HRT IS IMPORTANT AFTER MENOPAUSE

1. Hormone Replacement
Therapy
Sandeep Kumar B, M.Pharm

2. Introduction
 Hormone replacement therapy (HRT), also known as menopausal hormone
therapy (MHT) or postmenopausal hormone therapy (PHT, PMHT), is a form
of hormone therapy used to treat symptoms associated with female menopause.
 These symptoms can include hot flashes, vaginal atrophy,
accelerated skin aging, vaginal dryness, decreased muscle mass, sexual
dysfunction, and bone loss.
 They are in large part related to the diminished levels of sex hormones that occur
during menopause.
 The main hormonal medications used in HRT for menopausal symptoms
are estrogens and progestogens, among which progesterone is the major naturally-
occurring female sex hormone and also a manufactured medication used in
menopausal hormone therapy.
 Though both can have symptomatic benefits, progestogen is specifically added to
estrogen regimens when the uterus is still present.

3.  Since estrogen deficiency is a major cause of the long-term complications of
the menopause, estrogen replacement is the rational treatment to address
the cause of the problems after menopause .
 But as there are limitations of estrogen therapy as HRT, some other drugs are
also used besides estrogen
 Unopposed estrogen therapy promotes endometrial thickening and can
increase the risk of cancer, while progestogen reduces this risk.
 Androgens like testosterone are sometimes used as well.
 HRT is available through a variety of different routes.
 The results of the Women's Health Initiative (WHI) suggest both potential risks
and benefits across different organ systems.
 Long term follow up of the WHI participants, however, has found no
difference in all-cause, cardiovascular, or cancer mortality with HRT.

4.  Later studies suggested that risk can differ depending on route of
administration.
 "Bioidentical" hormone replacement – a development in the 21st century using
manufactured compounds having "exactly the same chemical and molecular
structure as hormones that are produced in the human body", and
 "Bioidentical" hormone replacement are based mainly on steroids from
plants – has inadequate clinical research to determine its efficacy and safety,
as of 2017.
 The current indications for use from the United States Food and Drug
Administration (FDA) include short-term treatment of menopausal symptoms,
such as vasomotor hot flashes or vaginal atrophy, and prevention
of osteoporosis.

5. Why Hormone Replacement Therapy?
 With a marked increase in longevity, women now spend 1/3 rd of their lives in
the post-menopausal period. It is estimated that 1/3 rd of total female
population are in menopause.
 Therefore they would have to cope with the post menopausal syndrome and
face the consequences.
 HRT relieves the well known symptoms of post menopausal syndrome .Again
women are now asking for a quality life after menopause.
 So HRT is a hot topic in this era as it is no more for symptomatic management
for PMS, but for the total management from prophylactic to curative .
 Since estrogen deficiency is a major cause of the long-term complications of
the menopause, estrogen replacement is the rational treatment to address
the cause of the problems after menopause .
 But as there are limitations of estrogen therapy as HRT, some other drugs are
also used besides estrogen What is hormone replacement ther

6. Medical uses
 Approved uses of HRT in the United States include short-term treatment of
menopausal symptoms such as hot flashes and vaginal atrophy, and prevention
of osteoporosis.
 The American College of Obstetrics and Gynecology (ACOG) approves of HRT
for symptomatic relief of menopausal symptoms, and advocates its use
beyond the age of 65 in appropriate scenarios.
 The North American Menopause Society (NAMS) 2016 annual meeting
mentioned that HRT may have more benefits than risks in women before the
age of 60.[14]
 A consensus expert opinion published by The Endocrine Society stated that
when taken during perimenopause or the initial years of menopause, HRT
carries fewer risks than previously published, and reduces all cause mortality
in most scenarios.
 The American Association of Clinical Endocrinologists (AACE) has also released
position statements approving of HRT in appropriate scenarios.

7.  Women receiving this treatment are usually post-, peri-, or surgically
menopausal.
 Menopause is the permanent cessation of menstruation resulting from loss of
ovarian follicular activity, defined as beginning twelve months after the final
natural menstrual cycle.
 This twelve month time point divides menopause into early and late transition
periods known as 'perimenopause' and 'postmenopause'.
 Premature menopause can occur if the ovaries are surgically removed, as can
be done to treat ovarian or uterine cancer.
 The Women's Health Initiative (WHI) was a study of over 27,000 women
beginning in 1991.
 Successive analyses have found sometimes contradictory results, with the
most recent publication in 2017 finding no difference for all cause mortality
with HRT.
 The effects of HRT on most organ systems vary by age and time since the
last physiological exposure to hormones, and there can be differences in
individual regimens, factors which have made analyzing effects difficult.
 Demographically, the vast majority of data available is in postmenopausal
American women with concurrent pre-existing conditions, and with a mean
age of over 60 years.

8. Medical uses
 Menopausal symptoms
 Heart disease
 Blood clots
 Stroke
 Endometrial cancer
 Breast cancer
 Colorectal cancer
 Ovarian cancer
 Sexual function
 Neurodegenerative disorders
 Muscle and bone

9. Menopausal symptoms
 HRT is often given as a short-term relief from menopausal symptoms
during perimenopause. Potential menopausal symptoms include:
 Hot flashes - vasomotor symptoms
 Vulvovaginal atrophy - atrophic vaginitis and dryness
 Dyspareunia - painful sexual intercourse due to vaginal atrophy and lack
of lubrication
 Bone loss - decreased bone mineral density, which can eventually lead
to osteopenia, osteoporosis, and associated fractures
 Decreased sexual desire
 Defeminization - diminished feminine fat distribution and accelerated skin
aging[18][19]
 Sleep disturbances and joint pain
 The most common of these are loss of sexual drive and vaginal dryness.[4][20]

10. Heart disease
 The effect of HRT in menopause appears to be divergent, with lower risk when
started within five years, but no impact after ten.There may be an increase in
heart disease if HRT is given twenty years post-menopause. There is, however, no
actual difference in long-term mortality from HRT, regardless of age.
 Women starting HRT less than 10 years after menopause had lower mortality
and coronary heart disease, without any strong effect on the risk of stroke
and pulmonary embolism. Those starting therapy more than 10 years after
menopause showed little effect on mortality and coronary heart disease, but an
increased risk of stroke. Both therapies had an association with venous clots and
pulmonary embolism.
 HRT also improves cholesterol levels. With menopause, HDL decreases,
while LDL, triglycerides and lipoprotein a increase, patterns that reverse with
estrogen. Beyond this, HRT improves heart contraction, coronary blood
flow, sugar metabolism, and decreases platelet aggregation and plaque formation.
HRT may promote reverse cholesterol transport through induction
of cholesterol ABC transporters.

11. Blood clots
 Effects of hormone replacement therapy on venous blood clot formation and
potential for pulmonary embolism may vary with different estrogen and
progestogen therapies, and with different doses or method of use. Comparisons
between routes of administration suggest that when estrogens are applied to the
skin or vagina, there is a lower risk of blood clots, whereas when used orally, the
risk of blood clots and pulmonary embolism is increased.
 Skin and vaginal routes of hormone therapy are not subject to first pass
metabolism, and so lack the anabolic effects that oral therapy has on liver
synthesis of vitamin K-dependent clotting factors, possibly explaining why oral
therapy may increase blood clot formation. While a progesterone and estrogen
together can decrease this risk, there is an increased risk of blood clots and
pulmonary embolism when estrogen and progestogen were combined, particularly
when treatment was started 10 years or more after menopause and when the
women were older than 60 years

12. Stroke
 Multiple studies suggest that the possibility of HRT related stroke is absent if
therapy is started within five years of menopause, and that the association is
absent or even preventive when given by non-oral routes.
 Ischemic stroke risk was increased during the time of intervention in the WHI,
with no significant effect after the cessation of therapy and no difference in
mortality at long term follow up. When oral synthetic estrogen or combined
estrogen-progestogen treatment is delayed until 5 years from menopause,
studies have suggested an association with hemorrhagic and ischemic stroke.
 The specific route of administration was important, finding that although oral
estrogen increased risk of stroke, absorption through the skin had no impact,
and vaginal estrogen actually had a decreased risk

13. Endometrial cancer
 In postmenopausal women, continuous combined estrogen plus progestin
decreases endometrial cancer incidence. The duration of progestogen therapy
should be at least 14 days per cycle to prevent endometrial disease.
 Endometrial cancer has been grouped into two forms in the context of hormone
replacement. Type 1 is the most common, can be associated with estrogen
therapy, and is usually low grade. Type 2 is not related to estrogen stimulation and
usually higher grade and poorer prognosis. The endometrial hyperplasia that leads
to endometrial cancer with estrogen therapy can be prevented by concomitant
administration of progestogen. The extensive use of high-dose estrogens for birth
control in the 1970s is thought to have resulted in a significant increase in the
incidence of type 1 endometrial cancer.
 Paradoxically, progestogens do promote the growth of uterine fibroids, and
a pelvic ultrasound can be performed before beginning HRT to make sure there are
no underlying uterine or endometrial lesions.[31]
 Research suggests there is insufficient high‐quality evidence to inform women
considering hormone replacement therapy after treatment for endometrial cancer.

14. Breast cancer
 Studies regarding the association of breast cancer with hormone replacement
have been mixed and vary with the type of replacement used; some
evaluations suggest an increased risk, though in others it is decreased.
 There is a non-statistically significant increased rate of breast cancer for
hormone replacement therapy with synthetic progesterone.[6] The risk may be
reduced with bioidentical progesterone, though the only prospective study
that suggested this was underpowered due to the rarity of breast cancer in
the control population. There have been no randomized controlled trials to
date. The relative risk of breast cancer also varies depending on the interval
between menopause and HRT and route of administration.
 The WHI also found a non-significant trend in the estrogen-alone clinical trial
towards a reduced risk of breast cancer, though estrogen is usually only given
alone in the setting of a hysterectomy due to the effect of unopposed
estrogen on the uterus.

15.  HRT has been more strongly associated with risk of breast cancer in women
with a lower range body mass indices (BMIs). No breast cancer association has
been found with BMIs of over 25. It has been suggested by some that the
absence of significant effect in some of these studies could be due to
selective prescription to overweight women who have higher
baseline estrone, or to the very low progesterone serum levels after oral
administration leading to a high tumor inactivation rate.
 For women who previously have had breast cancer, it is recommended to first
consider other options for menopausal effects, such
as bisphosphonates or selective estrogen receptor modulators (SERMs) for
osteoporosis, cholesterol-lowering agents and aspirin for cardiovascular
disease, and vaginal estrogen for local symptoms. Observational studies of
systemic HRT after breast cancer are generally reassuring. If HRT is necessary
after breast cancer, estrogen-only therapy or estrogen therapy with a
progestogen may be safer options than combined systemic therapy.

16. Sexual function
 HRT can help with the lack of sexual desire and sexual dysfunction that can occur
with menopause. Epidemiological surveys of women between 40–69 years suggest
that 75% of women remain sexually active after menopause. With increasing life
spans, women today are living one third or more of their lives in a postmenopausal
state, a period during which healthy sexuality can be integral to their quality of
life. A major complaint among postmenopausal women is decreased libido and
sexual function, and many may seek medical consultation. Several hormonal
changes take place during this period, including a decrease in estrogen and an
increase in follicle-stimulating hormone.
 For most women, the majority of change occurs during the late perimenopausal
and postmenopausal stages. Decrease in sex hormone-binding globulin (SHBG)
and inhibin (A and B) also occurs. Testosterone, a hormone more commonly
associated with males, is also present in women at a lower level. It peaks at age
30, but declines gradually with age, so there is little variation across the lifetime
and during the menopausal transition. With surgical menopause, testosterone
declines more sharply and can result in more severe symptoms. HRT can help with
sexual difficulties related to pain and lubrication.

17.  Not all women are responsive, especially those with preexisting sexual difficulties. Estrogen
replacement can restore vaginal cells, pH levels, and blood flow to the vagina, all of which
tend to deteriorate at the onset of menopause. Pain or discomfort with sex appears to be the
most responsive component to estrogen. It also has been shown to have positive effects on
the urinary tract. Reduced vaginal atrophy and increased sexual arousal, frequency
and orgasm have also been noted
 The effectiveness of hormone replacement can decline in some women after long-term use. A
number of studies have also found that the combined effects of estrogen/androgen
replacement therapy can increase libido and arousal over estrogen alone. Findings on a
relatively new form of HRT called tibolone, a synthetic steroid with estrogenic, androgenic,
and progestogenic properties, suggest that it has the ability to improve mood, libido, and
physical symptoms of surgically menopausal women to a greater degree than ERT. In various
placebo-controlled studies, improvements in vasomotor symptoms, emotional response, sleep
disturbances, physical symptoms, and sexual desire have been observed. Tibolone has been
used in Europe for almost two decades but is not available North America at this point.

18. Side effects
 Common:
 Headache
 Upset stomach, stomach cramps or bloating
 Diarrhea
 Appetite and weight changes
 Changes in sex drive or performance
 Nervousness
 Brown or black patches on the skin
 Acne
 Swelling of hands, feet, or lower legs due to fluid retention
 Changes in menstrual flow
 Breast tenderness, enlargement, or discharge
 Sudden difficulty wearing contact lenses
Uncommon
 Double vision
 Severe abdominal pain
 Yellowing of skin or eyes
 Severe depression
 Unusual bleeding
 Loss of appetite
 Skin rash
 Lassitude
 Fever
 Dark-colored urine
 Light colored stool
 Chorea

19. Contraindications
 Absolute contraindications
 Undiagnosed vaginal bleeding
 Severe liver disease
 Pregnancy
 Severe coronary artery disease
 Aggressive breast, uterine or ovarian cancer
Relative contraindications
 Migraine headaches
 History of breast cancer
 History of ovarian cancer
 Venous thrombosis
 History of uterine fibroids
 Atypical ductal hyperplasia of the breast
 Active gallbladder disease
(cholangitis, cholecystitis)
 Well-differentiated and
early endometrial cancer

20. DRUGS USED IN HRT
 1) Estrogens
 Oral: - Conjugated equine estrogen (CEE): 0.625 mg (Estrone Sulphate +
equilin sulphate +17 d dihydro equilin) Estradiol valerate (1, 2, 4 mg).
Estrial succinate (1, 2 mg).
 Transdermal (estradiol): - Patches: 25 micro gm, 50 micro gm / 24 hour
twice weekly. Gel : 75 micro gm / 24 hours daily.
 Sub cutaneous implant (estradiol): - 25 / 50 / 100 mg. 6 monthly.
 Vaginal: cream.

21.  2) Progestins:
 Oral route –. Norgestrol: 150 mg /day. Micronised progesterone: 200 mg
/day. Dydrogesterone: 20 mg / day. Medroxy progesterone acetate:
10mg/day. Norethisterone acetate : 0.7 – 2.5 mg/ day.
 Hormone releasing intra uterine system –. Levonorgestrel: 20 mcg / day.
Progestasert: 65mcg / day.
 Vaginal - natural progesterone gel / pessary.
 Transdermal - sequential / continuous patch.

22.  3) Tibolone
 Synthetic steroid, tissue specific HRT
 2 hydroxy metabolites are estrogenic
 D 4 isomer binds to progesterone & androgen receptors
 Addition of progesterone not required
 4) Androgen –
• Oral Tablets
• Implants-Pellets of 100 mg testosterone

23. DRUGS USED IN HRT - Regimens
 Estrogen alone: in post hysterectomy cases
 E + P Cyclic sequential: E on day 1-25; P on day 14 –25 (for climacteric
patients with intact uterus )
 Continuous sequential: E daily; P for 12 days at 16 days interval (for post
menopausal patients with intact uterus)
 Continuous combined: E + P taken daily
 Progesterone alone: cyclic / continuous
 Estrogen + Progesterone + Androgen