I. MENSTRUATION & PRIMARY AMENORRHOEA

Normal Menstruation

1. The hypothalamus secretes GnRH in a pulsatile fashion
2. GnRH stimulates the pituitary to release FSH and LH
3. FSH/LH promote ovarian follicular development and ovulation
4. The follicle secretes estrogen pre-ovulation
5. Post-ovulation, the corpus luteum secretes progesterone + estrogen - stimulating endometrial maturation
6. If no pregnancy occurs, estrogen/progesterone drop, triggering withdrawal bleeding

• Predominantly arterial (75%); 25% venous
• Contains tissue debris, prostaglandins, and fibrinolysin (which lyses clots - so no clots normally)
• Duration: 3-5 days (range 1-8 days is normal)
• Volume: average 30 mL; up to 80 mL is normal; >80 mL is abnormal (menorrhagia)

• Estrogen makes cervical mucus thinner, more alkaline - promotes sperm survival (fern pattern at ovulation, spinnbarkeit 8-12 cm)
• Progesterone makes mucus thick, cellular, no fern pattern

• No corpus luteum forms, so no progesterone effect
• Estrogen alone causes endometrial growth - eventually sloughs (variable timing, often <28 days)
• Common in first 12-18 months after menarche and premenopausally

Primary Amenorrhoea

Definition

• Primary amenorrhoea = absence of menses by age 13 when there is no visible development of secondary sexual characteristics, OR by age 15 in the presence of normal secondary sexual characteristics
• Failure to begin breast development by age 13 always warrants investigation
• These ages represent 2 standard deviations above the mean age of developing secondary sexual characteristics and menses

Diagnostic Key: Presence of Secondary Sexual Characteristics?

1. Hypergonadotropic Hypogonadism (high FSH, low estrogen - primary ovarian failure)
   • Turner syndrome (45,X) - most common cause; streak gonads
   • Other chromosomal/gonadal dysgenesis
   • When gonadal failure occurs with primary amenorrhoea, there is a high incidence of abnormal karyotype
2. Hypogonadotropic Hypogonadism (low FSH/LH, low estrogen - hypothalamic/pituitary cause)
   • Genetic disorders (e.g., Kallmann syndrome - anosmia + GnRH deficiency)
   • Other hypothalamic/pituitary dysfunction
   • CNS tumors, cranial irradiation

1. Outflow/Müllerian anomalies (normal karyotype 46,XX but absent uterus/vagina)
   • Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome - absent uterus + vagina, normal ovaries
   • Imperforate hymen or transverse vaginal septum (cryptomenorrhoea - blood accumulates)
2. Androgen Insensitivity Syndrome (AIS) - 46,XY; testes present but end-organ insensitivity to androgens; normal female external appearance; absent/scant pubic/axillary hair; absent uterus
3. Ovotesticular Disorder of Sexual Development

• Polycystic Ovarian Syndrome (PCOS)
• Hyperprolactinaemia
• Primary Ovarian Insufficiency (POF)
• Hypothalamic/pituitary lesions
• Functional hypothalamic amenorrhoea: eating disorders, weight loss, exercise, stress, obesity
• Thyroid disorders

Diagnostic Workup

1. Physical exam for secondary sexual characteristics + pelvic anatomy
2. Pregnancy test (hCG) - always first
3. Serum prolactin + TSH
4. FSH + estradiol - distinguish hypergonadotropic vs hypogonadotropic
5. Anti-Müllerian hormone (AMH) - useful
6. Karyotype if gonadal failure suspected

Treatment Principles

• Specific therapy targeting cause (medical or surgical)
• Hormone therapy to initiate/maintain secondary sexual characteristics
• Maximize bone mass (estrogen + calcium + vitamin D in low-estrogen states)
• Ovulation induction for those desiring pregnancy

II. FUNDAMENTALS OF REPRODUCTION, PLACENTA & MEMBRANES, FETUS

The Placenta

• Fetal part = chorionic sac (outermost fetal membrane - villous chorion)
• Maternal part = decidua basalis (derived from endometrium)

The Decidua (endometrium in pregnancy)

Placental Structure

• Cotyledons: The septa from decidua basalis project toward the chorionic plate and divide the fetal placenta into irregular convex areas called cotyledons
• Each cotyledon = 2+ main stem villi + many branch villi
• By end of 4th month, decidua basalis is almost entirely replaced by cotyledons

• Separates maternal blood (in intervillous space) from fetal blood (in villous capillaries)
• Early: thick (4 layers: syncytiotrophoblast, cytotrophoblast, connective tissue, endothelium)
• At term: very thin (mainly syncytiotrophoblast + endothelium)
• Hofbauer cells (fetal macrophages) are present in chorionic villi from early pregnancy

Placental Functions

1. Respiration - O2 in, CO2 out
2. Nutrition - glucose, amino acids, fatty acids in
3. Excretion - urea, creatinine, bilirubin out
4. Hormone production - hCG, hPL, estrogen, progesterone
5. Protection - partial barrier to microbes (not all viruses)
6. Immunologic - maternal antibodies (IgG) transferred to fetus

Umbilical Cord

• Contains 2 umbilical arteries (carry deoxygenated blood from fetus to placenta) and 1 umbilical vein (carries oxygenated blood from placenta to fetus)
• Embedded in Wharton's jelly (mucoid connective tissue)

Fetal Membranes

• Amnion - inner membrane; produces and contains amniotic fluid
• Chorion - outer membrane; fuses with amnion later in gestation
• By week 22, amnion and chorion fuse with each other and the decidua parietalis, obliterating the uterine cavity

Amniotic Fluid

• Produced by: fetal urine (major source after 12 weeks), fetal lung secretions, amniotic epithelium
• Absorbed by: fetal swallowing, membranous absorption
• Volume: ~30 mL at 10 weeks; ~350 mL at 20 weeks; ~700-1000 mL at term
• Functions: cushions fetus, allows movement, maintains temperature, prevents adhesions, lung maturation

III. DEVELOPMENT OF GENITAL ORGANS AND GONADS; CONGENITAL MALFORMATIONS

Sexual Determination

• Chromosomal sex determined at fertilization by sperm (X or Y)
• Male/female morphologic characteristics do NOT begin to develop until the 7th week
• Before week 7: indifferent (bipotential) stage - genital systems are identical

Development of Gonads

1. Mesothelium (mesodermal epithelium of posterior abdominal wall)
2. Underlying mesenchyme (embryonic connective tissue)
3. Primordial germ cells (earliest undifferentiated sex cells)

• Week 5: Thickened mesothelium on medial side of mesonephros forms the gonadal ridge; epithelial cords (gonadal cords) grow into underlying mesenchyme
• Week 7: Sex differentiation begins
• Genes required for bipotential gonad development: FOG2, WT1, NR5A1

• First recognizable at 24 days post-fertilization in endodermal cells of the yolk sac near allantois origin
• Migrate along dorsal mesentery of hindgut to reach gonadal ridges
• If PGCs fail to reach the gonadal ridges, gonads do not develop (gonadal dysgenesis)

Testicular Development (XY)

• The SRY gene (on Y chromosome) codes for testis-determining factor (TDF)
• TDF causes the medulla of the indifferent gonad to differentiate into a testis; cortex regresses
• Sertoli cells (from surface epithelium) form seminiferous tubules; produce AMH (Müllerian-inhibiting factor) which causes regression of paramesonephric ducts
• Leydig cells (from mesenchyme) produce testosterone - causes mesonephric (Wolffian) ducts to develop into male genital ducts (epididymis, vas deferens, seminal vesicles)
• DHT (dihydrotestosterone) causes external genitalia to masculinize

Ovarian Development (XX)

• Without SRY, the cortex of the indifferent gonad differentiates into an ovary; medulla regresses
• Ovary not histologically identifiable until ~10th week
• Cortical cords from surface epithelium break up into primordial follicles at ~16 weeks
• Each primordial follicle = primary oocyte surrounded by follicular cells
• Without AMH, paramesonephric (Müllerian) ducts develop
• Without testosterone, mesonephric (Wolffian) ducts regress

Development of Female Genital Tract

Paramesonephric (Müllerian) Duct Derivatives

• Endometrial stroma and myometrium derived from splanchnic mesenchyme
• Uterine development regulated by HOXA10 homeobox gene
• The vagina: upper 1/3 from Müllerian ducts; lower 2/3 from urogenital sinus

Development of Male Genital Tract

Congenital Malformations of Genital Organs

IV. MATERNAL PHYSIOLOGICAL CHANGES IN PREGNANCY

Pituitary Changes

• Anterior pituitary can double or triple in size (hyperplasia/hypertrophy of lactotrophs)
• Pituitary volume increases: 40% (2nd trimester), 75% (3rd trimester), 120% (immediate postpartum)
• Prolactin: ~10-fold increase throughout gestation (driven by placental estrogens)
• GH: Pituitary GH only in 1st trimester; placental GH variant takes over later - stimulates IGF-1
• LH and FSH: Concentrations decline (despite rising GnRH from placenta)
• ACTH: 2-4 fold increase (partly from placental production); diurnal variation is retained but blunted

Adrenocortical Changes

• CRH: Rises progressively in 2nd and 3rd trimester - largely from placenta
• Cortisol: Corticosteroid-binding globulin triples → total plasma cortisol increases
• Free (unbound) cortisol also increases - urinary free cortisol rises 2-3 fold in last 2 trimesters
• 11-β-hydroxysteroid dehydrogenase 2 in the placenta inactivates cortisol to cortisone, protecting the fetus; but 25% of fetal cortisol still derives from maternal cortisol

Renin-Angiotensin-Aldosterone System (RAAS)

• Renin (juxtaglomerular apparatus) converts angiotensinogen → Angiotensin I → Angiotensin II
• Aldosterone rises significantly in pregnancy
• Angiotensin II: pressor action + stimulates aldosterone secretion
• These changes lead to sodium and water retention (plasma volume expansion)

Cardiovascular Changes

• Plasma volume increases by 40-50% starting from 6-8 weeks
• Red blood cell mass increases by ~20-30% → physiologic dilutional anaemia
• Cardiac output increases by 30-50% (increased stroke volume + heart rate)
• Systemic vascular resistance decreases (progesterone effect)
• Blood pressure: falls slightly in 1st/2nd trimester (vasodilation), returns to near normal in 3rd

Renal Changes

• GFR increases by 40-50% early in pregnancy
• Creatinine and BUN are lower than non-pregnant values
• Glucosuria may occur (tubular maximum overwhelmed by high GFR)
• Physiological dilatation of ureters and renal pelvis (progesterone effect + mechanical)

Respiratory Changes

• Tidal volume increases by ~40%; respiratory rate unchanged
• Minute ventilation increases → mild respiratory alkalosis
• Functional residual capacity decreases (diaphragm elevated by gravid uterus)

Haematological Changes

• Leukocytosis (WBC rises to 9-12 × 10⁹/L; up to 25 in labour)
• Hypercoagulable state: Fibrinogen increases, factors VII, VIII, X, XII increase; protein S decreases → DVT risk
• ESR increases (not clinically useful in pregnancy)
• Platelets may decrease slightly

Endocrine - Thyroid

• TBG rises (estrogen-stimulated) → total T3 and T4 rise; free T3 and T4 remain normal
• First trimester: hCG has mild TSH-like activity → can transiently suppress TSH
• Iodine requirements increase

Musculoskeletal / Other

• Progesterone relaxes smooth muscle (GI: constipation, GORD; uterus: prevents premature contraction)
• Relaxin + progesterone: relax ligaments → pelvic girdle pain, lumbar lordosis
• Insulin resistance increases in 2nd/3rd trimester (hPL, cortisol, progesterone)
• Skin: hyperpigmentation (MSH rises), linea nigra, chloasma (mask of pregnancy), striae gravidarum

• Berek & Novak's Gynecology (Amenorrhoea chapter)
• Ganong's Review of Medical Physiology, 26th Ed. (Normal Menstruation)
• The Developing Human: Clinically Oriented Embryology - Moore & Persaud (Placenta, Genital development)
• Creasy & Resnik's Maternal-Fetal Medicine: Principles and Practice (Physiological changes in pregnancy)

1. Primary Amenorrhoea - Diagnostic Flowchart

2. Menstrual Cycle - Hormonal & Endometrial Changes

3. Placenta - Structure & Feto-Maternal Circulation

4. Gonad & Genital Organ Development - Embryology Flowchart

5. Maternal Physiological Changes in Pregnancy