Endocrine Physiology
Clinical Overview
Start from one idea: an endocrine gland is a thermostat with a chemical messenger. A controller senses a need, releases a hormone into the blood, a distant tissue responds, and the response is fed back to switch the controller off again. Everything in this chapter is a variation on that loop. Once you can draw the loop, you can place almost any abnormal result on it.
Endocrine physiology is therefore pattern recognition with feedback. The exam rarely rewards reciting hormone lists. It asks whether you can decide if a disorder is central, glandular, receptor-level, enzyme-level, pregnancy-modified, placental, iatrogenic or drug-induced. Draw the axis, place the abnormal hormone, then ask what feedback should have happened.
The same method works across the hypothalamus, pituitary, ovary, placenta, thyroid, adrenal, pancreas and parathyroid. A low target hormone with a high trophic hormone is usually primary gland failure. A low target hormone with low or inappropriately normal trophic drive is central failure. A high target hormone with suppressed trophic hormone suggests autonomous secretion or exogenous hormone. A normal total hormone with altered binding protein may hide an abnormal free hormone, or may simply reflect pregnancy physiology.
O&G adds three complications. First, pregnancy is itself an endocrine state: the placenta produces peptide hormones, steroid hormones, releasing hormones, growth factors and enzymes that alter maternal physiology. Second, the target tissues change their receptor expression: the myometrium becomes more responsive to oxytocin and prostaglandins near term; breast tissue is primed by oestrogen, progesterone, prolactin and placental lactogen; the liver changes binding proteins. Third, several disorders we manage are endocrine by mechanism even when they present as bleeding, infertility, miscarriage, hypertension, osteoporosis or fetal overgrowth.
The mechanism-to-clinical chain is the useful habit:
Continuous GnRH exposure -> pituitary receptor downregulation -> low LH/FSH -> ovarian suppression -> treatment effect in endometriosis/fibroids plus hypo-oestrogenic bone symptoms.
Placental lactogen, placental GH, progesterone and cortisol -> insulin resistance -> higher maternal glucose availability -> fetal hyperinsulinaemia if maternal glucose is excessive -> macrosomia and neonatal hypoglycaemia.
hCG stimulation of the TSH receptor -> lower early pregnancy TSH -> misdiagnosis risk if non-pregnant thyroid ranges are used.
Core Knowledge
Hormone Classes, Binding and Receptors
Hormone class predicts transport, receptor site and speed of action.
| Hormone class | Synthesis and transport | Receptor and speed | O&G examples |
|---|---|---|---|
| Peptide/protein | Transcribed and translated, often made as pre-prohormones; water-soluble; stored in granules | Cell-surface receptors; rapid second messengers, sometimes later gene effects | GnRH, LH, FSH, hCG, prolactin, insulin, oxytocin, vasopressin |
| Steroid | Synthesised from cholesterol; lipid-soluble; usually protein-bound in plasma | Intracellular/nuclear receptors; slower genomic effects | Oestradiol, progesterone, testosterone, cortisol, aldosterone |
| Amine | Derived from amino acids; behaviour varies | Catecholamines act rapidly at membrane receptors; thyroid hormone acts mainly through nuclear receptors | Adrenaline, noradrenaline, T3, T4 |
| Eicosanoid | Derived from arachidonic acid in membranes; local and short-lived | Local receptors; rapid paracrine effects | Prostaglandins in menstruation, cervical ripening, labour and PPH |
Only free hormone is immediately bioactive. Pregnancy changes binding proteins: oestrogen increases thyroid-binding globulin and cortisol-binding globulin, and lower albumin changes total calcium and free fractions of some drugs and hormones. This is why endocrine interpretation in pregnancy requires the question: am I measuring total hormone, free hormone, trophic hormone, or tissue effect?
Major receptor systems recur:
| Receptor system | Mechanism | High-yield example |
|---|---|---|
| G-protein/cAMP | Receptor activates adenylate cyclase and protein kinase A | LH, FSH, TSH, hCG, glucagon |
| Gq/IP3/calcium | Receptor releases intracellular calcium and activates protein kinase C | Oxytocin and smooth muscle contraction |
| Tyrosine kinase | Receptor phosphorylation activates intracellular cascades | Insulin and IGF signalling |
| JAK/STAT | Cytokine-type receptor activates transcription factors | Prolactin and growth hormone |
| Nuclear receptor | Hormone-receptor complex binds DNA response elements | Oestrogen, progesterone, cortisol, thyroid hormone, vitamin D |
Now that the messenger, its transport and its receptor are clear, two questions follow: what is the hormone actually made of, and who gives the order to release it. The steroid hormones that dominate O&G all come off one biochemical assembly line, so we build that line first; the hypothalamic-pituitary control system that switches it on and off comes immediately after.
Steroidogenesis: from the Gonane Nucleus to O&G Steroids
Steroidogenesis is the biochemical bridge between cell biology, puberty, the menstrual cycle, pregnancy, adrenal disease, contraception, menopause, hyperandrogenism and fetal sexual development. The safest way to learn it is not as isolated adrenal and ovarian diagrams, but as one shared pathway whose final products depend on which enzymes a cell expresses.
All steroid hormones share the gonane nucleus, also called the cyclopentanoperhydrophenanthrene nucleus; older or shortened teaching may refer to the steroid nucleus as cyclopentanophenanthrene. The point is the same: three six-membered rings and one five-membered ring fused together. This long word matters because it tells you what a steroid actually is: a rigid four-ring lipid scaffold, not a peptide, not a catecholamine and not a prostaglandin.
Think of the rings as A, B, C and D. Rings A, B and C are six-membered; ring D is the five-membered cyclopentane ring. Small chemical changes on this scaffold create large biological differences. Add a keto group at carbon 3 and a double bond in the A ring and the molecule behaves like a progestin/androgen precursor. Aromatise the A ring and remove the C19 methyl group and it becomes an oestrogen. Add hydroxyl groups at positions such as 11, 17, 18 or 21 and the molecule moves toward cortisol, aldosterone or other adrenal steroids. Reduce testosterone at the 5-alpha position and the same C19 steroid becomes dihydrotestosterone (DHT), a much more potent androgen at some target tissues.
The Primary payoff is this: steroid physiology is structure-function medicine. A small enzyme step can decide whether a fetus virilises, whether a follicle aromatises androgen into oestradiol, whether the adrenal makes cortisol or salt-retaining precursors, whether an endometrium is proliferative or secretory, and whether a lab test points to ovary or adrenal.
| Steroid family | Carbon skeleton | Key examples | O&G relevance |
|---|---|---|---|
| Cholestanes | C27 | Cholesterol | Parent substrate for all steroid hormones |
| Pregnanes | C21 | Pregnenolone, progesterone, cortisol, aldosterone | Corpus luteum, pregnancy maintenance, adrenal stress and salt balance |
| Androstanes/androstenes | C19 | DHEA, androstenedione, testosterone, DHT | Puberty, libido, hirsutism, virilisation, fetal external genital development |
| Oestranes | C18 | Oestrone, oestradiol, oestriol | Endometrium, breast, bone, vaginal epithelium, pregnancy oestrogen production |
The first committed step is always:
cholesterol -> StAR transport into mitochondrion -> CYP11A1 side-chain cleavage -> pregnenolone
StAR is the steroidogenic acute regulatory protein. It moves cholesterol from the outer to the inner mitochondrial membrane, where CYP11A1 (P450 side-chain cleavage enzyme) converts cholesterol to pregnenolone. This is the acute gatekeeper step: without cholesterol delivery into the mitochondrion, a steroidogenic cell cannot rapidly increase output even if the rest of the pathway is present.
Most steroidogenic enzymes are either cytochrome P450 enzymes or hydroxysteroid dehydrogenases. P450 enzymes usually add or remove oxygen-containing groups or cleave carbon bonds. HSD enzymes interconvert hydroxy and keto forms and shift double bonds. The practical exam rule is:
P450s define pathway direction; HSDs activate, inactivate or change steroid class.
| Enzyme | Common name | Main reaction | Why Primary candidates should know it |
|---|---|---|---|
| StAR | Steroidogenic acute regulatory protein | Cholesterol entry into mitochondria | Defective transport causes severe steroid failure |
| CYP11A1 | Cholesterol side-chain cleavage / P450scc | Cholesterol -> pregnenolone | First enzymatic step for every steroid |
| HSD3B2 | 3-beta-HSD / delta5-delta4 isomerase | Pregnenolone -> progesterone; DHEA -> androstenedione | Required for progesterone, cortisol and aldosterone pathway strength |
| CYP17A1 | 17-alpha-hydroxylase and 17,20-lyase | Creates 17-hydroxylated precursors and C19 androgens | Explains sex-steroid production and several CAH patterns |
| CYP21A2 | 21-hydroxylase | Progesterone/17-OH progesterone -> DOC/11-deoxycortisol | Commonest CAH enzyme defect |
| CYP11B1 | 11-beta-hydroxylase | 11-deoxycortisol -> cortisol | Defect causes androgen excess with mineralocorticoid hypertension physiology |
| CYP11B2 | Aldosterone synthase | Corticosterone -> aldosterone | Zona glomerulosa-specific mineralocorticoid endpoint |
| CYP19A1 | Aromatase | Androgens -> oestrogens | Granulosa, placenta and peripheral oestrogen production |
| SRD5A2 | 5-alpha-reductase type 2 | Testosterone -> DHT | External genital virilisation and DSD reasoning |
| SULT2A1 | Sulfotransferase | DHEA -> DHEAS | Adrenal androgen storage/transport form |
The Shared Trunk
Every pathway starts with cholesterol. From pregnenolone, the pathway can remain in the delta5 lane or be converted into the delta4 lane by 3-beta-HSD.
| Step | Product | Meaning |
|---|---|---|
| Cholesterol | C27 parent molecule | Comes from LDL uptake, HDL contribution and local synthesis |
| Pregnenolone | First C21 steroid | Parent for progesterone, androgens, cortisol and aldosterone |
| Progesterone | Delta4 C21 steroid | Corpus luteum/pregnancy hormone and adrenal intermediate |
| 17-hydroxypregnenolone / 17-hydroxyprogesterone | 17-hydroxylated C21 steroids | Gateway toward cortisol and androgens |
| DHEA / androstenedione | C19 androgen precursors | Weak androgens or substrates for testosterone/oestrogen |
| Testosterone / DHT | Active androgens | Receptor-mediated virilisation and androgenic clinical effects |
| Oestrone / oestradiol / oestriol | Aromatised C18 oestrogens | Female reproductive tract, bone, breast and pregnancy effects |
The carbon loss matters. Cholesterol is C27. Pregnenolone and progesterone are C21. Androgens are C19 because the side chain has been shortened. Oestrogens are C18 because aromatase removes the C19 methyl group and aromatises the A ring. That structural change is why oestrogens are not just "weak androgens"; they bind a different receptor family and have different tissue effects.
| Chemical change | Structural meaning | Clinical meaning |
|---|---|---|
| Side-chain cleavage | C27 cholesterol becomes C21 pregnenolone | The steroid pathway has begun |
| 17-hydroxylation | Adds a hydroxyl group at C17 | Opens the route to cortisol and sex-steroid precursors |
| 17,20-lyase activity | Shortens C21 steroid to C19 androgen | Creates DHEA/androstenedione androgen lane |
| 21-hydroxylation | Adds hydroxyl group needed for cortisol/aldosterone lanes | Defect causes common CAH physiology |
| 11-beta-hydroxylation | Final cortisol step from 11-deoxycortisol | Defect leaves mineralocorticoid precursors and androgen excess |
| Aromatisation | Aromatic A ring; C19 androgen becomes C18 oestrogen | Granulosa, placenta and adipose oestrogen production |
| 5-alpha reduction | Testosterone becomes DHT | External genital virilisation, hair follicle/skin androgen effect |
| Sulfation | Steroid made more water-soluble/reservoir-like | DHEAS as adrenal/fetal-adrenal precursor pool |
Sex Steroid Pathways
The sex-steroid pathway is a division of labour. Ovarian theca cells, granulosa cells, corpus luteum, placenta, adipose tissue, skin and adrenal cortex do not make the same products because they do not express the same enzymes.
| Pathway | Main sequence | Main site or lesson |
|---|---|---|
| Progesterone pathway | Cholesterol -> pregnenolone -> progesterone | Corpus luteum, placenta, adrenal intermediate |
| Delta5 androgen pathway | Pregnenolone -> 17-OH pregnenolone -> DHEA -> androstenedione -> testosterone | Human adrenal and gonadal androgen production often use this lane |
| Delta4 androgen pathway | Progesterone -> 17-OH progesterone -> androstenedione -> testosterone | Important for enzyme-defect reasoning |
| DHT pathway | Testosterone -> DHT by 5-alpha-reductase | External genital development, hair follicles and androgen-sensitive tissues |
| Oestradiol pathway | Androstenedione -> oestrone; testosterone -> oestradiol by aromatase | Granulosa cells, adipose tissue, placenta |
| Pregnancy oestriol pathway | Fetal adrenal DHEAS -> fetal liver 16-alpha hydroxylation -> placental aromatisation -> oestriol | Fetal-placental unit |
The two-cell, two-gonadotrophin model is steroidogenesis made clinical:
| Cell | Main trophic signal | Enzyme pattern | Product handed onward |
|---|---|---|---|
| Theca cell | LH | StAR, CYP11A1, CYP17A1, 3-beta-HSD | Androstenedione/testosterone precursors |
| Granulosa cell | FSH, later LH after luteinisation | Aromatase, 17-beta-HSD, later progesterone machinery | Oestradiol before ovulation; progesterone after luteinisation |
| Corpus luteum | LH or hCG | Strong cholesterol uptake and progesterone synthesis | Progesterone for secretory endometrium and early pregnancy support |
This explains several clinical patterns. In a normal follicle, LH-driven theca androgen is not the endpoint; it is substrate. FSH-driven granulosa aromatase converts it to oestradiol. In anovulation, granulosa maturation and cyclic progesterone exposure are inadequate, so the endometrium can see prolonged oestrogen without progesterone opposition. In PMOS (formerly PCOS) physiology, increased androgen production, insulin effects, low SHBG and follicular arrest interact; the problem is not merely "cysts".
Placental Steroidogenesis And The Fetal-Placental Unit
The placenta is powerful but incomplete. It makes abundant progesterone from maternal cholesterol, but it has little or no CYP17A1 activity, so it cannot independently make large amounts of C19 androgen precursor from progesterone. Pregnancy oestrogen production therefore depends on cooperation between placenta and fetus.
maternal cholesterol -> placental pregnenolone/progesterone
fetal adrenal DHEAS -> fetal liver 16-alpha hydroxylation -> placenta desulfation and aromatisation -> oestriol
This is why pregnancy oestriol is a fetal-placental signal rather than a purely maternal ovarian signal. It also explains why the fetal adrenal is large and steroidogenically important. The fetal adrenal produces DHEAS substrate for placental oestrogen synthesis, while placental progesterone and CRH participate in maternal-fetal endocrine timing.