Oestrogens & progestogens, Hormone antagonists/agonists (breast & prostate cancer), 5-alpha-reductase inhibitors, Phosphodiesterase inhibitors, Levothyroxine

What are oestrogen and progesterone used for?

1) Hormonal contraception

2) HRT to delay early menopause and treatment menopausal symptoms.

How do oestrogens & progestogens work/ MOA?

They suppress LH/FSH and hence ovulation.

What effects do oestrogens & progestogens have?

Reduced menstrual pain and bleeding, improves acne and alleviates vaginal dryness and 'hot flushes' during menopause.

Common adverse effects of oestrogens & progestogens?

Irregular bleeding and mood changes.

What can oestrogens & progestogens increase the risk of?

CVD and stroke (more relevant in women with risk factors).

May be associated with increased risk of breast and cervical cancer (small).

When are oestrogens & progestogens contraindicated?

Women with breast cancer.

When should CHC be avoided?

1) Personal or FHx of VTE

2) Thrombogenic mutation

3) Risk factors of CVD (>35 years, migraine with aura, heavy smoking Hx).

Who should not receive oestrogen-only HRT and why?

Women who have a uterus- endometrial benign prostatic enlargement.

Which drugs can reduce contraceptive efficacy of oestrogens and progestogens?

Cytochrome P450 inducers (e.g. rifampicin, carbamazepine)

Which drug can oestrogens and progestogens reduce the absorption of?

Lamotrigine.

Ethinylestradiol and estradiol are ...?

Oestrogens.

Levonorgestrel and desogestrel are ...?

Progestogens.

Who can receive oestrogen-only HRT?

Women who have had a hysterectomy.

What is preferred for isolated vaginal menopausal symptoms?

Vaginal oestrogen preparations.

What HRT regimens are available?

Cyclic (monthly bleed) or continuous (no bleed).

Which women usually receive cyclic HRT?

Women who are still having periods.

Which women usually receive continuous HRT?

Women who have been amenorrhoeic for >1 year.

When can a COC pill be started without additional contraception?

Within the first 6 days of the menstrual cycle.

What is required if the COC pill is started after day 6?

Barrier contraception or abstinence for 7 days.

What is the standard COC dosing schedule?

21 days of active pills followed by a 7-day pill-free interval.

What happens during the pill-free interval?

Withdrawal bleed.

What are 'everyday' COC pills?

Pills taken continuously, with inactive tablets on days 22–28.

Does missing one COC pill reduce contraceptive efficacy?

No significant reduction.

What is required if two or more COC pills are missed?

Additional contraceptive precautions for 7 days.

What baseline assessments are required before starting hormonal contraception or HRT?

Medical history, BP, BMI.

When should the first follow-up HRT/contraception review occur?

At 3 months.

How often is monitoring required after the first HRT/contraceptionreview?

Annually.

Can hormonal contraception be stopped abruptly?

Yes.

Letrozole, tamoxifen, anastrozole, bicalutamide and goserelin are all...?

Hormone antagonists and agonists used in breast and prostate cancer.

When are Tamoxifen, anastrozole, and letrozole used?

In estrogen-receptor (ER-positive) breast cancer- to reduce the risk of recurrent disease/ slow progression of advanced disease.

When are Leuprorelin, bicalutamide, and goserelin used?

In prostate cancer, as systemic antiandrogen therapy for hormone sensitive tissues that cant be resected.

What proportion of breast cancers are (ER) positive?

Approx 2/3.

How does oestrogen promote breast cancer growth?

By stimulating cell proliferation via oestrogen receptors.

MOA of tamoxifen?

A selective oestrogen receptor modulator (SERM)- it prevents oestrogen from binding to its receptor.

MOA of anastrozole and letrozole?

Aromatase inhibitors- inhibiting conversion of androgens→oestrogens via aromatase in peripheral tissues (fat, muscle).

Why are aromatase inhibitors superior to tamoxifen in post-menopausal women?

Because most oestrogen is produced peripherally, not by the ovaries.

Why are aromatase inhibitors ineffective in pre-menopausal women?

Ovarian oestrogen production continues despite aromatase inhibition.

Approximately what proportion of prostate cancers respond to hormone therapy?

90%

What hormone drives prostate cancer growth?

Androgens (e.g. testosterone).

MOA of goserelin, leuprorelin?

GnRH analogues- initially overstimulate LH release, then downregulate GnRH receptors, reducing LH and androgen levels.

How does bicalutamide work?

Directly blocks androgen receptors.

What adverse effects are common to tamoxifen and aromatase inhibitors?

Symptoms of oestrogen depletion (hot flushes, vaginal dryness, reduced bone density- basc menopausal symptoms)

What serious risks are associated with tamoxifen?

VTE and endometrial cancer.

What rare but serious adverse effects can occur with tamoxifen and aromatase inhibitors?

Agranulocytosis and liver failure.

What adverse effects are associated with anti-androgen therapy?

Hair loss, gynaecomastia (man boobs), mood disturbance.

What specific adverse effect is associated with bicalutamide?

Photosensitivity.

In which situations is tamoxifen contraindicated?

Pregnancy and breastfeeding.

When should aromatase inhibitors NOT be used?

In pre-menopausal women unless ovarian function is suppressed or ablated.

Why can GnRH analogues initially worsen prostate cancer symptoms? What serious complication can result from this?

1) Initial LH surge can stimulate tumour growth.

2) Spinal cord compression in patients with spinal metastases.

How does tamoxifen interact with warfarin?

It inhibits CYP2C9, increasing warfarin levels and bleeding risk.

Which SSRIs interfere with tamoxifen activation?

Fluoxetine and paroxetine.

How are tamoxifen, bicalutamide, and aromatase inhibitors administered?

Oral tabs.

How are GnRH analogues administered?

SC or IM injection or implant.

What contraception advice should be given with tamoxifen?

Avoid pregnancy; use barrier or non-hormonal contraception.

What monitoring is required during hormonal cancer therapy?

Liver function tests and FBC.

What anticoagulant is often preferred in cancer patients?

Low molecular weight heparin.

What drug class are finasteride and dutasteride?

5α-reductase inhibitors.

What are finasteride and dutasteride used for?

1) Improve LUTS in benign prostate enlargement.

2) Androgenetic alopecia (finasteride only)

What are LUTS?

Difficulty passing urine, urinary retention, and poor urinary flow due to BPE.

What is the role of 5α-reductase in the prostate?

It converts testosterone into more active metabolite dihydrotestosterone (DHT).

Why is dihydrotestosterone (DHT) important in benign prostatic enlargement?

DHT stimulates prostatic growth.

How long does it take for 5α-reductase inhibitors to have a clinical effect?

Upto 6 months.

Why are α-blockers often started before 5α-reductase inhibitors?

α-blockers provide faster symptomatic relief.

What are the most common adverse effects of 5α-reductase inhibitors?

Impotence and reduced libido.

What rare but serious adverse effects have been reported with finasteride?

Breast cancer and suicidal thoughts.

Why are 5α-reductase inhibitors contraindicated in women of childbearing potential?

They can cause abnormal development of external genitalia in a male fetus.

How might women be exposed to 5α-reductase inhibitors unintentionally? How can this be minimised?

By handling broken/crushed tablets or via semen during unprotected sex.

Use gloves and condoms.

Do finasteride and dutasteride have significant drug interactions?

No clinically important interactions.

How do 5α-reductase inhibitors affect PSA levels?

They suppress PSA progressively over 6 months.

What PSA strategy should be used after 5α-reductase inhibitor treatment?

Establish a new baseline PSA at 6 months

How should PSA be interpreted if baseline is unknown?

Double the measured value to estimate true PSA.

What drug class are sildenafil, tadalafil and vardenafil?

Phosphodiesterase (PDE) type 5 inhibitors.

What are PDE inhibitors used for?

1) Erectile dysfunction

2) Primary pulmonary hypertension.

How does cGMP cause an erection?

It activates protein kinase G, causing vasodilation of penile arteries and engorgement.

What is the role of PDE-5?

It degrades cGMP to GMP, terminating its effect.

MOA of PDE inhibitors?

Increase cGMP concentration in the penis, improving the likelihood of achieving an erection and prolonging its duration.

Why are PDE-5 inhibitors useful in pulmonary hypertension?

PDE-5 inhibition causes pulmonary arterial vasodilation, reducing pulmonary pressure.

What is the most common adverse effect of PDE-5 inhibitors?

Headache, flushing, dizziness, and nasal congestion.

What cardiovascular adverse effects may occur uncommonly with PDE inhibitors? What rare but serious cardiac event has been reported?

Hypotension and arrhythmias.

More seriously- ACS.

What is priapism?

A prolonged, painful erection without stimulation.

Why can PDE-5 inhibitors cause visual disturbances?

Inhibition of PDE-6 in the retina affects phototransduction.

In which cardiovascular conditions are PDE-5 inhibitors contraindicated?

Recent stroke, recent ACS, or significant CVD.

Why should PDE-5 inhibitors be used cautiously in hepatic or renal impairment?

Reduced metabolism and excretion increase the risk of toxicity.

Which drugs must NEVER be combined with PDE-5 inhibitors? Why?

Nitrates (excessive cGMP accumulation can cause severe hypotension and cardiovascular collapse) and nicorandil.

Which other drugs require caution when combined with PDE-5 inhibitors?

α-blockers and CCBs (other vasodilators).

How should α-blockers be spaced relative to PDE-5 inhibitors?

At least 4 hours apart.

Which drugs increase PDE-5 inhibitor plasma concentrations?

Cytochrome P450 inhibitors (e.g. amiodarone, diltiazem, fluconazole).

How does tadalafil differ from sildenafil?

Longer duration of action (up to 36 hours).

Can you take sildenafil with food?

Yes- but it delays absorption and onset of effect.

Does food affect tadalafil absorption?

No.

Does a PDE-5 inhibitor cause an erection without sexual stimulation?

No, sexual stimulation is required.

Why are recreational nitrates (“poppers”) dangerous with PDE-5 inhibitors?

They dramatically increase NO, causing severe hypotension and collapse.

What is levothyroxine used for?

Long term replacement of thyroid hormones in hypothyroidism.

Adverse effects of levothyroxine?

- GI upset

- Cardiac (palpitations/arrhythmias)

- Neurological (tremor/ restlessness/ insomnia)

- Weight loss

Why must levothyroxine be used cautiously in coronary artery disease?

It increases heart rate and metabolism, which may precipitate cardiac ischaemia.

How should levothyroxine be initiated in patients with coronary artery disease?

Start at a low dose and monitor carefully.

Why must corticosteroids be given before levothyroxine in hypopituitarism?

Prevent acute adrenal insufficiency (Addisonian crisis).

Which substances reduce GI absorption of levothyroxine?

Antacids, calcium salts, and iron salts- should separate by at least 4 hours.

Which drugs may increase levothyroxine requirements?

Cytochrome P450 inducers (e.g. phenytoin, carbamazepine).

How does levothyroxine affect diabetes treatment?

It may increase requirements for glucose-lowering medications.