menopause and HRT

1. Seminar on Menopause and
HRT
Dr Gitanjali

2. • Menopause is defined as the permanent cessation of menses. By convention the diagnosis of menopause is
not made until the individual has had 12 months of amenorrhea.
• Menopause is not just cessation of menstruation it is “depletion of ovarian follicles” leading to decrease in
ovarian hormones.
• Menopause is thus characterized by the menstrual changes that reflect oocyte depletion and subsequent
reduction in ovarian hormone production

3. Induced menopause may occur after:
• Chemotherapy
• Pelvic radiation, or,
• Bilateral oophorectomy
• Menopause is considered premature when it occurs before 40 years of age but is otherwise normal and not
surgical
• The climacteric, a term now used infrequently, refers to the time of waning ovarian function associated with
menstrual irregularity and vasomotor symptoms.
• Perimenopause is the time between the onset of the climacteric and the year after the last menses.
• Premenopause is the entire reproductive span before onset of the menopausal transition, and post
menopause is the span of life after menopause

4. The Menopausal Transition
• Menopausal transition is replacing perimenopause and climacteric as the preferred term to describe the
time of physiologic change around the cessation of ovarian function.
• This is the stage which precedes menopause, has an average duration of 4 years, with a range of 0–10 years.
• The mean age at which menopause occurs in developed countries is 51 years and may be increasing.
• The standard deviation around this mean is about 2 years. Approximately 95% of women experience
menopause by 55 years of age.

5. • Post menopause -the term post menopause is defined as dating from the final menstrual period, regardless
whether the menopause was induced or spontaneous.
• The post menopause lasts about 10–15 years and is followed by the senescence from about 65 years of age
to the end of life.
• Early Post menopause- This is the period within 2 years after menopause.
• Senescence -After the age of 60 years. Some use 65 years as the cut off age.
• There is staging of reproductive aging by STRAW (The stages of Reproductive Aging Workshop) where
relationship of final menstrual period and menstrual cycles with follicle stimulating hormone (FSH) levels
was taken into account, and in this staging reproductive years, menopause transition and post menopause
are divided into early and late.

6. Another Menopause Staging was First Published by Dr Behram Anklesaria in 1997
 Stage I: From the earliest perimenopausal symptom (usually vasomotor instability or menstrual irregularity) to menstrual cessation (menopause).
The stage can last from 3 years to 5 years.
 Stage II: “Five years after menopause.” This stage is further subdivided into Stage IIA and Stage IIB.
Stage IIA: “From the cessation of menstruation up to 1 year” (that is up to confirmation at menopause by WHO definition). The main symptoms of
menopause during this stage are vasomotor instability and urethral syndrome.
Stage IIB:From end of stage IIA up to 4 years.
The common issues here are:
• Atrophic symptoms, vaginitis, dyspareunia
• Urinary symptoms ,• Weight gain
• Skin and hair changes ,• Genital prolapse
• Late psychological symptoms
• Sexual disorders.
 Stage III: “From 5 years after menopause up to an indefinite period; probably life time.”
These are divided into the following:
• IIIA-Residual atrophic symptoms
• IIIB-Stage of ischemic heart disease and early osteoporosis
• IIIC-Very late complications like cerebrovascular changes and Alzheimer’s disease.

7. Factors Influencing Age of Menopause
Several factors appear to influence the age at which women experience menopausal symptoms and the final
menstrual period
• Menopause occurs approximately 1 year earlier in smokers
• Occurs earlier in nulliparous women
• Menopause may also occur earlier in women who have had ovarian cystectomies or unilateral
oophorectomies
• Ovarian drilling done for polycystic ovarian disease (PCOD)
• When patient get pelvic radiotherapy or chemotherapy
• In Indian women it is earlier so genetics or racial factors may also be contributing towards age of
menopause.

8. PHYSIOLOGY OF MENOPAUSE
• In females throughout reproductive life ovarian follicular depletion is occurring by atresia.
• This process starts earlier in foetal life itself.
• At 5 months of foetal age, the ovaries contain their peak number of primordial follicles, totaling
approximately 2 million.
• At birth, girls have 1 million primordial follicles, approximately 25% of which remain at puberty.
• During the reproductive years, many follicles will begin to develop during each ovulatory cycle; except
dominant follicle all other follicles become atretic. So only estimated 500–1,000 follicles remain in the
ovaries of a woman, 51 years of age.
• Some follicles persist for a few years after the menopause but these are poorly responsive.
• This progressive loss of follicles that goes on with aging is characteristic of all mammals studied to date;
however, what are the controlling factors for this process have not been well defined.

9. • Beginning as early as 10–15 years before menopause, there is shortening of the follicular phase of the cycle
and so the length of the menstrual cycle starts decreasing.
• This decrease in cycle length continues until the onset of the menopausal transition, when both the average
cycle length and the standard deviation of cycle length begin to increase as follicles are depleted and
ovulation occurs less frequently.
• Insufficient follicular development results in inadequate oestrogen production. With little oestrogen
available to stimulate the endometrium, amenorrhoea results
• There is good evidence that the timing of natural menopause is genetically programmed, but the specific
genes involved are yet to be well defined.
• Common allelic variants of the oestrogen receptor gene [oestrogen receptor- (ER-α) and ER-β] contribute to
the variability in the timing of menopause.
• In addition, all of the steroid receptors, as well as the proteins and enzymes involved in steroid biosynthesis
and metabolism, are known to be coded by polymorphic sites (genetic changes found in at least 1% of the
population).
• Because of this variability there are different timings of menopausal symptoms and intensity and duration of
symptoms are also variable

11. Hormonal changes
• A subtle rise in the concentration of FSH is the earliest and most consistent clinically measurable hormonal
change noted in studies of reproductive aging.
• An FSH level measured during the early follicular stage of the menstrual cycle that is greater than two
standard deviations above the mean level in women of reproductive age is a marker of impending
menopausal transition

12. • In the premenopause ovarian granulosa cells under the influence of FSH are producing oestrogens but
because of follicular atresia there is first fall of oestradiol and fall of inhibin B and this leads to increase in
level of FSH but there is further decrease in levels of oestradiol and it is oestrone that becomes main
dominant hormone because of peripheral conversion of testosterone into oestrone
• FSH->+ GC-> estrogen -Premenopause there is follicular atresia-> decrease in estardiol and Inhibin B ->
increase in FSH and further decrease estardiol -> Estrone becomes dominant

13. • A slow rise in FSH occurs first, followed by a rise in luteinizing hormone (LH) and a decline in oestradiol and
oestrone. ‘
• There are no abrupt changes in testosterone, but a gradual continuous decline occurs that begins before the
menopausal transition and this is because of aging of adrenal cortex and testosterone from adrenal cortex is
decreased because of aging starting from third decade onwards.
• Ovaries continue to produce androgens and so at menopause there is not much fall of testosterone.
• Luteinizing hormone levels remain normal initially, but it is also elevated as ovarian steroid secretion falls
and gonadotrophin-releasing hormone (GnRH) increases because of follicular atresis inhibin B levels are
decreased and this causes early selective increase in FSH.
• Inhibin A and B, hormones that are involved in directing follicular development suppress pituitary FSH
production. ‘
• As anovulation predominates in perimenopause period FSH and LH remain chronically elevated
• There is a 10-fold to 20-fold increase in the FSH level and a threefold to fivefold increase in the LH level, and
oestradiol levels fall below 50 pg/mL

14. • Even in menopause ovarian theca cells are producing androstenedione and testosterone under influence of
increased levels of LH, and they are the source of androgens in menopause and when we do oophorectomy
in women there is sudden fall of androgens because of loss of this source of androgens.
• By aromatisation adipocytes produce oestrone from testosterone and so in menopause oestrone becomes
dominant hormone.’
• Hormonal synthesis by the adrenal gland remains fairly constant, undergoing changes associated with aging,
not menopause per se
• Because of aging of adrenal gland levels of androgens fall up to 50% at 60 years of age as compared with
women at 40 years of age and after age 70, levels of Dehydroepiandrosterone (DHEA) and
Dehydroepiandrosterone sulphate (DHEAS) are 20% or less.

15. Final Hormonal Changes with Established Menopause
• The most significant findings are the marked reductions in E2 and oestrone (E1) levels.
• The serum E2 level is lower than the serum E1 level.
• Serum E1 is produced primarily by peripheral aromatisation of androgens, which are not as dramatically
affected by menopause.
• Postmenopausal levels of E2 average 15 pg/mL and range from 10 pg/mL to 25 pg/mL. In oophorectomised
women, levels are usually 10 pg/mL or lower.
• Serum E1 values average 30 pg/mL but may be higher in obese women, because aromatisation increases
because of increased mass of adipose tissue.
• Oestrone sulphate (E1S), an oestrogen conjugate that serves as a stable circulating reservoir of oestrogen,
has the highest levels of any oestrogen.
• In premenopausal women, E1S is usually above 1,000 pg/mL; in postmenopausal women, levels average 350
pg/mL.

16. • Androgens produced by adrenals are androstenedione, DHEAS, DHEA, testosterone and dihydrotestosterone
(DHT).
• However, DHEA, DHEAS, and androstenedione are considered proandrogens because they must be
converted to testosterone in order to be effective.
• Androgen biosynthesis occurs in the ovary and the adrenal under stimulation by LH and adrenocorticotropic
hormone (ACTH), respectively, along with intraglandular paracrine and autocrine regulatory mechanisms.
• Starting from the third decade of life, independent of menopausal transition, circulating Δ-5 androgen levels
fall linearly with age.
• After menopause thecal cell of ovary under influence of LH go on producing androgen, but after surgical
menopause or oophorectomy there is sudden fall of androgens to about 50% of preoperative values
whether hysterectomy with bilateral salpingo-oophorectomy was done in perimenopause or in menopause.

17. • Women undergoing the transition from pre- to postmenopause have some changes in androgens, with the
menopausal transition.
• Specifically, both androstenedione and testosterone decline 3 years before menopause, and some
fluctuations in the testosterone levels occur after menopause.
• However, immediately after menopause, it is decline in androstenedione which is greater than that of
testosterone; that is, in early postmenopause, testosterone levels may be indistinguishable from those in
premenopausal women.
• During postmenopause, virtually 100% of active sex steroids derive from the peripheral conversion of
precursors, mainly DHEA and DHEAS, to oestrogens and androgens.
• Ultimately, several years after the menopause, the levels of androstenedione and testosterone are
significantly lower than levels measured in premenopausal women

19. PROBLEMS ASSOCIATED WITH MENOPAUSE

20. EFFECT OF OESTROGEN DEFICIENCY
• Brain and Central Nervous System  Oestrogen receptors are abundant in the brain.
• Oestrogen is known to have a role in many brain processes, and the absence of oestrogen can result in
physiologic and symptomatic changes.
• Oestrogen is important for cerebral blood flow, cerebral glucose administration, synaptic activity, neuronal
growth, the survival of cholinergic neurons, as well as such complex functions as cognition.

21. Hot Flushes
• Hot flushes- are an early and acute symptom of oestrogen deficiency. They often begin in the
perimenopause when oestrogen levels characteristically fluctuate widely.
• It is the rapid fall in oestrogen level that precipitates the symptoms. Hot flushes typically last from 0.5 years
to 5 years after natural menopause but may persist as long as 15 years.
• They tend to last longer and be more severe with surgically-induced menopause.
• Night sweats can be more upsetting than daytime flushes because they disrupt sleep.
• Some women find that as a result of hot flushes they suffer from insomnia, which leads to: Irritability ,
Tiredness and Forgetfulness..
Thus, the prevalence of vasomotor symptoms varies widely across populations and is strongly influenced by
culture and ethnicity.

22. Physiology of Hot Flushes
• The proximate cause of hot flushes is not well understood, the episodes result from a hypothalamic
response (probably mediated by catecholamines) induced by a change in oestrogen status.
• The flush has been physiologically as : heat dissipation occurs through an increase in peripheral
temperature (e.g. in the fingers and toes); a decrease in skin resistance, associated with diaphoresis; and a
reduction in core body temperature
• Heart rate and skin blood flow peak within approximately 3 minutes of hot flush onset, which leads to
vasodilatation and decrease in internal temperature (0.1°–0.9°C) leads to a feeling of chill.
• Skin temperature returns to normal usually within 30 minutes.
• No significant change in blood pressure is associated with hot flashes
• There are hormonal correlates of flush activity, such as an increase in serum LH and plasma
propiomelanocortin peptides (ACTH, β-endorphin) at the time of the flush; however, these occurrences are
thought to be epiphenomena that result as a consequence of the flush and are not related to its aetiology.

23. Management
• Counselling the woman is most important.
• Pharmacological preparations:
• The gold standard of treatment for menopausal hot flushes is oestrogen therapy.
• Hormone therapy (HT) either oestrogens alone (in hysterectomised women) or in combination with
progestogen, in minimum dosage and for the shortest period of time are prescribed, they can be either by
oral route or transdermal route or transvaginal route or pellets of oestrogens.
• Tibolone is another drug which is found to be effective in hot flushes.
• The various nonpharmacological options for managing hot flushes are as follows:
• • Lifestyle modifications: – Adopting certain lifestyle measures can decrease the intensity and frequency of
hot flushes.
– Avoidance of triggering factors like stress, caffeine, alcohol, spicy foods, beverages
– Avoid smoking ,– Reduction of stress
—practice meditation, yoga, massage, paced breathing
– Staying in a cold environment, avoiding warm places
–– Exercise—undertake aerobic and weight-bearing exercises, exercise reduces hot flushes in 50% of cases,. –
Weight loss

24. Mood Changes and Cognitive Function
• Oestrogen has a positive effect on mood and contributes to a sense of well-being.
• The role of oestrogen deficiency in postmenopausal depression, declining cognitive function, dementia,and
Alzheimer’s disease is not clear.
• Migraines -Oestrogens and progestins affect central serotoninergic and opioid neurons. Alterations in the
level and cycling of these hormones may cause a change in the prevalence or intensity of headaches.
• Vision- There is an increased incidence of some vision-threatening conditions in postmenopausal women.
For example, idiopathic full-thickness macular degeneration predominantly affects women over 60 years.
There appears to be a hormonal component, because symptoms become more severe with menopause.
Changes in hormonal status may thus affect the physiology of the eye.
• Collagen -Oestrogen has a positive effect on collagen, which is important for bone and skin. Both oestrogen
and androgen receptors have been identified in skin fibroblasts.
• The loss of collagen is more rapid in the first few years after menopause, and 30% of skin collagen is lost
within the first 5 years after menopause.
• Reductions in collagen support and atrophy of the vaginal and urethral mucosa have been associated with a
variety of symptoms, including uterine prolapse and urinary incontinence

25. Urogenital Atrophy
It has been reported that as many as one-third of women aged 50 years and older experience urogenital
problems.
Oestrogen deficiency results in :
• Thin and paler vaginal mucosa ,• Loss of normal rugosities
• The moisture content is low
• The pH increases (usually pH > 5), and
• It may exhibit inflammation and small petechiae
• Cytology reveals a loss in superficial cells and an increase of basal and parabasal cells
• In reproductive-age women, the vaginal flora is dominated by lactobacilli.
• In postmenopausal women, the vagina is gradually repopulated with diverse flora, including pathogenic
organisms commonly found in urinary tract infections (e.g. coliform bacteria),
• The lower urinary tract and the genital tract in females have a common embroyological origin. Oestrogen
receptors have been reported in the trigone of the bladder and the proximal and distal urethra.

26. Functional changes which have been noted include the following:
• Elderly women have lower flow rates
• Higher bladder volume at the first sensation to void
• Increasing urinary residue
• Similarly, changes in collagen in the endopelvic fascia and periurethral tissue account for the hypermobility
and reduced urethral closure pressure and may thus explain the prevalence of stress incontinence.
Dry and atrophied vaginal and urethral epithelium can cause:
• Vaginal discomfort
• Itching
• Dyspareunia, and
• Recurrent vaginitis.

27. Weight Gain and Loss of Muscle Mass or Sarcopaenia
• The prevalence of obesity in adult women rises significantly each decade, until it begins tapering off late in
life.
• About 20% gain weight of about 4.5 kg in the 3 years surrounding menopause. While only 3% lose that
amount of weight.
Changes in Fat Distribution Although weight changes may be more strongly associated with aging than with
menopause,
• Women who have undergone menopause may have higher levels of body fat and a more central fat
distribution than age-matched controls.
• Women are losing more of lean muscle mass and gaining more of fat.
The effect of menopause on abdominal obesity is of major concern, since abdominal obesity has been shown
to be an independent predictor of Type 2 diabetes, dyslipidemia, hypertension, certain cancers, and
cardiovascular disease (CVD).

28. Causative Factors for These Changes
• The age-related decline in resting metabolic rate (RMR) and decreased physical activity, with or without
increased caloric intake, could easily result in weight gain.
• Changes in RMR have been observed, which may be due in part to a decline in fat-free mass or sarcopaenia.
• Loss of ovarian function and loss of interleukin in the luteal phase of the menstrual cycle may also contribute
to decreased RMR.
• Oestrogen has been found to influence eating behaviour and their loss causes weight gain in animals.
Prevention of Weight Gain
Life style modifications are the mainstay of prevention and control. Currently, the most effective behavioural
approach for management of overweight and obesity is a combination that includes:
• Reduced caloric intake (typically 1,000–1,200 kcal/day for women)
• Dietary fat reduction (30% of calories)
• Increased physical activity (at least 30–45 minutes of moderate-intensity activity on most days of the week)
when losing weight along with aerobic activity resistance and strength building exercises should also be started
to counteract the loss of lean muscle mass.
• Behavioural guidance.

29. Bone Loss (Osteoporosis) and Fracture Risk
• In women, peak bone mass is achieved by the second decade and begins to decrease thereafter after 35 years
of age.
• The most important risk factors for osteoporosis-related fractures are:
• Prior fracture(s) with trivial trauma as an adult,
• Low bone mineral density (BMD) in patients with or without fracture
• Advancing age
• Family history of osteoporosis, fractures in first-degree relatives
• Loss of more than 1.5 inches height loss
• Vitamin D deficiency
• Low calcium intake (< 300 mg per day)
• Tobacco use
• increased Alcohol intake
• Any condition that increases the risk of falling

30. • Postmenopausal osteoporosis is characterised by low bone mass and microarchitectural deterioration of
bone tissue leading to enhanced bone fragility and increased fracture risk.
• According to the World Health Organisation, osteoporosis is defined based on the following bone density
levels:
• Bone mineral density is compared to two norms—healthy young adults (T-score) and age-matched (Z-score)
• A T-score within 1 SD (+1 or –1) of the young adult mean indicates normal bone density
• A T-score of 1–2.5 SD below the young adult mean (–1 to – 2.5 SD) indicates low bone mass.
• A T-score of 2.5 SD or more below the young adult mean (> – 2.5 SD) indicates the presence of osteoporosis.
Oestrogen deficiency is a dominant pathogenic factor in bone loss.
This can be noted for the first time during perimenopause.

31. Role of Oestrogen in Osteoporosis
• Oestrogen action on bone is mediated by direct effects on bone through the oestrogen receptor and by
effects on collagen.
• The accelerated decline in bone mass that occurs with oestrogen deficiency is mediated by a variety of
mechanisms, but the primary event is increased resorption (osteoclastic activity), which becomes uncoupled
from bone formation (osteoblastic activity).
• There are also indirect effects mediated by parathyroid hormone and cytokines, which oppose the resorptive
effects.
• Osteoprotegerin (OPG), for example, a member of the TNF-receptor (tumor necrosis factor receptor) family,
is a soluble protein that inhibits osteoclastic bone resorption. OPG is secreted by osteoblasts and binds to OPG
ligand, a factor necessary for osteoclastogenesis.
• Serum levels of OPG appear to be significantly elevated in postmenopausal women with osteoporosis. In
addition, oestrogen enhances OPG secretion by osteoblasts in vitro, suggesting that OPG may have an
important role in the antiresorptive action of oestrogen on bone.
• In postmenopause, the positive effects of oestrogen on growth factors, calcitonin, vitamin D metabolism and
calcium absorption are also diminished.

32. • Three main sites of increased risk of fracture in postmenopause women are: 1. Wrist 2. Hip 3. Spine
• The most common fractures due to osteoporosis are vertebral fractures, and yet less than a third of all
vertebral fractures are clinically diagnosed
• Back Exercises for Kyphosis-. This is most effective when done in an upright, weight-bearing position.

33. Prevention and Management of Osteoporosis
• A management strategy focused on lifestyle approaches may be all that is needed for women who are at low
risk for osteoporotic fracture.
• These life style modifications are:
• No smoking
• Calcium 1,200–1,500 mg per day
• Vitamin D 400–600 IU per day
• But mainstay is exercise and these have to be weight bearing and resistance exercises, especially for back
muscles to prevent kyphosis, wrist muscles, to prevent fractures of wrist, to strengthen thigh and buttock
muscles to prevent fractures of hip bone

34. Several other agents are as effective as HT in preventing
fracture due to osteoporosis
• Bisphosphonates: Alendronate, risedronate, and ibandronate are commonly used for both prevention and
treatment of osteoporosis.
For prevention alendronate is available as a daily tablet of 5 mg and a weekly tablet of 35 mg.
For treatment of postmenopausal osteoporosis the doses available are 10 mg tablets daily and 70 mg tablets
weekly.
• Bisphosphonates in combination with oestrogen are more effective than either agent alone.
• Selective oestrogen receptor modulators (SERMs): SERMs (e.g., raloxifene are indicated for the prevention
and treatment of osteoporosis.
They are not indicated for the treatment of menopausal symptoms and may even aggravate hot flashes in
some women.Current venous thrombosis is an absolute contraindication. They have a favourable effect on lipid
profile and are cardioprotective. Available as 60 mg tab/ day for prevention as well as treatment.
• Calcitonin: The nasal spray used for osteoporosis treatment that inhibits bone resorption and reduces
fracture rates. Nasal irritation and cost limit its use. Calcitonin is available as a subcutaneous injection (about
100 IU per day) and as a nasal spray (about 200 IU per day) for treatment of postmenopausal osteoporosis.
• Parathyroid hormone (PTH e.g. teriparatide: Daily subcutaneous injections are used for osteoporosis
treatment.

35. • Tibolone is a synthetic steroid with oestrogenic, progestational and androgenic properties. It is metabolised
by local tissue enzymes and therefore provides a unique “tissue specific approach” to menopause.
• It treats climacteric symptoms and does not increase mammographic breast densities (although data on
breast cancer occurrence are not yet available).
• Tibolone seems to exert osteoprotective effects similar to oestrogen,
• The recommended dose is 2.5 mg daily.
• It increases libido, reduces hot flushes and so can be prescribed for that effect along with to prevent
osteoporosis.
• Osteoprotegerin: This is a new drug and it is a naturally occurring protein and is a negative regulator of
osteoclast formation that has shown promise as a potential treatment for osteoporosis.
• Zoledronic acid is new drug approved by FDA. A single intravenous infusion of Zoledronic acid 5 mg over 15-
minute period once in a year decreases bone turnover and improves bone density and is effective in reducing
hip, vertebral and other fractures

36. Cardiovascular Effects
• Total cholesterol rises at an accelerated rate after menopause
• This increase in total cholesterol results from increases levels of low-density lipoprotein cholesterol (LDL-C)
With the more dense forms predominating, and increases in very-low-density lipoprotein (VLDL) and
lipoprotein a [LP(a)]
• The oxidation of LDL-C is also enhanced.
• High-density lipoprotein cholesterol (HDL-C)
• Coagulation balance is not altered significantly with menopause because a counterbalance of changes
occurs;
• Blood flow in all vascular beds decreases after menopause
• Prostacyclin production decreases
• Endothelium levels increase
• Levels of angiotensin-converting enzyme decrease .

37. • Present Recommendations Specific recommendations from several sources currently include the following:
• Identify and treat all CHD risk factors
• Do not initiate HT for the prevention of CHD
• Do not initiate HT in patients with known CHD
• If CHD develops while on HT, consider other alternatives.
For prevention and to increase cardiorespiratory endurance 30 minutes/day of moderate aerobic activity is
recommended like walking at a brisk pace, or swimming, cycling, yoga, taichi, lawn mowing or any other
activity which causes repetitive movement of large muscles, along with proper diet

38. MENSTRUAL PROBLEMS
• The perimenopausal period begins 2–5 years before the final menstrual period and lasts for 1 year
thereafter.
• oestradiol levels do not gradually wane in the years before menopause but remain slightly elevated until 6
months to 1 year before follicular growth and development cease.
• The greatest concern about DUB is relative oestrogen excess with endometrial hyperplasia and neoplasia
although the usual finding is a non-neoplastic tissue with oestrogenic effects unopposed by progesterone.
• The menstrual cycle becomes irregular and unpredictable with both short and long follicular phases,
defective ovulation and anovulation and highly erratic cycles.
• This pattern of irregularity should be distinguished from regular menstrual cycles interspersed with
intermenstrual bleeding.
• Intermenstrual bleeding is associated with genital tract pathology
• Anovulatory menorrhagia is frequent in this period but age-related and pathology-related changes in the
uterus and ovaries may also be responsible.

39. CANCER SCREENING IN MENOPAUSE
• Leading cancers in women are:
• Breast cancer
• Cervical cancer
• Endometrial cancer. vip.persianss.
Recommendations for Screening for Breast Cancer Early diagnosis of breast cancer is important.
The 5-year survival rate depends on the stage at the time of diagnosis and ranges from 100% for stage 0–16%
for stage IV.

40. Management of Menopause
So when women come to us in menopausal transition we have to assess her for the high risk factor which
would influence her quality of life later on and these include following:
• Assess her weight and height and calculate her BMI
• Take family history of osteoporosis or fragility fractures or other risk factors for osteoporosis.
• History of diabetes, hypertension
• History of previous fracture
• History of any drug intake .• Family or past history of chronic heart disease
• Any history of breast cancer in the family
• Do her Pap smear if already not done and then every year till the age of 50 years
• Do TVS if not already done or if dysfunctional bleeding
• There is no need to do FSH or hormonal levels for diagnosis of menopause
• Advise mammography and BSE (breast self-examination) once in month
• Clinical breast examination (CBE) once in a year
• Mammography 1–2 years after 40 years and every year after the age of 50 years.

41. Lifestyle Modifications
• Avoid smoking
• Avoid alcohol
• Calcium 1,200–1,500 mg per day preferably from dietary sources
• Vitamin D 600 IU per day
• Exercise specially aerobic for cardiorespiratory and general fitness and weight bearing and resistance training
for sarcopaenia and loss of BMD.

42. • Exercise can be:
• Aerobic exercises like walking and dancing, cycling, tread mill every day for cardiorespiratory benefits
• Balance training like Tai Chi
• Flexibility and endurance like yoga
• Strength training and resistance training 2–3 times a week
• Meditation like yoga.

43. • Women should be informed about the various side effect of HT in the light of various studies like WHI, HERS,
Million Women Study by taking HRT for a long time, i.e. more than 5 years may lead to more incidence of
breast cancer, CHD and DVT and stroke.
• Advantages of Hormone Therapy Women must also be informed about the benefits of hormone therapy.
• Documented benefits of HT not directly related to menopausal symptoms include the following:
• Significant reductions in hip, vertebral, and total fractures with CEE/MPA
• Significant increases in spine and hip BMD with CEE/ MPA
• Decreases in biochemical markers of bone turnover that correlate with increases in BMD
• Aids in the prevention of osteoporosis
• Reductions in the risk of colorectal cancer

44. VARIOUS TYPES OF HORMONAL AND NON-HORMONAL
PHARMACOLOGICAL AGENTS AVAILABLE
• Natural Oestrogens ->Numerous natural oestrogen preparations are available, the principle products
available being estradiol, estrone and oestriol in that order of potency
• Oestradiol is most physiological oestrogen since it is the predominant circulating oestrogen in the
premenopausal reproductive women
• Oestrone is less potent than oestradiol. Both oestradiol and oestrone have been demonstrated to be
cardioprotective and osteoprotective
• Oestriol is a less potent natural oestrogen that has not yet been shown to be cardioprotective and
osteoprotective, but has a good local action on genitourinary structures and also controls vasomotor
symptoms.

45. Semisynthetic Oestrogens
• Because native steroids are relatively water insoluble, modifications of oestrogens for oral administration
and GI absorption includes conjugated oestrogens (oestrone sulphate, oestradiol valerate and conjugated
equine oestrogen), micronisation (micronised oestradiol).
• Oestradiol valerate: It is a natural human source of oestrogen which is chemically synthesised, provides rapid
relief from climacteric symptoms prevents postmenopausal osteoporosis, and cardiovascular risks.
Bioavailability is good.
• Only 3% is sufficient to exert effect on target organ.
• Micronisation of oestradiol results in good levels of systemic oestrogens, although it is rapidly metabolised
to oestrone and conjugated to oestrone-3-glucoronide in the liver

46. Synthetic Oestrogens
• Ethinyl oestradiol, quinestrol, and diethylstilboestrol, although used in contraceptives and other indications are
not used in HRT because of their increased potency and extended half-life.
• Oral and transdermal oestradiol have provided similar benefits in clinical studies.
• Oral and nonoral HT regimens appear to have an equal positive impact on relieving symptoms of oestrogen loss,
such as hot flashes, vulvovaginal atrophy, and loss of BMD.
• Combination of CEE 0.625 mg (conjugated equine oestrogen) with MPA 2.5 mg is as effective as CEE 0.3 mg/ MPA
1.5 mg.
• Now combined patches of oestrogen and progestogen are available for women with intact uterus and there is no
need to supplement oral progestogens.
A combined transdermal patch containing norethisterone acetate 0.25 mg per day and 17B oestradiol 50 microgram
per day is available.
Transdermal HRT has favourable effect on adverse effect on glucose and insulin levels, in contrast to oral therapy.
If patient is hysterectomised then no need to add progestogen.
But if patient has intact uterus, then progestogens are to be added.
Progestogens are added for endometrial protection only.
Disadvantage of oral route are:
• Increased VTE risk , Adverse lipid changes • ,Hepatic side effects •

47. Hormone Delivery System
• Additional investigations are required to clarify differences between hormone delivery systems.
• Because transdermal oestrogen bypasses first-pass metabolism in the liver.
• The transdermal delivery system makes it possible to achieve therapeutic concentrations in a steadier, smoother manner.
• Transdermal delivery also facilitates the use of lower doses than are required with oral delivery, with the benefit of reducing the potential for adverse
effects
. • In cases where we want to bypass liver we can use transdermal delivery system.
• Transdermal delivery system is available as patches, as gels, creams and now available as spray also.
• It is available as estradiol and other advantages of transdermal spray are that it does not cause irritation which is there with transdermal patch.
• Intranasal estradiol preparations are also available and patient satisfaction is there.
• Pellets of oestrogen are also available but the only negative point is that it requires office visit every 3–6 months. Sometimes some soreness at
implantation site is seen.
Transvaginal Route Drugs available as:
• Vaginal creams: Creams for local benefits are available, their absorption is limited and mainly used for local effects.
• Oestradiol ring releases 8 mg oestradiol per 24 hours at a constant rate. The ring is easy to insert and remove as it is soft and flexible. Each ring is to be
used continuously for 90 days and is well tolerated giving significant relief from vaginal dryness, itching, dyspareunia and dysuria.
• Vaginal tablets of oestradiol are also available.

48. • At the doses recommended in labelling, all of the lowdose vaginal oestrogen products approved in the United States for treatment of vaginal atrophy are equally
effective.
• The choice of treatment should therefore be individualised based on clinical experience and patient preference.
• Oestrogen cream is usually applied at a dose of 2–4 g/day for 2 weeks, at which point the dose should be lowered to the minimum necessary to improve symptoms.
• The sustained-release oestradiol ring is replaced every 90 days.
• The oestradiol tablet is usually inserted into the posterior vaginal vault once daily for 2 weeks, and the dose is then decreased to twice weekly.
Local oestrogen therapy is effective for symptoms of vaginal atrophy, although it is not effective for the management of vasomotor symptoms and cannot reduce the
risk for osteoporosis.
Vaginal oestrogen therapy reduces vaginal pH by restoring lactobacilli.
Vaginal oestrogen may also treat vaginal atrophy caused by treatment with gonadotrophin-releasing agonists and antagonists, aromatase inhibitors, and selective
oestrogen receptor modulators.
Local oestrogen therapy should be considered immediately following pelvic irradiation to stimulate epithelial regeneration.
When low-dose oestrogen is administered locally for vaginal atrophy, progestogen is generally not indicated.
Data are insufficient to recommend annual endometrial surveillance in asymptomatic women using vaginal oestrogen therapy. Vaginal oestrogen therapy should be
continued as long as women continue to have distressing symptoms.
Management of vaginal atrophy is similar for the group of women without a cancer history and for women treated for non–hormone-dependent cancer.
However, for women with a history of hormone-dependent cancer, management recommendations are individualised and vary based on each woman’s preference in
consultation with her oncologist
. Overall, subjective improvement occurs in 80–90 percent of women treated with local vaginal oestrogen

50. USE OF PROGESTERONE FOR HRT
• Progesterone generation by the ovaries grinds to a stop at menopause. Hence the need to replace progesterone with oestrogen.
• Currently, progesterones are viewed as endometrial protective agents. They are also used as progesterones only pills in perimenopause and control
DUB in anovular cycles.
• However, in hysterectomised patients, they are often not prescribed.
• The main reasons are patient’s intolerance to them, and the fear of their adverse effects on lipid profile and the breast.
• With the advent of natural progesterones and newer drug delivery systems we are able to bypass the first pass effect on the liver and we may have to
reconsider the incidence of adverse effects and intolerance.
• The currently available compounds are:
• Progesterone analogues -Dydrogesterone Hydroxyprogesterone Medroxyprogesterone acetate
• Testosterone analogues- Norethisterone, Norgestrel ,Levonorgestrel IUD
• Newer synthetic -Desogestrel ,progesterones, Norgestimate ,Gestodene
• Halogenated progesterone -Cyproterone acetate
• Antimineralocorticoid -Drospirenone Progesterone Regimes of Progesterone
• Therapy It has been given along with oestrogen regime
• The two main concerns are intolerance and adverse effects. Intolerance can be circumvented by assessing the individual patient’s symptoms, altering
the preparation, tailoring the dose and choosing a nonoral route of administration.

52. Present Scenario of HT Risks and Contraindications
• Key Points
• There may be a small increase in breast cancer risk after several years of HT, although this continues to be debated
Progestogens added to the HT regimen largely eliminate any increased risk of endometrial cancer.
If hysterectomy has been done then only oestrogen can be given
• The risk for venous thromboembolism (VTE) is increased approximately twofold in current, but not former, users of HT, although the
absolute risk is still very low
• Hormone therapy should be given for the shortest period in the smallest dosage possible for symptomatic relief only.

53. HT IN SPECIAL CIRCUMSTANCES
o Gallbladder disease: The risk of gallbladder disease (cholelithiasis, cholecystitis) and cholecystectomy is increased in women taking HT. This
effect was seen in women taking oestrogen only as well as oestrogen/progestin combination therapy. But after cholecystectomy HT can be
taken.
o Ovarian cancer: There may be a weak association between the prolonged use of oestrogen and ovarian cancer, but no epidemiological
evidence has been established.
o Myocardial infarction: There does not appear to be an overall effect on the rate of fatal myocardial infarction (MI) associated with an HT
regimen, although the EPT arm of the WHI trial noted an increase in the rate of nonfatal MI. The oestrogen only arm did not show an
increase in MI. HT should not be used in MI cases and if women who are using HT and MI occurs they should stop HT.
o Alzheimer’s disease:Hormone therapy adversely affects global cognition, which includes memory and other basic mental abilities including
concentration, language, and abstract reasoning. In particular, EPT doubled the risk of dementia in older women. In the ET group, there was
a weaker, but similar trend in the results.
o Colorectal cancer: The WHI oestrogen-progestin (EPT) arm confirmed that HT lowers the risk of developing colon cancer. The oestrogen-only
arm did not show a reduction in colon cancer. However, HT should not be used solely for colon cancer prevention and women taking HT still
need colorectal cancer screening at the recommended intervals.

54. Contraindications to HT
• Unexplained vaginal bleeding and pregnancy: These are temporary but absolute contraindications to HT.
• Past history of breast cancer or endometrial cancer: While usually considered contraindications to HT, short-term use for severe menopausal
symptoms may be considered with proper precautions.
• Women with a past history of venous thrombosis are at increased risk for recurrence; however, taking OCPs or HT confers an overall low increase to
this risk of recurrence.
• Family history of premenopausal breast cancer: In the Iowa Women’s Health Study there was not an increased incidence of breast cancer in HT users
with a family history of breast cancer, relative to those HT users without a family history of cancer.
• Hypertriglyceridaemia: Oral oestrogens are contraindicated because of the danger of precipitating pancreatitis. Transdermal oestrogens or
intravaginal oestrogens, which avoid the first-pass hepatic effect, do not carry this risk.
• Chronic liver disease: Oral HT is a relative contraindication. Again, transdermal and intravaginal oestrogen avoid the firstpass hepatic effect of oral HT.
• HT is not contraindicated in these clinical settings where many practitioners have often been reluctant (often unjustifiably so) to recommend oral
contraceptives; OCPs have much more potent oestrogenic effects than HT.
These conditions include: • Endometriosis • Fibrocystic breast changes • Hypertension • Mastalgia • Migraine headache • Obesity • Tobacco use •
Uterine leiomyomata (fibroids)
Gonadomimetic Agents->
A widely acting gonadomimetic hormone (with a combination of all oestrogenic, progestogenic and androgenic actions) known as Tibolone is also
included as a form of HRT.
The pharmacological agent is not an oestrogen, progestogen or androgen. It is called STEAR.

55. Temporal Implications of HRT Use
• Short-term HRT implies use for 2–3 years
• Long-term HRT implies use for more than 5 years. (This is to be differentiated from long cycle therapy)
• And now to add a multifocal aspect is: -HRT relayed placement: Where changes of the HRT types and forms are made over a period of time,
shifting from the initial use of oestrogen-progestogen therapy to gonadomimetic use, to raloxifene and finally in some handing over to the
nonhormonal agents or to vaginal oestriol.
• This placement of various therapies in a woman’s postmenopausal lifespan with a view to maximising benefits and minimising risks of
individual groups of hormones gives the women reason to want to continue with it over long-term.
• Concomitant multiple hormone therapy: Where simultaneous administration of some form of HRT takes place along with another HRT form
(e.g. oestrogenprogestogen combined with raloxifene, oestradiol combined with oestriol or another route (e.g. Oral EPRT with vaginal oestriol).
• Concomitant multimodal therapy: When HRT is variably combined with another therapeutic modality (e.g. HRT with bisphosphonates and
calcium, HRT with antioxidants, micronutrients, multivitamins, and calcium). These combinations may need to be considered for maximal
therapeutic outcomes. Hence, their duration of use would vary along with the risk benefit connotations and choice of the individual woman.
• Long-term intermittent therapeutic HRT: Implies the use of 6–12 weekly EPRT or local vaginal ERT intermittently for recurring urogenital
symptoms.

56. ANDROGENS IN MENOPAUSE
• While no testosterone products have received FDA approval for treating symptoms of sexual dysfunction in women, some women may benefit from
testosterone therapy.
• Now it is recommended that postmenopausal women may be candidates for testosterone therapy if they complain of symptoms of decreased sexual
desire associated with personal distress and are unable to identify another cause for their sexual concerns.
• Foremost, other physical, psychological, and emotional relationship factors that may influence sexual function must be ruled out. Once other factors
have been ruled out, the primary candidates for androgen therapy are women with significant, near-total androgen depletion.
• • These include women with loss of adrenal or ovarian function, which may be caused by Addison’s disease or
• • Bilateral oophorectomy.
• • Women with premature ovarian failure of autoimmune origin and •
• Women with Turner’s syndrome may also have abnormally low androgen levels and may benefit from androgen therapy.
• While transdermal patches are currently available for use in men, these patches are not appropriately dosed for use in women. Testosterone is readily
absorbed through the skin. Patches delivering lower doses of testosterone ranging from 150 mg per day to 300 mg per day are currently being studied
for use in women.
• Transdermal testosterone gels, creams, and ointments have been approved in the United States for use in men. However, because these products
deliver high doses, women may experience masculinising effects with their use. These formulations have not undergone rigorous trials and quality-
control testing. Still not approved by FDA for use in women
• Phytoestrogens and isoflavones: Soy products or isoflavones, either through diet or supplementation, may not reduce the incidence of hot flashes.
Inconsistencies among studies to date may be explained by different doses, products, sources, and processing.
Herbal preparations and dietary supplements: Black cohosh, dong quai, evening primrose oil, flaxseed, ginseng, progesterone creams, red clover, and
wild yam extract are commonly used but poorly studied. So to conclude HT is to be tailor-made according to needs of perimenopausal or
postmenopausal women and with informed consent and follow-up of these patients is must

57. Prescription Writing : Module 3
Prescription Writing Of MHT

58. References
• Clinical Practice Guidelines on Menopause 2012, updated 2015, Indian Menopause
Society
• Clinical Practice Guidelines on Post Menopausal Osteoporosis 2012, Indian
Menopause Society
• North American Menopause Society 2012, Indian Menopause Society
• NICE 2015
• Endocrine Society 2015
• 2016 IMS Recommendations on women’s midlife health and menopause hormone
therapy

59. Grades Of Evidence And
Recommendations :
• High Quality: A
• Moderate Quality: B
• Low Quality: C
•Very Low Quality: D Strength
of Recommendations:
• Strong Recommendations: “Recommend”
• Weak Recommendations: “Suggest”

60. Take Home Message
• Target population for initiation of HT is usually within 10 yrs of
menopause
• HT initiated in early postmenopausal period in healthy women is safe
• Like all medicines, HT needs to be used appropriately, but it is essential
that women in early menopause who are suffering menopausal symptoms
should have the option of using HT
Right woman, Right Age, Right HT, Right dose, Right route

61. Agenda
• Concepts and counseling in Hormone Therapy
• Therapeutic Lifestyle Management
• Calcium and Vitamin D
• Regimes of HT
, duration, starting and stopping HT
• Contraindications of HT

62. Agenda
• Use of HT in special situations
• Side effects of HT and their management
• Tibolone
• Raloxifene
• Guidelines

63. Therapeutic Lifestyle Management
3- Step Management of
Menopause
Eat Right Exercise
Medication

64. Therapeutic Lifestyle Management
• Physical
Exercise
• Nutrition
Activity, Targeted
• Avoid alcohol, tobacco
• Stress reducing strategies
• Meditation, Paced respiration
• Massage, Hobbies Nutrition
• Emotion stability
• Positive attitude
• Family involvement
• Spiritual Attitude
• Sleep

65. Living With Menopause-Physical
Fitness
Mind Your Body
• Aerobics
• Weight Bearing
• Flexibility
• Balance

66. Benefits Of Exercise
• Helps to maintain a healthy weight
• Increase in metabolic rate
• Improves bone density
• Coordination and balance
• Muscle strength and joint mobility
• Improves lipid profiles, reduces
CVD risk
• Improves genitourinary problems
• Relieves depression
• Induces sleep
• Improves quality of life

67. Physical Activity Vs. Exercise
• Physical activity is any bodily movement, produced by your muscles
• Exercise is a type of physical activity that is planned, structured,
repetitive and purposeful to improve or maintain some component of
your fitness or health
• Both are important for health

68. Intensive Counseling On Therapeutic
Lifestyle Management
• Physical Activity
• Exercise—Aerobic—CVS
• Strengthening, Resistance training—
Muscle
• Flexibility, Range of motion— Muscle,
Joints
• Ba la n ce a n d Post u re -
prevention of falls
• Bre a t h in g— Re spira t ory
system
• Kegels—pelvis

69. Exercise Prescription
Recommendations for Physical activity and Exercise
• Exercise should include aerobic, muscle strengthening, breathing and
balance
• 30 minutes of moderate-intensity physical activity mostly 5 days a week
• Muscle-strengthening activities should be included at least 2 days/week
• 30 minutes/day – For fitness and reduced risk of chronic disease
• 60 minutes/day – For prevention of weight gain
• 60–90 minutes/day – To avoid regain of weight loss

70. Living With Menopause-
Balanced And Nutritious
Diet

71. Recommendation
• Sugar 6 tsp/day
• Salt 1.5tsp or 3-5 gms/day
• Oil 2 level tbs /day
• Fruit- 100 gms/day
• Vegetables- 300 gms/day
• Drink 8 glasses of water every day
• Add powdered flaxseed, cinnamon, fenugreek, saunf in salads and curds

72. Recommendation
• Snack on two to four nuts like almonds, walnuts or dried-fruit like da
and seeds like pumpkin, sunflower
• Foods that are rich in phytoestrogens include lentils, kidney beans, a
and soybean

73. Tea, Coffee And Diary Products
• Avoid more than 200 mg/day of caffeine
• Limit intake of tea and coffee to 3 cups a day
• 1 cup (150 mL) of brewed coffee is equal to 120 mg of caffeine
• 65 mg for 1 cup of instant coffee and tea
• Consume a minimum of 500–600 mL of milk or curds (low fat) to build on calcium bank in bones
• Support it with lots of vitamin C-rich fruits/vegetables to favor
calcium absorption

74. Living With Menopause- Sleep Hygiene
• Go to bed and get up at the same time
each day
• Sleep in a dark quite room at a
•
comfortable temperature
• Avoid large meals, exercise, caffeine,
nicotine, and liquid two hours before
sleep
M a i n t a i n d i m l i g h t b e d r o o m
environment with no gadgets around
Mind Your Sleep

75. Living With Menopause-
Mental Well Being
Mind Your Mind
• Be a Learner
• Pursue a Hobby
• Continue working
• Read, Converse

76. The greatest mistake in the treatment of
diseases is that there are Physicians for the body
and Physicians for the soul although the two
cannot be separated
- Plato

77. Living With Menopause-
Spirituality
• Prayer
• Meditation
• Be Positive
• Live without expectation
Mind Your Soul

78. • Bond with Family and
Friends
• Participate in Social
Activity
• Enjoy Conversation
• Be Happy and Contended
Mind Your Emotions
Living With Menopause-
Emotional Well Being

79. Living With Menopause - Nutrition
The Recommended Dietary Allowance (RDA) of calcium and Vitamin
D for Adult Indian
• Calcium — >800 mg/day— 1,200mg/day
Upper limit of normal —2,500mg/day
• Vitamin D — 1500-2000 IU
Upper limit of normal—10,000 IU

80. Prescription Writing -Nutrition
• Assess the total calcium intake from dietary sources and if needed,
supplements are used to correct the deficient balance. The intake
should exceed >800 mg/day (Grade B)
• Risk of CV events, calculi are not observed with the recommended
doses of calcium
• Prevention of kidney stones is possible if calcium is taken in the
prescribed dose with sufficient fluids and prefer citrate

81. Healthy Balanced Diet—
Calcium Deficiency
calcium
• Lactose intolerance and limited use
of dairy products
• Consume large amounts of protein
or sodium, it increases
excretion
• High oxalate diets
• Aging
• Vitamin D deficiency
• Long-term treat
stero ids, thyro
thiazide diuretic
• Bowel or digestive
ability to abso
inflammatory bo
disease

82. Choosing Calcium Supplements— Factors
To consider
• Amount of calcium
- Elemental calcium is the actual amount of calcium in the supplement
that the body absorbs for bone growth and other health benefits
• Tolerability
• Absorbability
• Cost
• Relation to meal

83. Types Of Calcium Supplements
Common Calcium
Supplements
% of Elemental
Calcium
Calcium mg/ 1000 mg
of salt
Calcium Carbonate 40 400
Calcium Citrate 21 241
Calcium Gluconate 9 93
Calcium Lactate 13 184
Calcium Phosphate Tribasic 38 388
Naturally derived calcium forms like dolomite, oyster shell, bone meal
may contain lead and other toxic minerals

84. Calcium carbonate Vs. Calcium citrate
Calcium Carbonate Calcium Citrate
Needs acid to dissolve
and for absorption
Doesn’t require stomach acid for
absorption
Less stomach acid as we age-
need more may cause poor
absorption
People
absorbed
over age 50- better
To be taken with
meals
May be taken anytime
Least expensive form of calcium May cost more
Calcium gluconate, calcium lactate, and calcium phosphate have less
calcium than the carbonate and citrate forms

85. Calcium Supplements
• Limit 500 mg calcium at one time from food
and/or supplements
• Spread calcium sources throughout the day
• Start supplements with 500 mg calcium
daily for about a week, gradually adding
more to reduce side effects
• Absorption of calcium is decreased when
taken with foods rich in fires and fat, Iron,
zinc, spinach, coffee, alcohol and antacids

86. Calcium Supplements
• Thyroid medications, corticosteroids, tetracyclines and
anticonvulsants and calcium should be taken separately
• Contraindicated in patients with hypercalcaemia, renal insufficiency
and with caution in nephrolithiasis
• Excess amounts more than 2,500 mg a day - effect kidneys and can
reduce the absorption of other minerals like iron, zinc and
magnesium

87. Vitamin D
• Vitamin D and its active metabolite 1,25-dihydroxyvitamin D
•
(1,25(OH)2D) have classical actions on calcium balance and bone
metabolism
The intestine cannot absorb calcium and phosphate adequately due
to insufficient 1,25(OH)2D, leading to secondary hyperparathyroidism
and a lack of new bone mineralization
• Individuals who have more vitamin D are able to absorb more calcium
• In combination with adequate vitamin D, calcium levels of about 800
mg per day can be achieved by a healthy diet that includes daily
intake of calcium rich foods

88. Vitamin D- Sunlight

89. Despite the sunny climate there is widespread vitamin D deficiency in
Asian Indians of all age groups including children, pregnant women and
adult males and females living in urban and rural areas in India
Sun Exposure And Limitation For Vitamin D
Synthesis- Vitamin D Deficient Population

90. Vitamin D Deficient Population
• Age 50 or older- the skin becomes less effective with advancing age a
• Dietary intake is low
• Low exposure to sun
• Dark skin
• Pollution

91. Vitamin D Deficient Population
• Overweight/ Obesity
• Gastric bypass surgery
• Milk allergy or lactose intolerance
• Liver or digestive diseases, such as Crohn's disease or celiac

92. Vitamin D From Sunlight Exposure
• Amount varies with time of day,
a n d sk in
se a son , la t it u de
pigmentation
• It is preferable to get vitamin D
through sunlight by exposing 20% of
body surface area at least 30 minutes
between 10 am and 3 pm, depending
on the season, latitude, altitude,
pollution, and skin pigmentation

93. Vitamin D From Sunlight Exposure
• The sunlight between 11 am to 2 pm is preferably the best
• Clothing, sunscreen, window glass and pollution reduce amount
produced

94. Vitamin D
Necessary For Calcium Absorption
• Choose a supplement with vitamin D unless
obtaining vitamin D from other sources
• Follow age group recommendation. Avoid
going over a daily combined total of 2,000 IU
from food and supplements
• It’s not necessary to consume calcium and
vitamin D at the same time to get the benefit
of enhanced calcium absorption

95. Management Of Vitamin D Deficiency
• Cholecalciferol (vitamin D3) tablet or powder 60,000 IU/once a week
for eight weeks preferably with milk or
• One IM injection of 6,00,000 IU is given to correct the deficiency (not
to be repeated before three months and may be given after
confirmation of persisting low levels of vitamin D )
Maintenance therapy(from natural sources or supplements) is advised
after correction of the deficiency
•

96. Maintenance Therapy
• Cholecalciferol tablet or powder 60,000 IU once a month in summer o
winter or
• Vitamin D supplements by oral spray or oral tablets of 2,000 IU/day, o
• Injection of Cholecalciferol 3,00,000 IU IM, twice a year or 6,00,000 I
• Cholecalciferol, 1,000 IU daily, will raise blood levels, on average, by
ng/mL

97. Hormone Therapy Terminology
• HT/MHT—Hormone therapy
• HRT- Hormone replacement therapy as in premature menopause
• ET - Estrogen therapy
• EP - Estrogen Progesterone therapy
• AT-Androgen therapy

98. Menopausal Hormone Therapy
Wide range of hormonal products:
• Natural Estrogens
• Progestogens
• Androgens
• Tibolone

99. Types Of Estrogens
Natural Estrogens - Menopausal HT
• Native Estrogen – 17 beta Estradiol, Estrone, Estriol
• Conjugated Equine Estrogen
Synthetic Estrogens - Oral contraceptives
• Ethinyl Estradiol

100. Natural Estrogens Used
For Menopausal HT

101. Synthetic Estrogens Used For
Menopausal HT
• Synthetic estrogens: estrogenic synthetic molecules (ethinyl estradiol
usually used in oral contraceptives)
• High potency with regard to adverse hepatic effects and potential
secondary risks (hypertension and thromboembolic disease) but low
doses used in HRT
• Hepatic potency is 4 to 18 times higher than native estrogens

102. Potency
• Estriol is least potent short acting estrogen
• Conjugated Equine estrogen contains mixture of estrogens
• Estradiol is 12 times more potent than estrone and 80 times more
potent than Estriol

103. Dosage—Standard And Low-dose Oral And
Transdermal Estrogens
Dosage of Estrogen
Estrogens Ultra
low
Low Standar
d
High
Conjugated equine
estrogens (mg)-oral
0.15 0.3, 0.45 0.625 1.25
17β-estradiol (mg) oral 0.5 1 2 4
Estradiol valerate (mg)-oral 1 2
Transdermal 17β-estradiol
(µg)
14 25 50 100

104. Low Dose Adjustive Therapy
• Biological variables with the sex steroid synthesis and function
• Variable response of an individual to estrogen deficiency
• Application of the pharmacodynamics of various hormones and regimes
to suit an individual woman’s need
• Start with age appropriate low dose therapy

105. Lower HT Doses —Why?
• One type of HT cannot fit all populations of postmenopausal women
• Benefits of HT can be maintained with lower doses than previously used
whilst minimizing risks and possibly side effects
• Improved continuance and compliance to achieve potential long-term
health benefits
• Efficacy in prevention of osteoporosis is not compromised

106. Exceptions To Low Dose Therapy
• Premature ovarian failure
• Severe osteoporosis
• Predominance of psychological problems, e.g. climacteric depression

107. Non-oral Routes-Indications
Indications for use of the transdermal route first line:
Transdermal estrogen has a neutral effect on triglycerides, C-reactive protein,
and sex
hormone binding globulin
•
•
• Triglyceridemia, Hyperlipidemia
Increased C-reactive protein
• Migraine
Diabetes

108. Non-oral Routes-Indications
• Controlled hypertension
• Existing gall bladder disease
• Obesity
• Smoking
• Previous venous thromboembolism
• Varicose veins
• Personal preference

109. Synthetic Estrogens – Not
Used For MHT
• Ethinyl estradiol, Mestranol
• 750-1000 times more potent than natural estrogens
• Enhances hepatic effects which increases synthesis
factors, angiotensin, SHBG
of clotting

110. Role Of Intrauterine
Levonorgesterol System
• During perimenopause
• Contraception
• Control of bleeding -AUB
• Women with side effects for oral progestogens

111. Overcoming Side Effects Of
Progesterone In HT
Natural Progesterones
• Choosing natural progesterone
metabolically friendly
and Dydrogesterone which are
• Early reports on neutral effect on breast

112. Overcoming Side Effects Of
Progesterone In HT
Androgenic progesterones
• Implicated in increased risk of:
• Breast cancer
• CVD events
• Blunt beneficial effect of estrogen on lipids
• Useful for hemostatic control in AUB

113. Progesterone After
Surgical Menopause
• Residual ovarian tissue— Endometriosis, frozen pelvis
• Residual endometrium— Endometrial ablation, supracervical
hysterectomy

114. Concepts In Prescribing HT
• Different routes of administration
• Potentially different effects
• Risks and benefits differ at different age group
• Response to HT may differ among individuals and also in the same
individual over period of time
Individualization or Personalization of HT

115. Concepts In Prescribing HT
• Identify goal of treatment
• Rule out contraindications
• Counseling, Variable response
deficiency
of an individual to estrogen
• Timing (window of opportunity)
• Early start
• Maintenance of estrogenic benefits

116. Concepts In Prescribing HT
• Patient selection
• Avoiding generalized prescribing
• Personalization
• Tailoring dose to patient
• Continuation and tapering the dose with age

117. Concepts In Prescribing HT
• Selection of type of estrogen, type of progesterone
• Route of therapy
• Dosage-minimum effective dose
• Risk/Benefit analysis
• Tailor Evaluate response
• No mandatory time limit
• Follow up annually

118. Benefits Of Hormone Therapy
• 3 most beneficial effect of estrogens - symptom relief, urogenital
atrophy and bone
• The most effective treatment for vasomotor symptoms is HT (GRADE
A)
• Progesterones or low dose oral contraceptive pills can be used in the
menopause transition phase for relief of symptoms (GRADE A)
• Vaginal estrogen therapy - most effective in the treatment of
urogenital atrophy (Grade A)

119. Benefits Of Hormone Therapy
• Chronic therapy for atrophic vaginitis requires the use of the smallest
effective dose; treatment can be continued indefinitely although
safety data from studies do not go beyond 1 year (GRADE C)
• Recurrent Urinary T
ract Infection after ruling out other causes
(GRADE A)

120. Benefits Of Hormone Therapy
• EPT/ET- for prevention and treatment of osteoporosis; reduces the
risk of spine, hip and other osteoporotic fractures by 33-40% ( GRADE
A)
• HT for bone protection within ten years of menopause (GRADE B)

121. Benefits Of Hormone Therapy
• Improves quality of life. Estrogen can be prescribed to enhance
mood in women with estrogen deficiency related depressive
symptoms. The effect appears to be greater for perimenopausal
symptomatic women than for postmenopausal women (Grade A)

122. Possible Benefits Of Hormone
Therapy
• Decrease in the risk for Type 2 diabetes (GRADE B)
• Decreases the abdominal obesity (GRADE B)
• Estrogens - protective effect on OA (GRADE B)
• Estrogen benefits verbal memory over the short period after surgical
menopause (GRADE B)
• Reduces the neovascular macular lesions (GRADE C)

123. Before Prescribing MHT
• Dialogue and documentation
• Medical conditions and risks should be identified
• Pre HT tests conducted
• Dose, duration and follow up is clearly indicated
• Addition of progestogens - Intact uterus, endometriosis, stage I & II
endometrial CA and supracervical hysterectomy
• Offer hormone therapy, if not contraindicated

124. Communication
• Dialogue and documentation
• The physician should discuss with the woman about
(a) the benefits, risks and side effects of HT
(b) the types of HT available, and the options suitable for her
(c) the way treatment will be monitored
(d) how long HT might be used
(e) economic consideration
(f) other available options
This will improve compliance of treatment

125. WHI-E: Number Of Events
Per 10,000 Women Per Year Of CEE Therapy

126. Interpretation Of Risk
• Rare = Rare >1/10,000 and <1/1,000 women per year
• Very Rare = Less than or equal to 1 per 10,000 women per year

127. Explaining HT: Benefits
WHI- Number Of Less Events on Estrogen vs. Placebo per 10,000 Women
per year of HT Use between the age group of 50-59 years R (GRADE A)
Disease Number of Less Events with
Estrogens
Myocardial Infarction 12
Breast Cancer 8
Number of Less Events with E/ E+P
Total Deaths 10
Adverse Events 18
Fractures 5
Colorectal Cancer 6

128. Disease Estrogen WHO/ CIOMS
definition of
Risk
Estrogen +
Progesteron
e
WHO/ CIOMS
definition of Risk
VTE 4 Rare >1/10,000
and <1/1,000
11 Rare
>1/10,000
and <1/1,000
Stroke 1 Rare >1/10,000
and <1/1,000
4 Rare
>1/10,000
and <1/1,000
Breast 5 Rare
>1/10,000
and <1/1,000
CVD 5 Rare
>1/10,000
Based on WHI- Number Of Excess Events on HT vs Placebo
per 10,000 Women per year of HT Use between the age group of 50- 59
years - R (GRADE A)

129. Absolute Risk Of Breast Cancer
Risk Factor Risk per 1000
women
Extra Breast Cancer
Baseline Risk 45 -
HT 5 Y (CEE + MPA) 47 2
HT 15 Y (CEE + MPA) 57 12
Menopause after 54 58 13
BMI > 31 59 14
Lifetime Excess Alcohol 72 27

131. HT- Breast
Perception
• All types of HT cause an increased risk of breast cancer within a short
duration of use
Evidence
• The risk of breast cancer associated with MHT in women over 50 is
complex (B)
• Any possible increased risk associated with MHT may be decreased by
selecting women with lower baseline risk including low breast density and
by providing education on preventive lifestyle measures (reducing weight,
reducing alcohol intake, increasing physical activity) [D]

132. HT- Breast
Perception
• All types of HT cause an increased risk of breast cancer
Evidence
• WHI cohort showed a small increase in risk of breast cancer of about eight extra
cases per 10,000 women per year. Risk was not increased in first-time hormone
users [GRADE A] The MHT attributable risk is small and decreases when treatment
stops [B]
• The increased risk is primarily associated with the addition of a synthetic
progestogen to estrogen therapy and to duration of use [B]
• The risk may be lower with micronized progesterone or dydrogesterone [C]

133. HT - Breast
There is a lack of safety data supporting MHT use in
breast cancer survivors

134. Cardiovascular System -HT
Perception
• HT increases the risk of coronary heart disease (CHD) throughout the
whole postmenopausal period
Evidence
• HRT in women aged 50 – 59 years does not increase CHD risk in
healthy women and may even decrease the risk in this age group and
all-cause mortality. [Grade A]

135. • Data on daily continuous combined estrogen–progestin are less robust
but other combined therapy regimens appear to be protective as
shown in Danish and Finnish studies [A]
• Recent meta-analyses and WHI 13-year follow-up data all show a
consistent reduction in all-cause mortality for MHT users [A]
• It is not recommended to initiate MHT beyond age 60 years solely for
primary prevention of CHD [A]
Cardiovascular System -HT

136. Summary
CHD
• Women within 10 years of menopause 0.89
women more than 20 years after menopause
Breast
where as it is 1.7 in
• In new users – hazard ratio > by year 5 and fails to be significant at
any point during the trial
• With estrogen alone no increase over a 7 year period

137. • Oral estrogen is contraindicated in women with a personal history of
VTE [A]
• Transdermal estrogen should be first choice in obese women with VMS [B]
• VTE risk increases with age and with thrombophilic disorders
• The risk of VTE increases with oral MHT but is rare below age 60
Venous Thromboembolism

138. Venous Thromboembolism
• Observational studies and biological plausibility point to a lower risk
with low-dose transdermal therapy
• Some progestogens may be associated with a greater VTE risk [C]
• The incidence of VTE is less frequent amongst Asian women [C]
• Population screening for thrombophilia is not indicated prior to MHT use
[C]

139. HT - Bone
Perception
• HT should not be used for bone protection because of its unfavorable
safety profile
• Recommendations by health authorities (EMEA, FDA) limit the use of
HT to a second-line alternative
• HT could only be considered when other medications failed, were
contraindicated or not tolerated, or in the very symptomatic woman

140. HT - Bone
Evidence
• For the age group 50–59, HT is safe and cost-effective
• Overall, HT is effective in the prevention of all osteoporosis-related
fractures, even in patients at low risk of fracture [GRADE A]

141. HT - Bone
Perception
• HT is not as effective in reducing fracture risk as other products
(bisphosphonates, etc.)
Evidence
• Although no head-to-head studies have compared HRT to
bisphosphonates in terms of fracture reduction, there is no evidence
to suggest that bisphosphonates or any other antiresorptive therapy
are superior to HRT

142. HT —Benefit Risk Analysis
Assess patient criteria
- Symptomatic woman with interest in MHT who is:
- Age < 60 Y or
- < 10 Y since menopause
If age > 60 or >
10 y
since menopause
Consider other
options
Present Consider other
options
YES
Consider circumstances where MHT should not be used
(TABLE 4)
Avoid if:
-Unexplained vaginal bleeding
- Stroke, TIA, MI, PE, VTE
- Breast or endometrial cancer
- Active Liver Disease

143. Exercise caution in women with:
- Diabetes
-Hypertriglyceridemia
- Active gallbladder disease
- Increased risk of Breast cancer or CVD
- Migraine with aura
Consider other
options
ABSENT
ACCEPTABLE
Present
Evaluate Cardiovascular Risk Consider other options
Evaluate Breast Cancer Risk
High to
Moderate Consider other options
High
ACCEPTABLE

144. ACCEPTABLE
Uterus Present?
Estrogen plus
Progestogen
Tibolone
Estrogen Alone
YES NO
Evaluate Breast Cancer
Risk

145. Patient Characteristics That May Be Favorable
For Estrogen/Androgen
Combination
• Surgical menopause
• Continued VMS despite estrogen replacement
• Decreased well-being despite estrogen replacement
• Acquired sexual desire dysfunction
• In India, androgen formulations for use at menopause are unavailable
Tibolone is a good alternative

146. Prescribing HT
Important points to consider
• When to Start ?
• What Therapy? Which route? Which regime?
• Tackling side effects
• How long to give ?
• When to Stop ?

147. Starting HT
• Explain to women
• To report at 1, 3-month review appointment, that unscheduled
vaginal bleeding is a common side effect of HRT within the first 3
months of treatment
• It will take 3-4 weeks for control of symptoms

148. Prescription Writing For
Menopausal Symptoms
Menopausal Hormone Treatment
Uterus Intact Post
Hysterectomy
First Line
Management
Estrogen
Therapy
Estrogen
Progesterone
Therapy
HT should be limited to symptomatic patients without excess risk
of heart disease, stroke or breast cancer

149. Estrogen Progesterone Therapy
• Unopposed estrogen prescribed for postmenopausal women who have
had a hysterectomy
• Estrogen and Progesterone is prescribed for a women with uterus,
this reduces the risk of Endometrial Hyperplasia and Cancer
associated with unopposed estrogen therapy

150. Route Of Administration
Oestrogen
• Oral, Transdermal, Vaginal
Progestogen
• Oral, Vaginal, Intra-uterine

151. How HT Is Given?

152. Prescription Writing For
Menopausal Symptoms
Estrogen Therapy
Tab CEE 0.3 mg, 0.625 mg
17 beta-estradiol 1,2 mg/ Estradiol valerate
1,2 mg daily orally
Transdermal 17 beta–estradiol 25 – 100 gms
Tab Tibolone 2.5 mg daily

153. Prescription Writing For
Menopausal Symptoms
Estrogen progesterone therapy in women with uterus in the peri and early
menopause
Continuous sequential EPT
•17 beta- estradiol/ Estradiol valerate 1
mg/ 2 mg or
•Oral CEE 0.3 mg/ 0.625 mg or estradiol
valerate 1mg/ 2 mg or
•Transdermal 17 beta estradiol 25-100 gms
daily
•And 10 mg dydrogesterone or micronized
progesterone 200 mg 10-14 days.

154. Continuous Sequential EPT
•
• Estrogen is used everyday, with progesterone added cyclically for
10–14 days during each month
Uterine bleeding occurs in about 80% of women when progestogen is
withdrawn, although bleeding can begin 1–2 days earlier, depending
on the type and dose of progestogen used
• In a typical continuous-cyclic regimen, progestogen is started on day
1 or day 15 each month

155. Estradiol/Dydrogesterone 1/10 Or
Sequential regimen
• Estrogen deficiency symptoms in postmenopausal women ≥6 months since last menses

156. Prescription Writing For
Menopausal Symptoms
Estrogen progesterone therapy in women with uterus in the post menopausal
women
Continuous combined EPT
•17 beta- estradiol and dydrogesterone 5 mg
daily
•CEE 0.3 mg/ 0.625 mg, 17 beta-estradiol/
estradiol valerate 1 mg/ 2 mg or transdermal
17- beta estradiol 25-100 µgms daily and
micronized progesterone 100 mg daily
•Tibolone 2.5 mg daily

157. Continuous Combined EPT
• Continuous-combined EPT
• Fixed doses of estrogen and progesterone are administered everyday
• Approximately 40% incidence of irregular spotting or bleeding in the f

158. Estradiol/Dydrogesterone 1/5:
Combined
Estrogen deficiency symptoms in postmenopausal women ≥12 months since
last menses

159. Perimenopausal Women
• The options available are monthly cyclic and sequential regimens
• Continuous combined regimens should not be used in perimenopausal
of the high risk of irregular bleeding

160. Postmenopausal Women
• Continuous combined therapy is the regime of choice and induces
endometrial atrophy

161. Problems From HT
• Bleeding problems
• Insufficient symptomatic response
• Side effects

162. Questions To Ask?
• When does the bleeding occur with respect to the estrogen and
progesterone phase?
• How long and how much?
• History to rule out poor
conditions
compliance, drug interactions medical

163. Bleeding- Problem Of Compliance
• Scheduled or withdrawal bleeding—with the cyclic, cyclic combined
• and sequential EPT
• Unscheduled or irregular bleeding with continuous combined EPT

164. Causes Of Abnormal Bleeding
• Poor compliance- missing tablets especially progesterone
• Poor gastrointestinal absorption-IBS, Coeliac disease, Crohn’s
• Asynchrony of endogenous and exogenous hormones (in pre and
perimenopausal women)- in a regular cyclical woman add
progesterone from the 11th day before her expected cycle to mimic
her natural cycle length
• Premenopausal woman with erratic cycles- an OCP unless
contraindicated is good option or adjust the dose and type of
progesterone

165. Causes Of Abnormal Bleeding
• Atrophic endometrium —commonly seen with continuous combined
regimes
• Coagulation defects—thrombocytopenia, von Willebrand’s disease,
on warfarin or high dose aspirin
• Drug interactions- Broad spectrum antibiotics may cause intestinal
hurry and effect the absorption of hormones

166. Gynecological disorders
• Endometrial hyperplasias, polyps fibroids, adenomyosis,
endometritis, endometrial cancer
• Cervical polyps, erosions cancer
• Atrophic vaginitis, cancer of the vagina or vulva
• Hypothyroidism

167. When To Investigate?
• Routine endometrial surveillance is not needed
• With cyclical regimes if bleeding starts at the start of progesterone
therapy, or these change in the duration or intensity of blood flow
which is normal for that woman with continuous combined regimes-if
bleeding is heavy or continuous and continues after 6- 12 months of
use
• In women with a high risk for uterine cancer

168. Insufficient Response
Poor compliance
• Missed tablets, Vomiting
• Non-adherent patches
Poor absorption
• Check blood levels

169. Insufficient Response
Concomitant testosterone deficiency
• Especially BSO, Loss of libido, Fatigue
Other co-existing conditions

170. Other Co-existing Conditions
• Differential diagnosis for Vasomotor symptoms, Calcium channel
blockers, nicotinic acid, anti estrogens like raloxifen & tamoxifen,
GnRH analogues, aromatase inhibitors, bromocriptine,
cephalosporins, calcitonin, metronidazole, alcohol
- Thyroid disease
- Pheochromocytoma
- Carcinoid
- Renal neoplasia
• TB
• Recurrent UTI

171. Dealing With ET/EPT Side Effects
Side Effects
Fluid Retention
•Restrict salt intake; maintain adequate water intake exercise; try a
herbal diuretic or mild prescription diuretic
Bloating
•Switch to low-dose transdermal estrogen; lower the progestogen
dose a level that still protects the uterus; switch to another progestin
or to micronized progesterone

172. Dealing With ET/EPT Side Effects
Side Effects
Breast Tenderness
• Lower the estrogen dose; switch to another estrogen; Restrict salt
intake; switch to another progestin; cut down on caffeine and
chocolate
Headaches
• Switch to transdermal estrogen; lower the dose of estrogen and/or
progestogen; switch to a continuous combined regime switch to
progesterone or 19 norpregnane derivatives; ensure adequate water
intake; restrict salt, caffeine, and alcohol intake

173. Dealing With ET/EPT Side Effects
Side Effects
Mood changes
• Lower the progestogen dose; switch progestogen; switch from
systemic progestin to the progestin IUS; change to a continuous-
combined EPT regimen; ensure adequate water intake; Restrict
intake of salt, caffeine and alcohol
Nausea
• Take oral estrogen tablets with meals or before bed; switch to
another oral estrogen; switch to transdermal estrogen; lower the
estrogen or progestogen dose

174. Contraindications Of HT
• Active endometrial and gynecological hormone dependent cancers
• Active breast cancer, estrogen progestogen receptor positive cancers
known or suspected pregnancy
• Undiagnosed, abnormal vaginal bleeding
• Severe active liver disease with impaired or abnormal liver function
• Previous personal or family history of venous thromboembolism
• Systematic lupus erythematosus

175. Use With Caution
• Migraine headaches
• Superficial thrombophlebitis
• Strong family history of breast cancer
• Uterine fibroids
• Endometriosis
• Gallbladder disease

176. Stop Treatment
• If migraine appears for the first time or if headache gets worsened
• Blurring of vision or any symptoms suggesting of vascular occlusion
• If jaundice appears
• If there is significant rise in blood pressure
• HT to be stopped 4–6 weeks before elective surgery

177. Hormone Therapy & Pre-
existing Conditions
Conditions HT
Asthma Small increase risk, no worsening of pre- existing
disease
Breast Cancer Vaginal estrogen not contraindicated
Coronary Heart
Disease
• Should not be initiated for primary or secondary
prevention
• Transdermal route preferred and natural
progesterones

178. Hormone Therapy & Pre-
existing Conditions
Conditions HT
Diabetes mellitus Increased risk of osteoporosis,
not contraindicated
Fibroids Can cause enlargement
Liver Disease Transdermal route preferred, liaise with
gastroenterologists
Gallbladder disease Increased risk of gallbladder disease
Migraine Not contraindicated, transdermal route
preferred

179. Hormone Therapy & Pre-
existing Conditions
Conditions HT
Otosclerosis Insufficient evidence to contraindicate
Parkinson’s Disease May reduce risk of Parkinson’s disease,
not
contraindicated
Post-transplant Should be considered, increased risk of
osteoporosis
Renal failure Should be considered, increased risk of
early menopause

180. Hormone Therapy & Pre-
existing Conditions
Conditions HT
Rheumatoid Arthritis Increased risk of osteoporosis,
Increase in ‘flares’
Systemic lupus erythematosus Increased risk of osteoporosis,
Increase in ‘flares’
Thyroid Disease Increased risk of osteoporosis,
notcontraindicated
Venous Thromboembolism Vaginal estrogens, Transdermal
estrogens not contraindicated

181. Hormone Therapy & Pre-
existing Conditions
Conditions Hormone Therapy
Previous abnormal smears/
cervical cancer
Not Contraindicated
Endometrial cancer
Hyperlipidemia
Hypertension
Ovarian cancer
Past history of benign breast
Disease
Contact lens wearers

182. Hormone Therapy & Pre-
existing Conditions
Conditions Hormone Therapy
Depression
Not Contraindicated
Hyperlipidemia
Melanoma
Obesity
Sickle cell anemia
Smoking
Valvular heart disease

183. Follow Up
• Review:
• After one month for efficacy and side effects, check weight and
• After 3 months to assess effects and compliance

184. Follow Up
• Then annually for efficacy, side effects and compliance, check weight and
blood pressure, a physical examination, update of medical and family
history, relevant laboratory and imaging investigations, a discussion on
lifestyle, and strategies to prevent or reduce chronic disease. review
regarding continuing /modifying HT
• Evaluation to rule out pelvic pathology (endometrial hyperplasia and
cancer)For women with persistent unscheduled bleeding while taking HT
• Emphasizing importance of adhering to age-appropriate breast cancer
screening

185. • Premature menopause - Hormone Therapy:
Up to natural age of menopause; further continuation of
therapy according to the indication and the need (Grade C)
• Natural menopause:
Safety data of EPT therapy with CEE+MPA is 3-5 years with ET
safety data for use is 7 years of treatment with 4 years follow-up
Duration Of Therapy

186. • Role of extended use of Hormone Therapy is a shared decision
• between the woman and the physician (Grade A)
• Stopping HT: May be abrupt or the dose and duration may be tapered
(Grade C)
Indian Menopause Society 2013:
Duration Of Therapy

187. Duration Of Therapy
Patients likely to consider continuing therapy include those who:
• Fail attempt to stop EPT
• Are at high risk for fracture, or
• Alternative therapies are not appropriate

188. Follow Up Investigations
• Baseline investigations annually or earlier :
- Routine blood and urine examination
- Blood sugar
- Lipid profile
• Pelvic USG , Mammography
• Pap Smear every 3 years
• DXA once in two - five years [optional]

189. Switch Of Regimens
• From OCPs to HT
• Switch directly to MHT at the end of OCPs
- Age of 45-50 years
- Serum FSH:LH ratio of > 1, FSH > 30 IU/L

190. Switch Of Regimens
• Switching form sequential to continuous combined therapy /tibolone
• Natural age of menopause,
• Six months amenorrhea
Note: Dose of estrogen in OCPs in India– Ethinyl estradiol (EE) 20µg,
30µg,50µg

191. Tibolone
• Oestrogenic action on bone , vagina, vasomotor symptoms and lipids
• Progestogenic & antiestrogenic action on endometrium and breast
• Androgenic action on mood and libido

192. Tibolone
Specific Indications:
• Mood & libido
• Adverse effects with conventional HRT
• Older women
• Family history of breast cancer
• History of endometriosis, fibroids
• Add back therapy with GnRH analogues

193. Tibolone
• 2.5 mg single daily dose orally
• 1.25 mg equally effective
Adverse Effects
• Nausea & weight gain
• No change in HDL level
• Increases risk of recurrence in breast cancer survivors

194. Tibolone
Not recommended within 1 year of menopause because of risk
of irregular vaginal bleeding

195. Tibolone
• Contraindications for Prescribing Tibolone
• Undiagnosed genital bleeding
• Women over 60 years, women with risk factors for stroke,
• e.g. Hypertension, smoking, diabetes and atrial fibrillation
• Known past or suspected breast cancer known or suspected estrogen-
malignant tumor, endometrial hyperplasia

196. Tibolone
Contraindications for Prescribing Tibolone
• Previous or current venous thromboembolism (VTE) [deep vein
thrombosis (DVT), pulmonary embolism], known thrombophilic
disorders (e.g. Protein C, protein S or antithrombin deficiency)
• History of arterial thromboembolic disease [e.g. angina, myocardial
infarction, stroke or
• Transient ischemic attack (TIA)], acute liver disease or with
abnormal liver function tests, porphyria

197. Tibolone
Tibolone Drug Interactions
• May enhance the effect of anticoagulants
• Rifampicin, antiepileptic medicines such as carbamazepine,
phenytoin, phenobarbital, primidone and barbiturates such as
of
amobarbital (amylobarbitone) may reduce the blood levels
tibolone
• Women with diabetes may need an increase in the dose of their
antidiabetic medicine (insulin or oral antidiabetic medicine)

198. Tibolone
thromboembolic
• Treatment should be discontinued if signs of
complications occur
, if results of liver function tests become
abnormal, or if cholestatic jaundice appears
• The occurrence of vaginal bleeding or spotting soon after starting
treatment with tibolone may be due to the residual effects of
endogenous or exogenous estrogens

199. Tibolone
• Bleeding commencing after 3 months of treatment or persistent
bleeding should be appropriately investigated. In most cases, no
apparent cause of bleeding is found
• As with all steroids with hormonal
examination is advisable
activity, yearly medical

200. Prescription Writing For
Menopausal Symptoms
Non Hormonal Treatments for Relief of Menopausal Symptoms
• Gabapentin: 300 mg TID × 6 weeks–3 months
• Venlafaxine: 25–75 mg/day
• Paroxetine: 7.5–20 mg/day
• Fluoxetine: 10–20 mg/day
• Isoflavones: 70 mg–100 mg daily × 6 weeks–3 months (equal
producer patients have to be identified)
• Lycopene: 18–24 mg daily

201. Prescription Writing For
Menopausal Symptoms
Premature Menopause
• Cyclic sequential EPT regime till the age of natural menopause
• Low dose oral contraceptive pill may be used till the natural age of
menopause if not contraindicated

202. Prescription Writing For
Menopausal Symptoms
• Sexual Dysfunction
• Tibolone 2.5 mg OD × 6 weeks– 3 months
• Vaginal estriol succinate cream 0.5 mg or Tab estriol 1 mg, 2 mg/ vagi
equine estrogen if urogenital atrophy is present

203. Prescription Writing For
Menopausal Symptoms
Urogenital Symptoms in Menopause
• Vaginal estriol succinate cream 0.5 mg or oral Tab estriol 1 mg, 2 mg
or vaginal conjugated equine estrogen 0.625 mg daily for 2 weeks
followed by biweekly application for 6–12 weeks at bedtime, may be
continued for 1 year
• Lactic acid wash daily
No routine monitoring of endometrial thickness

204. Genitourinary Syndrome-
Vaginal Estrogen Therapy
Indications in postmenopausal women
• Vaginal symptoms
• Recurrent urinary tract infections
• Overactive bladder
• Vaginal surgery---Pre and postoperative
• Pap’s smear---After a short course of therapy

205. Advantages/Disadvantages
• Avoids enterohepatic circulation
• No endometrial stimulation
• No progesterone
• No systemic side effects
• Mainly local effects
• Acceptable following estrogen dependent cancers after counseling
• Mode of administration

206. Vaginal Preparations- India
• Conjugated equine estrogen (Premarin) 0.3-2.5mg/day
• Estriol(Evalon) creams . 03mg-0.5mg/day
• Estriol (Evalon) Tablets1-2mg/day
• Estradiol tablet, 10-25mcg (E 2)

207. Recommendations
• Treatment should be started early and before irrevocable atrophic
changes have occurred
• Treatment needs to be continued to maintain the benefits
• All local estrogen preparations are effective and patient preference
will usually determine the treatment used

208. Recommendations
• Delay in starting local treatment will reduce degree of response
• Initial loading dose to stimulate receptors followed by
maintenance dose once or twice per week
low

209. Length Of Therapy
• Vaginal ET should be continued as long as distressful symptoms
remain

210. • The method of use, benefits and adverse effects of systemic HT cannot be extrapolated to the low dose
vaginal preparations

211. SERM –
Selective Estrogen Receptor Modulator
• Raloxifene is the first of a benzothiophene series of antiestrogens to
be labeled a SERM
• Lasofoxifene
• Droloxifine
• Idoxifene and
• T
oremifene are similar SERM agents (but they are still considered
experimental)

212. Raloxifene
Tissue selectivity
• Agonist - Bone
- Lipid Metabolism
• Antagonist - Uterine Endometrium
- Breast Tissue

213. Place In Therapy
Treatment & Prevention of post – Menopausal osteoporosis
Role of Raloxifene is being evaluated in:
• Advanced breast cancer
• Chemoprevention of breast cancer
• Cardioprotection
Not for symptom control

214. Dosage And Administration
• Recommended dosage is Raloxifene 60 mg once daily, which may be
administered any time of day without regard to meals

215. Contraindications
• Pregnancy
• Active or past history of venous thromboembolic events, including
deep vein thrombosis, pulmonary embolism, and retinal vein
thrombosis
• Hypersensitive to Raloxifene or other constituents of the tablets

216. Assess The Profile Of The Woman To Individualize
Treatment
Type and stage of menopause
• Surgical menopause–E only/Tibolone
• Perimenopause–Cyclical Progesterone/OCP/HT cyclical
• Early Menopause <12 months–EPT (More estrogens) sequential
• Late Menopause <12 months–EPT continuous combined/tibolone
(Lowest estrogens/transdermal)

217. Assess The Profile Of The Woman To Individualize
Treatment
• Premature Menopause–OCP/HT sequential regime
• Urogenital Atrophy- Local estrogens
• Evaluate women’s need and preference
• Evaluation of women’s individual risk factors

218. Review Of Treatment
No Symptom Relief or has Side Effects Change dose OR Therapy
6 – 8 Weeks
Symptom Relief
No Symptom Relief or has Side Effects
Symptom Relief
6 – 8 Weeks
Change dose
OR Therapy
6-12 months review
Review of:
• Efficacy
• Side – effects/ Risks
Specialist Review
Recurrence of Symptoms
Non- MHT MHT Vaginal Estrogen Therapy

219. Tips On HT Use
• Hysterectomy- Only Tibolone
• Perimenopause- Cyclical Progesterone/OCP
• Early Menopause- More Estrogens
• Late Menopause- Lowest Estrogens
• Postmenopause, low libido- Tibolone
• Premature Menopause- OCP/HT
• Urogenital Atrophy- Local estrogens

220. Tips On HT Use
• Women aged <50: benefits of HRT far outweigh the risks, HRT should
be offered
• Women aged between 50 and 60 with menopausal symptoms:
benefits of HRT outweigh the risks
• Women aged >60: benefits of HRT equal the risks, treatment should
be individualized
• Women aged >70, the risks tend to outweigh the benefits

221. Management Of Osteoporosis
Postmenopausal Women (Asymptomatic)
1 major risk factor or any
2 other risk factors
BMD by DXA at Hip/ Spine
Normal Osteopenia Osteoporosis Severe Osteoporosis
>5 yrs postmenopause <5yrs postmenopause

222. No Risk
factors
Menopausal
Symptoms
No
Menopausal
Symptoms
1 major risk factor
> 2 other risk
factors
Follow up 2
years later
Reinforce
lifestyle
changes
HT
, Tibolone
Bisphosphonates
HT
, Tibolone
Bisphosphonates
Raloxefene
Strontium renelate
Bisphosphonates,
HT
,
Raloxefene
Strontium
renelate
Teriparatide,
Bisphosphonate
,
Calcitoin
No
Menopausal
Symptoms
Normal Osteopenia Osteoporosis Severe Osteoporosis
MHT WITHIN 10 YRS OF MENOPAUSE

223. Postmenopausal woman with fragility fracture
Immediate pain relief, surgical management, calcium, Vit. D
supplementation
Investigation- essential, rule put secondary causes
Physio-therapy Rehabilitation
Emotional, Social Support
Identify factors for recurrence
Aim independence at home and work
Lifestyle Management
Pharmacotherapy
Teriparatide
Bisphosphonates
Calcitonin-pain relief in vertebral
fracture
Follow- up Multidisciplinary Management
BMD (spine, hip) by DXA (repeat after 1-2 years)
Bone markers for monitoring therapy

224. Guidelines: Module 4
Guidelines Recommendations Of MHT

225. Guidelines
Indian
Menopause
Society, 2013
International
Menopause
Society, 2016
North American
Menopause Society,
2012
Age of
Initiation
• Begins within 10 years of menopause or < 60 years of
age - ‘Window of Opportunity’ (support
safe use for at least 5 years in healthy women
initiating treatment before age 60)
Duration of
use
• Premature menopause: MHT upto natural age of
menopause 3-5 years
• Continuation of therapy should be decided at the
discretion of the well-informed woman and her health
professional

226. Guidelines
Indian
Menopause
Society, 2013
International
Menopause
Society, 2016
North American
Menopause Society,
2012
Monitoring
• Pre-HT work-up (Indian MS)
• Initial follow-up at 3 months (NAMS)
• Annual follow-up – physical, laboratory/imaging (All)
• Discussion on lifestyle strategies to prevent or reduce
chronic disease (All)
• Currently no indication for increased mammographic
or cervical smear screening.
• Annual mammograms should be proposed in case of
high breast density in women using MHT.