HRT

Question 1

Core principle of HRT formulation

Answer 1

• Route of delivery determines safety, dose and clinical effect
• Same hormone can be beneficial, ineffective, or dangerous depending on formulation
• Formulation and administration are pharmacologically critical

Question 2

Local vs systemic delivery in HRT

Answer 2

Systemic:
• Drug enters bloodstream and affects whole body
• Oral tablets, patches, nasal sprays

Local:
• Drug acts at site of application
• Vaginal creams, pessaries, rings

Principle:
• High local concentration + low systemic exposure = fewer adverse effects

Question 3

Hormones used in HRT

Answer 3

Oestrogens:
• Estradiol, estrone, estriol
• Ethinylestradiol, mestranol

Progestogens (if uterus present):
• Drospirenone, levonorgestrel, norethisterone acetate, tibolone

Reason:
• Oestrogen alone → endometrial hyperplasia & cancer
• Progestogen protects endometrium

Question 4

Available HRT formulations

Answer 4

Systemic:
• Oral tablets
• Transdermal patches
• Nasal sprays

Local:
• Vaginal creams
• Pessaries
• Vaginal tablets
• Vaginal rings

Question 5

Oral HRT pharmacology

Answer 5

• Immediate‑release tablets
• First‑pass metabolism via portal vein and liver CYP3A4
Consequences:
• Drug destruction
• Higher doses required
• Fluctuating plasma levels
Bioavailability ≈10%

Question 6

Clinical risks of oral HRT

Answer 6

Due to liver exposure:
• Increased VTE
• Increased stroke risk
• Gallbladder disease (gallstones)

Question 7

Why oral estradiol dose is larger than patches

Answer 7

Oral: 0.45–2 mg/day
Transdermal: 25–100 µg/day

Reason:
• First‑pass hepatic metabolism destroys large fraction of drug

Question 8

Advantages of transdermal HRT patches

Answer 8

• Bypass first‑pass metabolism
• Lower clot risk
• Lower dose required
• Steady hormone levels
• Better adherence
• Removable

Question 9

Disadvantages of patches

Answer 9

• Skin irritation
• Only suitable for potent drugs
• Skin permeability limitations

Question 10

Structure of a transdermal patch

Answer 10

Components:
• Release liner
• Adhesive
• Drug matrix/reservoir
• Backing layer (occlusive)
• Optional rate‑controlling membrane

Backing is occlusive → hydrates skin → ↑ absorption

Question 11

Drug release from patches

Answer 11

Daily dose = patch surface area × flux
Flux units: µg·cm⁻²·h⁻¹
Provides near‑constant controlled release

Question 12

Skin barrier to transdermal drugs

Answer 12

• Main barrier: stratum corneum
• Highly lipophilic
• Blocks hydrophilic drugs

Question 13

Ideal properties for transdermal drugs

Answer 13

• MW < 500 Da
• Moderate lipophilicity (logP 1–4)
• Highly potent (microgram doses)
Permeability depends on:
• Partition coefficient
• Diffusion coefficient
• Concentration gradient
• Skin thickness

Question 14

Why patches reduce clot risk

Answer 14

Oral oestrogen:
• Liver exposure → ↑ clotting factors → ↑ VTE

Transdermal:
• Bypasses liver → lower VTE risk

Question 15

Nasal HRT delivery

Answer 15

• Absorption via vascular nasal mucosa
• Avoids first‑pass metabolism
• Systemic effect similar to patches

Question 16

Vaginal ring HRT example

Answer 16

Estring®
• Estradiol hemihydrate 2 mg
• Releases 7.5 µg/day
• Duration 90 days
• Silicone elastomer ring

Question 17

Why only ~35% drug released from vaginal ring

Answer 17

• Excess drug maintains concentration gradient
• Ensures steady diffusion and controlled release

Question 18

Radiopacity in vaginal rings

Answer 18

• Barium sulfate added
• Allows X‑ray localisation

Question 19

Vaginal creams in HRT

Answer 19

Examples:
• Ovestin® (estriol 0.1%)
• Gynest® (estriol 0.01%)

Uses:
• Vaginal atrophy
• Dyspareunia
• Pruritus

Estriol chosen → weak oestrogen → minimal systemic exposure

Question 20

Vaginal tablet example

Answer 20

Vagifem® estradiol 10 µg
• Local effect only

Question 21

Advantages of intravaginal HRT

Answer 21

• Direct delivery
• Avoids first‑pass metabolism
• Minimal systemic exposure
• Continuous local release

Question 22

Limitations of vaginal HRT

Answer 22

Does NOT:
• Treat hot flushes
• Suppress ovulation
• Provide contraception

Question 23

Reservoir vs matrix systems

Answer 23

Reservoir:
• Drug core + membrane controlled release (rings, IUS)

Matrix:
• Drug dispersed in polymer (patches)

Hybrid:
• Combination concept (implants)

Question 24

Why vaginal doses are very small

Answer 24

• Direct tissue delivery
• No liver metabolism
• No distribution losses
• No protein binding losses

Question 25

Clinical decision making in HRT

Answer 25

Hot flushes → patch or oral High VTE risk → patch Vaginal dryness → vaginal therapy Poor adherence → patch/ring Cannot swallow → patch or vaginal

Question 26

Key exam facts about HRT formulations

Answer 26

• Oral HRT higher systemic risk • Transdermal safer systemic option • Vaginal local treatment only • First‑pass metabolism explains dose differences • Estriol preferred locally • Barium sulfate radiopaque • Drug MW & lipophilicity determine patch suitability

Question 27

MCQ: Why oral estradiol dose higher?

Answer 27

Extensive first‑pass hepatic metabolism destroys drug

Question 28

SAQ: Postmenopausal woman with vaginal atrophy only

Answer 28

Local vaginal estriol (cream/pessary/ring) for high local effect with minimal systemic exposure