue can convert DHEA into testosterone and DHT and use those androgens to activate receptor-specific cellular pathways.

Estrogen cannot replace that pathway because it cannot activate the androgen receptor and cannot be converted backward into androgen precursor.

The most scientifically accurate conclusion is therefore not that estrogen fails.

It is this:

Estrogen successfully supports estrogen-responsive tissue biology. But female genital tissue also has androgen-responsive biology, and the two systems are not interchangeable.

A complete model of vulvar and vestibular health must include both.

---

By Laura Kelly, DAOM, L.Ac., Dipl. OM — Developer of the Tissue Response Model of midlife vaginal health.  A California-licensed primary care provider and nationally board-certified clinician with a clinical focus on women’s health and healthy aging. Research Scholar, Ronin Institute. ORCID: 0000-0001-6586-7308.  More about Dr. Kelly

Last scientifically reviewed: July 2026

Educational note: This article provides general scientific education and is not a diagnosis or individualized treatment recommendation. Persistent vulvar, vaginal, urinary, sexual, or sensory symptoms should be assessed by an appropriately qualified clinician. Hormonal treatment decisions should be made with a healthcare professional familiar with the individual’s medical history.

References

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   3. Portman DJ, Gass MLS; Vulvovaginal Atrophy Terminology Consensus Conference Panel. Genitourinary syndrome of menopause: new terminology for vulvovaginal atrophy from the International Society for the Study of Women’s Sexual Health and The North American Menopause Society. Menopause. 2014;21(10):1063–1068. https://doi.org/10.1097/GME.0000000000000329

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   8. Labrie F. Intracrinology and menopause: the science describing the cell-specific intracellular formation of estrogens and androgens from DHEA and their local action and inactivation in peripheral tissues. Menopause. 2019;26(2):220–224. https://doi.org/10.1097/GME.0000000000001177

   9. Labrie F, Luu-The V, Labrie C, Simard J. DHEA and its transformation into androgens and estrogens in peripheral target tissues: intracrinology. Frontiers in Neuroendocrinology. 2001;22(3):185–212. https://doi.org/10.1006/frne.2001.0216

   10. Cellai I, Filippi S, Comeglio P, et al. Testosterone positively regulates vagina nitric-oxide-induced relaxation: an experimental study in rats. Journal of Endocrinological Investigation. 2022;45(6):1161–1172. https://doi.org/10.1007/s40618-022-01743-4

   11. Biehl C, Plotsker O, Mirkin S. A systematic review of the efficacy and safety of vaginal estrogen products for the treatment of genitourinary syndrome of menopause. Menopause. 2019;26(4):431–453. https://doi.org/10.1097/GME.0000000000001221

   12. Labrie F, Derogatis L, Archer DF, et al. Effect of intravaginal prasterone on sexual dysfunction in postmenopausal women with vulvovaginal atrophy. The Journal of Sexual Medicine. 2015;12(12):2401–2412. https://doi.org/10.1111/jsm.13045

   13. Davis SR, Baber R, Panay N, et al. Global consensus position statement on the use of testosterone therapy for women. The Journal of Clinical Endocrinology & Metabolism. 2019;104(10):4660–4666. https://doi.org/10.1210/jc.2019-01603