Hormone therapy in Ammenorrhea
• A.Mehdizadeh .MD
• Prof. of Gyn.
• Iran Medical School
Definition of amenorrhea
• No period by age 14 in the absence of
secondary sexual characteristics
• No period by age 16 regardless of the
presence secondary sexual characteristics
• Secondary amenorrhea means lack of period
at least 3 of the previous cycle interval or 6
months of amenorrhea
Hormone therapy in ammenorrhea
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Hypothyroidism
Hyperprolactinemia
Anovulation
Hypothalamic ammenorrhea
Premature ovarin failure
• Hormon therapy in ammenorrhea
• In the absence of exogenous estrogen
treatment, they are at risk for developing
osteopenia and osteoporosis.
• Early coronary heart disease .
• Developmentof symptoms of estrogen
deficiency such as vasomotor flushes and
genito-urinary atrophy that can be
debilitating.
Hormon therapy in ammenorrhea
• Unless
there
is
a
specific
contraindication to its use, women with
POF should receive exogenous estrogen
therapy.
• Other strategies for protecting bone and
heart health, including exercise, diet,
adequate calcium and vitamin D intake,
and the avoidance of smoking.
Hormon therapy in ammenorrhea
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1- Absolute contraindications:
Known or suspected breast cancer
Known or suspected endometrial cancer
Undiagnosed abnormal genital bleeding
Active thromboembolic disorders
Active liver & gallbladder diseases
Hormon therapy in ammenorrhea
2-Relative contraindications:
Heart diseases
Migraine headaches
History of liver disease
History of gallbladder disease
History of endometrial cancer
History of thromboembolic events
Hormone replacement therapy
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Sequential estrogen- progestin therapy
Continuous estrogen- progestin therapy
Estrogen only therapy
Seasonal regimen
Progestin intrauterine device
Estrogen formulation and routes of
administration
• Oral administration :
Conjugated estrogen (0.625& 1.25 mg )
Micronized estradiol (1mg )
Ethinyl estradiol (o.o5mg & 5 mg )
• Transdermal administration
• Vaginal administration- low dose method
• Vaginal method- standard dose method
• Estradiol implants
• Percutaneous estrogen
• Intranasal administration
Hormon therapy in ammenorrhea
• Oral contraceptives also may be used but
contain greater amounts of hormones than
are required and may thus be reserved for
those who want to prevent even the
possibility of random ovulation and
pregnancy.
• Androgen treatment cannot be
recommended for women with
POF.(acnea,hirsutism,hyperlipidemia)
Progesterone regimens
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Medroxy progesterone acetate 5 mg
Norethindrone acetate 1 mg
Norethindrone 0.7 mg
Micronized progesterone 200 mg
• Progestin intrauterine device( Mirena- IUS)
Progestin for hysterectomized
women
• In some special conditions should take :
1 - history of pelvic endometriosis
2- supracervical hysterectomy
3- history of endometrial carcinoma
4- history of endometrioid tumor of ovary
Hormon therapy in Ammenorrhea
• It is important to emphasize to young women
with POF that they are distinctly different from
older postmenopausal women and that the
balance between the risks and benefits of
hormone therapy for them also differs from that
in postmenopausal women.
• Because they are significantly younger, Their
baseline risks for cardiovascular disease and
breast cancer are much lower than those for
older postmenopausal women.
Hormon therapy in Ammenorrhea
• Moreover, without estrogen therapy,
their risk for later coronary heart
disease may be increased, rather than
decreased.
• Hormone therapy should continue up to
at least age of 50, in much the same
way as endogenous hormone
production does in normal women.
Hormon therapy in Ammenorrhea
• Although the likelihood of achieving pregnancy
after diagnosis is only about 5-10%, some
women with POF do conceive and
approximately 80% of their pregnancies end in a
healthy live birth.
• However, there is no evidence that any form of
treatment other than egg donation and IVF can
increase the chance for pregnancy.
Psychological and Emotional Support
• Profound grief and a sense of loss for the children, are
common in women after diagnosis of POF.
• It also is important to emphasize that the diagnosis of
POF does not imply or predict premature aging in any
other way, something that many women
understandably may fear.
• . Women with POF also are at risk for developing
related depression and anxiety disorders.
• Consequently, refer them to a support group and to a
therapist .
Oral Administration
The relative potencies of
commercially available estrogens are
of great importance when
prescribing estrogen, and the
clinician should be familiar with the
potencies.
Oral Administration
Transdermal Patch Administration
• The patches first used , contained an alcohol reservoir;
but In the current generation of patches, the hormones
are dissolved and distributed throughout the adhesive
matrix.
• In a study of women who had previously discontinued
patches because of skin irritation (contact dermatitis),
skin reactions were less common with the newer matrix
patches.
• The patches are designated according to the amount of
estradiol delivered per day: from 14 to 100 micg.
Transdermal Patch Administration
• The first-pass effect may be important for
lipoprotein effects. because , increase
catabolism of LDL and increase production of
apoprotein A-I with oral estrogen, but no
effect with transdermal estrogen
• Transdermal administration of 50 /mic,g
estradiol twice a week is as effective as 0.625
mg oral conjugated estrogens.
Clotting Factors
• First-pass hepatic metabolism affects the
synthesis of clotting proteins, markers of
coagulation that can influence the risk of
thrombosis and coronary heart disease
events.
• Oral estrogen increases factor VII and
prothrombin I and 2 fragment, whereas
transdermal estrogen decreases factor VII.
Clotting Factors
• Estrogen users who carried a factor V Leiden
mutation or a prothrombin mutation had a 25fold higher risk of VTE than did women who
did not use estrogen and did not have either
mutation.
• The women with a prothrombotic mutation
who used transdermal estrogen had a VTE risk
that was similar to that of women with a
prothrombotic mutation who did not use
estrogen.
Myocardial Infarction Risk:
• Both oral and transdermal
administration of hormone
therapy are associated
with a decrease in
myocardial infarction risk
in observational studies.
Effects in Smokers:
• POF women who smoke may have a better
cardiovascular response to transdermal estrogen
than to oral estrogen.
• Smokers receiving transdermal estradiol
have decreased plasma viscosity and
thromboxane B2 levels.
• These results raise the possibility, that
smokers may represent a group of women for
whom transdermal estrogen would be an
advantage.
Carbohydrate Metabolism:
• There is little difference between the oral
and transdermal methods of delivery on
carbohydrate metabolism.
• Both methods have a beneficial impact on
central abdominal fat content, glucose levels
and insulin resistance, associated with a
reduced risk of developing adult-onset
diabetes mellitus.
Breast Cancer Risk
• Oral estrogens/progesterone decreased
(IGF-I) by 26% and increased (SHBG) by
96% ,whereas no change occurred with
transdermal estradioI.
• High IGF-l and low SHBG levels are
associated with increased breast cancer
risk.
Colorectal Cancer Risk
• In a case-control study, both oral and
transdermal hormone therapy reduced
the risk for developing colorectal cancer.
• When transdermal therapy involved
estrogen alone, the benefit was even
greater
Vaginal Administration of Estrogen-Very
Low-Dose Method
• Some patients do not gain full relief from the
symptoms of vaginal atrophy with oral or
transdermal administration of estrogen.
• In addition, there are many women who
desire the genitourinary effects of estrogen
but either must or wish to avoid systemic
therapy.
• Vaginal treatment is especially helpful when
a rapid response is desired.
Vaginal Administration of Estrogen-Very
Low-Dose Method
• Many clinicians believe that estrogen administered
intravaginally is not absorbed, and systemic effects
can be avoided. This is not the case.
• Estrogen in creams is absorbed very readily from a
vagina with immature, atrophic mucosa.
• Indeed, the initial absorption is rapid, and
relatively high circulating levels of estrogen are
easily reached.
• As the vaginal mucosa matures, absorption
decreases.
Vaginal Administration of Estrogen-Very
Low-Dose Method
• This decline takes approximately 3-4 months,
after which lesser but still significant absorption
takes place.
• Effective treatment of vaginal atrophy with
minimal absorption can be achieved with the
administration of 0.3 mg conjugated estrogens,
2-3 times per week.
• Treatment with a vaginal cream longer than 6-12
months requires endometrial surveillance.
Vaginal Administration of Estrogen-Very
Low-Dose Method
• Estring is a 55-mm diameter silicone ring
that contains 2 mg estradiol, with a
release rate of 7.5 micg/day for 90 days.
• No change in endometrial thickness was
observed after I year of treatment.
Vaginal Administration of Estrogen-Very
Low-Dose Method
• Vagifem is a tablet that contains 25 micg
estradiol, and the initial dose of I tablet daily
produces relief from atrophic symptoms
within 2 weeks.
• Endometrial thickness has been reported to
not change from baseline
• smaller dose tablet, 10 micg, also improves
vaginal atrophy, but it is not as effective as the
larger dose.
Vaginal Administration of Estrogen-Standard
Dose Method
• A vaginal ring (FemRing) that releases
estradiol acetate provides 50 or 100 micg
estradiol per day over a 3-month time span.
• Blood estradiol level is similar to those
achieved with oral and trans dermal
methods.
• Endometrial protection requires the addition
of a progestin in the presence of a uterus.
Estradiol Implants
• Estradiol pellets are available in doses of 25, 50,
and 75 mg for subcutaneous administration twice
yearly.
• Significant blood levels of estradiol wiIl persist for
up to 2 years after the last insertion.
• Women receiving pellets be monitored with
blood estradiol levels, and levels greater than 200
pg/mL (and preferably, 100 pg/mL) should be
avoided by a greater interval between insertions.
Percutaneous Estrogen
• Transdermal estradiol can also be
administered by a gel, emulsion, or spray.
• The gel, is applied once daily on an arm,
anywhere from the wrist to the shoulder, or
the thigh, without rubbing or massaging .
• The emulsion, usuaIly two packets are
applied daily.
• transdermal spray, the usual dose is one
spray daily to the forearm .
Estrogen-Progestin Sequential and Continuous
Regimens
• Hormone therapy initially consisted only of sequential
regimens that were logical reflections of the cyclic estrogen
and progesterone patterns in a menstrual cycle manner.
• Clinical trials established the doses and durations for
progestin administration that would effectively protect the
endometrium against unchecked proliferation.
• Progestin withdrawal bleeding occurs in 80-90% of women
on a sequential regimen, and for this reason the continuous
combined method of treatment evolved to improve patient
continuance that was adversely affected by bleeding and
other symptoms triggeredby the cyclic hormonal changes.
• The addition of a daily dose of a progestin to
the daily administration of estrogen allowed
the progestin dose to be smaller, provided
effective protection against endometrial
hyperplasia, and resulted in amenorrhea
within I year of treatment in 80-90% of
patients.
• In the sequential regimen, estrogen is
administered daily and progestins for 2 weeks
of every month, using the comparable doses
of the following progestins.
• 5 mg medroxyprogesterone acetate, or
• 0.7 mg norethindrone, or
• 1.0 mg norethindrone acetate, or
• 200 mg micronized progesterone.
• In the daily continuous, combined regimen, progestins are
combined with estrogen in the
• following comparable doses .
• 1.5 or 2.5 mg medroxyprogesterone acetate, or
• 0.35 mg norethindrone, or
• 0.5 or 1.0 mg norethindrone acetate (0.1 mg dose is available), or
• 100 mg micronized progesterone or
• 2 mg drospirenone or
• 2 mg dienogest.
• These hormonal regimens are combined with daily calcium
supplementation (500 mg with a meal) and vitamin D (1,000-2,000
Iu daily).
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There has been a progressive decrease in dose used for hormone therapy. For
many years, the standard dose of estrogen was 0.625 mg conjugated estrogens,
1-2 mg micronized estradiol, 1-2 mg estradiol valerate, or equivalent doses of
other estrogens such as 5 micg ethinyl estradiol.
Lower doses have been proven 0n the average to be as effective as these
"standard" doses, providing clinicians and patients with more options.
Conjugated estrogens in a dose of 0.3 or 0.45 mg effectively produce a gain in
bone density when combined with 1.5 mg medroxyprogesterone acetate, and a
dose of 0.5 mg micronized estradiol produces comparable effects.
The 0.45/1.5 mg and 0.3/1.5 mg conjugated estrogens/ medroxyprogesterone
acetate combinations improve vaginal atrophy, reduce hot flushing,
and improve measures of sexual function in a pattern that is quantitatively and
qualitatively similar to the 0.62512.5mg combinationwith less mastalgia
• Two metabolites of progesterone,
allopregnanolone and pregnanolone, are
believed to be responsible for progesterone's
unique sedative effect.
• Treatment regimens with micronized
progesterone should be taken at bedtime, and
these estrogen-progesterone combinations
are a good choice for women with sleep
difficulties.
Progestational Side Effects
• Many women do not tolerate treatment with
progestational hormones.
• Typical side effects include breast tenderness, bloating,
and depression.
• changing to a regimen containing norethindrone or
norethindrone acetate has been beneficial
• Can the progestational agent be administered less
frequently?
• Daily combination program effectively prevents
endometrial hyperplasia.
• A sequential regimen that incorporates progestin
exposure for less than 14 days has over time an
increased risk of endometrial hyperplasia. .
• Experience with extended cycle regimens is very
limited.
• The administration of medroxyprogesterone acetate
every 3 months was associated in I study with longer,
heavier menses and unscheduled bleeding and a 1.5%
incidence of hyperplasia at I year, whereas in another
study, overall bleeding was less, but the incidence of
hyperplasia was approximately4%.
• An annual endometrial biopsy is strongly
recommended in estrogen users exposed only
intermittently to progestin treatment
• Some patients are very sensitive to medroxyprogesterone
acetate.
• these patients are often relieved of their symptoms by
,switching to norethindrone.
• Progesterone can be administered in a vaginal gel that
allows the delivery of very low doses that can
effectively protect the endometrium with low
systemic levels because of a first-pass effect on the
uterus.
• The administration of 90 mg every 2 days produces
secretory changes in the endometrium.
Activated Protein C (APC)
Resistance and Risk of VTE.
• Oral estrogen increases APC resistance,
whereas transdermal estrogen has no
significant effect on this marker.
• Based on this difference, one would
predict that transdermal delivery of
estrogen would be less likely than oral
delivery of estrogen to be associated
with venous thromboembolism (VTE).
Transdermal Patch Administration
• The concentration of estrogen in the hepatic
portal system after oral administration is 4-5
times higher than that in the periphery.
• Because of first-pass metabolism in the liver,
oral estradiol results in a circulating estrone to
estradiol ratio of approximately 3; with
transdermal administration the ratio is I.
Metabolic Syndrome
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• In a 3-month randomized trial involving
50 obese women with metabolic
syndrome, oral estradiol therapy
worsened markers of the metabolic
syndrome, including insulin resistance,
suggesting a worsening of cardiovascular
risk, whereas transdermal estradiol had
minimal effects.
Vaginal Administration of Estrogen-Very
Low-Dose Method
• long-term treatment requires US monitoring
of endometrial thickness with biopsy when
indicated.
• For women who are breast cancer survivors
and are considering this treatment, clinicians
and patients must accept a small but real
unknown risk
Lipids and Hepatic Enzymes
• Both oral and transdermal estrogen
reduce total cholesterol, LDL cholesterol,
and lipoprotein(a).
• Compared with transdermal estrogen,
oral estrogen produces significantly
greater elevations in HDL cholesterol
and increases triglycerides, whereas
transdermal estrogen decreases
triglyceride levels.