what you need to know about hormone replacement therapy at primary care level

1. Menopause & HRT
Dr. Vairam
24/2/2021

2. SBA question 1

3. SBA question 2
A 52 year old client experiencing symptoms of menopause is interested in taking
hormone replacement therapy with conjugated estrogen (Premarin).
Which conditions may be a contraindication for HRT for this client? Select all that
apply.
a. History of type 2 diabeted melitus.
b. History of deep vein thrombosis.
c. History of breast cancer with “lumpectomy” treatment.
d. History of hyperlipidemia, controlled by drug therapy.
e. History of two cesarean sections.

4. Menopause is a state of natural ovarian senescence with
accompanying estrogen deficiency. It also refers to states of ovarian
failure and ovarian destruction/removal with accompanying estrogen
deficiency. (Amenorrhea for 1 year.)
—Premature Menopause- refers to menopause in a
woman aged below 40 years.
—Early Menopause -refers to menopause in a woman aged
50 years
to 59 years.
—Late Menopause -refers to menopause in a woman aged
60 years and over.
—Surgical menopause- refers to menopause occurring as a
result
of surgical removal of both ovaries in a woman.
—Medical menopause- refers to menopause occurring as
a result of permanent damage to both ovaries in a woman
following either chemotherapy or radiotherapy.

5. What is Menopausal transition?
— Menopausal transition: from the first features of approaching
menopause until up to 1year after final menstrual period
— Associated with significant hormonal variability over time
— Overall, decline in estrogen levels over the menopausal transition

6. Signs and Symptoms
During the Menopausal Transition
Adapted from Bungay G et al. Br MedJ1980;281:181–3;
Van Keep PA et al. Maturitas1990;12:163–70.
Vasomotor Symptoms
Sleep Disorders
Mood Changes Urogenital Atrophy
Dyspareunia
Osteoporosis
Atherosclerosis
Coronary Heart Disease
Cerebrovascular Disease
40 yrs
Menopause
50 yrs 60 yrs
Menstrual Disorders

7. DIAGNOSIS OF MENOPAUSE
a. Clinical Criteria
1.age around menopause ( around 50 years )
2.no periods for 12months
3.menopausal symptoms
However, where in doubt, laboratory testing of
FSH may support the diagnosis
b. Laboratory Criterion
1. FSH level > 35miu/ml

9. Premature menopause
• Women with premature menopause should be considered as a group with
special needs compared to those with natural menopause.
• Premature menopause is associated with a lower risk of breast cancer, but
with a higher risk and earlier onset of osteoporosis and cardiovascular
disease.
• HT should be started as soon as possible. HT is to be continued until the
typical natural normal age of menopause. Higher doses of HT may be
required in these women for symptom relief. The risks of HT attributable to
these young women are likely to be smaller and the benefits potentially
greater than those in older women.

10. HRT

11. HRT (hormone replacement therapy):
• The combination therapy of estrogen plus a progestogen
• Formerly, known as hormone replacement therapy (HRT)
and now known as hormone therapy (HT)
Definition

12. Estrogen
• Hormone produced by the ovaries (small amounts by adrenal
gland and adipose tissue)
• Responsible for typical female sexual characteristics (breasts,
pubic/armpit hair)
• Controls growth of the lining of the uterus early in the menstrual
cycle
• Instrumental in bone formation

14. Symptoms of estrogen deficiency
-Decreased libido
-Dry skin, loss of hair
-Lack of focus
-Mood swings
-Hot flashes
-Night sweats
-Painful intercourse
-Insomnia
-Irregular periods

15. Causes of estrogen deficiency
•Menopause
•Premature ovarian failure
•Hyperprolactinemia
•Type 1 Diabetes
•Use of GnRH analogues with endometriosis

16. Progesterone
• The “other” sex hormone
• Produced by the ovaries after ovulation (corpus luteum)
• Prepares the body for pregnancy, or induces a period by dropping
low if pregnancy does not occur
• Necessary to balance estrogen
• Production peaks by age 25 and gradually declines after that

17. Symptoms of progesterone deficiency
-Painful breast changes
-Excessive hair growth
-Receeding of head hair (extreme cases)
-Insomnia
-Increased PMS symptoms
-Anxiety
-Infertility
-Heavy periods
-Weight gain

18. Drawbacks of progesterone deficiency
Pre-menopausal women:
• Endometrial hyperplasia, a precursor for uterine cancer
• Chronic anovulation, which leads to increased imbalance of
estrogen:progesterone
Post-menopausal women:
• Levels fall to zero, compared to estrogen which only declines 40-
60%
• Many of the ‘typical’ menopausal symptoms therefore can be
attributed to lack of progesterone

19. Causes of progesterone deficiency
•Peri-menopause & Menopause
•Anovulation as a result of:
-Polycystic ovarian syndrome (PCOS)
-Immature hypothalamic-pituitary-ovarian (HPO) axis
-Low estrogen (excessive exercise, low body fat)
-Stress—> “Progesterone steal theory”- progesterone used by
the adrenal glands to make cortisol
• The hypothalamic-pituitary-ovarian (HPO) axis must be viewed as an
entity that works in concert to allow for procreation by means of cyclic
production of gonadotropic and steroid hormones
• The hypothalamic-pituitary-ovarian (HPO) axis is a tightly regulated
system controlling female reproduction. HPO axis dysfunction leading to
ovulation disorders can be classified into three categories defined by the
World Health Organization (WHO).
• Group I ovulation disorders involve hypothalamic failure characterized as
hypogonadotropic hypogonadism
• Group II disorders display a eugonadal state commonly associated with a
wide range of endocrinopathies
• Group III constitutes hypergonadotropic hypogonadism secondary to
depleted ovarian function
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466056/

20. Indication of HRT
•Relief of menopausal symptoms
•Prevention of osteoporosis
•To maintain the quality of life in menopausal years
Special group of women to whom HRT should be prescribed:
•Premature ovarian failure
•Gonadal dysgenesis
•Surgical or radiation menopause

21. Benefits of HRT
•Improvement of vasomotor symptoms (70- 80%)
• Improvement urogenital atrophy
• Increase in bone mineral density (2–5%)
• Decreased risk in vertebral and hip fractures (25–50%)
• Reduction in colorectal cancer
• Possibly cardioprotection

22. HRT & Osteoporosis
• HRT prevents bone loss and stimulate new bone formation. HRT
increases bone mineral density by 2–5% and reduces the risk of
vertebral and hip fracture (25– 50%). Estrogen is found to play a
direct role, as receptors have been found in the osteoblasts.
• Women receiving HRT should supplement their diet with an extra
500 mg of calcium daily
• Total daily requirement of calcium in postmenopausal women is1.5
g
Osteoporosis affects mostly postmenopausal women: 30-50% of
women will suffer a clinical fracture and the associated morbidity in
the course of their lifetime and 70% of hip fractures occur in women
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4520366/

23. HRT & Cardioprotection
• LDL on oxidation produces vascular endothelial injury and
foam cell (macrophage) formation. These endothelial
changes ultimately lead to intimal smooth muscle
proliferation and atherosclerosis.
• Estrogen prevents oxidation of LDL, as it has got antioxidant
properties
HRT has beneficial cardiovascular effects in younger women while it
may have detrimental effect on coagulative balance and vascular
inflammation and has little effect on cardiovascular functions in older
women
In early postmenopausal women, ovarian hormone replacement may be
cardioprotective because of the responsiveness of the endothelium to
estrogens that also buffer the detrimental effects upon coagulation
In late postmenopausal women ovarian hormones have either a null
effect or even a detrimental effect because of the predominance of the
procoagulant or plaque-destabilizing effects over the vasoprotective
effect
https://pubmed.ncbi.nlm.nih.gov/17308159/#:~:text=In%20early%20postmenopausal%20women%2C%20like,the%20detrimental%20effects%20upon%20coagula
tion.

24. Contraindications to HRT
• Undiagnosed genital tract bleeding
• Estrogen dependent neoplasm in the body
• History of venous thromboembolism
• Active liver disease
• Gallbladder disease
HRT may not be contraindicated in women who are keen to be on
HRT but have a past history of breast cancer or endometrial cancer that
is considered cured. In such cases please consult your Gynaecologist
http://www.myhealth.gov.my/en/hormone-replacement-therapy
QUESTION:
Can HRT be prescribed for a patient who’s has had a past history of
cured breast/endometrial cancer???

25. Risk of HRT
Endometrial cancer:
• When estrogen is given alone (unopposed estrogen therapy)
to a woman with intact uterus, it causes endometrial
proliferation, hyperplasia and carcinoma. It is therefore
advised that a progestogen should be added to ERT to
counter balance such risks
Breast cancer:
• Combined estrogen and progestin replacement therapy,
increases the risk of breast cancer slightly
• Adverse effects of hormone therapy are related to the dose
and duration of therapy

26. Venous thromboembolic ( VTE)
• VTE has been found to be increased with the use of combined oral estrogen
and progestin
• Transdermal estrogen use does not have the same risk compared to oral
estrogen
Coronary heart disease (CHD)
• Combined HRT therapy shows a relative hazard of CHD
• Hypertension has not been observed to be a risk of HRT
Lipid metabolism:
• An increased incidence of gallbladder disease has been observed following
ERT due to rise in cholesterol (in bile)
• Dementia, Alzheimer disease are increased
In the present study, transdermal treatment was the safest type of hormone replacement
therapy when risk of venous thromboembolism was assessed. Transdermal treatment
appears to be underused, with the overwhelming preference still for oral preparations.
Overall, 5795 (7.2%) women who had venous thromboembolism and 21 670 (5.5%)
controls had been exposed to hormone replacement therapy within 90 days before the
index date. Of these two groups, 4915 (85%)and 16 938 (78%) women used oral therapy,
respectively, which was associated with a significantly increased risk of venous
thromboembolism compared with no exposure (adjusted odds ratio 1.58, 95%
confidence interval 1.52 to 1.64), for both oestrogen only preparations (1.40, 1.32 to 1.48)
and combined preparations (1.73, 1.65 to 1.81). Estradiol had a lower risk than
conjugated equine oestrogen for oestrogen only preparations (0.85, 0.76 to 0.95) and
combined preparations (0.83, 0.76 to 0.91). Compared with no exposure, conjugated
equine oestrogen with medroxyprogesterone acetate had the highest risk (2.10, 1.92 to
2.31), and estradiol with dydrogesterone had the lowest risk (1.18, 0.98 to 1.42).
Transdermal preparations were not associated with risk of venous thromboembolism,
which was consistent for different regimens (overall adjusted odds ratio 0.93, 95%
confidence interval 0.87 to 1.01).
https://www.bmj.com/content/364/bmj.k4810

27. Postmenopausal women taking combination estrogen-
progestin have a small but definite increased risk for
developing heart disease, breast cancer, stroke,
and blood clots when compared with women not taking
hormone therapy
The risks for women taking estrogen therapy alone
without progesterone include an increased risk
for stroke and blood clots

28. Timing of Initiation of HRT
• Initiation of HT should be done in relation to proximity to
menopause
• Thus, best to start HT between the ages of 50-59 years, or
within 10 years of the menopause
• After the age of 60 years, HT should not be initiated
unless there is a compelling indication
• For those with premature menopause, HT should be
recommended and started as soon as possible - COCP

29. Duration of HRT use
• Generally, use of HRT for a short period of 3– 5 years have been
advised
• Reduction of dosage should be done as soon as possible
• Considering the risks, hormone therapy should be used with the
lowest effective dose and for a short period of time
• Menopausal women should maintain optimum nutrition, ideal body
weight and perform regular exercise

30. Holistic Approach to Menopause
Management
▪ lifestyle modifications
▪ proper diet
▪ regular exercise
▪ cessation of smoking
▪ avoidance of alcohol abuse
However, HT is the overall approach to the management of
menopause

31. Counselling and Decision-Making
• Woman should be counselled regarding the risks vs benefits of HT in simple
terms;
• Informed about the potential side-effects based on special concerns
applicable to her current situation before starting HT.
• Explanation on risks should be made in absolute numbers as this would be
more appropriate rather than in percentages or relative risks, as follows:
• Also need to take the woman’s own preferences and expectations in
managing.
• Only by that the woman can make an informed, individual decision on
whether or not she would want to take HT.

32. Pre-treatment Evaluation
• Taking a medical history, relevant family history and physical examination
(weight, height, BMI, blood pressure and breast examination).
• Besides that, a bimanual vaginal examination and cervical cytology should be
done. Relevant investigations such as laboratory or imaging can be included
but these are not mandatory. These include mammography / sonography,
cardiovascular risk profiles including lipid profile, diabetes screening, full blood
count etc.
• Mammography should be undertaken according to age and national
guidelines. Assessment of bone mineral density (BMD) should be considered
on a case-to-case basis.
• Other tests done on a case-to-case basis, e.g. liver function tests, thyroid
profiles, ultrasonography of the pelvis.

33. RegimeDose
ESTROGENONLY…
• Continuous or cyclical ( 3weeks on and 1week
off).
• -for VMS, atrophic vaginitis and urethritis
a/w estrogen deficiency: 0.2-1.25mg daily
• For osteoporosis : 0.625mg daily dose required
for
bone mass conversion
• Female hypoestrogenism: 0.3 – 1.25mg
daily depending on individualized
assessment.
1)PREMARIN® (oral
conjugated
estrogens USP
0.625mg
• Estrogen only pills 28 pills in 1pack for
continous regime.
2)Progynova 1mg
or 2 mg
tablets(estradiol
valerate 1.0 mg or
2.0 mg)
for women with intact uterus, addition of
progestrogens is
essential
No need to add progesteron for women w/o uterus

34. Routes of administration
1)Oral medication
2)Transdermal routes include: patch, gel and implant.
There is no symptomatic benefit of one route of administration over the other for
systemic ET.
Both oral and non-oral routes have advantages and disadvantages.
Transdermal routes have the advantage of avoiding the first-pass liver effect, and
may be more favourable than oral routes, especially with regard to VTE and
cardiovascular risks.
3)Estrogen administered vaginally When used for the treatment of vulvo-vaginal
symptoms, consideration should be given to the use of local vaginal products.
The use of vaginal estrogen products for the treatment of atrophic vaginitis is well
documented.
Creams have the advantage over tablets in their ability to be applied directly to the
vulva and vulvo-vaginal area and provide flexibility in dosing and frequency of
administration. The most widely prescribed local vaginal therapy for vaginal atrophy
is conjugated equine estrogens ( CE ) cream.
Studies have shown the effectiveness of CE cream in reducing the sign of atrophic
vaginitis as measured by effects on the vaginal maturation index ( VMI ).
Even the use of low dose vaginal estrogens, given daily or twice weekly have
proven effective for the same purpose.

35. Follow-up Assessment & Frequency
• Annual risk-benefit assessment should be carried out.
• The same procedures as in the “Counselling” visit and the “PreTreatment
Evaluation” should be considered.
• Timely mammography is the key, including genital tract cancer studies, e.g.
cervical cytology and other investigations.
• A 12-monthly follow-up assessment is recommended.
• As for mammography, if the initial mammogram is normal, 2-3 yearly
mammography is recommended.

36. Conclusion
Used by the right woman, at the right dose, HRT can:
• Relieve vasomotor and other menopausal symptoms
• Provide protection against bone loss (second line)
• Provide acceptable bleedingpatterns
• Individualized HRT choice
—Besides the role of life-style modifications and dietary
adjustments in the prevention of menopause-related
disease, HT remains a principal tool in preventing
menopause-related illnesses and maintaining quality
of life in the post-menopausal woman.

37. What is available in KKM

42. MDM Y.E.T
74yo Para 2, LCB 1978, Teacher
U/L:
1. Hypertension on metoprolol 100mg BD
Gynaecological hx: SVD 1976 & 1978
No surgical hx
Menstrual hx: 11-50(7/28-30) no dysmenorrhoea/menorrhagia
No known allergy
Family hx: hypertension
Patient was 1st referred to gynae clinic in 2001 (55yo) for irregular PV bleeding on HRT (non
bleeding HRT) which she has been having for the past 5 years. She attained menopause at the
age of 50 and was was started on HRT soon after due to vasomotor symptoms mainly hot
flushes and disturbed sleep.
HRT history;
1995 - Premarin (oestrogen only)
September 2000 - Plentiva 5 (oestrogen & progesterone)
July 2001 - Activelle (oestrogen & progesterone) —> was on this when referred to HPP
Clinically she was pink. No breast mass or mass per abdomen. TAS done ET was 5mm.
Case Study

43. Activelle was continued and during the next few visits, patient still had complains of
irregular PV bleeding (2004).
QUESTION:
How would you manage this patient now

44. Repeated TAS showed ET 10mm and HRT was withheld.
She was then admitted for Hysteroscopy DD&C.
Pap smear and pimple sampling taken was negative for malignancy. Endometrial polyp
was benign.
Mammogram was normal.
After results were obtained she was started on Livial (tibolone) in 2005 and has no further
PV bleeding. She has annual clinic visit & 2 yearly mammogram, does her blood workup at
private (no results in ticket-patient claims normal).
Patient is currently 74 years and on HRT for 26 years since her menopause at the age of
50. All investigations are normal and patient has no complaints.
QUESTION:
Would you consider to stop the HRT or continue? How would you counsel her if you plan to
stop ?

45. She was advised to stop her HRT, however, patient insisted to continue the medication as
she’s worried of the menopausal symptoms will recur despite adequate counselling by the
gynaecologist.
Annual follow up date was given and Livial + Rocaltriol was continued.
Tibolone is a synthetic steroid, a norethisterone de-rivative, metabolized to molecules that
have affinity for the estrogen, progesterone and androgen receptors, which has been
described as a selective estrogenic activity regulator (STEAR)

47. References
—
www.thebms.org.uk
—as attached in google
drive.
—alth.about.com
—www.cancer.org
— www.mims.com/malaysia
—www.millionwomenstudy.org
—www.nhlbi.nih.gov/whi/factsht.ht
m
-women’s health initiative.