GOVERNMENT COLLEGE OF NURSING,

VADODARA

SUBJECT: Obstetrics And Gynecology

TOPIC : Hormonal Replacement Therapy

Submitted To Submitted by
Mrs Kaveri N. Pandya Ms Gudiya Singh
Lecturer CL- 1 F.Y .[Link] .Nursing
GCON, Vadodara Roll No : 10

Submitted On
 Hormonal replacement therapy

Objectives:
1. Recognize menopausal symptoms & consequences
2. Classify drugs used to alleviate such symptoms that are
used as Hormonal Replacement Therapy [HRT]
3. Expand on the mechanism of action, indications,
preparations, side effects & contraindications of such
agents.
 Definition
Menopause: menos'(month) 'pausis'(cessation),so menopause means a complex
physiological changes that occur at the time when the last period ends generally aswomen get
older and lose fertility (age late 40s).

Characteristics of menopause: low estrogen and progesterone, low androgen, highFSH &
LH, high insulin resistance. (the aim of hormone replacement therapy is to boost these
hormones)

Menopause Normal menstruation

Symptoms & consequences of

Menopause

Immediate Intermediate Long term

● Hot flushes/night ● Dyspareunia & vaginal

sweat(vasomotor dryness. (caused by
● Osteoporosis
symptoms). atrophic vaginitis due
to thinning of vaginal ● CVS Risks; ↑
● Insomnia,anxiety &
mucosa) LDL/HDL ratio,
irritability.
● Urethral syndrome coronary heart
● Mood disturbance.
(dysuria, urgency & disease, stroke, etc
● Reduction in
frequency) ● CNS deficits,
sexuality & libido.
● Incontinence, Difficulty Alzheimer's,
● Poor concentration.
in voiding. Dementia
● Memmory loss
● Increased bruising.
● Generalized ache &
pain.
 Definition
Hormonal Replacement Therapy (HRT): Is a system of medical treatment that is designed to artificially boost female
hormones, in hope to alleviate symptoms caused by decrease in their circulating levels. Thedecrease in the hormonal
level appears In ⅓ of total female population (Perimenopause & postmenopause). Maybe natural, pathological or
induced.

Administration
Given for short term: never exceed 5 years to control menopausal symptoms without allowing ampletime for
malignant transition that might be induced by estrogen.
Long-term administration: was only indicated in osteoporosis & CVS protection but now better drugsare
available.

Agents Used in
Management of
Menopausal
Symptoms
Hormonal Non-hormonal

Estradiol Fluoxetine

Estrogen1 Conjugated estrogens Clonidine

Esterified estrogens Gabapentin

Progestins2
Physical activity
Phytoestrogens
1
One of the symptoms of menopause
Androgen3 Tibolone is low estrogen, so weuse estrogen
replacement to alleviate the
symptoms. Estrogen has some
undesirable side effects.
Selective
2
Tamoxifen We add progestins with estrogenbut
Estrogen not if there is a hysterectomy.
Replacement
Raloxifine 3
Responsible for sexual arousal
Modulators (given only if there is loss of libido &
(SERM) orgasm)
 In nature:

Androstenedione Aromatase Estrone*

Testosterone Aromatase Estradiol**

Dehydrogenase
As therapy:
● Estradiol :Oral bioavailability is low due to its rapid oxidation in the liver soused
only in transdermal patch, subcutaneous implant, etc
● Conjugated estrogens: mixture of Na salts of sulfate esters of estrone & equilin
*ovaries & adrenal in premenopausal. **Adrenal in
● Esterified estrogens. menopause. **ovaries in premenopausal

What does estrogen do?

It binds with its receptors Types of estrogen receptors (ER):
• ER α : mediates female hormonal functions. They are located in
(Endometrium, breast, ovaries, hypothalamus,…) in female genitalia (to produce the
sexual effect)
• ER β: mediates other hormonal functions. They are located in (brain, bone, heart, lungs,
kidney, bladder, intestinal mucosa, endothelial cells,….).
Estrogens bind to ERm(α or β) that exist either:
1. Cytoplasmic: mediates its genomic actions (hours to days time scale) and this kind of
receptors are important for development, neuroendocrine, metabolism.
2. Membranous: G protein estrogen receptors →2nd messenger → ↑ Ca or cAMP or↑
mitogen activated protein (MAP) Kinase* → mediates its non-genomic actions** →
seconds to minutes time scale. E.g. receptors of: nitric oxide, neurotransmitters,
endometrium, etc

Genomic effects: when the hormone enters the cell

and binds with intracellular receptors → binds to
hormone response element → gene activation →
transcription
→ translation → protein → effects.e.g(increase
cells proliferation).

*activate transcription factors to promote

mitogenesis.
**There will be no activation of DNA, instead wherewill
be enzyme phosphorylation.
* CONT’D
I. Oral: Conjugated equine (venous thromboembolism is a serious side effect),
Estradiol valerate , Estriol succinate.
II. Transdermal (estradiol):
✓ Patches (24 hour twice weekly)
✓ Gel (24 hours daily).
III. Subcutaneous implant (estradiol): 6 monthly.
IV. Vaginal cream: as such or as rings pessaries.

● In menopause: Not given unless presence of symptoms; alone only after hysterectomy or
with progestin as HRT (never exceed 5 years administration) to avoidcancer.
● Improves vaginal dryness by ↑ epithelial thickness & vascularity, collagen content (topical
‘pessaries or rings’ and systemic estrogens preparation ‘oral, transdermal patches, or
subcutaneous implant’ are effective)
● Increases bone density by ↑ calcitonin release from thyroid to ↓osteoclastic [Link]
act synergistically by blocking corticosteroid induced bone resorption. (Decrease incidence of
hip fracture).
● Protects CVS by enhance vasodilatation via ↑ neritic oxide production & ↑ HDL & ↓ LDL thus ↓
atherosclerosis & ischemic insults (HRT started at the beginning of menopause will prevent
CVS problems, however HRT increases CVs problems in long term; since it may cause
deep venous thrombosis → embolism to lung, brain,etc….
● Improves hot flushes & night sweats.
● Controls sleep disturbance & mood swings by acting on norepinephrine, dopamine &
serotonin at reticular formation.
● Improves urethral & urinary symptoms by ↑ epithelial thickness & vascularity, collagen content
at urethra & norepinephrine transmission that contract sphincters& relax detrusor muscles of
the urinary bladder, and thus improves the urinary continence.
● Improves insulin resistance & glycemic control in diabetics.
● Improves cognitive function via ↑ expression of estrogen receptor in brain & by ↓
amyloid deposition thus preventing Alzheimer's.
● Delays parkinsonism by acting on dopamine system in midbrain.
● Other uses:
✓ Contraception.
✓ Primary ovarian failure.
✓ Amenorrhea & Hirsutism caused by excess androgens.

❖ Irregular vaginal bleeding (patients discontinue HRT5).

❖ Breast tenderness (patients discontinue HRT5).
❖ Nausea.
❖ Vaginal discharge.
❖ Fluid retention, Weight gain.
❖ Spotting or darkening of skin (on face) (chloasma/‫)وحمة‬.

Absolute
● Undiagnosed vaginal bleeding because we suspect cancer
● Severe liver disease.
● Thromboembolic manifestations.
● Cancer in: endometrium ,breast (hormone sensitive), ovaries

● With contraception
● With (SERM): additive side effects for both drugs.
● With Aromatase inhibitors: ↓ efficacy.
● With Corticosteroids: ↑ side effects.
 Progestins
● In nature:

General
Information ➢ Produced by Adrenal glands, Gonads, Brain, Placenta
➢ The synthesis is induced by LH
➢ Are precursors to estrogens, androgens, and adrenocortical steroids.

Cholesterol Pregnenolone Progesterone

● As therapy:
❏ Progesterone is degraded in GIT, so can be given only parenterally
❏ Progestins are synthetic progestogens that have effects similar to progesterone
(progestinic effects) but are not degraded by GIT, so we cangive it orally
❏ Progestin preparations as in contraceptive pills

● What does progesterone do? Binds to its receptors. There are two typesof
M.O.A progesterone receptors [PR]: PR-A & PR-B.
● They could exist in the cytoplasm to mediate genomic long term effects
● They could exist in the membrane to mediate non-genomic rapid effects

❖ In menopause: As HRT, usually given in combination with estrogen Some use italone in
Indications risk of cancer but does not ↓ all menopausal symptoms
❖ Protects against possibility of estrogen induced endometrial cancer (Estrogen ↑cell
growth. If unopposed → endometrial cell lining can show atypical hyperplasia on the
other hand, Progesterone beneficially matures endometrial cell lining ‘becomes
differentiated’ & ↑ apoptosis of atypical cells).
❖ Progesterone (natural) protects against breast cancer development by
anti-inflammatory & apoptotic mechanisms, but this effect is not as clear with synthetic
progestins. Mammography recommended every 6 months. To make sure if there is
breast cancer or not
❖ Confers neuroprotection (mild effect)
❖ Controls insomnia & depression (little effect)
❖ Counteract osteoporosis bc it is directly +ve (stimulate) osteoblasts
❖ Other uses:
✓ Contraception (Estradiol + Progestins)
✓ Dysmenorrhea
Menopausal symptoms (Estradiol + Progestins given together
Important note if we have menopause lady and here uterus is present we DON’T give estrogen alone, ifthere is no
uterus we use estrogen ALONE
Administration Cont’D

❏ Mood changes e.g. anxiety, irritability.

ADR
s ❏ Headache, dizziness, drowsiness
❏ Nausea, vomiting, abdominal pain or bloating (distention).
❏ Hirsutism, masculinization (Not with new preparations)

● Oral: Micronized progesterone or progestins

● IntraUterine(IU): as Levonorgestrel or Progestasert
● Vaginal: natural progesterone gel, pessary.
● Transdermal: sequential (replaced daily), continuous patch.

Benefits Risks

● Definite benefits: ● Definite risks:

➢ Alleviates symptoms of ➢ Endometrial cancer (estrogen
menopause (vasomotor, only)
genitourinary) ➢ Venous thromboembolism (long
➢ Osteoporosis (Definite increase term) because estrogen increase the
in bone mineral density and coagulability
probable decrease in risk of ➢ Breast cancer (long term 5 yrs.)
fractures) Note: the risk of CVS problems and
● Uncertain benefits: breast cancer with HRT is more than
➢ Cognitive functions their benefits
(Alzheimer's symptoms)
 selective estrogen receptors modulators

An ideal SERM for use as HRT should be agonistic in brain, bone, cardiovascular
system (not necessarily the liver), vagina & urinary system but antagonistic in
breast & uterus, so it will not cause breast or uterine cancer like estrogen

Raloxifene Tamoxifen

Antagonist in breast and uterus and agonist Antagonist in breast and partial
in bone agonist in bone and endometrium
(may lead to endometrial cancer).

● Very effective preventing vertebral ● Increase the risk of venous

bone fracture thrombosis
● Has no effect on hot flushes or
● tends to precipitate vaginal
increases hot flushes
● Cardiovascular problems less atrophy & hot flushes
compared to Estrogen
● Increase the risk of venous
thrombosis
● For osteoporosis use of
bisphosphonate is better than SERMs

Brain Uterus Vagina Breast Bone CVS

Estradiol ++ ++ ++ ++ ++ ++

Ideal SERM ++ — ++ — ++ ++

Tamoxifen — + — — + +

Raloxifene — — — — ++ +

Has good
Not effect in bone
Ideal
 Hormonal replacement therapy
Phytoestrogens Androgen

● supplements from plants Testosterone is responsible forsexual

containing isoflavones (soya arousal in females
beans, flaxseeds) or lignans
(whole grains).
● Avoid in estrogen dependent
breast cancer

● They mimic action of estrogen on

estrogen receptor-β: alleviate
symptoms related to hot flushes,
mood swings, cognitive functions&
possess CVS protective actions.(data
limited on their efficacy)
● They block actions mediated by
estrogen receptor-α in some target
tissues: lower risks of developing
endometrial & breastcancer.

It is given as the sole therapy to

menopausal women in whom their
menopausal symptoms are focused onlack
of sexual arousal. It is given as adjuvant to
combined estrogen & progestin if all other
menopausal symptom exist.
● N.B. Tibolone, is a synthetic steroid
drug with estrogenic,
progestogenic, and weak
androgenic actions8, can be effective
in some women bc it has some
androgen agonistic properties9
(androgens use is not approved by
FDA in women)
 Non-Ho r m o n a l a g e n t
Fluoxetine Selective Serotonin Reuptake Inhibitor (SSRI) reduces vasomotor symptoms

Clonidine ● (centrally acting antihypertensive, alpha 2 agonist)

● helps with vasomotor symptoms. (female slides)

Gabapentin ● Anticonvulsant
● reduces severity and frequency of hot flushes (only female slides)

Physical activity exercise, smoking cessation and relaxation of mind will improve symptoms
of menopause (e.g. hot flushes) and fall prevention strategies prevents
chances of fracture.

The women’s health initiative and HRT

● Menopausal Hormone Therapy: For decades, hormone therapy widely used in menopausal
symptoms. (only male slides)
● Estrogen has been used alone in menopausal women who have had their uterus removed. (Maleslides)
● Progestin, the synthetic form of an estrogen-related hormone called progesterone, is combinedwith estrogen
in menopausal women who still have their uterus. (only male slides)
● The Women’s Health Initiative (WHI), a 15-year research program launched in 1991, addressed themost
common causes of death, disability, and poor quality of life in postmenopausal women.
● The research program examined the effectiveness of hormone replacement therapy in women. In2002,
findings from two WHI clinical trials examined:
1. The use of estrogen plus progestin in women with a uterus
2. The use of estrogen only in women without a uterus.
● In both studies, women were randomly assigned to receive either the hormone medication orplacebo.
● In both studies, when compared with placebo, the hormone medication (whether estrogen plus progestin or
estrogen only) resulted in an increased risk of stroke and blood clots. In addition, theestrogen plus progestin
medication resulted in an increased risk of heart attack and breast cancer.
● These concerns are one reason that many women are turning to mind and body practices andnatural
products to help with menopausal symptoms.
 Estrogen
Admin. ● Orally (Conjugated equine, Estradiol valerate and estriol succinate).
● Also available as: Transdermal patches (estradiol), Subcutaneous
implant (estradiol) and Vaginal cream.

Indications ● Improves ● Protects CVS in ● Contraception.

vaginal dryness by short use, however ● Primary ovarian
↑ epithelial HRT increases CVs failure
thickness & problems in long ● Amenorrhea and
vascularity, term. hirsutism.
collagen content ● Improves hot ● Improves cognitive
● Increase bone flushes & night function
density. sweats. ● Controls sleep
● Improves insulin ● Improves urethral disturbance &
resistance., & urinary mood swings
symptoms.

ADRs Breast tenderness. Spotting and darkening of the skin. Spotting

Vaginal discharge. or darkening of skin

Inter. ● Other ● With Aromatase ● With

contraceptives. inhibitors. corticosteroids.

Progestin SERM

Indications ● Protect against estrogen information An ideal SERM for use as HRT
induced endometrial and should be agonistic in brain,
breast cancer.
bone, CV system (not necessarily
● Confers neuroprotection.
● Controls insomnia and the liver), vagina & urinary
depression system but antagonistic in breast
● Dysmenorrhea. & uterus.
● Menopausal symptoms

Effects Raloxifen: Tamoxifen:

Antagonist in Antagonist in
Admin. ● Progesterone can be given onl
breast and uterus breast and
parentally
● Progestins are not degraded by and agonist in partial agonist
GIT, so we can give it orally bone. in bone and
● Oral Micronized progesterone 1-very effective endometrium.
or progestins preventing
● IntraUterine (IU): Levonorgestrel vertebral bone Increase the risk
or Progestasert fracture of venous
● Vaginal: natural progesterone 2-Has no effect on thrombosis &
gel /pessary. hot flushes or
tends to
● Transdermal: sequential increases hot
precipitate
(replaced daily) / continuous flushes
3-CVs problems
vaginal atrophy
patch.
less compared to & hot flushes
Estrogen
 Phytoestrogens Androgen
information ● Supplements from plants;
containing isoflavones (soya Testosterone is responsible for
beans, flaxseeds) or lignans sexual arousal in females.
(whole grains).
● Avoid in estrogen dependent
breast cancer

Interaction N.B. Tibolone, is a synthetic steroid

drug with estrogenic, progestogenic,
and weak androgenic actions.
(synthetic form of androgen, to given
to menopausal women in whom their
menopausal symptoms are focused on
lack of sexual arousal)

Benefits and Risks of HRT

Benefits Risks

Definite benefits: Definite risks:

Osteoporosis (Definite increase in bone mineral ● Endometrial cancer (estrogen only)
density; probable decrease in risk of fractures). ● Venous thromboembolism (long term)
Uncertain benefits: ● Breast cancer (long term 5 yrs.)
Cognitive functions.

Note: the risk of CVS problems and breast cancer with HRT is more than their benefits

Non-hormonal agents
Fluoxetine (SSRI) reduces vasomotor symptoms

Clonidine (centrally acting antihypertensive, alpha 2 agonist) helps with

vasomotor symptoms.

Gabapentin (anticonvulsant) reduces severity and frequency of hot flushes

Physical activity exercise, smoking cessation and relaxation of mind

 BHIBLIOGRSPHY

1) Chintamani, Lewis." Medical Surgical Nursing", edition 2013,

published by Elsevier, page no. 752

2) Suddarth's and Brunner, Text book of Medical Surgical

Nursing, 12th edition, published by Wolters Kluwer, page no.
1494-1495.

3) [Link] replacement

4) [Link]

5) [Link]