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Ovarian and Uterine Changes During the Menstrual Cycle

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I. Ovarian Changes

1. Follicular Phase (Days 1-14)

• The theca interna cells of the follicle secrete androgens, which are then aromatized to estrogen (17β-estradiol) by the granulosa cells - this is the primary source of circulating estrogen.
• Rising estradiol levels exert positive feedback on the pituitary, triggering the LH surge (around day 13-14).

2. Ovulation (Day ~14)

3. Luteal Phase (Days 14-28)

• The corpus luteum secretes both estrogen and progesterone.
• Its growth depends on an adequate blood supply - VEGF is essential for this vascularization.
• If pregnancy does not occur, the corpus luteum regresses (luteolysis) by day 26-28, and progesterone/estrogen levels fall sharply, triggering menstruation.
• If pregnancy occurs, hCG from the trophoblast maintains the corpus luteum, which persists until the placenta takes over steroidogenesis.

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II. Uterine (Endometrial) Changes

• Stratum functionale - the superficial two-thirds, shed during menstruation; supplied by long, coiled spiral arteries
• Stratum basale - the deep layer, never shed; supplied by short, straight basilar arteries; source of endometrial regeneration

1. Menstrual Phase (Days 1-4)

• Spiral artery vasospasm and endometrial ischemia
• Breakdown of lysosomes with release of proteolytic enzymes
• Prostaglandin F2α (PGF2α) plays a key role - it is a potent vasoconstrictor that amplifies vasospasm and stimulates myometrial contractions to expel sloughing tissue
• The stratum functionale is shed as menstrual flow; menstrual blood is ~75% arterial, contains fibrinolysin (which prevents clotting under normal flow) and tissue debris

2. Proliferative Phase (Days 5-14) - "Follicular" / "Pre-ovulatory" Phase

• The endometrium thickens rapidly from day 5 to day 14
• Uterine glands elongate but do not yet secrete
• The stroma and spiral arteries grow
• Cervical mucus becomes copious, watery, elastic - when spread on a slide it produces a characteristic "ferning" pattern, and channels form that allow sperm penetration

3. Secretory Phase (Days 15-28) - "Luteal" Phase

• Proliferation slows; the endometrium becomes highly vascularized and slightly edematous
• Uterine glands become coiled, tortuous, and accumulate glycogen in subnuclear vacuoles (visible by PAS staining); by days 19-20 they secrete fluid into the lumen
• Spiral arteries continue to elongate and coil
• Stromal edema develops progressively
• By around day 22-24, stromal cells develop an eosinophilic pattern resembling decidua (pseudodecidual change)
• Secretory activity is maximal around postovulatory days 6-7, exactly when a fertilized blastocyst would arrive for implantation
• Cervical mucus becomes thick, non-elastic, and scanty - and no longer "ferns" on a slide (sperm cannot penetrate)
• ~2 days before menses, a wave of polymorphonuclear leukocytes infiltrates the stroma, heralding breakdown

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Summary Table

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Menstrual Cycle - 1st Year MBBS Physiology

Definition & Basic Facts

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I. Hormonal Control - The Axis

Hypothalamus  →  GnRH (pulsatile)
       ↓
Anterior Pituitary  →  FSH + LH
       ↓
Ovary  →  Estrogen + Progesterone
       ↓
Feedback to Hypothalamus & Pituitary

• Follicular phase - Rising estradiol → Negative feedback → suppresses FSH/LH
• Midcycle - When estradiol reaches ≥200 pg/mL → Positive feedback → triggers the LH surge → ovulation
• Luteal phase - Progesterone (from corpus luteum) → Negative feedback → suppresses FSH/LH

Exam tip: Estradiol is unique - it causes negative feedback at low levels and positive feedback at high levels. This is called the "switch" in feedback.

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II. Two-Cell Two-Gonadotropin Theory

• LH acts on Theca interna cells → produces androgens (androstenedione, testosterone)
• Androgens cross to granulosa cells
• FSH acts on Granulosa cells → activates aromatase → converts androgens to estradiol

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III. Ovarian Cycle (What happens in the ovary)

Anatomy of the Ovary:

Phase 1: Follicular Phase (Days 1-14)

1. At birth, ~2 million primordial follicles exist; by puberty, <300,000 remain
2. Each cycle, FSH stimulates several primordial follicles to enlarge and form an antrum (fluid-filled cavity) - these become antral/secondary follicles
3. By Day 6, one follicle becomes dominant (Graafian follicle); the rest undergo atresia (apoptosis)
4. The Graafian follicle produces increasing amounts of estradiol
5. Estradiol levels peak just before day 14

Phase 2: Ovulation (Day ~14)

1. Estradiol ≥200 pg/mL triggers the LH surge (positive feedback)
2. The distended follicle ruptures within 24-36 hours of the LH surge
3. The secondary oocyte (arrested at metaphase II) is released into the peritoneal cavity
4. The fimbriae of the fallopian tube pick up the ovum
5. Minor peritoneal bleeding may cause mittelschmerz (mid-cycle pain)

Phase 3: Luteal Phase (Days 15-28)

1. The ruptured follicle fills with blood → corpus hemorrhagicum
2. Granulosa + theca cells proliferate → Corpus luteum (yellowish, lipid-rich)
3. Corpus luteum secretes both progesterone + estrogen; progesterone dominates
4. VEGF is essential for corpus luteum vascularization and survival
5. If no pregnancy: Corpus luteum degenerates by Day 25-26 → becomes corpus albicans (white scar tissue) → estrogen/progesterone fall → menstruation begins
6. If pregnancy occurs: hCG from trophoblast maintains corpus luteum → no menstruation

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IV. Uterine Cycle (What happens in the endometrium)

• Stratum functionale (superficial 2/3) - shed each month; supplied by spiral arteries
• Stratum basale (deep 1/3) - never shed; source of regeneration; supplied by basilar arteries

Phase 1: Menstrual Phase (Days 1-4)

• Corpus luteum regresses → estrogen and progesterone withdrawal
• Spiral artery vasospasm → ischemia of stratum functionale
• Prostaglandin F2α (PGF2α) - potent vasoconstrictor; amplifies vasospasm; drives myometrial contractions to expel tissue (responsible for menstrual cramps/dysmenorrhea)
• Stratum functionale is shed as menstrual flow (~30-80 mL)
• Menstrual blood: 75% arterial, 25% venous; contains fibrinolysin (prevents clot formation under normal flow)

Phase 2: Proliferative Phase (Days 5-14)

• Endometrium regenerates and thickens rapidly (days 5 to 14)
• Uterine glands: straight and elongating (not secreting)
• Spiral arteries grow
• Cervical mucus: copious, watery, elastic → shows "ferning" pattern on a glass slide → forms channels that allow sperm penetration

Phase 3: Secretory Phase (Days 15-28)

• Endometrial growth slows; becomes edematous and highly vascular
• Uterine glands: coiled, tortuous, fill with glycogen vacuoles (PAS-positive) and begin secreting
• Spiral arteries: elongated and coiled
• Around Day 22-24: stromal cells take on a decidua-like appearance (pseudodecidual change)
• Secretory activity is maximal at postovulatory days 6-7 - optimal window for blastocyst implantation
• Cervical mucus: thick, scanty, non-elastic → no ferning → blocks sperm penetration
• 2 days before menses: polymorphonuclear leukocyte infiltration signals imminent endometrial breakdown

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V. Hormonal Changes Summary (The Classic Diagram Pattern)

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VI. Other Cyclic Changes

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VII. Key Points for Exam (MBBS Must-Know)

1. Day 1 = First day of bleeding (not day of ovulation)
2. Ovulation always occurs 14 days before the next period, regardless of cycle length
3. LH surge triggers ovulation; occurs ~24-36 h before rupture
4. Secretory phase = constant 14 days; Proliferative phase = variable (determines cycle length)
5. Ferning of cervical mucus = follicular phase (estrogen effect); absent in luteal phase (progesterone)
6. PGF2α = key mediator of menstruation and dysmenorrhea (NSAIDs work by blocking prostaglandin synthesis)
7. Corpus luteum lifespan = 14 days without pregnancy; maintained by hCG in pregnancy
8. Inhibin (from granulosa cells) selectively inhibits FSH - ensures only one dominant follicle
9. Estrogen up-regulates progesterone receptors; without prior estrogen, progesterone has minimal effect
10. Mittelschmerz = mid-cycle pain from minor peritoneal bleeding at ovulation

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Spermatogenesis

Definition

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Site of Spermatogenesis - Seminiferous Tubule

• Sertoli cells - large columnar cells extending from basal lamina to the lumen; nurse cells that support germ cell development
• Germ cells - arranged in layers from basal (least mature) to luminal (most mature)
• Leydig cells - in the interstitium between tubules; produce testosterone in response to LH

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Three Phases of Spermatogenesis

Phase 1: Proliferative (Mitotic) Phase

• Spermatogonia (diploid, 2n) lie on the basal lamina
• They undergo mitotic divisions to produce:
  • Type A spermatogonia - self-renewing stem cells (maintain the germ cell pool)
  • Type B spermatogonia - committed progenitors that differentiate further
• Type B spermatogonia divide mitotically to produce primary spermatocytes (2n, 4C after DNA replication)
• Descendant cells remain connected by cytoplasmic bridges - ensures synchronized development of each clone

Phase 2: Meiotic Phase

• Primary spermatocytes (2n, 4C) → Secondary spermatocytes (n, 2C)
• This is the longest step (primary spermatocytes stay in prophase I for weeks)
• Homologous chromosomes separate; crossing over occurs → genetic diversity

• Secondary spermatocytes (n, 2C) → Spermatids (n, 1C = haploid)
• Sister chromatids separate
• Each primary spermatocyte ultimately yields 4 spermatids

Phase 3: Spermiogenesis (Metamorphosis)

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Structure of the Mature Spermatozoon

• Acrosome = lysosome-like organelle; contains hyaluronidase, acrosin, proteases → released during acrosomal reaction to penetrate zona pellucida of ovum

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Hormonal Control of Spermatogenesis

Hypothalamus → GnRH (pulsatile)
    ↓
Anterior Pituitary → FSH + LH
    ↓              ↓
  Sertoli cells  Leydig cells
  (FSH)          (LH)
    ↓              ↓
  ABP, Inhibin   Testosterone
    ↓
  Supports spermatid maturation

• FSH acts on Sertoli cells → produces Androgen Binding Protein (ABP), inhibin; facilitates last stages of spermatid maturation
• LH acts on Leydig cells → produces testosterone → essential for spermatogenesis (especially maturation of spermatids to spermatozoa)
• Inhibin (from Sertoli cells) → selectively inhibits FSH (negative feedback)
• Stages from spermatogonia → spermatids are androgen-independent; maturation of spermatids → spermatozoa requires androgens acting via Sertoli cells

Temperature requirement

• Scrotal position outside the body
• Countercurrent heat exchange between spermatic arteries and veins
• Cryptorchidism (undescended testis) → infertility due to elevated temperature

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Further Maturation After Spermatogenesis

• Spermatozoa leave the tubules non-motile
• They gain progressive motility during passage through the epididymis (stored here for months)
• After ejaculation into the female tract, capacitation occurs over 4-6 hours: inhibitory factors washed away, cholesterol removed from membrane, Ca²⁺ influx → whip-like motility and acrosomal reaction preparedness
• Fertilization occurs in the ampulla of the uterine tube

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Note on Blood-Testis Barrier (BTB)

Definition

Structure / Components

1. Mechanical (Anatomic) Component

• Tight junctions (occluding junctions) between adjacent Sertoli cells - the most important component
• Myoid cells (muscle-like contractile cells) that surround the outer wall of seminiferous tubules
• Capillary endothelial cells also regulate molecular traffic (secondary role)

2. Functional (Immunological) Component

• Restricted lymphocyte populations within the germinal epithelium
• T-suppressor cell tolerance generated by small, continuous leak of sperm antigens from anatomically weaker areas (rete testis, efferent tubule, epididymis)
• Sertoli cells secrete immunosuppressive molecules: galectin-1, TGF-β, interferon-γ, soluble Fc receptor, and androgens - which create a local immunosuppressive environment

What the BTB Creates

Functions of the BTB

1. Immunological protection - Sperm are first produced at puberty, long after the immune system has become competent. Sperm antigens are recognized as "foreign" (non-self). The BTB isolates haploid germ cells (secondary spermatocytes, spermatids, spermatozoa) from the immune system, preventing autoimmune destruction.
2. Creates a specialized microenvironment - The luminal fluid differs markedly from plasma: very low protein and glucose, but rich in androgens, estrogens, K⁺, inositol, glutamic acid, and aspartic acid. ABP (secreted by Sertoli cells) maintains high testosterone concentration in tubular fluid.
3. Protection from noxious agents - Prevents bloodborne toxins, drugs, and pathogens from reaching developing germ cells.
4. Osmotic gradient - Helps maintain fluid movement into the tubular lumen.

Note: Steroids (testosterone) penetrate the BTB with ease. Some proteins also pass between Sertoli and Leydig cells in a paracrine manner.

How Germ Cells Cross the BTB

• New tight junctions form below the migrating cell
• Old tight junctions dissolve above the cell
• The barrier is never actually breached - it moves around the cell

Clinical Significance

Key exam point: The BTB develops at spermarche (puberty). Before puberty, testicular injury does NOT cause antisperm antibodies. After puberty, it does.

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1. Effects of Estrogen on Reproductive Organs

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A. Uterus

B. Fallopian Tubes

• Stimulates ciliary activity (aids ovum transport)
• Increases peristaltic contractility to move sperm toward the ovum
• Stimulates secretory activity of tubal epithelium

C. Vagina

• Stimulates proliferation and cornification of vaginal epithelium (protective stratified squamous lining)
• Cornified cells can be identified in vaginal smear (used as an indirect indicator of estrogen activity)
• Makes vaginal secretion more acidic (protective against infection)

D. Ovary

• Promotes proliferation and development of granulosa cells
• Upregulates FSH receptors on granulosa cells (amplifies response to FSH)
• Upregulates LH receptors on granulosa cells (prepares for LH surge response)

E. External Genitalia & Female Secondary Sex Characteristics (at Puberty)

• Growth of labia majora, labia minora, and clitoris
• Development of the mons pubis and characteristic fat distribution
• Pubic and axillary hair growth (androgenic component, but estrogen contributes)
• Pigmentation of labia

F. Breasts

• Essential for breast development
• Stimulates proliferation of mammary ducts and growth of nipple/areola
• Increases fat deposition giving breasts their female shape
• Stimulates prolactin secretion from the anterior pituitary
• Blocks prolactin's action on breast tissue (so lactation doesn't occur before delivery despite high prolactin)

G. Bone

• Stimulates pubertal growth spurt
• Causes closure of epiphyseal plates (limits final height)
• Anti-osteoporotic - maintains bone mineral density

H. HPO Axis Feedback

• Low levels - negative feedback on hypothalamus and anterior pituitary (suppresses FSH/LH)
• High levels (≥200 pg/mL) - positive feedback → triggers the midcycle LH surge → ovulation

I. Metabolic Effects

• Decreases LDL cholesterol (cardioprotective before menopause)
• Increases HDL cholesterol
• Promotes subcutaneous fat deposition (female body contour)

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Summary Table: Estrogen vs Progesterone on Reproductive Organs

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2. Indicators of Ovulation

A. Basal Body Temperature (BBT) Chart

• A rise of ~0.5°C (>0.5°F) in basal body temperature occurs 1-2 days after ovulation
• Sustained elevation throughout the luteal phase
• Caused by the thermogenic effect of progesterone from the corpus luteum
• Method: measure oral/rectal temperature with digital thermometer before getting out of bed each morning
• Limitation: tells you ovulation has already occurred (retrospective); not useful for timing intercourse prospectively

B. Cervical Mucus Changes (Billings/Ovulation Method)

• Around ovulation: mucus becomes copious, clear, slippery, and elastic (like raw egg white)
• Spinnbarkeit - can be stretched 8-12 cm into a long thread without breaking
• Ferning pattern - when dried on a glass slide, forms a fern-like arborizing pattern due to high estrogen (seen in anovulatory cycle with estrogen also)

• After ovulation (progesterone dominance): mucus becomes thick, scanty, cellular - ferning disappears

C. LH Surge Detection (Ovulation Predictor Kit)

• A surge in LH triggers ovulation; ovulation occurs ~9-36 hours after the LH peak
• Urinary LH can be detected by over-the-counter ovulation predictor kits
• Most useful for timing intercourse - most fertile period is 48 h before ovulation
• Limitation: presence of LH surge does not guarantee ovulation will actually occur

D. Serum Progesterone Level

• A serum progesterone >3 ng/mL (~10 nmol/L) measured approximately 7 days after expected ovulation (mid-luteal phase, Day 21 in a 28-day cycle) confirms that ovulation occurred
• Most reliable laboratory confirmation of ovulation

E. Mittelschmerz

• Mid-cycle pelvic/lower abdominal pain caused by rapid expansion of the dominant follicle and/or minor peritoneal bleeding at follicle rupture
• Unilateral, brief, occurring ~Day 14
• Clinical sign of impending ovulation

F. Premenstrual Symptoms (Moliminal Symptoms)

• Bloating, breast tenderness, mood changes, food cravings in the 7-10 days before menses suggest an ovulatory cycle (due to progesterone)
• Absence is not conclusive for anovulation

G. Ultrasound (Gold Standard for Clinical Use)

• Pre-ovulation: growth of fluid-filled dominant follicle (>18 mm = mature)
• Post-ovulation: collapse of dominant follicle, appearance of corpus luteum, characteristic echogenicity of secretory endometrium
• Most accurate non-invasive method

H. Endometrial Biopsy (Historical)

• Secretory endometrium on biopsy confirms progesterone action and therefore ovulation
• No longer used routinely to assess fertility

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Summary of Indicators

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3. Precocious Puberty

Definition

• Girls: before 8 years (some guidelines: <7 years in white girls, <6 years in black girls)
• Boys: before 9 years

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Classification

Type 1: Central (True) Precocious Puberty = GnRH-Dependent

• Due to premature activation of the HPO axis (hypothalamus begins pulsatile GnRH secretion early)
• Gonadotropins (FSH and LH) are elevated
• Complete puberty with all secondary characteristics
• Isosexual (appropriate to genetic sex)

Key concept: Kisspeptin (KISS1) and its receptor GPR54 are essential regulators of GnRH secretion. Activating mutations cause precocious puberty; loss-of-function causes hypogonadotropic hypogonadism.

Type 2: Peripheral (Precocious Pseudopuberty) = GnRH-Independent

• Sex steroid secretion occurs independent of LH/FSH (gonadotropins are suppressed)
• Due to autonomous production of sex steroids

Type 3: Incomplete (Benign Variants) - Not True Precocious Puberty

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Tanner Stages of Puberty in Girls (for reference)

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Clinical Features of Precocious Puberty

• Early development of secondary sex characteristics (breast, pubic/axillary hair, menarche)
• Accelerated linear growth (tall initially for age)
• Early epiphyseal fusion → premature growth arrest → short final adult height
• Psychological and psychosocial disturbances
• Bone age advanced beyond chronological age

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Investigations

1. Bone age (wrist X-ray) - advanced in true precocious puberty
2. Serum FSH, LH, estradiol/testosterone - elevated in central; suppressed in peripheral
3. GnRH stimulation test - pubertal LH response confirms central (GnRH-dependent) precocity
4. MRI brain - mandatory to rule out CNS lesions in central precocious puberty
5. Pelvic/adrenal ultrasound - to detect ovarian/adrenal tumors
6. 17α-hydroxyprogesterone, DHEAS - to rule out CAH

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Treatment

Key exam points:

• GnRH analogues used continuously (not pulsatile) → downregulation of receptors → suppress axis
• Treatment is most effective for final height if started before age 6
• After stopping GnRH analogue, normal puberty resumes
• A testicular insult before puberty does NOT cause antisperm antibodies (no haploid cells yet)

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