Comprehensive Notes on Estrogen Deficient Skin and MEP Technology

Introduction to Skin Aging and the Essential Role of Estrogen

• Skin aging is defined as a complex process resulting from a multifactorial combination of chronological, environmental, genetic, and hormonal influences.

• Intrinsic aging in women is significantly driven by the onset of menopause, which initiates a phase of accelerated skin aging.

• Estrogen is categorized as an essential component for skin health and overall wellness.

• The biological presence and utility of estrogen in the skin are confirmed by the presence of specific estrogen receptors located on crucial structures:

  • Keratinocytes.

  • Fibroblasts.

  • Blood vessels.

  • Hair follicles.

• While estrogen receptor signaling is described as extremely complicated and not fully understood, two distinct modes of action for estrogen's effects on skin cells have been identified.

Genomic and Non-Genomic Signaling Pathways of Estrogen

• The Genomic Pathway:

  • This pathway is DNA-related.

  • It serves to maintain skin structure and thickness.

  • It promotes the production of essential proteins, specifically keratin and collagen.

  • It supports skin nourishment through angiogenesis, ensuring adequate blood flow to the skin.

• The Non-Genomic Pathway:

  • This pathway involves a signal cascade rather than direct DNA interaction.

  • It reduces local inflammation within the skin tissue.

  • It inhibits the growth of unwanted facial hair.

  • It maintains skin elasticity by inhibiting elastase enzymes.

  • It preserves moisture content by increasing capillary permeability.

• Estrogen also facilitates a positive feedback loop: the presence of estrogen has been shown to increase the population of estrogen receptors within the cells. This relationship is critical because as estrogen levels decline during menopause, the number of available estrogen receptors also declines.

Characteristics and Progression of Estrogen Deficient Skin (EDS)

• Estrogen Deficient Skin ($\text{EDS}$) typically affects women entering menopause in their $\text{40s}$.

• Clinical manifestations of $\text{EDS}$ include:

  • Persistent dryness.

  • Significant loss of collagen.

  • Reduced activity in keratinocytes and fibroblasts.

  • Increase in visible wrinkles.

  • Skin thinning and atrophy.

  • Impaired or slowed wound healing.

• Dryness is the skin symptom most frequently associated with menopause by women, often secondary to symptoms like hot flashes and insomnia.

• Many patients remain unaware that these cutaneous changes are directly linked to declining estrogen levels rather than just chronological time.

Statistical Analysis of Collagen Loss

• Collage loss is a lifelong process that begins as early as the early $\text{20s}$, occurring at a rate of approximately $1\% \text{ to } 1.5\%$ per year.

• Dermal collagen decline accelerates steeply at the onset of menopause.

• $30\%$ of all dermal collagen is lost within the first $5\,\text{years}$ of menopause.

• Subsequent years after this initial phase see an additional loss of $2\%$ per year.

• This rapid decline is the primary reason women report that their skin appears to have aged "overnight."

• Research indicates that this drastic loss is more closely correlated with the duration of estrogen deficiency (postmenopausal age) than with chronological age.

Therapeutic Options: Historical and Modern Approaches

• Efforts to treat the structural manifestations of $\text{EDS}$ have historically utilized several methods:

  • Topical Estrogen: Effective for benefits in aging skin but carries risks of telangiectasias (spider veins) and potential health risks from systemic absorption.

  • Hormone Replacement Therapy ($\text{HRT}$): While $\text{HRT}$ can offer ancillary skin benefits, skin improvement is not its primary intended purpose. It requires constant safety monitoring, blood work to assess therapeutic levels, and evaluation for side effects.

  • Selective Estrogen Receptor Modulators ($\text{SERMs}$): Includes phytoestrogens such as Genenstein.

  • Genenstein: Shown to be a safer alternative for treating $\text{EDS}$, but its biological potency is significantly inferior to synthetic estrogens, leading to lower patient satisfaction.

MEP Technology: A Novel NEARA Approach

• $MEP$ stands for Methyl Estradiol Propanoate.

• $MEP$ is not a hormone; it is a synthetic estrogenic sterile ester.

• It is classified as a Non Hormonal Estrogen Receptor Activator ($\text{NEARA}$).

• The primary mechanism of $MEP$ is to bind to cutaneous estrogen receptors without inducing effects elsewhere in the body.

• It provides the beneficial effects of estrogen in the skin while avoiding the risks associated with systemic hormonal distribution.

Clinical Safety and Metabolism of MEP

• A safety study was conducted by Doctor Zoe Drayloz and published in the Journal of Drugs and Dermatology.

• Methodology:

  • $MEP$ was applied to the face twice daily for $12\,\text{weeks}$.

  • Blood draws were taken at baseline and at week $12$ to evaluate systemic absorption and tolerability.

• Metabolic Process:

  • Upon reaching the bloodstream, $MEP$ is quickly broken down by esterases (enzymes naturally circulating in the blood).

  • These esterases convert $MEP$ into carboxylic acid and alcohol.

  • Carboxylic acid is an inactive metabolite of $MEP$ that does not activate estrogen receptors and is subsequently excreted from the body.

• Results:

  • No adverse events or safety issues were reported after the $12\text{-week}$ period.

  • Tolerability was rated as excellent by both the investigator and the participants.

  • Blood tests confirmed the rapid conversion to an inactive metabolite, ensuring no systemic effects.

Efficacy and Histological Evidence for MEP

• An efficacy study including $80$ postmenopausal women (ages $53 \text{ to } 80\,\text{years}$) was performed.

• Criteria: Participants were amenorrhea for between $3 \text{ to } 10\,\text{years}$ and had no history of $\text{HRT}$ use.

• Design: A $3:1$ randomization between $MEP$ plus vehicle vs. vehicle alone (thickened water with no occlusive agents).

• Statistically significant improvements were observed at week $14$ in:

  • Dryness.

  • Dullness.

  • Skin thickness.

  • Laxity.

  • Erythema.

  • Atrophy.

  • Fine lines.

• Histological Sub-study ($9$ individuals):

  • Four out of nine subjects showed a measurable increase in fibroblast staining positively for estrogen receptors.

  • At baseline, no detectable estrogen receptor positivity on fibroblasts was present.

• ComparisonSummary: Unlike standard estrogen, which stays intact in the bloodstream to cause systemic effects, $MEP$ is absorbed and binds to skin receptors but is inactivated immediately upon entering the blood.

Emepelle Product Line Formulations: Meppel, Imapel, and Imipal

• The Meppel line is specifically designed for visible signs of $\text{EDS}$.

• Imipel Serum:

  • Contains $MEP$ technology.

  • Niacinamide: Inhibits melanosome transfer to even skin tone, improves fine lines, and supports the skin barrier.

  • Antioxidants: Vitamin C, Vitamin E, and Ferulic Acid.

  • Pentapeptide 28: Supports cellular vitality and natural repair processes.

  • Dipeptide four: Provides protection against environmental stress and oxidative damage.

  • Tetrapeptide 26: Regulates circadian rhythms to enhance UV defense during the day and DNA repair at night.

  • Hyaluronic Acid: Enhances skin moisture and water retention.

• Imapel Night Cream:

  • Contains $MEP$ technology and Niacinamide.

  • Vitamin A: Provided as Retinol and Hydroxypentacolone retinoate to reduce wrinkles and pigmentation.

  • Tetrapeptide 26: Aids in nightly rejuvenation and skin circadian rhythm.

  • Matrixyl 3000: A combination of Palmitoyl tripeptide one and Palmitoyl tetrapeptide seven; enhances cell proliferation and extracellular matrix renewal.

  • Moisturizing agents: Shea butter, grapeseed oil, and apricot kernel oil to improve the skin barrier.

Clinical Study on Combination Serum and Night Cream Use

• A study by Doctor Joel Cohen, published in the Journal of Drugs and Dermatology, evaluated $14$ postmenopausal women (ages $53 \text{ to } 68\,\text{years}$) over $20\,\text{weeks}$.

• Participants applied Imapel Serum in the morning and Imappel Night Cream in the evening.

• Age-Based Outcomes:

  • Younger participants (ages $53 \text{ to } 60$) showed significant improvement in approximately $8\,\text{weeks}$.

  • Older participants (over $60\,\text{years}$) required up to $20\,\text{weeks}$ for significant improvement.

• Scientific Implication: This suggesting that patients who have been amenorrhea longer have more dormant or lost estrogen receptors, requiring more time to rebuild the pathways and restore receptor population.

Targeted Periorbital Care: Imipal Eye Cream

• A study conducted by Doctor Joel Cohen and Doctor Janine Downey focused on $42$ postmenopausal women (ages $50 \text{ to } 65\,\text{years}$) using Imipal eye cream twice daily for $12\,\text{weeks}$.

• Visible improvement in periorbital skin was observed within $4\,\text{weeks}$.

• Key Ingredients of the Eye Cream:

  • $MEP$ Technology.

  • Caffeine: Enhances microcirculation to reduce puffiness.

  • Vitamin E: Protects against lipid peroxidation.

  • Argeroline: A peptide that combats wrinkles and oxidative stress.

  • Hyaluronic Acid: Provides essential hydration.

  • Persian silk tree and Horse chestnut extract: Improve circulation to target dark circles and puffiness.

  • Verbascum thaspis extract: Provides anti-inflammatory benefits.

• The strategy of Imapal products is to utilize complete formulas that address both the root cause of $\text{EDS}$ via $MEP$ as well as secondary concerns through established dermatological ingredients.