טפולים לא הורמונליים בגיל המעבר

?למי זה מתאים

?איזה טפולים קיימים

2017-ר יוסף מאי "ד

Treatment of Symptoms of the Menopause: An Endocrine Society Clinical Practice Guideline

•Cynthia A. Stuenkel, Susan R. Davis, Anne Gompel, Mary Ann Lumsden, M. Hassan Murad, JoAnn V. Pinkerton, and Richard J. Santen University of California, San Diego, Endocrine/Metabolism (C.A.S.), La Jolla, California 92093;

Monash University, School of Public Health and Preventive Medicine (S.R.D.), Melbourne 03004, Australia; Universite´ Paris Descartes, Hoˆ pitaux Universitaires Port Royal-Cochin Unit de Gyne´ cologie Endocrnienne (A.G.),

Paris 75014, France; University of Glasgow School of Medicine (M.A.L.), Glasgow G31 2ER, Scotland; Mayo Clinic, Division of Preventive Medicine (M.H.M.), Rochester, Minnesota 55905; University of Virginia, Obstetrics and

Gynecology (J.V.P.), Charlottesville, Virginia 22908; and University of Virginia Health System (R.J.S.), Charlottesville, Virginia 22903 Objective: The objective of this document is to generate a practice guideline for the management

and treatment of symptoms of the menopause. Participants: The Treatment of Symptoms of the Menopause Task Force included six experts, a methodologist, and a medical writer, all appointed by The Endocrine Society. Evidence:

The Task Force developed this evidenced-based guideline using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe the strength of recommendations and the quality of

evidence. The Task Force commissioned three systematic reviews of published data and considered several other existing meta-analyses and trials. Consensus Process: Multiple e-mail communications, conference calls, and one

face-to-face meeting determined consensus. Committees of The Endocrine Society, representatives from endorsing societies, and members of The Endocrine Society reviewed and commented on the drafts of the guidelines. The

Australasian Menopause Society, the British Menopause Society, European Menopause and Andropause Society, the European Society of Endocrinology, and the International Menopause Society (co-sponsors of the guideline)

reviewed and commented on the draft. Conclusions: Menopausal hormone therapy (MHT) is the most effective treatment for vasomotor symptoms and other symptoms of the

climacteric. Benefits may exceed risks for the majority of symptomatic postmenopausal women who are under age 60 or under 10 years since the onset of

menopause. Health care professionals should individualize therapy based on clinical factors and patient preference. They should screen women before initiating MHT for cardiovascular and breast cancer risk and

recommend the most appropriate therapy depending on risk/benefit considerations. Current evidence does not justify the use ofMHT to prevent coronary heart disease, breast cancer, or dementia. Other options are available for those with vasomotor symptoms who prefer not to use MHT or who have contraindications because these patients

should not useMHT. Low-dose vaginal estrogen and ospemifene provide effective therapy for the genitourinary syndrome of menopause, and vaginal moisturizers and lubricants are available for those not choosing hormonal therapy. All postmenopausal women should embrace appropriate lifestyle measures. (J Clin Endocrinol Metab

100: 3975–4011, 2015) ISSN Print 0021-972X ISSN O

חלון ההזדמנות של הטיפול ההורמונלי

טפול מקומי לנרתיק

•Topical non-hormonal options should be the first-line treatment in women with a history of

breast cancer, particularly those receiving tamoxifen or aromatase inhibitors. Women with breast cancer who do not respond to

non-hormonal treatment may consider vaginalestrogens after discussion with the woman’s

oncology team and menopause specialist.

טפולים לא הורמונליים לנרתיק

Vaginal bioadhesive moisturisers are a more physiological way of replacing vaginal secretions than vaginal gels such as K-Y GEL. They are

hydrophilic and rehydrate vaginal tissues, providing a reasonable alternative to vaginal estrogen. Lubricants should have similar osmolality and pH to that of physiological vaginal secretions.

GYNOMUNAL® VAGINAL GEL

NON- HORMONAL SAFE AND EFFECTIVE MANAGAMENT OF

VAGINAL ATROPHY ASSOCIATED SIGNS AND SYMPTOMS

Gynomunal Ingredients

Hyaluronic Acido Forms a moisturizing, non-sticky, invisible film

o natural support of epithelial formation

Vitamin E

o Lipid-soluble antioxidant concentrated in vaginal cell membranes

o Protects cell walls from free radicals damage

o Has anti-inflammatory properties

HOPS Extract(humulus lupulus

o Relief of pain and itching

Liposomes: Long –Lasting Vaginal Hydration

non-keratinized-אפיתל. 1 Epithel קרטיןללא שכבת ,.כמו בעור , קרןLamina-מתחתיה שכבה . 2 Propria ובה יש רשת ורידים

Venous, כוורת, דופןדקי Plexus ,וקצוות עצבים, ניקוז לימפה ./ העשרה . כלי הדם הנעשים גדושים בדם בזמן גירוי מיני

הלייזרהרחבה של רשת הורידים בעקבות Neovascularization לתת הסבר לשיפור עשויה

.Rejuvenationשל הנרתיק כ ,לובריקציה, הסיכוך

1+2 =Mucosa = Epithel + Lamina Propriaבתקופה המנופאוזה יכולה הרירית . מיקרון100-200כ

. מיקרון50לכלרדת

הקרובים סיבי רוחב מעגליים -Muscularis-שריר. 3ומחוצה להם סיבי (כטבעות סביב הנרתיק ) למוקוזהיותר יש . אין קו הפרדה ברור בין שתי שכבות סיבי השריר. אורך

כטבעת ) המעגלית(הצירקולריתהמגדירים את שכבת השריר ״ המייצר טונוס לנרתיק ויתכן שהשפעה עליו ספינקטר״

המונח מעליו ושליטה טובה לשופכןמייצרת תמיכה טובה יותר . יותר למתן שתן

Adventitia.4השכבה הפנימית של הנרתיק היא רקמת חיבור בלתי סדירה

. עושר כלי דם ועצבים, עם סיבים אלסטיים

FemiLift Single Use Hygienic Vaginal Probe:

Y. Tadir

Alma Laser

0 0+ 3 Months 6 Months

“Macro”: Vag. Rejuvenation

Process

H&E staining.Vaginal mucosa before treatment (a, c)and 2 months after treatment (b, c).

the atrophic mucosa (epithelium) is very thin, formed by few layers of cells, and the epithelial-connective Junction.

The epithelium appears much thicker, constituted by many layers with visible largeintermediate and shedding superficial cells.

The underlying connective tissue is providedwith papillae indenting the epithelial-connective junction.

Comparative microphotographs (before and 2 months after

treatment) of atrophic vaginal mucosa demonstrate striking structural recovery at two months after treatment in all the patients

(Paper #1)

Jan.2015

TWO PAPERS at the same time: Italy – (Using DEKA CO2 LASER)1. Microscopic and ultrastructural modifications of postmenopausal atrophic vaginal mucosa after fractional CO2 laser treatment. Zerbinati, et al. Laser Med. Sci.

Squamous Epitheium: Restoration, with a significant storage of glycogen in the epithelial cells.

lamina propria, active fibroblasts synthesized. New components of the extracellular matrix including collagen and ground substance (extrafibrillar matrix) molecules.

Differently from atrophic mucosa, newly-formed papillae of connective tissue in the epithelium and typical blood capillaries penetrating inside the papillae, were observed.

These findings clearly coupled with striking clinical relief from symptoms.

Jan.2015

2. An Ex. Vivo study: Salvatore, et al. Menopause.

חלופות לטיפול הורמונלי

טיפול לא תרופתיטיפול תרופתי

"(טבעי)"

טיפול תרופתי לא הורמונאליSSRI( ציפרלקס, סרוקסאט)

SNRI( ויאפקס, אפקסור)

GABAPENTIN (נאורונטין)

CIMIDONA (black Kohosh)

alternatives to HRTA recent meta-analysis of a few randomisedcontrolled trials has shown a marginal benefit of

clonidine (centrally-acting alpha adrenergic agonist) over placebo, for hot flushes.(25-50-75 mcg X2/d).

A significant amount of evidence exists for the efficacy of SSRI’s such as fluoxetine (prisma, flutin, prozac) and paroxetine (seroxate) in treating vasomotor symptoms; the most convincing data are for the SNRI (venlafaxine-efexor, viepax) at a dose of 37.5 mg bd in cancer survivors. The most common side effect, nausea, limits the usefulness of this agent

.

Powerpoint Templates Page 17

NICE

National Institute for Health and Care Excellence

הנחיות ועצות לשיפור שמספק גוף ציבורי בלתי תלוי הוא

.באנגליההמצב הבריאותי והסוציאלי

י מועצה בלתי תלויה של מומחים "ההמלצות שנכתבו ע

. מיועדות לכל סוגי היועצים הרפואיים ולמטופלים, בתחום

Recent high quality evidence shows

that selected antidepressants are

equivalent to very low dose estrogen

for vasomotor symptoms and sleep,

and gabapentin (anti-epileptic drug) has a

similar efficacy.

.

יעילות טיפולים תרופתיים לא הורמונליים

SeroxatEffexor XR Viepax XR

Cipralex

תופעות לוואי

"טבעי"ל יפוט

אסטרוגנים-פיטו

שחור-קוהוש

דיקור

Feb. 2015

OH

HO

Phytoestrogens

פיטואסטרוגנים

2014

2014

PhytoestrogensData from some of the better researched phytoestrogen

containing preparations appear to demonstrate some

benefits, not only for symptom relief, but also on the

skeleton and cardiovascular system.

Efficacy for vasomotor symptom relief is lower than with

traditional HRT (maximally 60% symptom reduction

compared to 90–100% with traditional HRT).

There are as yet no hard data on major outcome

measures such as coronary heart disease and fractures.

Soy food linked to prolonged survival in certain breast cancer patients

Zhang FF, et al. Dietary Isoflavone Intake and All-Cause Mortality in Breast

Cancer Survivors: the Breast Cancer Family Registry. Cancer. Published online

March 6, 2017. doi: 10.1002/cncr.30615Univadis08/03/20175 viewsNew research indicates that dietary soy products are safe and even beneficial for women diagnosed with breast cancer. Published online in the journal Cancer , the findings may help resolve the long-running debate surrounding soy’s potential link to breast cancer outcomes as a result of its oestrogen-like properties.

Isoflavones, the component of soy with oestrogen-like

properties, have been shown to slow the growth of breast cancer cells in laboratory studies, and epidemiological analyses in

women with breast cancer found links between higher isoflavone intake and reduced mortality.

The new study examined the relationship between dietary intake of isoflavones and death from any cause in 6,235 American and

Canadian women diagnosed with breast cancer. Over a median

follow-up of nine years, women with breast cancer who

consumed high amounts of isoflavones had a 21 per cent lower risk of dying than women who consumed low amounts. This decrease was largely confined to women with hormone receptor-negative tumours and women who were not treated with anti-oestrogen therapy. However,

other research has suggested that the isoflavones may reduce the effectiveness of hormone therapies for breast cancer.

In contrast, high isoflavone intake was not associated

with greater mortality among women receiving hormonal therapy.

Explain that there is some evidence that isoflavonesmay relieve vasomotor symptoms.

However,

explain that:

-Preparations vary

-The safety of different preparations is uncertain and

interactions with other drugs have been reported.

….specific phytoestrogen supplementations

(EXAMP: ALTERNA, MAGNOLIA) were

associated with modest reductions in the

frequency of hot flashes and vaginal dryness

but no significant reduction in night sweats.

Conclusions

Black Cohosh

קוהוש שחור

(Cimicifuga Racemosa)

אינדקסקופרמן

גלי : תסמיני גיל המעבר11מדד מספרי הבודק

, מלנכוליה, עצבנות, נדודי שינה, כאבים, חום

, כאבי מפרקים או כאבי שרירים, חולשה, סחרחורת

דפיקות לב ותחושה שחרקים זוחלים , כאבי ראש

(. (formicationלעור מעל או מתחת

והפרעות אורוגניטלייםבהמשך נוספו תסמינים

סימפטום מדורג על פי חומרת כל . ביחסי מין

3= אין סימפטומים ו= 0כאשר )סימפטומים

הציון . והסכום הכולל מחושב, (החמורים ביותר

.נקודות51המקסימאלי הוא

MRS – menopausal rating scale

psychological symptoms: 0 to 16 scoring points ( 4 symptoms: depressed, irritable, anxious, exhausted)

somato-vegetative symptoms: 0 to 16 points (4 symptoms: sweating/flush, cardiac complaints, sleeping disorders, joint & muscle complaints)

urogenital symptoms: 0 to 12 points (3 symptoms: sexual problems, urinary complaints, vaginal dryness).

RemifemineR

0

5

10

15

20

25

30

35

0 2 4 8 12

PLACEBO

REMIFEMINE

Weeks

Stoll W. Therapeutikon 1:23, 1987

=Black Kohosh

השפעה על תסמיני המנופאוזה

שחור-תכשירי קוהוש

A 2012 Cochrane review analyzed 16 RCTs of 2,027

perimenopausal or postmenopausal women treated with black

cohosh using a median daily dose of 40mg for a mean duration

of 23 weeks. There was no significant difference between

black cohosh and placebo in the frequency of hot flashes. Data

on safety were also inconclusive. The authors concluded that, at

this time, there is insufficient evidence to support the use of

black cohosh for menopausal symptoms. Level I evidence

Black Cohosh

Explain that there is some evidence that

black cohosh may relieve vasomotor

symptoms.

However,

explain that:

-Preparations vary

-The safety of different preparations is uncertain and

interactions with other drugs have been reported.

Selective ER modulators ?

Modulation of serotonergic pathways ?

Antioxidant and anti-inflammatory effects ?

סימידונה• Product characteristics:• Composition Active substance: Dry extract, from

Cimicifugae rhizoma (Black cohosh) Excipients: Povidone,cellulose microcrystalline, lactose monohydrate, magnesiumstearate, silica colloidal anhydrous, croscarmellose sodium.

• Information for diabetics : 1 tablet contains 0.004carbohydrate exchange units. The product containslactose (44 mg per tablet).

• Galenic Form and Active Substance per Unit: Tablet. 6.5mg dry extract (Ze 450) from Cimicifugae rhizoma der4.5 – 8.5:1, extraction solvent 60% ethanol (V/V).

• Indications: For the alleviation of complaints duringmenopause (hot flashes, excessive perspiration, sleepdisorders, nervousness and depressive moods).

שבועות12, נשים180

Black cohosh and fluoxetine in the treatment of postmenopausal symptoms: A prospective, randomized trial

Advances in TherapyMarch 2007, Volume 24, Issue 2, pp 448–461

•Authors Mesut Oktem•Derya Eroglu et al.

1.Department of Obstetrics and GynecologyBaskent University School of Medicine MaltepeAnkaraTurkey

2.Department of PsychiatryTurkey

The objective of this study was to evaluate the efficacy of fluoxetine and black cohosh in the treatment of women with postmenopausal symptoms. A total of 120 healthy women with menopausal symptoms were recruited to this prospective study with a follow-up period of 6 mo. They were randomly assigned to 1 of 2 groups and were treated with fluoxetine or black cohosh. After entry into the study, patients were examined at the first, second, third, and sixth months of the treatment period. The women kept diaries in which they reported the daily number and intensity of hot flushes and night sweats. In addition, at the beginning and end of the third month, they completed questionnaires consisting of a modified Kupperman Index, Beck’s Depression Scale, and a RAND-36 Quality-of-Life Questionnaire. Statistically significant differences were noted in the Kupperman Index and Beck’s Depression Scale at the end of the third month in both groups compared with baseline values. In the black cohosh group, the Kupperman Index decreased significantly compared with that in the fluoxetine group by the end of the third month. On the other hand, in the fluoxetine group, Beck’s Depression Scale decreased significantly compared with that in the black cohosh group. Monthly scores for hot flushes and night sweats decreased significantly in both groups; however, black cohosh reduced monthly scores for hot flushes and night sweats to a greater extent than did fluoxetine. At the end of the sixth month of treatment, black cohosh reduced the hot flush score by 85%, compared with a 62% result for fluoxetine. By the sixth month of the study, 40 women had discontinued the study—20 (33%) in the fluoxetine group and 20 (33%) in the black cohosh group.

Compared with fluoxetine, black cohosh is more effective for treating hot flushes and night sweats. On the other hand, fluoxetine is more effective in improvements shown on Beck’s Depression Scale.

1

Cimidona – excellent safety profile

Ze 450 – Study overview

47

Safety – Focus on the estrogen receptor

48

Cimicifuga extract Ze 450 showed in vitro an inhibition of proliferation in a MCF-7 human breast cancer cell line2

Henneicke-von Zepelin et al.4 were able to show by means of a pharmacoepidemiologic observational retrospective cohort study that

there is probably no higher risk for breast cancer recurrence for women having black cohosh treatment compared to untreated women

1Viereck, V. et al. TRENDS in Endocrinology and Metabolism (2005);16; 5: 214-221

2Garita-Hernandez, M. et al. PlantaMed (2006); 72: 317-323

3Burdette JE, et al. J Agric Food Chem (2003); 51: 5661-5670

4Rhuy MR, et al. J Agri Food Chem (2006); 54: 9852-9857

5Hui Z, et al. Journal of Ethnopharmacology(2012); 142;3: 769-775

Mode of action of Ze 450

49

Cimicifuga extracts do not have an estrogenic effect 1,2,3

There is a great body of evidence that Cimicifuga extracts have central (neuro-hormonal) effects 1,2,3,4,5

Several studies suggest a partial agonistic action at the serotonin receptors (5-HT), the dopamine receptor and the μ-opiate

receptor 3,4 – for the latter the clinical relevance is questionable

1Viereck, V. et al. TRENDS in Endocrinology and Metabolism (2005);16; 5: 214-221

The mode of action of Cimicifuga is not yet enlightened into detail

2Garita-Hernandez, M. et al. PlantaMed (2006); 72: 317-323

3Burdette JE, et al. J Agric Food Chem (2003); 51: 5661-5670

4Rhuy MR, et al. J Agri Food Chem (2006); 54: 9852-9857

5Hui Z, et al. Journal of Ethnopharmacology(2012); 142;3: 769-775

Schellenberg et al. 2012 – Summary

50

Ze 450 is a effective and well-tolerated non-hormonal alternative to HRT

Schellenberg R., Saller R., Hess L., Melzer J., Zimmermann C., Drewe J., Zahner C. Evidence-Based Complementary and Alternative Medicine (

Dose-dependent effect of Ze 450

Both, 6.5 and 13 mg decreased significantly the severity of climacteric symptoms in the total KMI, compared to placebo

For patients with severe symptoms (KMI > 34) only the high dose (13 mg Ze 450) was effective

General Quality of Life increased also dose dependently

Lopatka et al. 2007 – Reduction of the MRS II score

51

Overall MRS IIp < 0.0001

* MRS = Menopausal Rating Scale II

Already after one month, Ze 450 alleviates the menopausal symptoms reaching significance after 4 months of treatment

Drewe et al. 2013 – Observational long-term study

52

442 women, mean age 52.3 yrs., with menopausal complaints

9 months (3 + 6 months)

Treatment with 13 mg Ze 450/d for 3 months Further 6 months treatment either with 13mg/d or switch to 6.5 mg/d

1st : Changes in total Kupperman Index (KMI)2nd : Analysis of each subitem of the KMI

Drewe et al., Phytomedicine (2013)

Treatment of unselected patients with 13 mg or 6.5 mg Ze 450, under daily practice condition

Lopatka et al. 2007 – Improvement of the sub-items

53

Effect of Ze 450 on the MRS II sub-item score

Baseline

1 month

4 month

Ze 450 significantly reduces the severity of every symptom after four months of treatment

The improvement was indicated already after one month of treatment

Drewe et al. 2013 – Reduction of the KMI

54

Significant reduction of the Kupperman Index (KMI) after 3 and 9 months treatment

After 3 months treatment with 13mg Ze 450 the KMI was significantly reduced

The extension treatment further decreases the KMI significantly - independent of the dose

Baseline

HD (13 mg)

LD (6.5 mg)

n = 238 n = 131n = 372

Cimidona-נתוני בטיחות מהעלון לרופא

Ze450כל טבלייה מכילה במדויק את אותה כמות של החומר הפעיל בסימידונה•( השחורמהקוהושהממוצה )

לא צפויות אינטראקציות בין תרופתיות •

postנתוני מחקרים וכן מידע )GIמרבית תופעות הלוואי המדווחות הינן של •marketing מתוכן , ל"ת5.4%-מטופלות מעידים על אחוז של כ2800-שנאספו על כ

ויתר המקרים לא שויכו ספציפית לטיפול עם , היו קלות ולא דרשו הפסקת טיפול97%(סימידונה

:אך ההנחיות הן , מסימידונהלא דווחו מקרים חריגים של נזקים בכבד שנגרמו •

ידועהכבדיתמחלה /אין לתת למטופלות עם נזק–

צבע , חולשה ואובדן תאבון, עייפות חריגה:יש להפסיק מתן במקרים של –סימנים אשר עשויים להצביע –שתן או צואה כהים , צהוב בעור או בקרנית

על נזק כבדי

או אם יש , בחזהתחושת מתח יש להתייעץ עם רופא במקרים של תחושת נפיחות או •הכתמה דמית או דימום מחזורי , דימום

55.1Data on File – Zeller Safety Data

.2Cimidona PI as approved by the Israeli MOH

Efficacy of Ze 450 – Summary

56

Ze 450 dose dependently decreases the whole set of menopausal symptoms

Mild to moderate symptoms can successfully be treated with 6.5mg of Ze 450; severe symptoms can be treated with

13mg

Ze 450 reduces the symptoms already after one month; symptoms are decreased further with thecontinuation of the

treatment (6 weeks treatment recommended in the SPC)

Patients may successfully be switched from HRT to Ze 450

תודה על ההקשבה

COMPARISON OF NEW MINIMALLY INVASIVE ER:YAG LASER TREATMENT AND HORMONAL REPLACEMENT THERAPY IN THE TREATMENT OF VAGINAL ATROPHYGaspar Adrian (AR) [1][1] University of Mendoza

TITLE.AUTHOR/S.ABSTRACT.

Objective: The objective of this study was to comp are the efficacy and safety of two minimally invasive procedures for treatment of vaginal atrophy; a new Er:YAG laser procedure and hormonal replacement therapy with estriol. Method: 50 vaginal atrophy patients were randomly divided in two equal groups. Group A patients were

submitted to long term estriol therapy: 0.5 mgr/day 3 times a week during 2 weeks, followed with the same estriol dosage twice a week for 4 weeks. B group patients firstly got the same short term estriol

therapy for 2 weeks, followed with 3 sessions of ErYAG laser treatment, with 3 weeks interval between

the sessions. Therapy efficacy was measured using maturation value, pH value, VAS scores for atrophy

symptoms: Dyspareunia, Dryness, Irritation and Leukorrhea. On 6 patients from each group biopsies

were taken (before and 3 months post-op). Follow-ups were at 1 month, 3 months and 6 months after the therapy.

Results: Both groups showed improvement in atrophy, but laser therapy showed better and longer lasting effects. Maturation value in A group improved from 22,5 points to 24,7 points at 6 months follow-up. In comparison to that B group improvements was from 20,8 points to 47,9 points. pH value improved at 3 months for 7,2% in A group, and for 17,6% in B group. Dyspareunia in A group improved for 48%, and in B group for 72%; Dryness in A group for 68%, in B group for 76%; Irritation in A group for 48%, in B group for 60% and Leukorrhea in A group for 81%, while in B group for 94%. Both groups tolerated the therapy well and adverse effects were mild and transient.

Conclusions: Hormonal replacement therapy is considered to be the first choice for vaginal atrophy, but this new minimally invasive Er:YAG laser procedure seems to be safe and efficacious alternative with potential to offer to vaginal atrophy patients longer period of symptom free life.

58