HRTHRT

By By

Dr. Khattab KAEODr. Khattab KAEO Prof. & Head of Obstetrics and Prof. & Head of Obstetrics and

Gynaecology DepartmentGynaecology DepartmentFaculty of Medicine, Al-Azhar University, Faculty of Medicine, Al-Azhar University,

DamiettaDamietta

Only a small proportion of postmenopausal Only a small proportion of postmenopausal women receives HRT for any length of women receives HRT for any length of

time. time.

Hormonal need in post-menopause actually Hormonal need in post-menopause actually is very individual. is very individual.

It may be that each organ has its own It may be that each organ has its own oestrogen threshold, which varies among oestrogen threshold, which varies among

women. women.

The distribution of The distribution of & & estrogen receptors estrogen receptors varies between ethnic groups, individuals varies between ethnic groups, individuals

& with age.& with age.

Thereby, >30% of menopausal women on Thereby, >30% of menopausal women on adequate HRT still have atrophic vaginitisadequate HRT still have atrophic vaginitis

Benefits & Indications:Benefits & Indications: For max benefit, it may be advocated to start HRT For max benefit, it may be advocated to start HRT

perimenopausally. perimenopausally. Women should be counselled that it may take up to Women should be counselled that it may take up to

6 months to establish HRT. 6 months to establish HRT.

1. Improves menopausal symptoms, it 1. Improves menopausal symptoms, it requires 4-6w.requires 4-6w. Abrupt withdrawal of Abrupt withdrawal of estrogen is likely to return hot flashs estrogen is likely to return hot flashs So, withdrawal should be very slow. So, withdrawal should be very slow.

2- Better 2- Better memorymemory. It affects cerebral . It affects cerebral vascular direction (considered as an vascular direction (considered as an antioxidant). HRT may reduce the antioxidant). HRT may reduce the risk of Alzeheimer disease risk of Alzeheimer disease & improves & improves cognitivecognitive performance in affected women performance in affected women DementiaDementia occurs less frequently, an occurs less frequently, an effect which is related to duration & effect which is related to duration & dose of therapy. dose of therapy.

Benefits & Indications:Benefits & Indications: 3- Protects against osteoporosis 3- Protects against osteoporosis

((maintains bone density). maintains bone density). However, serum EHowever, serum E22 levellevel of <100 of <100 pmol/L will not protect against pmol/L will not protect against osteoporosis or CVS disorders. osteoporosis or CVS disorders.

It prevents the early accelerated It prevents the early accelerated bone loss & 50% of the bone loss & 50% of the osteoporosis-related fractures. It osteoporosis-related fractures. It does not repair >5% of the does not repair >5% of the damage. Once oestrogen is damage. Once oestrogen is withdrawn, the rapid Ca losswithdrawn, the rapid Ca loss returnsreturns.. So, for osteoporosis, So, for osteoporosis, HRT should be given for HRT should be given for lifelife. .

4- Prevention of myocardial infarction: 4- Prevention of myocardial infarction: Coronary artery disease kills more Coronary artery disease kills more women than do endometrial cancer, women than do endometrial cancer, breast cancer & osteoporosis combinedbreast cancer & osteoporosis combined

Estrogens in addition reduce insulin resist Estrogens in addition reduce insulin resist

Estrogens dilate coronary arteries, inhibit Estrogens dilate coronary arteries, inhibit incorporation of fat in the vessel wall & incorporation of fat in the vessel wall & improve the mechanical efficiency of improve the mechanical efficiency of the heart. the heart.

HRT reduces the risk of heart attacks by HRT reduces the risk of heart attacks by 50%. 50%.

Oral oestrogen intake increases LDL Oral oestrogen intake increases LDL catabolism. On the other hand, it catabolism. On the other hand, it increases HDL synthesis. increases HDL synthesis.

5- Control symptoms 5- Control symptoms attributable to urogenital attributable to urogenital atrophy. atrophy.

6- May reduce colon cancer. 6- May reduce colon cancer.

Risks and problems: Risks and problems: 1- Women may 1- Women may re-ovulatere-ovulate on on

high-dose HRT! high-dose HRT! 2- 2- Endometrial carcinomaEndometrial carcinoma: : ERT ERT 5-x increased risk. 5-x increased risk. However HRT is protectiveHowever HRT is protective3- The risk of 3- The risk of DVTDVT is 3-x is 3-x

increased (5 increased (5 15/10 15/1055). ). The risk is highest in the 1st The risk is highest in the 1st

year & is dose-related. year & is dose-related. The trans-dermal route has no The trans-dermal route has no

effect on clotting. effect on clotting.

Risks and problems: Risks and problems: The patient should be counselled for the The patient should be counselled for the

rare complications of DVT & breast rare complications of DVT & breast cancer, but emphasize that she is more cancer, but emphasize that she is more likely to die from complications of not likely to die from complications of not taking HRT. taking HRT.

4- There is a slight increase in the risk of 4- There is a slight increase in the risk of breastbreast cancercancer after 10 y of use. Malign. after 10 y of use. Malign. takes 10 y to be clinically detectable. takes 10 y to be clinically detectable.

The belief that ERT promotes rather than The belief that ERT promotes rather than initiates, breast cancer is highly plausible.initiates, breast cancer is highly plausible.Risk patients are those with: family history, Risk patients are those with: family history,

early menarche, late menopause, dense early menarche, late menopause, dense breasts, regular alcohol intake, etc. breasts, regular alcohol intake, etc.

Lower dose, shorter term ERT and regular Lower dose, shorter term ERT and regular mammography are advocated in these mammography are advocated in these women. women.

5- Skin reaction in 17% of cases using transdermal ERT.

6- Initial breast tenderness and increased vaginal discharge.

7- The rate of non-compliance is 80%.

8- Tachyphylaxis: Women on estr-ogen implants may return earlier than the expected 6 months for re-implantation, usually with re-currence of psychological sympt.

E2 levels may be found well above those existing premenopausal.

9- Initial irregular bleeding (spotting in the 1st 6 months) may be accepted

After 6 months a biopsy is carried out.

10- Withdrawal bleeding with 'cyclic' HRT. Heavy bleeding necessitates reducing estrogen, reducing progest-ogen or changing the type of progest

Continuous progestogen administr. endometrial atrophy with significant incidence of IUB in the first few mon.

Bleeding during progestogen therapy can be managed by doubling the progestogen dose.

11- PMS-like symptoms. Continuous 11- PMS-like symptoms. Continuous regimens eliminate this problemregimens eliminate this problem. . Or Or progestogen is given every 3 months. If progestogen is given every 3 months. If still intolerable, ERT with yearly hystero-still intolerable, ERT with yearly hystero-scopy & biopsy is indicated. scopy & biopsy is indicated.

12- Persistent breast tenderness. A differ-12- Persistent breast tenderness. A differ-ent oestrogen preparation is prescribed, ent oestrogen preparation is prescribed, a constant dose of progestogen is given a constant dose of progestogen is given or 1000-3000 mg of evening primrose is or 1000-3000 mg of evening primrose is added. added.

13- Persistent menopausal symptoms. A 13- Persistent menopausal symptoms. A different estrogen preparation or route different estrogen preparation or route is prescribed. is prescribed.

Contraindications:Contraindications:

Hypertension, varicose veins, VTE, DM, Hypertension, varicose veins, VTE, DM, endometriosis and fibroids are endometriosis and fibroids are classically cited as contraindications. classically cited as contraindications.

However, there is little, if any, evidence However, there is little, if any, evidence that they should be so. that they should be so.

There is There is nono real contraindication. real contraindication.

If an episode of DVT had occurred with a If an episode of DVT had occurred with a predisposing factor (pregnancy for ex) predisposing factor (pregnancy for ex) it should not be cited as contraindica-it should not be cited as contraindica-tions although a non-oral route would tions although a non-oral route would be appropriate. be appropriate.

1- The only real contraindication to HRT is a 1- The only real contraindication to HRT is a history of recent history of recent breastbreast cancer. Even with cancer. Even with a positive family history mammo- gram is a positive family history mammo- gram is not not a necessary pre-requisite, especially a necessary pre-requisite, especially in young women where mammogram is in young women where mammogram is difficult to interpret. difficult to interpret.

Low doses of oestrogens, which are pro-Low doses of oestrogens, which are pro-tective against osteoporosis and cardio-tective against osteoporosis and cardio-vascular diseases, are not associated vascular diseases, are not associated with increased risk of breast cancer. with increased risk of breast cancer.

ERT can be administered to women who ERT can be administered to women who have had ER -ve breast tumours and -ve have had ER -ve breast tumours and -ve axillary lymph nodes.axillary lymph nodes.

Breast fibroadenoma is not a contra-Breast fibroadenoma is not a contra-indication to HRT.indication to HRT.

2- After hysterectomy BSO for 2- After hysterectomy BSO for malignancy, there is no malignancy, there is no evidence that oestrogen evidence that oestrogen therapy is likely to increase the therapy is likely to increase the risk of recurrence even in risk of recurrence even in oestrogen-dependent tumours oestrogen-dependent tumours such as cancer ovary and such as cancer ovary and endometrium.endometrium.

Risks and benefits are to be Risks and benefits are to be considered on an individual considered on an individual basis. basis.

Types: * ERT for hysterectomized women or women

with intact uterus with yearly endometrial sampling. Conjugated estrogens (oral tab &

vaginal cream), E2 (tab, SQ implants & transdermal patches) & oral EE2 tab. Implants is the most

effective means of delivering E. Patches (Estra-derm, 2, 4 or 8mg) are to be applied twice/w on

the buttocks but not on a sun-exposed area or breasts, with regular site rotation. SQ implants

(100mg) are inserted every 6 months in the anterior abdominal wall. E vaginal cream is

applied OD for 2 w, then twice/w for a max of 3 months without progestogen if the woman has

a uterus.

The oral route has a potentially favourable effect on the HDL/LDL ratio, while the transdermal & SQ routes are safer in women with a

history of VTE because they avoid

the liver. Implants avoid nausea. Most of the oral E2 is metabolized to E1. The aim of ERT is to achieve a pre-menopausal estrogen levels. Natural estrogens can do avoiding the more potent synthetic E in CO pills, designed to over-ride normal ovarian function.

* ‘Cyclic HRT’ with intact uterus or to a woman whose uterus has been removed to alleviate severe endometriosis. Oestrogen is given for 25 days or continuously. 5-10 mg MPA is given for the last 10 ±3 days of the 25 days cycle. Withdrawal bleeding occurs 2-3 days after the last dose of progestin. When withdrawal bleeding takes place every 2-3 months, there is no concern But when it occurs during the E-only phase, an endometrial biopsy should be considered. Withdrawal bleeding is common with the short (7 day) course of progestogen, while PMS and loss of libido may occur with the longer course.

* ‘Continuous HRT’. Only 5 mg MPA is used. When amenorrhoea is achieved, it may be possible to reduce MPA dose to 2.5 mg. Progetogen is added for the last 12 days. This regimen has a higher rate of unpredictable bleeding especially during the first year of therapy.

* Tibolone (Livial) maintains bone density. It is a weak * Tibolone (Livial) maintains bone density. It is a weak estrogenic, progestogenic & androgenic synthetic steroid estrogenic, progestogenic & androgenic synthetic steroid which suppresses FSH and to a lesser extent LH. It is which suppresses FSH and to a lesser extent LH. It is suitable for long-term use. It has a low incidence of suitable for long-term use. It has a low incidence of withdrawal bleed. withdrawal bleed.

*Selective estrogen receptor modulators (SERMs) Under *Selective estrogen receptor modulators (SERMs) Under certain conditions ER-certain conditions ER- & ER- & ER- have opposite effects. have opposite effects. SERMs have estrogen agonist effects on desired target SERMs have estrogen agonist effects on desired target tissues such as bones, vaginal epithelium & CVS, and tissues such as bones, vaginal epithelium & CVS, and estrogen anta-gonism on the endometrium and breast. estrogen anta-gonism on the endometrium and breast. Examples: Lamoxifen & Raloxifine (Evesta). Tamoxifen use Examples: Lamoxifen & Raloxifine (Evesta). Tamoxifen use results in a strikingly favorable cardiac risk factor profile. results in a strikingly favorable cardiac risk factor profile. Total cholesterol & fibrinogen levels decrease. A major side Total cholesterol & fibrinogen levels decrease. A major side effect is depression. Also, there is increase in VTE and effect is depression. Also, there is increase in VTE and endometrial cancer. endometrial cancer.

Follow-up:Follow-up: I- Serum EI- Serum E22 level should be assayed every 6 months part- level should be assayed every 6 months part-

icularly before re-inserting an implant to avoid tachy-icularly before re-inserting an implant to avoid tachy-phylaxis. phylaxis. The tissue level of E2 following HRT will vary The tissue level of E2 following HRT will vary according to: 1- The individual's endogenous production according to: 1- The individual's endogenous production of estrogens via aromatization of androgens (this may of estrogens via aromatization of androgens (this may vary from organ to organ). vary from organ to organ).

2- The route of ERT: Only transdermal or percutan. E2 is 2- The route of ERT: Only transdermal or percutan. E2 is absorbed as such. absorbed as such.

3- The type of ERT: 17-β E2 stimulates less SHBG than 3- The type of ERT: 17-β E2 stimulates less SHBG than conjugated equine oestrogen (CEE). conjugated equine oestrogen (CEE).

4- The N4- The Noo & receptivity of estrogen receptors. & receptivity of estrogen receptors. II- Serum FSH cannot be used as a monitor, because its II- Serum FSH cannot be used as a monitor, because its

level is regulated also by inhibin. level is regulated also by inhibin. III- Annual reassessment of the dose, pelvic exam, III- Annual reassessment of the dose, pelvic exam,

mammogram and pap smear are advised. The dose can mammogram and pap smear are advised. The dose can be titrated according to its ability to maintain BMD, be titrated according to its ability to maintain BMD, reduce vaginal pH, favourably change the lipid profile. reduce vaginal pH, favourably change the lipid profile. Begin with a low dose. Begin with a low dose.

Thank youThank you