Oestrogen Signalling in the Ageing Face and Clinical Implications for Aesthetic Practice

Introduction and Demographic Shifts in Aesthetic Medicine

• The Changing Demographic: The fastest-growing demographic in aesthetic medicine is not the traditional 28-year-old patient; rather, it is the 48-year-old patient.

• Biological Versus Chronological Aging: Within the decade of the 40s, the biological changes occurring are not strictly general aging but are significantly driven by endocrine changes.

• Educational Gap in Medical Training:     * Many practitioners were trained during an era when hormone therapy was deemed controversial.     * Amanda Sable notes her own medical school experience involved only a single lecture on menopause during undergraduate years.

• Core Objective of Study: The focus is not on the prescription of hormones itself, but on understanding the underlying biology—specifically oestrogen beta ($ER\beta$) signaling—and how this biology influences the outcomes of aesthetic treatments already being delivered.

• Growth Potential: Women aged $40$ to $60$ years represent the fastest-growing aesthetic demographic.

• Perimenopause Timing: Perimenopause typically begins $5$ to $10$ years prior to the last menstrual period, leading to a period of accelerated structural change in the skin.

• Shift in Treatment Philosophy: There is a global shift from mere volume replacement toward biological outcomes and regenerative medicine. This is evidenced by the global decline in filler volume sales and an increasing focus on biological optimization and receptor biology.

The Biology of the Four Oestrogens

Oestrogen is not a single entity but exists as multiple forms with varying potencies, receptor binding affinities, and genomic outputs. As women enter perimenopause and menopause, the balance of these oestrogens shifts.

Estrone ($E1$)

• Dominance: Becomes the dominant circulating oestrogen after menopause.

• Production: Produced via the aromatization of androgens; primarily sequestered in adipose tissue.

• Binding Affinity: Significantly lower binding affinity for the estrogen beta ($ER\beta$) receptor compared to estradiol ($E2$).

• Genomic Output:     * Results in reduced transcription of $COL1A1$ and $COL3A1$, which are the genes encoding the alpha-one chains of type one and type three collagen.     * Reduces activation of hyaluronan synthase two ($HAS2$), the enzyme responsible for dermal hyaluronic acid synthesis.     * Leads to less suppression of matrix metalloproteinases (MMPs), specifically $MMP1$ (interstitial collagenase) and $MMP9$ (gelatinase B).     * Metaphor: Sable describes this state as "the lights are on, but the genomic drive is reduced."

Estradiol ($E2$)

• Dominance: The primary ovarian oestrogen.

• Binding Affinity: Possesses the highest affinity for both oestrogen receptor alpha ($ER\alpha$) and oestrogen receptor beta ($ER\beta$), with $ER\beta$ being the predominant receptor in the skin.

• Mechanism of Action: When $E2$ binds to $ER\beta$, the receptor dimerizes (two units pair together) and translocates into the nucleus. It then binds to Estrogen Response Elements ($EREs$) on the DNA.

• Genomic Output:     * Upregulates $COL1A1$ and $COL3A1$ gene transcription, increasing type one and type three collagen synthesis.     * Stimulates $HAS2$, increasing hyaluronic acid ($HA$) production.     * Suppresses inflammatory transcription factors, including Activator Protein 1 ($AP\text{-}1$) and Nuclear Factor Kappa B ($NF\kappa B$).     * Reduces expression of $MMP1$ and $MMP9$, resulting in increased matrix synthesis and reduced matrix degradation.

Estriol ($E3$)

• Production: Predominantly produced by the maternal placental unit during pregnancy.

• Potency: Roughly $1/10$th the potency of estradiol, depending on the tissue context.

• Binding Affinity: Significantly lower affinity for both $ER\alpha$ and $ER\beta$ compared to $E2$; characterized by a shorter half-life and weaker transcriptional drive.

• Clinical Use: Used in topical formulations (common in the US) marketed as safer due to weaker activity in breast tissue.

• Aesthetic Limitations: While it may offer mild epidermal benefits (hydration and barrier function), it lacks the ability to robustly stimulate dermal extracellular matrix production. Sable describes it as a "soft glow" rather than a "full structural rebuild."

Estetrol ($E4$)

• Production: A naturally occurring oestrogen produced in the fetal liver during pregnancy; enters maternal circulation via the placenta.

• Mechanism: Acts as a Selective Estrogen Receptor Modulator ($SERM$). It exhibits tissue-specific signaling effects, acting as an agonist in some tissues and remaining neutral in others.

• Clinical profile: Used in newer oral contraceptives due to a favorable hepatic and thrombotic profile.

• Dermal Status: There is currently no robust evidence that $E4$ produces the same degree of collagen or $HA$ upregulation as $E2$. It is currently viewed as a "promising" but not yet equivalent dermal regenerative hormone.

The Mechanism of the Estrogen Receptor Beta ($ER\beta$) in Skin

• Distribution: $ER\beta$ is expressed in dermal fibroblasts, keratinocytes, and endothelial cells.

• Process of Activation:     1. Binding: Estradiol binds to $ER\beta$ at the cell membrane or in the cytoplasm.     2. Dimerization: The receptor undergoes conformational change and dimerizes.     3. Translocation: The complex moves into the nucleus.     4. Binding DNA: It binds to specific specific sequences known as Estrogen Response Elements ($EREs$).     5. Transcription: Initiates the transcription of genes vital for the extracellular matrix ($ECM$).

• Functional Outcomes of $ER\beta$ Activation:     * Collagen: Increases transcription of $COL1A1$ (tensile strength) and $COL3A1$ (elasticity and early repair).     * Hyaluronic Acid: Upregulates $HAS2$ for dermal hydration and turgor.     * Anti-Degradation: Suppresses $AP\text{-}1$ and $NF\kappa B$, which normally drive the expression of $MMP1$ (degrades collagen) and $MMP9$ (degrades elastin).

Structural Consequences of Reduced Oestrogen Signalling

When estradiol levels fall and estrone becomes dominant, the balance of the extracellular matrix shifts toward degradation.

• Collagen: Reduced transcription leads to fragmented collagen, dermal thinning, and reduced tensile strength.

• Hyaluronic Acid: Drop in signaling reduces $HAS2$ activity, affecting structural water binding capacity, resilience, turgor, and hydration.

• Elastin: Preservation of elastin is lost. Normally, oestrogen preserves elastin by suppressing inflammatory pathways and MMPs. Without signaling, $MMP$ activity rises, and elastin fragmentation accelerates.

• Clinical Ceiling: Most aesthetic treatments (energy-based devices, biostimulators, wound healing) depend on fibroblast function. If the signaling environment is suboptimal, the clinical "ceiling" or maximum response to these treatments is lowered.

High Frequency Ultrasound Evidence

Measurements of dermal thickness provide tangible evidence of hormonal influence:

• Post-menopausal Skin: Measured dermal thickness of approximately $0.76\,mm$.

• Pre-menopausal Skin: Measured dermal thickness in the same area of approximately $1.4\,mm$.

Real-World Comparison: Case Study of Two 60-Year-Old Nurses

Sable compares two patients to demonstrate the long-term impact of receptor biology. Both were born in Australia, are Fitzpatrick III, have similar sun exposure, and similar BMIs.

Patient Profiles

• Nurse A:     * $4$ Pregnancies.     * Total hysterectomy at age $26$.     * No exogenous hormones (HRT) used since the hysterectomy.     * BMI: $22$.

• Nurse B:     * $6$ Pregnancies.     * Reached menopause at age $57$.     * Commenced HRT at age $56$.     * BMI: $21.5$.

Treatment and Financial Comparison (Last 12 Months)

• Injectable Intervention for Nurse A:     * Three sessions of Botox.     * Three sessions of PLLA (Poly-L-lactic acid).     * Kaha.     * Dermal filler.     * Skin boosters.     * Total Spend: High (requires significant structural correction).

• Injectable Intervention for Nurse B:     * Three sessions of Botox.     * One syringe of hyaluronic acid ($HA$) filler to the lips.     * One session of Profilo.     * Total Spend: Approximately $1/3$ of Nurse A's annual spend.

Findings

• Despite the chronologically identical age, Nurse A appears significantly more aged than Nurse B.

• This suggests that lifetime estradiol exposure and oestrogen beta signaling fundamentally govern the substrate of the skin that aesthetic practitioners try to manipulate.

Conclusion: The Medicalization of Aesthetic Practice

• Role of the Doctor: In clinical markets like Australia, many injectors are nurses who cannot prescribe systemic hormones. Doctors have a unique ability to assess perimenopause and manage menopause.

• Holistic Health: Oestrogen influences not just collagen but also bone density, cardiovascular function, cognitive health, and urogenital integrity.

• Philosophical Shift: Menopause is a systemic transition, not just a skin event. Aesthetic medicine should focus on maintaining function, structure, and "health span."

• Future Direction: Just as medicine explores peptides, exosome, and biologics, hormonal optimization should be viewed as a tool to support the systems that maintain structure, rather than just injecting to replace lost structure.