Hormonal Replacement

Therapy

Błażej Męczekalski

History of Hormone

therapy

• 1895 Rudolph Chrobak treated climacteric

symptoms by oral administration of ovarian tissue

• 1927 the first estrogenic preparation (Progynon;

Schering) was available for therapy

• 1932 Geist and Spillman administered estrogen

to postmenopausal women for the treatment of
hot flushes, sweating

• 1936 menopause was recognized and

characterized as an increase in pituitary
gonadotropins and a decrease in estrogen
secretion

History of Hormone

therapy

• 1923 oestrone identification

(Allen, Doisy)

• 1930 estriol
• 1932 estradiol

Progestins

• Are compounds that exhibit

progestational activity

• protection the endometrium by

opposing the proliferative effect
of estrogens

Progestins types

• Natural - progesterone is the only

natural progestin; term „natural”
signifies that the compound is
found in living organism

• Synthetic - classified on the basis

of their chemical structure

Synthetic Progestins

classification

1. Related to progesterone
• A. Pregnane
• a) Acetylated : MPA, Cyproterone,

Megestrol

• b) Non-acetylated : Dydrogesterone
• 2. 19-non-pregnane
• a) Acetylated : Nomegestrol
• b) Non-acetylated : Demegestrone,

Trimegestrone, Promegestrone

Synthetic Progestins

classification

2. Related to Testosterone
• A. Estranes : Norethisterone,

Norethynodrel, Tibolone

• B. 13-Ethylgonanes :

Levonorgestrel, Desogestrel,
Norgestimate, Gestodene

Synthetic Progestins

classification - Generations

• I generation : Norethisterone
• II generation : Levonorgestrel
• III generation : Desogestrel,

Norgestimate, Gestodene

Progestins - Administration

Routes

• Oral
• intramuscular
• vaginal
• percutaneous
• intranasal
• sublingual

Progesterone Effect

• Mediated by an intracellular

receptor located in the nucleus of
the target cells

• 2 progesterone receptor proteins

in humans have been described

• these 2 proteins are encoded by a

single gene

Estrogen Classification

• Steroidal : estrone, estradiol,

ethinyl estradiol

• Nonsteroidal: tamoxifene,

raloxifene,

Estrogen Classification

• Steroidal
• a) natural ( found in human and

other animal species) : estrone,
estradiol, estrone-sulphate

• b) synthetic ethinyl estradiol,

tamoxifen, raloxifen

Estrogen Classification

• Nonsteroidal
• a) natural ; plant estrogens

( phytoestrogens such as genistein
and daidzein)

• b) synthetic

Ethinyl Estradiol

• Introduced as first synthetic orally

active estrogen in 1938

• to date the most effective oral

estrogen to be used in most
combined oral contraceptives

Estradiol Valerate

• Developed in 1953
• better absorbed than estradiol
• active duration 14-21 hours

Conjugated Estrogen

• The most frequently used drug for

treartment of menopausal
symptoms in US

• drug was introduced in 1942

17 beta estradiol

• In Europe one of the most

common compounds used

• half-life 12-14 hours
• following the multiple-dose oral

administration of 1mg the mean
serum level ranges from 57-60
pg/ml

Transdermal Gel

• Described as percutaneous

administration

• absorption trough the skin is

proportional to the surface of
application and inadequate dosing
may lead to interindividual and
intraindividual fluctuations

Transdermal Estradiol

Patches

• Contain different amounts of

estradiol delivering between 25-
100 microgram

• stimulation of hepatic protein

synthesis is largely avoided with
TTS

Estrogen Molecular

Action

• Genomic effect ( trough nuclear

action)

• Non-genomic ( trough non-nuclear

action);

- is based on a rapid onset via

uncharacterized membrane
receptors

Hormonal Replacement

Therapy

• The mosts effective treatment to relieve

menopausal symptoms

• Decreases fracture risk associated with

osteoporosis

• Probably can be responsible for the decrease of

Alzheimer disease progress

• Decreases colon cancer risk
• Influence on the primary and secondary prevention

of cardiovascular disease is controversial

• Increases the risk of thromboembolism (3-4x)

Osteoporosis – diagnosis

and treatment

Błażej Męczekalski

Osteoporosis

• Decreased bone mass density
• Microarchitecture deterioration
• Increased risk of fractures

Pathogenesis

• Causes
• - failure to achieve optimal peak

bone mass

• Bone mass loss caused by increased

bone resorption

• Inadequate repalcement of lost bone

as a result of decreased bone
formation

Risk factors for

osteoporosis

• Female sex
• Menopause
• Genetics/family history
• Race : Blacks and Mexican American are

protected

• Smoking
• Alcohol drinking
• Inactivity
• Leanness
• Diseases associated with secondary amenorrhea

Clinical symptoms

• Pain
• Fractures
• -vertebral crush fractures
• Hip fractures
• Colle’s fractures (distal radius)

Osteoporosis

Classification

• Primary: without associated diseases
- senile or postmenopausal

(involutional (95% of all patients most
frequent in elderly white women

- Idiopathic (occuring in middle age)
- Juvenile (occuring during adolescence

or 20s)

Osteoporosis

Classification

• Cushing’s syndrome
• Chronic liver disease
• Turner’s syndrome
• Immobilization
• Heparin therapy
• Alcoholism
• Diabetes mellitus
• Malabsorption
• Pregnancy and lactation
• Female athletes
• Anorexia nervosa

Who is at risk

• Medications – glucocorticoids
• Medical conditions - male

hypogonadism, amenorrhea > 6
months, primary
hypoparathyroidism, chronic liver
disease, male absorption,
thyrotoxicosis

Who is at risk

• Previous fracture
• Rhose at risk of falling
• Family history
• Low body weight
• Increasing age
• Low calcium intake, smoking,

menstrual irregularity, premature

ovarian failure, immobilisation,

exessive exercise

The problem

• 60% of women over 60
• 30% of men over 60
• Mortality in those with hip and

vertebral fractures is 5x age-
matched controls

Diagnosis

• Dual-beam X-ray absorptiometry
• Others : Dual-beam photon

absorptiometry, computerized
tomography, skeletal ultrasound

• Markers of bone resorption and

bone formation (wide variations)

Diagnosis T score

• T score matched with a young

adult mean

• Z score – age-matched
• O - -1 NORMAL
• -1 - -2.5 OSTEOPAENIA
• < -2.5 OSTEOPOROSIS

Non-Pharmacological

Management

• Stop smoking
• Diet : calcium rich foods: milk

cheese , yoghurt, fish, green
vegies, almonds, tofu

• Avoid calcium inhibitors - caffeine
• Falls prevention
• Weight bearing exercise

Management Goals

• Prevent further fractures
• Diminish pain
• Maintain mobility
• Reduce morbidity and mortality

Pharmacological

approaches to

osteoporosis

1. Antiresorptive agents
-calcium
-Vitamin D
-Estrogen
-SERMSs
-Calcitonin
-biphosphonates
2. Bone-forming agents
- Floride
- Androgens
- Parathyroid hormone

Optimal Daily Calcium

Intake

• Adolescents 1200-1500 mg
• Adults 1000 mg
• Women
• -pregnant or lactating 1200 mg
• - postmenopausal, on estrogen 1000 mg
• Postmenopausal, not on estrogen 1500 mg
• Elderly, (age > 65) 1500 mg