THE EFFECTIVE, CUTTING-EDGE, HORMONE-FREE LASER TREATMENT FOR VULVOVAGINAL DISEASES

VULVOVAGINAL ATROPHY VAGINAL TIGHTENING (DESCENSUS VAGINAE) GENITOURINARY SYNDROME OF MENOPAUSE MILD STRESS The best alternative to hormonal therapy and surgery

. Most of the urogenital diseases connected with the menopause follow a reduction in the production of estrogen by the ovaries. This involves the gradual thinning of genital epithelial tissues, vaginal and vulvar mucosa, which reduce in thickness and moistness becoming more fragile, irritable and sensitive to trauma.

. Hormonal therapy has been for a long time the gold standard for postmenopausal symptoms. Urological symptoms such as Stress Urinary Incontinence deriving from childbirth and natural ageing process and affecting the pelvic floor structure have been historically treated by mean of surgery restoring the vaginal anatomy.

Juliet represents a minimally invasive, effective and hormone-free treatment option for all women who do not wish invasive and/or hormone based options.

MCL31 IV 100 0117 EN 2 Advantages in application and technology

Application Technology

. Fast, painless, discreet and easy to use . Er:YAG wavelength for best results and less side effects

. No anesthesia necessary . Ablative and sub-ablative mode (thermal mode)

. No surgery, minimal downtime . More than 2,000 Er:YAG lasers worldwide

. No risk for infection or bleeding . Over 15 years experience in Erbium technology

MCL31 IV 100 0117 EN 3 Device specifications

Laser: MCL31 Dermablate (Er:YAG), Class 4

Wavelength: 2,940nm

Fluence: Max. 250 J/cm²

Pulse duration: 100 – 1,000 µs

Frequency : 1 – 20 Hz

Modes: Gyn C, Gyn W, Ablation, Therm, MicroSpot

Handpieces Gyn: Steri-Spot, V-Spot 90°*, V-Spot 360°*

Additional handpieces: MicroSpot*, VarioTEAM*

Dimensions: 36 x 60 x 93 cm (W x D x H)

Weight: Ca. 75 kg

* optional

MCL31 IV 100 0117 EN 4 Why an Erbium:YAG Laser

100000

10000

1000 Deoxyhemoglobin

] -1 100 Water Protein

10 Melanin

1

Oxyhemoglobin 0.1

Absorption[cm Coefficient

0.01

Scattering 0.001

0.0001 100 200 300 400 500 1000 2000 3000 4000 5000 10000 Wavelength [nm] MCL31 IV 100 0117 EN 5 Why an Erbium:YAG Laser

Tissue

Ablation (Vaporisation) Heating

Er:YAG Necrosis CO2

Er:YAG Laser CO2 Laser

2,940nm: water absorption peak Lower water absorption

Ablation layer by layer Deep, uncontrolled ablation

Controlled thermic effect, Uncontrolled thermal effect, no thermal damage necrosis areas Cold ablation possible No cold ablation possible

MCL31 IV 100 0117 EN 6 Intravaginal handpieces

V-Spot*

With 90° reflecting gold-coated With 90° or 360°reflecting gold-coated mirror, for SINGLE USE mirror, for MULTIPLE USE

Handpiece Optic for Handpieces Optic for Steri-Spot V-Spot * optional MCL31 IV 100 0117 EN 7 Additional handpieces

MicroSpot* VarioTEAM*

Fractional handpiece Ablative handpiece with 13x13 mm spot and variable cover rate with variable spot size 1-6 mm

for the treatment of the vulva, it allows for a for different ablative treatments complete therapy of vulvovaginal disorders in the vulvar area * optional MCL31 IV 100 0117 EN 8 Micro-Spot Technology

. Squared spot of 9 x 9mm, consisting of 169 MicroSpots

. MicroSpot optic with stable and precise micro lens array technology

. Selective treatment of only “fractions” of the tissue in the form of a grid

. Triggers skin renewal and collagen formation with rapid wound healing supported by the untreated skin

. Very low risk of side effects

Laser beam entrance

Pattern on the Micro lens array Fractional laser beam treated area

MCL31 IV 100 0117 EN 9 Variable pulse length

. The adjustable pulse length allows for both cold ablative and thermal treatment

. This maximizes the results reducing the amount of sessions to two

EPITHELIUM

LAMINA PROPRIA

MAZ* MAZ* MAZ*

GYN C GYN W Pulse length 300 µs 1,000 µs

Effect on the tissue Cold ablation Sub-ablative thermal treatment

MCL31 IV 100 0117 EN 10 * MAZ = Microscopic ablation zone by Dr. Bettina A. Buhren & Dr. Peter A. Gerber, Hautklinik Düsseldorf Indications

1. Vulvovaginal Atrophy

. Women undergoing menopause often experience a number of symptoms including vaginal dryness, itching, painful intercourse, poor lubrication, decreased libido and poor vaginal muscle elasticity and tone

. This condition is also described as Vaginal Atrophy and it follows a reduction in the production of estrogen by the ovaries and is found in 10-40% of post-menopausal women. It involves the gradual thinning of genital epithelial tissues, vaginal and vulvar mucosa, which reduces in thickness and becomes more fragile, irritable and sensitive to trauma

. Women with untreated vaginal atrophy often suffer from vaginal paresthesia, a feeling of dryness, itching, burning and even pain during sexual intercourse and can be a contributing factor in urinary incontinence and for many women leads to an overall lack of quality of life

Premenopausal vaginal tissue Postmenopausal vaginal tissue

MCL31 IV 100 0117 EN 11 Indications

2. Vaginal Tightening (First-degree Descensus Vaginae)

. Descensus of the vagina occurs when, due to factors like vaginal births, weakness of the connective tissue, heavy physical work, ageing processes and hormone deficiencies, the pelvic floor tissue slackens, leading to a bulging of the vaginal walls

. The mild descensus of the vagina is often experienced as an excessively wide vagina and most women refer to it complaining a loss of vaginal tightness

. This is directly related to reduction in friction during intercourse and thus to a decrease or loss of sexual gratification.

Normal vagina Enlarged vagina

MCL31 IV 100 0117 EN 12 Indications

3. Genitourinary Syndrome of Menopause (GSM)

. The term Genitourinary Syndrome of Menopause* refers to a complex of symptoms, which are essentially caused by the post-menopausal hormone deficiency described in case of vaginal atrophy

. GSM is chronic, if not treated it advances and can interfere with the quality of life

. It is estimated that one in two women in menopause is affected by this complex of life-quality-impairing disorders such as vaginal dryness, burning, paresthesia, restricted capacity for sexual pleasure due to decreased lubrication or even pain during intercourse, as well as , and repeated bladder infections.

. Genital symptoms: vaginal dryness, burning, irritation

. Sexual symptoms: poor lubrication, dyspareunia

. Uro-gynecological symptoms: urgency, urge incontinence, dysuria

*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. Portman et al., Menopause. 2014 Oct;21(10):1063-8.

MCL31 IV 100 0117 EN 13 Indications

4. Mild Stress Urinary Incontinence

. The term Stress Urinary Incontinence (SUI) refers to the involuntary loss of urine during coughing, sneezing or physical exertion. The underlying cause of this condition is often the decreased stability of the connective tissue and a loss of support of the urethra

. It is a quite widespread disease prevalent in women after their first birth (24% to 29%) and in women undergoing menopause because of the reduction in estrogen production. Similarly, frequent exercise in high-impact activities can cause athletic incontinence to develop

. Women with Stress Urinary Incontinence have an altered connective tissue metabolism, which causes decreased collagen production and which may result in insufficient support of the urogenital tract.

Normal pelvic floor muscle Weak pelvic floor muscle

MCL31 IV 100 0117 EN 14 Mechanism of action

. Juliet is a minimally invasive treatment, the goal of which is to restore the original metabolism of connective tissue by stimulating new collagen production

. As a result of laser irradiation the intermolecular crosslinks of the triple helix of collagen shorten, which leads to the immediate tightening of collagen fibrils by two-thirds of their length

. This leads to an improvement in the condition of the vaginal skin and in the tone of the pelvic muscle, strengthening the vaginal tissue that contributes to support of the interior tissue and wall

. The inner mucosa regains elasticity and lubrication, showing improved thickness and softness

MCL31 IV 100 0117 EN 15 Mechanism of action

The wall of the vagina is composed of the following layers:

. Epithelium: internal lining of epithelial tissue made up of squamous epithelial cells . Lamina propria: connective tissue that supports the mucosa and connects it with the muscularis . Muscularis: muscle tissue . Adventitia: connective tissue interlaced with elastic fibers, attaches the vagina to surrounding organs

Objective of the laser treatment is to reach the Lamina propria, elastic and rich in collagen that can be stimulated.

MCL31 IV 100 0117 EN 16 Mechanism of action

. This action continues its beneficial effect even after the treatment is finished: for this reason, many women report further improvements during the first months post-treatment

Phase I Phase II Phase III 48 – 72 h 1 Month After 1 month

. Early thermal effect . Proliferation . Remodeling . Edema, collagen and elastin . Formation of new collagen . New vascularization, shrinking fibers Improved lubrication

MCL31 IV 100 0117 EN 17 Mechanism of action

. There are indications in the scientific literature that vaginal laser therapy can lead to an improvement in symptoms of atrophy. Histological studies by Prof. R. Milani of Monza, Italy have already shown how the vaginal epithelium regenerates following laser therapy and further clinical observations support this rationale

. The rationale for applying laser treatment for mild descensus of the vagina, which is often experienced as an excessively wide vagina and can lead to a decrease in sexual pleasure for a couple, is that it tightens the connective tissue and improves blood circulation in the vaginal epithelium

. Clinical observations, according to which an improvement of continence occurs following Erbium laser treatment of the vagina, suggest that here a regeneration of connective tissue results in improved urethral closure

MCL31 IV 100 0117 EN 18 Preparation & Aftercare

. Inclusion criteria: normal cell cytology (PAP smear), negative urine culture, vaginal canal, introitus and vestibule free of injuries and bleeding

. Exclusion criteria: pregnancy, injury or/and active infection in the treatment area, undiagnosed vaginal bleeding and active menstruation, intake of photosensitive drugs

. Immediately before the laser treatment: the patient’s vagina (vestibule, introitus and vaginal canal) must be thoroughly washed and the disinfecting solution carefully dried off and removed from the mucosa

. After the laser treatment: No special post-op therapy needed. No sexual activities for a period of 72 hours after each of the treatment sessions.

. Cave: with a history of genital herpes for the prevention assign velacyclovir in standard dose for three days before and after the procedure.

MCL31 IV 100 0117 EN 19 Dual-phase treatment concept

The intravaginal Juliet treatment consists of 2 phases: . firstly an ablative phase, whose goal is to drill very small holes in the superficial layers of the mucosa by mean of a mechanical effect; . secondly, a thermal phase, whose goal is to produce a thermal effect, reaching the collagen fibers in the lamina propria and stimulating the collagenogenesis. The two phases are performed one immediately after the other.

MCL31 IV 100 0117 EN 20 Phase 1: Ablative fractional mode

• Insert the handpiece in the vagina to the cervix/vaginal vault (7 to Mode Gyn C 10cm) with the mirror in the upward position Handpiece Steri-Spot or V-Spot 90° • Perform the treatment by rotating the handpiece by 45⁰ (line to line) between laser pulses Fluence 15 – 35 J/cm2 * • When the of 360⁰ rotation is completed (8 pulses), withdraw the Pulse duration 300 µs handpiece 1 cm Interval 0.5 - 2 s (according user’s experience) • Repeat the process until the 2cm indicator on the handpiece is visible ° outside of the vagina Rotation angle 45 (line to line)

* depending on the severity of the condition; general rule is: the thinner the vaginal skin, the lower the fluence MCL31 IV 100 0117 EN 21 Phase 2: Thermal mode

• Re-insert the handpiece in the vagina to the cervix/vaginal vault (7 to Mode Gyn W 10cm) with the mirror in the upward position Handpiece Steri-Spot or V-Spot 90° • This time, perform the treatment by rotating the handpiece by 22.5⁰ (line and dot) between laser pulses Fluence 6 – 12 J/cm2 * • When the of 360⁰ rotation is completed (16 pulses), withdraw the Pulse duration 1,000 µs handpiece 0.5cm Interval 0.5 - 2 s (according user’s experience) • Repeat the process until the 2cm indicator on the handpiece is visible ° outside of the vagina Rotation angle 22.5 (line and dot)

* depending on the severity of the condition; general rule is: the thinner the vaginal skin, the lower the fluence MCL31 IV 100 0117 EN 22 Phase 3: Treatment of vestibule and introitus area

• Treat the area with single spot technique Mode N25% • Perform 1 to 3 passes according to patient’s condition* Handpiece MicroSpot handpiece • Local anesthesia (e.g. Pliaglis from Galderma) is recommended in case Fluence 15 – 30 J/cm2* of hypersensitive patients Pulse duration 300 µs Interval 0.5 - 2 s (according user’s experience)

N25% Mode

4

N25 8 Hz 70 µm

* depending on the severity of the condition; general rule is: the thinner the vaginal skin, the lower the fluence MCL31 IV 100 0117 EN 23 Clinical results

International studies show the efficacy of the Erbium:YAG technology

The Juliet procedure is performed by the MCL31 Dermablate Erbium:YAG laser system. At 2,940 nm, the laser is at the peak for water absorption. And, with the ability for both short and long pulses, studies show that it is more effective than other options.

. Over 1,000 patients showed excellent improvement with a high level of patient satisfaction (97%) and no adverse effects. Average pelvic floor muscle pressure improved by 60%, vaginal canal shrinkage by 17% and almost 70% of urinary incontinence patients were dry after 120 days(1).

. In a study of 70 patients, Er:YAG achieved better and more long-lasting results than the CO2 treated ones. Patient (2) discomfort during the treatment, as well as in the post-op period, was significantly higher in the CO2 group .

. In a study of 37 patients, 100% of patients reported, 6 months after the treatment, improvement in vaginal tightness. 84% reported better sex. In addition, 84% of patients affected by SUI reported significant improvement in the Q-tip test score(3).

1 Saraçoğlu, F. (2013). Overview of Cosmetic Gynecology, LA&HA, Vol. 2013, (1) 2 Gaspar, A. (2013). Evolution of minimally invasive laser treatments for Vaginal Atrophy. LA&HA, Vol. 2013, No 1. 3 Leshunov EV, Martov AG. (2015). Application of laser technologies for treatment of urinary in women of reproductive age. 2015 Jan-Feb;(1):36-40.

MCL31 IV 100 0117 EN 24 Clinical results

Histological preparation Hematoxylin & Eosin - SETTINGS: Fluence 20 J/cm2 | Pulse duration 300 µs (GYN C)

The sample at day 0 shows an altered epithelium stratification with presence of cornification and superficial areas, characterized by very low cellularity.

The epithelium appears atrophic and a flattening of the dermal papillae at the dermo-epidermal junction can be recognized.

100 µm

Day 0 – before the treatment

Pictures by courtesy of: University of Milano-Bicocca, San Gerardo Hospital, Monza, Italy - Department of Obstetrics and Gynecology, Chief Prof. Rodolfo Milani

MCL31 IV 100 0117 EN 25 Clinical results

Histological preparation Hematoxylin & Eosin - SETTINGS: Fluence 20 J/cm2 | Pulse duration 300 µs (GYN C)

At day 7 (after one treatment) the pavement epithelium appears well organized, with compact structure and presence of several nuclei, both in the deeper and superficial layers.

The depth of the dermal papillae appears moreover increased, showing good tissue vitality.

100 µm

Day 7 – after 1 treatment

Pictures by courtesy of: University of Milano-Bicocca, San Gerardo Hospital, Monza, Italy - Department of Obstetrics and Gynecology, Chief Prof. Rodolfo Milani

MCL31 IV 100 0117 EN 26 Clinical results

Histological preparation Hematoxylin & Eosin - SETTINGS: Fluence 20 J/cm2 | Pulse duration 300 µs (GYN C)

100 µm 100 µm Day 0 – before the treatment Day 7 – after 1 treatment

Pictures by courtesy of: University of Milano-Bicocca, San Gerardo Hospital, Monza, Italy - Department of Obstetrics and Gynecology, Chief Prof. Rodolfo Milani

MCL31 IV 100 0117 EN 27 Clinical results

Two-photon microscopy image Hematoxylin & Eosin - SETTINGS: Fluence 20 J/cm2 | Pulse duration 300 µs (GYN C)

Day 0 – before the treatment Day 7 – after 1 treatment

split epithelium with few and multilayered well organized epithelium pyknotic nuclei with presence of nuclei Pictures by courtesy of: University of Milano-Bicocca, San Gerardo Hospital, Monza, Italy - Department of Obstetrics and Gynecology, Chief Prof. Rodolfo Milani

MCL31 IV 100 0117 EN 28 Clinical results

Polarized light microscopy image Hematoxylin & Eosin - SETTINGS: Fluence 20 J/cm2 | Pulse duration 300 µs (GYN C)

30 days after 1 treatment Neocollagenogenesis and Angiogenesis processes are still visible; a re-gained uniformity of the tissue is the evidence of efficient tissue regeneration.

In addition, the new collagen formation can be recognized through the white stripes visible in the deeper layers.

200 µm

Day 30 – after 1 treatment

Pictures by courtesy of: University of Milano-Bicocca, San Gerardo Hospital, Monza, Italy - Department of Obstetrics and Gynecology, Chief Prof. Rodolfo Milani

MCL31 IV 100 0117 EN 29 Clinical results

Polarized light microscopy image Hematoxylin & Eosin - SETTINGS: Fluence 20 J/cm2 | Pulse duration 300 µs (GYN C)

200 µm 200 µm

Day 7 – after 1 treatment Day 30 – after 1 treatment

Pictures by courtesy of: University of Milano-Bicocca, San Gerardo Hospital, Monza, Italy - Department of Obstetrics and Gynecology, Chief Prof. Rodolfo Milani

MCL31 IV 100 0117 EN 30 Bibliography

Application of laser technologies for treatment of urinary stress incontinence in women of reproductive age E.V. Leshunov, A.G. Martov (2015) Urologiia, Jan-Feb;(1):36-40.

Female intimate surgery: review of methods and trends Ya.A. Yutskovskaia, E.V. Leshunov, V.D.Trufanov

Efficacy of Erbium:YAG laser treatment compared to topical estriol treatment for symptoms of genitourinary syndrome of menopause. A. Gaspar, H. Brandi, V. Gomez, D. Luque (2016) Lasers Surg Med. Aug 22.

Genitourinary syndrome of menopause: an overview of clinical manifestations, pathophysiology, etiology, evaluation, and management. J. Gandhi, A. Chen, G. Dagur, Y. Suh, N. Smith, B. Cali, S.A. Khan (2016) Am J Obstet Gynecol. Dec;215(6):704-711

Evolution of minimally invasive laser treatments for Vaginal Atrophy A. Gaspar (2013) LA&HA, Vol. 2013, No 1.

Genitourinary syndrome of menopause and the use of laser therapy J. Hutchinson-Colas, S. Segal (2015), Maturitas, Dec;82(4):342-5.

Rationale and design for the Vaginal Erbium Laser Academy Study (VELAS): an international multicenter observational study on genitourinary syndrome of menopause and stress urinary incontinence M. Gambacciani, M. G. Torelli, L. Martella et al. (2015), Climacteric, 18:sup1, 43-48

Vaginal erbium laser: the second-generation thermotherapy for the genitourinary syndrome of menopause M. Gambacciani, M. Levancini & M. Cervigni (2015), Climacteric, 18:5, 757-763.

MCL31 IV 100 0117 EN 31 Bibliography

Laser Vaginal Tightening (LVT) – evaluation of a novel noninvasive laser treatment for vaginal relaxation syndrome E. Jorge, P. Gaviria, A. Jose, L. Lanz (2015), J. LAHA, Vol. 2012, No.1; pp. 59-66.

First assessment of short-term efficacy of Er:YAG laser treatment on stress urinary incontinence in women: prospective cohort study N. Fistonić, I. Fistonić, A. Lukanovič, Š. Findri Guštek, I. Sorta Bilajac Turina & D. Franić (2015), Climacteric, 18:sup1, 37-42.

Minimally invasive laser procedure for early stages of stress urinary incontinence (SUI) I. Fistonić, Š. Findri Guštek, N. Fistonić (2012), J. LAHA, Vol. 2012, No.1; pp. 67-74.

Treatment of Vaginal Relaxation Syndrome with an Erbium:YAG Laser Using 90° and 360° Scanning Scopes: A Pilot Study & Short-term Results L. Min Seok (2014), Laser Ther. Jul 1;23(2):129-38.

Novel Minimally Invasive VSP Er:YAG Laser Treatments in Gynecology Z. Vizintin, M. Rivera, I. Fistonić, et al. (2012), J. LAHA, Vol. 2012, No.1; pp. 46-58.

Erbium laser in gynecology Z. Vizintin, M. Lukac, M. Kazic & M. Tettamanti (2015) Climacteric, 18:sup1, 4-8.

A minimally invasive treatment method for lichen sclerosis E.V. Leshunov, I.V. Kvach, Ya.A. Yutskovskaya

MCL31 IV 100 0117 EN 32 www.juliet-laser.com