yerevan state medical university department of obstetrics

Yerevan State Medical University Department of Obstetrics and

Gynecology

Climacterium and Menopause Assoc. Prof. Syuzanna Babloyan

Thank you !

HORMONE REPLACEMENT THERAPY (HRT)Evidence-based

Guidelines

Dr Mahdy El- Mazzahy Damietta general Hospital

7th International Annual Congress “Alexandria” 12- 2002

Introduction• HRT does not suit everyone. • Each woman needs to be aware of the

benefits and potential risks of HRT (pros and cons) so that she can make an informed decision.

• Our duty as clinicians is to ensure that women are provided with consistent and up-to-date information

HRT and Menopausal Symptoms

VASOMOTOR HOT FLUSHES includes night sweats

Grade A• HRT is an effective treatment for

hot flushes

• Tibolone is effective for alleviating the severity and reducing the frequency of hot flushes

N.Z Guidelines May 2001N.Z Guidelines May 2001

VASOMOTOR HOT FLUSHES (includes night sweats)

Grade B• Unopposed estrogen may be effective

for reducing the waking episodes that are associated with sleep disruption.

• There is no evidence that HRT is effective for vasomotor symptoms such as headaches and dizziness.

N.Z Guidelines May 2001

Vaginal atrophy

Grade A• Low dose topical estrogen is an

effective treatment• E3 (estriol) therapy is also effective but

requires either the addition of progestogen or close monitoring of the endometrium

• Tibolone has been shown to be effective for vaginal atrophy


PSYCHOLOGICAL SYMPTOMS• These include

depression, mood changes, anxiety, irritability, loss of libido, lack of energy and memory loss.

PSYCHOLOGICAL SYMPTOMS

Grade A• Estrogen is not an effective treatment

in elderly women with established Alzheimer's disease

• The addition of low doses of androgens to HRT provides relief in women with either a premature or surgical menopause who suffer from low libido ( for <2 years).



Grade A• Tibolone is effective in providing

relief from low libido in postmenopausal women

• Estrogen replacement therapy is not an effective treatment for loss of libido in postmenopausal women. N.Z Guidelines May 2001


There is insufficient or inconsistent evidence that HRT

1. Improves measures of cognition

2-Prevents or delays the onset of Alzheimer's disease

3-Elevates mood or relieves depression

HRT and risk of cancer

• Continuous combined HRT was associated with an increased breast cancer risk if used for four years or more

• However this increased risk dissipates quickly once use is discontinued.

(NICHD) study November 29,2002. (WHI) July 2002

RISK OF BREAST CANCER

RISK OF BREAST CANCER

• Inspite of an increased risk of breast cancer diagnosis, the mortality from breast cancer is unchanged

. (WHI) July 2002

RISK OF ENDOMETRIAL CANCER

Grade A• Unopposed estrogen therapy should

not be used in women with a uterus because of an increased risk of endometrial cancer.

• Women who have had a hysterectomy may take unopposed estrogen therapy

RISK OF ENDOMETRIAL CANCER

A• Combined continuous

regimens offer better protection of the endometrium than sequential regimens.

• N.Z Guidelines May 2001

RISK OF OVARIAN CANCER

Grade A• There is no conclusive

evidence that combinedregimens HRT either increases or decreases the risk of developing ovarian cancer.


RISK OF OVARIAN CANCER

• Researchers from the National Cancer Institute (NCI) have found that women in a large study more than 44000 women who used estrogen replacement therapy after menopause were at increased risk for ovarian cancer.

July 2002 JAMA

HRT and Osteoporosis

The silent killer

HRT and OsteoporosisGrade A

• HRT and Bisphosphonates has positive effects on bone density in postmenopausal women whether or not they have osteoporosis


HRT and OsteoporosisGrade B

• Maintaining HRT use decreases the risk of vertebral and non-vertebral fractures in women after surgical menopause ,early postmenopausal women and in women with established osteoporosis

HRT and OsteoporosisGrade B

• Selective Estrogen Receptor Modulators (SERMs) may be useful in the prevention of vertebral fractures in women who cannot use HRT or bisphosphonates.

• N.Z Guidelines May 2001

ACOG issues New Recommendations On SERMS

• ACOG recommends Raloxifene in the prevention of osteoporosis in women at risk for the disease, and in the prevention of bone fractures in women who already have osteoporosis

• ACOG recommends that SERMS can not be used in women with a history of blood clots.

• SERMS increase vaginal dryness and hot flashes.

ACOG. October,2002

•HRT and cardiac risk

HRT and cardiac risk

• Unlike earlier observational studies that suggested the possibility of some protection against heart disease, recent studies showed a small but significant increased risk of non-fatal heart attacks

HRT and cardiac risk• The Heart and Estrogen Replacement

Study (HERS) is the first published randomized placebo controlled study of HRT in 2763 women with established coronary artery disease (HERS I 1998)

• (HERS II) is follow up study of HERS I the report was published in the July 2002 issue of The Journal of the American Medical Association (JAMA).

HRT and cardiac riskHERS II trial results confirm the

initial findings of HERS I• increased risk of coronary events

in the early years of treatment • increase in thromboembolic

events in the HRT group compared with placebo mainly seen in the first year of use

HRT and cardiac riskGrade B

• HRT is contraindicated for secondary prevention of further coronary disease because of lack of documented efficacy and a possible early excess mortality.

the Women's Health Initiative (WHI)study

• This randomized controlled trial examined the risks and benefits of long-term combined HRT use in 16.608 asymptomatic postmenopausal women compared to the placebo group

• The trial has been halted prematurely, after 5. years of an 8-year study, due to an increased risk of invasive breast cancer. .

July 2002 JAMA

The Women's Health Initiative (WHI) Study

• The another WHI trial on estrogen use alone is continuing, because of no increased risk for breast cancer in this study.

• The report was published in the July, 2002, issue of JAMA

The key findings after five years / 10,000 women per year

• Breast cancer increased from 30 to 38 cases ( did not appear in the first four years of use).

• Coronary heart disease increased from 30 to 37 cases (appeared in first year of use )

• Stroke increased from 21 to 29 cases (were greatest during the first 2 years )

• Blood Clots: increased from16 to 34 cases

July 2002 JAMA


The benefits were • A reduction in colorectal cancer from

16 to 10 casesThe reduced risk of colorectal cancer emerged after 3 years

• Hip fracture (reduced from 15 to 10)

July 2002 JAMA


New Study of the National Institute of Child Health and Human Development (NICHD)

November 29, 2002

• Unlike the WHI, this study looked at pill

and patch hormone users as well as

several types of hormone regimens in

3,823 postmenopausal women

ACOG. November 29,2002

New Study of the National Institute of Child Health and Human Development (NICHD)

Results were consistent with the recent Women's Health Initiative

• Continuous combined HRT was associated with an increased breast cancer risk if used for five or more years.

• no association between breast cancer risk and the regimens of either estrogen-alone or sequential HRT .

• However, the study found this increased risk dissipates quickly once use is discontinued.

ACOG. November 29,2002

ConclusionAn Important Note: Research Continues, Recommendations

May Change

1-HRT is not recommended for routine use in the menopause.

2-HRT must be used for as short a time as possible with lowest effective dose .

ACOG. August,2002

Conclusion (cont.)3- The results of the WHI study confirm

what is already known about the long-term risks of HRT, including breast cancer and venous thromboembolism.

4-HRT has not been proven to be beneficial in primary and secondary prevention of coronary heart disease in fact may result in a small increased rate of CHD.

Conclusion (cont.)

5-ACOG continues to recommend that decisions regarding HRT therapy must be made between the woman and her physician on an individual basis.

6- HRT is the most effective treatment of menopausal symptoms .

ACOG. July, 2002

Conclusion (cont.)

7-For patients with osteoporosis, other preventive therapies such as bisphosphonates and SERM are available. However, for women at risk of osteoporosis who also have vasomotor menopausal symptoms, HRT can be of benefit . . ACOG. August,2002

MenopauseMenopause – is a time of

cessation of ovarian function and amenorrhea.

Hormonal characteristics of menopause

•↑ Honadotropins•↓ Oestrogens

Symptoms of MenopauseI group:

• Psychological (irritability, depression, insomnia, lack of concentration, fatigue, ↓ libido)

• Circulatory (hot flushes, sweating, headache, hypotonia, hypertonia, chills).

II group:

• Urogenital (dryness of vagina, dyspareunia, dysuria, stress incontinence)

• Skin changes (dryness of skin, wrinkles, hair loss)

III group (late symptoms)

• Osteoporosis

• Cardiovascular accidents

Management of menopause

• Lifestyle• Diet• Vit. A, E, C• Tranquilizers• Phyto-oestrogens• Biphosphonates• HRT (hormone replacement therapy) – short-

and long- therm estrogen therapy

Contraindications for HRT

• Tumour of uterus, ovaries, breasts• Unexplained uteral bleeding• Acute thrombophlebitis• Thromboembolic disease• Hepatic and renal disfunction• Diabetes mellitus

Investigations before HRT

• USI of genitalia, breasts• Pap smear• General examination (BP, blood

sugar, lipid profile, coagulation tests)

Premenstrual syndrome (PMS) (Premenstrual tension)

Symptom complex recognized by cyclic changes associated with ovulatory cycles.

PMS•Occurs prior to menstruation (lutheal stage of M.c.)•Alters daily activity

Types of PMS

• Neuropsychological• Fluid retention• Headache• Stroke

Rare types of PMS• Hyperthermy• Ophthalmoplegy• Cyclic bronchial asthma• Cyclic vomiting• Cyclic stomathitis

Aetiology• ↑ oestrogens, ↓progesterone• ↑ progesterone (hyperactivity of

corpus luteum)• ↑ prolactine• ↑ Vasopressin• ↑ aldosterone• ↓ serotonin (action on CNS)

Clinical featurespsychological disturbances

• Depression• Emotional lability• Irritability• Anxiety• Hostility

Physical symptoms

• Breast tenderness• Abdominal bloating• headache• Weight gain• Fluid retention

General symptoms• Fatigue• ↑ appetite• ↑ craving for some food• Alteration of libido• Disturbances of sleeping• Lack of concentration

Treatment• Lifestyle• Diet• Vitaminotherapy (Vit B group, E), mineralotherapy (Ca drugs, Mg

drugs)• Diuretics• Selective serotonin reuptake inhibitors (SSRI)• Anxiolytics, antidepressants• Dopamine agonist• Hormonal therapy:

oMicronized progesteroneoDanazoloGnRH analoguesoCombined oral contraceptives (coc)

Polycystic ovarian syndrom and hyperandrogenic

anovulationYerevan State Medical University

Department of Obstetrics and GynecologyAssoc. Prof. - Syuzanna Babloyan

Thank you !

SERMs - Prof.S.N.Panda - 45th. AICOG 1

What is behind these beautiful women?

Estrogen


That Nourishes & Nurtures

womanhood

The Feminine Hormone Estrogen

But Estrogen is an ambivalent steroid hormone, erratic,

inconsistent & mercurial in behavior.


Effects of Estrogen at Various Sites in the Body

Tissue Effect of Estrogen Stimulation

Clinical Effect of Stimulation

Clinical Effect of Absence of Stimulation

Bone Increased deposits of calcium into bone

Increased bone density Osteoporosis

Brain Blocks the release of ovarian estrogen

None Hot flashes, sleep disorders, mood changes, problems with memory? Alzheimer’s disease??

Breast Stimulates growth of breast tissue Bigger breasts,? Increased

risk of breast cancer, increased sensitivity of the breast,

Smaller breasts

Blood Clotting Increased risk of blood clots No change in clotting

Blood Fats Increased HDL, decreased LDL, decreased Cholesterol,

Decreased HDL, increased LDL, increased Cholesterol

Skin Increased fat deposits in skin Softer skin Thinner skin, liver spots, dry skin

Uterus Increased stimulation of uterine lining and muscle

Heavier cycles, increased risk of uterine cancer

No periods

Vagina Increased thickening of skin, better blood supply to tissue

Vaginal discharge, feelings of pelvic congestion

Dryness, vaginal infections, painful sex, incontinence of urine, pelvic weakness


Molecular Action of Estrogen

Adopted from George et al

hsp90 – heat shock protein90



Adopted from Stanley J Birge et al

AP I – activator proteinCRP – co regulator proteinER – estrogen receptorERE – estrogen response elementPoly II – polymerase IITATA- adenine-thymine-rich sequence important for gene transcription


Estrogen Receptor

Two types have been so far identified : - α and β


Illustration by Anne Erickson


Estrogen Receptor Distribution

• α & β -CNS, blood vessels, bone, heart, breast, ovary, uterus, testes, prostate

• α - Liver• β - Lungs, kidney, bladder,

intestines

Adopted from George GJM Kuiper et al

* Based on the level of ER mRNA levels * Awaits confirmation till subtype specific

monoclonal antibodies are available




• α homodimer• β homodimer• α & β heterodimer• Non-genomic effects

Adopted from George GJM Kuiper et al

Alternating estrogen signaling pathways


Molecular Action of EstrogenDifferent response in different tissues

Adopted from Lewis J. Kleinsmith Ph.D, Donna Kerrigan M.S., Jeanne Kelly


Estradiol

Adapted from Howell A, Osborne CK, Morris C, Wakeling AE. ICI 182, 780 (Faslodex®), development of a novel, "pure" antiestrogen. Cancer 2000; 89: 819.

Molecular Action of


SERM(Tamoxifen)

Adapted from Howell A, Osborne CK, Morris C, Wakeling AE. ICI 182, 780 (Faslodex®), development of a novel, "pure" antiestrogen. Cancer2000; 89: 819.

Molecular Action of


Estrogen Receptor Down regulator A Promising Area of Research

Adapted from Howell A, Osborne CK, Morris C, Wakeling AE. ICI 182, 780 (Faslodex®), development of a novel, "pure" antiestrogen. Cancer2000; 89: 819.

Molecular Action of


Mechanism of Tissue Response - Summary

Oestrogen Receptor Ligand Complex

Oestrogen Receptor

LigandE / SERM / PE/ERD

DNA Oestrogen Response element

Gene Transcription

Tissue Response

Coregulatory Proteinsα / β

Agonistic & or Antagonistic

AF 1 & 2


Selective Ostrogen Receptor Modulators

Estrogens

Anti Estrogens

SERMs

SERMs- designed to act in specific ways at each of the oestrogen receptor sites in different tissues

ERDR

Phytoestrogens


Designer drugs which exhibit tissue specific desirable Estrogenic & Antiestrogenic

actions in different tissues

“Designer Estrogens”“Fantasy Estrogens”

They have the potential of providing a new paradigm for maintaining the health of

women.

Selective Ostrogen Receptor Modulators


• Mer 25 (1958)• Clomiphene1. Tamoxifen

• Toremifene• Droloxifene• Iodoxifene

2. Raloxifene3.Ormeloxifene

As of TodaySelective Ostrogen Receptor Modulators


The Ideal Selective Ostrogen Receptor Modulator

The perfect SERM

The ideal SERM is one that prevents bone loss, has no risk of uterine or breast cancer, a +ve effect on lipids & cardiovascular system, relieves PMS and maintains cognitive function of the brain

The Search goes on

Adopted from – Rita de Cassia M Dardes & V Craig Jordan


The Ideal Selective Ostrogen Receptor Modulator

The perfect SERM

TISSUEEndometriumBreastVaginaBoneLiver/CVSCNS

Perfect AEAEEEEE

E-Estrogenic, AE-Anti Estrogenic

Tamo E

AEAEEEAE

Ralo AEAEAEE

E+E?

Ormelo

AE AE E E E E

The Search goes on


“There is no cure for birth and death save to enjoy the interval”

--Santayana

Selective Estrogen Receptor Modulators promise to make the interval really

enjoyable for women, though the final words on Mode Of Action of Estrogen, Estrogen Receptors and SERMs are yet

to be said.


THANK YOUSERMs

Women have reason to say

SERMs have the potential of providing a new paradigm for

maintaining the health of women.

yerevan state medical university department of obstetrics

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