Intracrine signalling is the production of active hormones inside the same cell that uses them, from a circulating precursor. In vulvar and vaginal tissue, cells take up DHEA and convert it into active androgens and estrogens that act within that cell.
Key points
● Vulvar and vaginal tissue carries the enzymes to convert DHEA into active androgens and estrogens, and does so.
● The tissue cannot make DHEA itself — it depends entirely on circulating supply.
● Circulating DHEA falls by roughly 60% by the postmenopausal years.
● In intracrine tissues, locally generated active steroids are largely used and metabolized within or near the cells in which they are formed. Serum hormone concentrations therefore do not directly measure tissue-level intracrine activity.
Vaginal evidence cannot automatically be applied to the vulva. However, the vagina, vestibule, and inner vulvar tissues form a contiguous biological environment, and studies show substantial—though incomplete—overlap in their microbial communities. Vaginal findings may therefore provide relevant supporting evidence for adjacent vulvar tissue, particularly when direct vulvar studies are limited.
How do hormones normally reach tissue?
In the standard model, a gland releases a hormone into the bloodstream and it travels to distant tissue. Ovaries make estrogen; estrogen circulates; tissue receives it. This is endocrine signalling, and it is correct as far as it goes.
It is incomplete for vulvar and vaginal tissue after menopause, because some tissues do not wait for finished hormones. They take in a precursor and manufacture what they need on site.
What does "intracrine" mean?
Intracrine signalling means a cell makes an active hormone inside itself, from a precursor, and uses it there — without the hormone leaving the cell. The term was introduced in 1991 to describe this local formation and action of steroids.[1]
|
Mode |
Where the hormone is made |
Where it acts |
Measurable in blood? |
|
Endocrine |
A gland |
Distant tissue |
Yes |
|
Paracrine |
One cell |
Neighbouring cells |
Sometimes |
|
Autocrine |
One cell |
Back on itself |
Sometimes |
|
Intracrine |
Inside the target cell |
Inside that same cell |
No |
In intracrine signalling the hormone is synthesised, binds its receptor, does its work and is inactivated, all within one cell.[2] There is nothing released to measure.
What is DHEA, and why does it matter here?
DHEA is a hormone precursor made mainly by the adrenal glands, and is close to biologically inactive on its own.[3] Its significance is entirely what tissues make from it.
DHEA is not a message. It is material.
Circulating DHEA begins declining from around age 30 and falls by roughly 60% by the postmenopausal years.[3] Unlike estrogen, this decline has no single event. After ovarian production ends, DHEA becomes the principal source of sex steroids available to peripheral tissue.[2,3]
Has this been demonstrated in human tissue?
Yes. A 2021 study examined vaginal tissue from postmenopausal women aged 60 to 82 and found four things directly.[3]
|
Finding |
Detail |
|
The enzymes are present |
Androgen-synthesising enzymes (HSD17β3, HSD17β5, all three 5α-reductase isoforms) expressed at higher levels than in ovarian tissue |
|
Conversion occurs |
Given DHEA at physiological concentrations, cells produced androstenedione, then testosterone, then DHT — measured by mass spectrometry |
|
The hormones act |
Newly made androgens activated androgen-responsive genes; blocking the androgen receptor abolished the effect |
|
The receptor is abundant |
In vaginal smooth muscle cells the androgen receptor was the most expressed steroid receptor measured |
Earlier work had shown this machinery in animal tissue.[4] This established it in the tissue actually under discussion.
Can vaginal tissue make its own DHEA?
No. It can use DHEA efficiently but cannot produce it.
In the same study, enzymes for the earliest steps of steroid synthesis — those building DHEA from cholesterol — were expressed at less than a tenth of ovarian levels. Meanwhile the enzyme freeing usable DHEA from its stored sulphated form was expressed at more than double ovarian levels, and the enzyme inactivating DHEA at less.[3]
That is a tissue configured to consume a supply it cannot generate.
### Signal and substrate Estrogen is a signal; DHEA is material. A signal instructs tissue what to do. Material determines whether it can. After menopause the machinery persists — what declines is the supply reaching it.
Why doesn't a blood test show this?
Because locally made hormones are used and inactivated inside the cell and do not re-enter circulation in meaningful quantity.[1,2] A serum panel measures what is in the blood, which is by definition not this.
Clinical practice reflects that. Diagnosis of genitourinary changes at menopause is made from history and examination; no laboratory test confirms it, and routine testing has no diagnostic role except to exclude other conditions.[5]
So a normal hormone panel establishes that circulating levels are normal. It does not establish that tissue-level hormone activity is adequate. Those are different claims, and conflating them is among the most common errors in midlife care.
Does the tissue make estrogen or androgens from DHEA?
Predominantly androgens. In the human vaginal cells studied, aromatase — which converts testosterone to estradiol — was almost undetectable, while androgen-producing enzymes were abundant. Estradiol was not detected at any DHEA concentration.[3]
This matters because androgen signalling governs functions estrogen does not reliably cover: vascular response, sensory nerve function, and the tissue architecture underlying comfort and arousal.[6,7]
This is a primary mechanism through which healthy vulvovaginal tissue maintains function. It operates alongside estrogen signalling, not instead of it.[7]
Frequently asked questions
Is DHEA a hormone? DHEA is a hormone precursor. It is a steroid, but close to inactive until tissue converts it into testosterone, DHT or estrogens. Its effects depend entirely on what the receiving tissue does with it.
Can I test my intracrine capacity? No. There is no clinical assay for tissue-level hormone activity. Anyone offering to measure it is selling something that does not exist.
Why are my hormone levels normal if I have symptoms? Blood levels report circulation. Intracrine hormone production happens inside cells and never reaches the bloodstream. Normal serum results and significant tissue-level symptoms are entirely compatible.
Does intracrine production stop at menopause? No. The enzymatic machinery persists after menopause. What declines is DHEA, the substrate it depends on.[2,3]
Is intracrine signalling unique to vaginal tissue? No — it occurs in many peripheral tissues, including skin and bone.[2] Vulvar and vaginal tissue is notable for the abundance of its androgen-producing enzymes and the density of its androgen receptors.[3]
What's established, and what isn't
Established: the enzymatic machinery exists in human vaginal tissue; conversion of DHEA to active androgens occurs; the resulting androgens activate androgen-dependent genes; the tissue cannot synthesise DHEA de novo; circulating DHEA declines substantially with age.[1–3]
Inferred: that variation in local conversion capacity explains variation in symptoms between women. Mechanistically coherent; not demonstrated at the individual level.
Not established: any clinical test of tissue-level hormone activity.
The 2021 study states its own limits: smooth muscle cells rather than epithelium, and postmenopausal tissue only.[3]
Where this leads
|
Question |
Article |
|
Why did estrogen only partly work? |
|
|
What is DHEA and does route matter? |
|
|
How does this fit midlife change overall? |
Educational note: For educational purposes only; not intended to diagnose, treat, cure or prevent any medical condition. Persistent or new symptoms should be evaluated by a qualified healthcare provider.
By Laura Kelly, DAOM, L.Ac., Dipl. O.M. 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
References
1. Labrie F. Intracrinology. Mol Cell Endocrinol. 1991;78(3):C113–C118. doi:10.1016/0303-7207(91)90116-A
2. Labrie F. Intracrinology and menopause: the science describing the cell-specific intracellular formation of estrogens and androgens from DHEA and their strictly local action and inactivation in peripheral tissues. Menopause. 2019;26(2):220–224. doi:10.1097/GME.0000000000001177
3. Cellai I, Di Stasi V, Comeglio P, et al. Insight on the intracrinology of menopause: androgen production within the human vagina. Endocrinology. 2021;162(2):bqaa219. doi:10.1210/endocr/bqaa219
4. Bertin J, Dury AY, Ouellet J, Pelletier G, Labrie F. Localization of the androgen-synthesizing enzymes, androgen receptor, and sex steroids in the vagina. J Sex Med. 2014;11(8):1949–1961. doi:10.1111/jsm.12589
5. Portman DJ, Gass ML. Genitourinary syndrome of menopause: new terminology for vulvovaginal atrophy. Menopause. 2014;21(10):1063–1068. doi:10.1097/GME.0000000000000329
6. Traish AM, Vignozzi L, Simon JA, Goldstein I, Kim NN. Role of androgens in female genitourinary tissue structure and function. Sex Med Rev. 2018;6(4):558–571. doi:10.1016/j.sxmr.2018.03.005
7. Simon JA, Goldstein I, Kim NN, et al. The role of androgens in the treatment of genitourinary syndrome of menopause (GSM): ISSWSH expert consensus panel review. Menopause. 2018;25(7):837–847. doi:10.1097/GME.0000000000001138
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