Hormone Therapy and Current Concepts

Dr.K.Prabha Devi,M.D,D.G.O Prof. of OB & Gynaecology NRI Medical College Chinakakani

Introduction

Average life span of women . 1/3rd of life is postmenopausal. Majority of menopausal complaints are due of ovarian hormones. Menopausal symptoms need relief. Prevention of effects of long term E deficiency is definitely required.

Menopause

Impact of postmenopausal Estrogen deprivation. - Short term consequences * Vasomotor symptoms. * Atrophic changes of GT Sexual dysfunction. * Psycho physiological effects: - Long term consequences * Cognition and Alzheimers disease. * CVD * Osteoporosis. * Urogenital atrophy.

HRT

To overcome the short and long term consequences of E deficiency. Objective of HRT is to ensure the potential benefits and minimize the risks. Special cases POF, Gonadal dysgenesis. Surgical or radiation menopause.

What are the hormonal therapies (as per I.M.S 2003)

HRT ? HT ? ET ? Estrogen therapy. EPT ? Estrogen _ Progesterone therapy EAT Estrogen + Androgen CCEPT Combined continuous E + PT CSEPT - Combined sequential E + PT

Hormonal Therapies
1.
2. 3.

4.

Gonadal HT E, P, & Androgen. Hormone stimulants - / SERMS Gonado mimetics / STEAR Natural plant hormones (Phyto Estrogen)

Non hormonal therapies

Herbs Micronutrients Antioxidants Calcium Biphosphonates Calcitonin Others.

Functional & need based classification of HT use

a) b)

c)

Short term therapeutic HT 2-5yrs (for Menopausal symptoms). Short term preventive HT 5yrs (Surgical Menopause) Long term preventive HT > 5yrs ( Local vaginal E for vaginal symptoms) Intermittent therapeutic or preventive HT ( Urogenital symptoms occur life long)

d)

Functional & need based classification of HT use

e) Relayed placement (Therapeutic or preventive) When types of HT are being changed over time for ex. Every 5-7yrs in a planned manner. f) Concomitant multiple hormone therapy (Therapeutic or preventive). Eg: Estrogen and Progesterone or raloxifene. Estradiol combined with local estriol.

Functional & need based classification of HT use

g) Multidimensional therapy: (Therapeutic or prevention) HT with biphosphonates, calcium or with antioxidants or micronutrients and multivitamin.

E receptors

E receptors + in almost all tissues from crown to toe. Two types of receptors. ER Alfa (original) ER Beta (recently discovered receptor). Progestogen & Androgens also have receptors to different tissues. ER alfa is always an activator. ER Beta inhibits action of ER alfa.

Benefits of HRT 2 large studies (WHI, MWS)

Vasomotor symptoms Urogenital symptoms and improved sexuality risk of osteoporosis, and fracture. risk of colorectal cancer risk of stroke Alzheimers disease.

Biochemical effects of estrogen

Effect on Lipid profile

Raises HDL Lowers LDL Reduces LDL oxidation Lowers Lipoprotein(a) Triglycerides are raised. These effects are attenuated by addition of Progestins.

Effect on Endothelial function

Vasodilatory and anti-platelet aggregatory action by - Increased synthesis of Nitric oxide, Prostacyclin. - Decreased synthesis of Endothelin 1.

Biochemical effects of estrogen (contd.)

Effect on Blood clotting factors - Fibrinolytic action by decreased synthesis of clotting Factor VIII, Fibrinogen and Plasminogen Activator Inhibitor-1 (PAI-1). - Thrombotic action by decreased synthesis of Antithrombin III and Factor S.

Effect on Atherosclerosis - Decreased levels of all inflammatory markers synthesized by endothelium (except CRP which is synthesized in liver). - Makes plaque unstable by inducing enzymes Matrix Metalloproteinase.
Improves left ventricular diastolic filling by improving compliance.

HT - use or not to use

Main indication is to control menopausal symptoms. To improve quality of Life. Ideally stop HT after 4 to 5yrs. HT fracture risk & appropriate therapy for osteoporosis. Not appropriate for primary and secondary cardio protection.

HT - use not to use

HT leads to small to breast Cancer incidence, which with age and duration of treatment Risk of T.E. Mx and therapy should be reviewed annually with risk benefit counselling .

When should E T be initiated ?

If woman is asymptomatic it should not be before menopause.
If woman is symptomatic can be started in the perimenopausal period.

Hormonal agent and Routes of Administration

Estrogens used are natural. Types: CEE (Conjugated equine estrogen) - 17 estradoil 1 or 2mg. - Esterified estrogens. - Estradiol valerate 1.5 to 3mg.

Oral E regimen CEE 0.625 or 1.25mg / day in hysterectomized woman. E + cyclic progestin. E for 25 days P for the last 12-14days. C-Combined E + P therapy Prevents Endo hyperplasia - may be irregular bleeding.

S.D Implants

17 estradoil - 25 mg 50mg 100mg for 6 months.

Used for patients of hysterectomized.

Percutaneous Egel

1gm of gel delivers 1mg of Estradoil daily. Applied on to the skin over ant. Abd. Wall or thigh. Transdermal patch: - 3.2 mg of 17 estradiol releases 50g of estradiol in 24 hrs (twice a week).

Vaginal cream / 25mg atrophic vaginitis. Progestin MPA, (2.5 TO 5 mg/day) Micronized, progesterone 100-300mg/day Dydrogesterone 5 to 10mg /day.

Hormonal agent and Route of Administration

Routes Oral, vaginal, Transdermal 0.05 -0.1mg of 17 estradoil Parenteral (I.M), S.C.pellets of 17 Estradoil of 25-100mg.

* Oral E enters into hepatic circulation (First pass effect)

Hormonal agent and Route of Administration

Causes alteration in hepatic protein synthesis, Lipid Profile, and bile composition. fasting serum triglycerides levels. Transdermal significant fall in triglycerides level. - Mechanism not clearly understood. Vaginal ring delivery system is highly promising Effective for 3 months. Vaginal cream and pessaries for relief of symptoms of vagina and urinary tract atrophy.

Hormonal Therapy

Combined ET + P in intact uterus. Continuous E + P in Premature ovarian failure, postmenopausal Cyclic E + P - in perimenopausal.

* T.D.E + P either oral, vaginal ring, or pessary can be used.

Hormonal agent and Route of Administration

With intact uterus E alone should not be given. P should be added to the regimen for 1214days. I.U.C.D of progesterone can be used in ET patients.

HT Endometrial changes

Changes like: Endometrial polyps which will respond to E but not to P. Endometrium shows either - secretory - atrophic. - decidual or - Proliferative Others Eosinophilic - Squamous Metaplasia - Papillary syncytical

Guidelines to the use of ET HT to Postmenopausal Women

Detailed history / personal, medical past. Age of Menopause. The symptoms for which the patient requires relief. H/o abnormal bleeding either in perimenopausal or postmenopausal . H/o surgical menopause with or without removal of ovaries. H/o any radiation.

History : - Symptom, Periods and contraceptive. - Vasomotor symptoms - Vaginal dryness - Other symptoms - Contraception.

Gyn History: - Hysterectomy - Oophorectomy Past Medical and Surgical history: - Risk factor for osteoporosis, CVS (Severe HTN, DM) confirmed DVT or P.E, migraine. - Current medications - does she take alternate or complementary therapy.

Guidelines to the use of ET HT in Postmenopausal Women

Family H/o age of menopause of Mother and sibling. H/o premature menopause. H/o Medical disorders, CVS, DM, Stroke, Cancer & other risk factors like osteoporosis or bowel cancer.

Thorough physical examination

General examination of all systems to exclude cardiac, liver, thyroid and gall bladder problems. Breast examination. Per abdomen. - P/s to exclude uterine & ovarian - P/v Pap Smear.

Investigations

U/S scan of abdomen + pelvic organs. TVS to measure Endo Thickness & ovarian volume. EB if any abnormal bleeding. TVS + hysteroscopy for recurrent episodes of bleeding.

Place of Mammography

If any doubt about breast mass Mammography before HRT. During follow up yearly is not cost effective. It depends upon discretion of clinician based on clinical exam.

Risk factors for CVS disease to be excluded

HT, WT, BMI Hip Waist ratio, B.P. Lipid Profile, CBP. LFT Total cholesterol. Triglycerides. HDL & LDL, Blood sugar. Coagulation factor like fibrinogen, AT III, Platelets, Prothrombin, C-R Protein. Urine test Routine.

The following tests are indicated

TSH for +ve history when hot flushes do not subside with HRT. FSH , Estradiol Premature ovarian failure. Tests to assist risk of - Past or family H/o thrombosis - unexplained TE event - AT III, protein, & S - LA & CA EB - Post menopausal bleeding, recent irregular bleeding, previous use of unoppsed E in the presence of uterus.

The following tests are indicated

B.M.D Some consider it is a baseline indication with 1-2yrs follow up.

L.F.T Suspected or recent history of liver disease.

Follow up Schedule for patients on H.T

After 1month, 3 months, 6 months and yearly. At each visit ascertain the relief of menopausal symptoms. At each visit WT, BMI, Compliance of therapy should be assessed. Enquire any abnormal bleeding. Clinical breast exam. Mammography, u/s scan annually or SOS.

Follow up Schedule for patients on H.T

BSE every month. Annual lipid profile, esp. triglycerides. Sugar & thyroid function to be rechecked as indicated. Pelvic T.V.S or T.R.S for ET, screening for ovarian size, masses, assess for growth of fibroids if any. Bone dexa scan every 1 or 2 yrs. Reassess and document the indications for HT the dosage schedule.

Follow up Schedule for patients on H.T

Assess individual risks and benefits of continuing therapy and discuss any recent development and alternate therapies. Coagulation profile, endometrial sampling hysteroscopy. Number of office visits to be kept minimum. Each visit remind women to maintain life style changes, normal BMI, exercise, diet and to avoid smoking.

Contraindications (Absolute)

Undiagnosed abnormal vaginal bleeding. Endometrial / gynaecological / hormone dependant cancers, breast cancer. Impaired Severe active liver disease Thrombophlebitis past / present.

Relative contraindications

Migraine Strong family H/o breast cancer Uterine fibroids. Endometriosis Gall bladder disease. Past H/o pancreatitis.

Side effects of systemic HRT

Predominantly Estrogenic, and Progestogenic. Estrogenic, - Leg pains - Breast tenderness - Nausea, Headache bloating - Dysphasia, vaginal discharge.

Side effects

Progestogenic: - Acne, Breast tenderness. - bloating. - Headache, backache, Dizziness. - Greasy skin, fatigue, poor sleep. - Wt gain, Abd. Cramps - Anxiety, irritability, poor concentration, restlessness.

Risks of HT

Definite Uterine cancer If ET used alone 8 to 10 times. Probable Breast cancer 35% if used over 5yrs. - Gall bladder 2 to 3 times. - Cardiovascular disease in the early 1-2yrs of use.

Currently enlarged canvas of HT action

Osteoporosis. Estrogen and bones are old friends. Osteoprotective. Now recommended (Post WHI trial) conventional EPT is initiated for both menopausal, for prevention and treatment of osteoporosis.

HRT and Preexisting diseases

How should treatment be modified. Management issues in premature menopause: Fertility and contraceptive. May require ART. Woman need ET until average age of menopause. HRT COP No evidence regards the use of biphosphonates or Raloxifene, or alternative and complementary therapy.

HRT & DM

Incidence of CHD with diabetic women 5 to 6 fold higher. Menopause - the risk of CHD. ERT - 30 50% risk of CHD Protection action of E is multi factorial. Careful monitoring if given EPT. Tibolone - CHD.

HT - Epilepsy

Anti epileptic drug except - Sodium valproate enhances the metabolism of estrogen.

Gall stones Can HRT be prescribed

ET alters the composition of bile. After removal of stone.

Benign Breast Disease

Not a contraindication to HRT. No overall effect on breast cancer.

History of Breast Cancer

ET if E receptors ve. ERT to be started 5yrs after disease free interval but prone for high risk of osteopososis.

Smoking

Risk of MI and strokes. No evidence of risk enhancement with HRT. Advice to give up smoking. To be treated like normal PM women.

PCOD - A follow up 5yrs is suggested. - H/o endometrial cancer risk of recurrence with HRT is unknown. - Even following adenocarcinoma of the cervix ERT is advised.

Hormone Therapy Effects on Cardiovascular system

W.H.I - Combined E P are showed a statistically significant increase in Cardiovascular changes. - E as only arm did not show significant or in CV events. Younger women taking E experience a reduced risk - WHI conclude that HT is not a viable intervention for primary prevention of CHD.

Secondary Prevention (HERS)

No significant difference in secondary CV events in the group given HRT, and placebo.

E.R and Atherosclerosis Trial

No significant difference in disease progression between Treatment & placebo (CCE + MPA 0.625 + 2.5mg ).

Secondary prevention trails

No significant difference in atherosclerosis progression and CV events between the groups. HRT and heart conclusion HRT is not a viable intervention for primary prevention of CHD. Women with existing atherosclerosis should not be given HRT with aim of reduction of future CV events. Addition of MPA does not the risk. Starting HRT early for menopause before the onset of atherosclerosis, may be protective.

Effect on stroke incidence

WHI showed in incidence of ischemic stroke in both E.P and E only group.
HERS trial found no difference in the risk of stroke in the treated and placebo group.

Effect on stroke incidence conclusions

P.M women should not be gives E treatment for a vascular event in the expectation that recurrent vascular events would be prevented by initiation of E.

WHI effect on venous thrombosis

2 fold increase of DVT in E+P HT. If E only arm, there was a in DVT, but in the PE is not significant. The risk is more in 1-2yrs of Treatment. Family H/o TE, should be evaluated to rule out thrombophilia before start of HT.

Effect on Breast Carcinoma

Current users have high risk and the risk with the duration of use. Current users have only localized disease and have less metastatic disease. There was no effect on family H/o breast cancer. Risk was higher in lower body weight women taking HRT.

Other options in elderly Biphosphonates

With Low estradoil therapy for genitourinary effects. Enhanced effect in B.M.D by combining CEE + Biphosphonates. Osteoporosis benefits similar for Tibolone and raloxifene. Phytoestrogens No action on osteoprotective and fracture risk.

Alveolar bone & Tooth loss

Convention EPT alveolar bone and tooth loss. Though some evidence that BMD in P.M woman is correlated well with no. of teeth. ET is protective against tooth loss and periodantal diseases in both past & current users.

ET promotes oral health Prevent gingival inflammation . Prevent Consequent loss of teeth. No evidence published regards benefit of tibolone, raloxifene or Phytoestrogen on alveolar bone and tooth loss.

ET Visual acuity

E benefits vision disorders. Visual acuity improved. incidence of glaucoma by protective against the glutamate toxicity. macular degeneration. Early menopause increase risk of macular degeneration due to decline of E No data is available regards the effects of Tibolone, raloixifene or Phytoestrogen on any opthalmic effect.

Emerging fact & figures About Colon cancer

Colonorectal risk is prevented largely by E Duration of E use increases the protective effects. Reduces incidence of mortality by 50%. E along with aspirin incidence of adenomatous polyps. Also inhibits promotion of existing cancer. No role of protection by Phyto, or Tibolone or raloxifene.

Relief of vasomotor symptoms

E is effective in treating hot flushes. Improvement is noted < 4weeks. Maximum therapeutic response usually by 3 months. Should be continued for at least 1yr. The most common indication for prescription of HRT. Often used for fewer than 5 yrs. E is more effective than SSRI on Clonidine.

Urogenital symptoms and sexuality

Respond well to E vaginally or systemically. Improvement may take several months. Long term treatment often is needed as symptoms can recur. Urinary incontinence is not improved by systemic therapy. Sexuality may be improved with E but is also may need the addition of Testosterone in young oophorectomized.

Osteoporosis

HRT the risk of spine and hip and other osteoporotic fractures. Most studies suggest that continuous and life long HRT is required to be an effective method of preventive fracture. The efficacy of alternatives such as biphosphonates is uncertain. HRT is significantly cheaper.

How E prevents fracture

Inhibits osteoclastic activity intestinal calcium absorption. of vitamin D renal conservation of calcium. Supports survival of osteoblasts

HRT - Risks

risk of breast cancer. risk of endometrial cancer with unopposed E. risk of VTE risk of gall bladder disease.

Endometrial Cancer

Unopposed E . The relative risk 2.3. Risk with prolonged use (RR 9.5 10yrs) Risk remain for 5 or more years after stopping (RR2-3) The risk is not completely eliminated with progestogen. No risk with CCHRT.

VTE

For non users over 5yrs the incidence of VTE. - 3 : 1000/ 50-59 yr - 8 : 1000/ 60-69 yr. The No.of additional VTE with healthy women or HRT 5yrs. - 4 : 1000 (50-59yrs) - 9 : 1000 (60-69yrs) VTE is more likely in the Ist yr of life. age, obesity and thrombophilia risk of VTE Using HRT after VTE has risk of recurrence in 1st yr of use. Transdermal HRT lowers risk than oral.

Gall bladder disease

HRT appears to the risk. The risk with age and obesity.

Risk of Breast cancer with HRT

HRT confers a similar degree of risk in late natural menopause. For every year, the menopausal is naturally delayed the risk by 2.8%. With HRT the risk of by 2.3% / per year. Risk is dependant on duration of HRT. Effect is not sustained if HRT is stopped. 5yrs after stopping, the risk is the same as for the women who never had HRT.

Risk of Breast cancer with HRT

Risk with HRT is dependant on the regimen. Greatest with CEP HRT. Less with Unopposed E (but risk of endometrial cancer. Combined HRT accounts for extra 3breast cancers / 1000 women who start it at the age of 50yrs and use for 5 yrs.

All risk estimates are based on start HRT at 50. This effect is not seen in women who start it early for premature menopause. risk is in Nulliparous women, - High BMI - In women delay the 1st birth - Family h/o of cancer.

HRT - Uncertainities

CVD Dementia Ovarian cancer Quality of life.

CVD

Role of HT in primary or secondary prevention is uncertain and should not be used. The timing, dose and possibly type of HRT, may be determinant. Woman in the (WHI) who start HRT <10yr of the menopause had a lower risk of CHD than who started later.

Dementia and cognition

E may delay or the risk of A.D but does not improve established disease. Not clear to start HRT at what critical age or optimal duration of therapy to prevent dementia.

Ovarian cancer

There is risk if used long term > 10yrs with E alone. The risk is not seen with CCT Currently insufficient evidence is available to recommend.

Quality of life

Although some studies have shown improvement in both symptomatic and asymptomatic women, others have not.

Tibolone

Steroid (19- non testosterone) weekly E, P, & Androgenic prevents - Osteoporosis - Atrophic changes in vaginal and hot flush. - Lipids - Endometrial atrophy.

Tibolone

Dose of 2.5 mg/day. Beneficial effects - more effective on sexual symptoms than ERT. Vasomotor symptoms equal to ERT Endometrial thickness more than E + P. Better used if menopause >1yr, to avoid break through bleeding.

SERMS
Raloxifene. Tissue specific in action. Use for prevention and treatment of osteoporosis.

B.M.D risk of vertebral fracture by 30 50%. Serum LDL and HDL 2 levels. Inhibits the E receptor at breast and endometrial tissue. Risk of breast cancer and endometrial cancer are . risk of DVT Dose 60-120 mg/day

Phyto estrogens - Natural

hot flushes by FSH & LH and GH & prolactin. Effect on vagina is contraversial. Soya is rich to phytoestrogen. Rice, pomegranate, apple, wheat, garlic, oats, coffee, barley, cherries, yeast and potato. Iso flavone legumen of soyabean 60-70% E like action reduces hot flush.

Cardioprotective ( LDL HDL)

Cholesterol lipoprotein levels. Prevents T x A2 and thereby inhibits aggregation of platelets. Several mechanisms are involved in the prevention of atherosclerosis. B.M.D. Phytoestrogens are alternative to HRT. No data on fracture reducion.

How long HRT can be continued?

Benefits of HRT well established. A post menopausal woman must be counselled adequately about benefits and risks. Once screening properly for HRT and monitored, can be continued as long as the woman desires the benefits.

Summary

Evidence based counselling. Mx with hormones will enhance acceptance and continuation of therapy and help preventing lot of suffering with better quality of life to their difficult phase in a women's life.

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