MG lecture 8 FInal extra practice

Male hypogonadism

Inadequate testosterone production or androgen action → ↓ libido/sexual function + reduced secondary sexual characteristics, muscle mass and bone density; treated with testosterone replacement when fertility is not the primary goal.

Benign prostatic hyperplasia (BPH)

Testosterone → 5α-reductase → DHT → androgen receptor stimulation in prostate → prostate enlargement and lower urinary tract obstruction.

Androgenetic alopecia

DHT acts on genetically sensitive scalp follicles → progressive follicle miniaturization → shorter/thinner hairs and patterned hair loss.

Hirsutism

Excess androgen production or increased follicular androgen sensitivity → excessive terminal hair growth in androgen-dependent areas in women.

Precocious puberty

Premature activation of the HPG axis → early GnRH/LH/FSH and sex hormone production → early secondary sexual development and accelerated bone maturation.

Prostate cancer and androgens

Testosterone/DHT → androgen receptor signalling → stimulates growth and survival of androgen-sensitive prostate cancer cells.

HPG axis

Hypothalamic GnRH → anterior pituitary LH/FSH → gonads → sex hormone production + gametogenesis; sex hormones provide negative feedback.

GnRH secretion pattern

Pulsatile GnRH stimulates LH/FSH secretion, whereas continuous GnRH stimulation causes receptor desensitisation/downregulation → ↓ LH/FSH.

LH in males

LH stimulates Leydig cells → ↑ testosterone synthesis.

FSH in males

FSH stimulates Sertoli cells → supports spermatogenesis and production of androgen-binding protein/inhibin B.

LH in females

LH stimulates ovarian steroid production and the mid-cycle LH surge triggers ovulation.

FSH in females

FSH stimulates follicular growth and granulosa-cell oestrogen production.

Oestrogens

Oestradiol/oestrone/oestriol/ethinyl oestradiol → bind nuclear ERα/ERβ → receptor-DNA interaction → altered gene transcription controlling reproductive, metabolic and bone effects.

Oestradiol

Main and most potent endogenous oestrogen during reproductive life → regulates female reproductive tissues, menstrual cycling and maintenance of bone.

Oestrone

Weaker endogenous oestrogen that becomes relatively more important after menopause.

Oestriol

Weak endogenous oestrogen produced especially in large amounts during pregnancy.

Ethinyl oestradiol

Synthetic orally active oestrogen resistant to rapid metabolism → commonly used in combined hormonal contraception.

Oestrogen receptor mechanism

Oestrogen diffuses into cells → binds ERα/ERβ → receptor dimerisation → binding to oestrogen response elements → altered gene transcription.

Oestrogen effects on bone

Oestrogen suppresses osteoclast formation/activity and helps maintain bone mass → deficiency after menopause promotes osteoporosis.

Oestrogen feedback at low/moderate levels

Oestrogen provides negative feedback to hypothalamus/pituitary → ↓ GnRH, FSH and LH secretion.

Oestrogen and ovulation

Sustained high oestradiol near mid-cycle switches to positive feedback → large LH surge → follicular rupture and ovulation.

Tamoxifen

SERM that antagonises oestrogen receptors in breast tissue → ↓ ER-dependent tumour growth; used particularly in ER-positive breast cancer.

Tamoxifen tissue selectivity

Oestrogen antagonist in breast but partial agonist in tissues such as bone and endometrium → useful against breast cancer but can stimulate the uterus.

Tamoxifen important adverse effects

Partial oestrogenic activity → ↑ venous thromboembolism risk and ↑ risk of endometrial hyperplasia/cancer.

Clomiphene

SERM that blocks oestrogen feedback at hypothalamus/pituitary → ↑ GnRH → ↑ FSH/LH → follicular development and induction of ovulation.

Why clomiphene induces ovulation

Hypothalamus perceives reduced oestrogen signalling → negative feedback is removed → gonadotropin secretion rises → ovarian follicle maturation and ovulation.

Raloxifene

SERM with oestrogen agonist effects on bone and antagonist effects in breast with little uterine stimulation → ↓ postmenopausal bone loss.

Raloxifene in osteoporosis

Mimics beneficial oestrogen signalling in bone → ↓ osteoclast-mediated resorption → helps preserve bone density.

Raloxifene important advantage

Protects bone without substantial stimulation of breast or endometrial tissue → useful in selected postmenopausal patients.

Progestogens

Progesterone and synthetic progestins → activate intracellular progesterone receptors → make endometrium secretory, reduce uterine contractility and suppress gonadotropins.

Progesterone

Major post-ovulation hormone from the corpus luteum → converts proliferative endometrium into secretory endometrium and supports implantation/pregnancy.

Progesterone feedback

Progesterone provides negative feedback on hypothalamus/pituitary → ↓ GnRH and particularly suppresses the LH surge → helps prevent ovulation.

Progesterone and cervical mucus

Progesterone/progestins make cervical mucus thick and viscous → reduces sperm penetration.

Progesterone and uterus

Progesterone decreases uterine contractility and maintains a secretory endometrium → supports pregnancy.

Mifepristone

Competitive progesterone receptor antagonist → removes progesterone support of endometrium/pregnancy + increases uterine sensitivity to prostaglandins → used for medical abortion.

Mifepristone in medical abortion

Blocks progesterone → decidual/endometrial breakdown and cervical changes; followed by a prostaglandin such as misoprostol to induce uterine contractions.

Testosterone

Main endogenous androgen → androgen receptor activation → male reproductive development, libido, secondary sexual characteristics, anabolic effects and support of spermatogenesis.

Androgen receptor mechanism

Testosterone/DHT enter cells → bind intracellular androgen receptor → receptor dimerises and binds androgen response elements → altered gene transcription.

Testosterone anabolic effects

Androgen receptor activation → ↑ protein synthesis, muscle mass and bone growth + ↑ erythropoietin/erythropoiesis.

Testosterone androgenic effects

Promotes male genital development, secondary sexual characteristics, libido, sebaceous activity and body/facial hair.

5α-reductase

Enzyme that converts testosterone → DHT in tissues such as prostate, skin and hair follicles.

DHT

Dihydrotestosterone is formed from testosterone by 5α-reductase → binds androgen receptor more potently → strong effects on prostate, external genitalia and hair follicles.

Testosterone vs DHT

Testosterone mediates many systemic androgenic/anabolic effects, whereas DHT is a more potent androgen especially important in prostate, skin and hair follicles.

Androgen excess in females

Excess androgen signalling → hirsutism + acne + menstrual disturbances and, when severe, virilisation such as voice deepening.

Nandrolone

Anabolic androgenic steroid → strong protein-anabolic effects with relatively reduced androgenic activity compared with testosterone in some tissues.

Why nandrolone is relatively less androgenic

In 5α-reductase-rich tissues nandrolone is converted to a weaker androgenic metabolite → its anabolic effects are relatively more prominent.

Stanozolol

Synthetic anabolic androgenic steroid → promotes protein synthesis and tissue anabolism with an altered anabolic-to-androgenic ratio compared with testosterone.

Androgenic vs anabolic effects

Androgenic effects concern reproductive/virilising actions, whereas anabolic effects concern protein synthesis, muscle and bone growth; complete separation is not possible because both use the androgen receptor.

Testosterone replacement

Testosterone/esters/transdermal preparations/oral undecanoate → replace deficient androgen signalling → treat symptomatic male hypogonadism.

Testosterone esters

Esterification slows release from intramuscular depots → prolongs testosterone exposure and reduces dosing frequency.

Transdermal testosterone

Skin-delivered testosterone → avoids first-pass hepatic metabolism and provides relatively stable systemic concentrations.

Oral testosterone limitation

Unmodified oral testosterone undergoes extensive hepatic first-pass metabolism → poor bioavailability.

Testosterone undecanoate

Lipophilic testosterone ester absorbed partly through intestinal lymphatics → reduces first-pass hepatic loss and allows oral administration.

Why testosterone replacement does not restore fertility

Exogenous testosterone suppresses GnRH/LH/FSH and lowers intratesticular testosterone → spermatogenesis can decrease despite normal blood testosterone.

Gonadotropins for male fertility

hCG/LH activity stimulates Leydig-cell testosterone + FSH stimulates Sertoli cells → restores spermatogenesis in hypogonadotropic hypogonadism.

hCG

Mimics LH at the LH receptor → stimulates Leydig cells → ↑ intratesticular testosterone production.

Pulsatile GnRH therapy

Physiological intermittent GnRH administration → maintains pituitary responsiveness → ↑ LH/FSH → stimulates gonadal steroid production and fertility.

Continuous GnRH agonists

Triptorelin and related agonists initially stimulate GnRH receptors but persistent exposure causes receptor desensitisation/downregulation → profound ↓ LH/FSH and sex hormones.

GnRH agonist flare

Initial continuous GnRH agonist treatment briefly ↑ LH/FSH and gonadal hormones before receptor downregulation causes suppression.

Triptorelin

Long-acting GnRH agonist given continuously → pituitary GnRH receptor downregulation → ↓ LH/FSH → ↓ testosterone/oestrogen.

Triptorelin in prostate cancer

Continuous GnRH agonism → ↓ LH → ↓ testicular testosterone → removes androgen stimulation of prostate tumour cells.

Triptorelin in precocious puberty

Continuous GnRH receptor stimulation → suppresses premature LH/FSH release → lowers gonadal sex hormones and halts early pubertal progression.

Cyproterone acetate

Androgen receptor antagonist with progestogenic activity → directly blocks androgen action + suppresses LH/testosterone production → reduces androgen-dependent effects.

Cyproterone acetate in women

↓ Androgen receptor signalling and androgen production → can reduce severe hirsutism/acne in selected patients.

Cyproterone acetate in men

Antiandrogenic + antigonadotropic effects → lowers androgen action in conditions requiring strong androgen suppression.

Finasteride

Selective 5α-reductase inhibitor, mainly type II → ↓ conversion of testosterone to DHT → reduces DHT-dependent prostate growth and hair-follicle miniaturisation.

Finasteride in BPH

↓ Prostatic DHT → gradual reduction in prostate volume → improves urinary obstruction symptoms over time.

Finasteride in androgenetic alopecia

↓ Scalp DHT → slows follicle miniaturisation → reduces hair loss and can promote maintenance/regrowth.

Finasteride vs androgen receptor blockers

Finasteride lowers DHT formation but leaves the androgen receptor functional, whereas drugs such as cyproterone directly block androgen receptor signalling.

Combined contraceptive pill

Oestrogen + progestin → negative feedback suppresses FSH/LH and prevents LH surge/ovulation; progestin also thickens cervical mucus and makes endometrium less receptive.

Oestrogen role in combined contraception

Suppresses FSH and follicular development + stabilises endometrium → contributes to ovulation suppression and cycle control.

Progestin role in combined contraception

Strongly suppresses LH surge/ovulation + thickens cervical mucus + induces endometrial changes → main contraceptive component.

Combined pill and ovulation

Steady oestrogen/progestin exposure → continuous negative feedback → no normal mid-cycle LH surge → ovulation is suppressed.

Combined pill and cervical mucus

Progestin → thick, viscous cervical mucus → sperm penetration becomes difficult.

Combined pill and endometrium

Progestin-dominant hormonal environment → endometrium becomes less proliferative/receptive → additional contraceptive effect.

Withdrawal bleeding with combined pill

Hormone-free/placebo interval → fall in exogenous oestrogen/progestin → endometrial shedding → withdrawal bleed rather than a normal ovulatory menstruation.

Progestin-only pill

Progestin → markedly thickens cervical mucus + alters endometrium and, depending on preparation, suppresses ovulation → prevents pregnancy without oestrogen.

Combined pill vs progestin-only pill

Combined pill reliably suppresses ovulation through oestrogen/progestin feedback, while the progestin-only pill relies strongly on cervical mucus and variably suppresses ovulation.

Why oestrogen increases thrombosis risk

Hepatic oestrogen effects increase several coagulation factors and alter anticoagulant balance → ↑ venous thromboembolism risk, especially with additional risk factors.