Human Reproduction

HUMAN REPRODUCTION — COMPREHENSIVE CHAPTER NOTES

INTRODUCTION TO HUMAN REPRODUCTION

**Human reproduction** is sexual and viviparous. The key reproductive events include:

**Gametogenesis**: Formation of gametes (sperms in males, ovum in females)

**Insemination**: Transfer of sperms into the female genital tract

**Fertilisation**: Fusion of male and female gametes to form zygote

**Implantation**: Attachment of blastocyst to uterine wall

**Gestation**: Embryonic development

**Parturition**: Delivery of the baby

All these events occur after **puberty**. Unlike males where spermatogenesis continues throughout life, females stop forming new ova around age 50 (menopause).

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THE MALE REPRODUCTIVE SYSTEM

Location and External Anatomy

The male reproductive system is located in the **pelvic region**. It comprises:

A pair of **testes** (primary sex organs)

**Accessory ducts** (rete testis, vasa efferentia, epididymis, vas deferens)

**Accessory glands** (seminal vesicles, prostate, bulbourethral glands)

**External genitalia** (penis)

Testes Structure and Function

**Location**: The testes lie outside the abdominal cavity within the **scrotum** (a pouch of skin).

**Temperature regulation**: The scrotum maintains testicular temperature **2–2.5°C lower** than normal body temperature (≈ 34°C), essential for **spermatogenesis**. This is why tight clothing or heat exposure reduces male fertility.

**Testicular anatomy**:

Each testis is oval, approximately **4–5 cm long** and **2–3 cm wide**

Contains about **250 testicular lobules** (compartments)

Each lobule has **1–3 highly coiled seminiferous tubules** where sperms are produced

Microscopic Structure of Seminiferous Tubule

The seminiferous tubule is lined by two cell types:

**1. Spermatogonia (male germ cells)**:

Diploid cells (46 chromosomes)

Undergo mitotic division → Primary spermatocytes

Also undergo meiotic division → sperms

**2. Sertoli cells (supporting cells)**:

Provide **nutrition to germ cells**

Secrete anti-Müllerian hormone (AMH)

Create blood-testis barrier

Facilitate spermiation (release of mature sperms)

**Interstitial spaces** (between tubules) contain:

**Leydig cells (Interstitial cells)**: Synthesise and secrete **androgens** (testosterone) — male sex hormones

Blood vessels and immunologically competent cells

Accessory Ducts and Glands

**Duct system** (transports sperms):

**Seminiferous tubules** → **Rete testis** → **Vasa efferentia** (multiple small ducts)

**Vasa efferentia** → **Epididymis** (stores and matures sperms; one per testis, located on posterior surface)

**Epididymis** → **Vas deferens** (ascends into abdomen, loops over urinary bladder)

**Vas deferens** + **Seminal vesicle duct** → **Ejaculatory duct** → **Urethra**

**Urethra** extends through penis, opens at **urethral meatus**

**Accessory glands** (produce seminal plasma):

**Seminal vesicles** (paired): Rich in **fructose, calcium, and enzymes**

**Prostate gland**: Produces secretions for seminal plasma

**Bulbourethral glands** (Cowper's glands, paired): Produce **lubricating mucus** for penis

**Seminal plasma** = Secretions of all accessory glands; combined with sperms forms **semen**.

Penis Structure

**Male external genitalia**

Composed of special erectile tissue allowing **erection** for insemination

**Glans penis**: Enlarged tip, covered by loose skin fold called **foreskin** (prepuce)

Covered by **sensitive mucous membrane**

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THE FEMALE REPRODUCTIVE SYSTEM

Location and Components

Located in the **pelvic region**, consisting of:

A pair of **ovaries** (primary sex organs)

A pair of **oviducts (fallopian tubes)**

**Uterus (womb)**

**Cervix**

**Vagina**

**External genitalia**

A pair of **mammary glands** (breasts)

All are structurally and functionally integrated for **ovulation, fertilisation, pregnancy, birth, and lactation**.

Ovaries

**Structure**:

Located one on each side of **lower abdomen**

Size: **2–4 cm long**

Connected to pelvic wall and uterus by **ligaments**

Covered by **thin epithelium** enclosing **ovarian stroma**

**Ovarian stroma zones**:

**Peripheral cortex**: Contains primary and secondary follicles; site of oogenesis

**Inner medulla**: Contains blood vessels and connective tissue

**Function**: Produce **female gamete (ovum)** and **steroid hormones** (estrogen and progesterone)

Oviducts (Fallopian Tubes)

Length: **10–12 cm**

Extend from periphery of ovary to uterus

**Three regions**:

**Infundibulum**: Funnel-shaped, closest to ovary; possesses **fimbriae** (finger-like projections) that collect ovum after ovulation

**Ampulla**: Wider middle section where **fertilisation typically occurs**

**Isthmus**: Narrow portion joining uterus

Uterus

**Single, pear-shaped organ** (inverted pear)

Also called **womb**

Supported by **ligaments** attached to pelvic wall

Opens into vagina via **cervix**

**Cervical canal**: Cavity of cervix, forms part of **birth canal** (with vagina)

**Three-layered uterine wall**:

**Perimetrium**: Thin external membranous layer

**Myometrium**: Thick middle layer of **smooth muscle** — contracts strongly during labour

**Endometrium**: Inner **glandular lining** — undergoes **cyclical changes** during menstrual cycle; site of implantation

Vagina

Muscular tube extending from cervix to external opening

Forms lower part of **birth canal**

Lined by **stratified squamous epithelium**

Normally acidic pH (protective against infections)

External Genitalia (Vulva)

**Mons pubis**: Fatty cushion covered by skin and pubic hair

**Labia majora**: Fleshy folds extending from mons pubis, surround vaginal opening

**Labia minora**: Paired tissue folds under labia majora

**Hymen**: Membrane partially covering vaginal opening; can tear during first intercourse, sports, or injuries (not reliable indicator of virginity)

**Clitoris**: Small finger-like structure at junction of labia minora; highly sensitive; homologous to penis

Mammary Glands

**Structure**:

Paired structures (breasts) containing **glandular and fatty tissue**

Each breast divided into **15–20 mammary lobes**

Each lobe contains **alveoli** (clusters of secretory cells)

**Milk production pathway**:

**Alveoli**: Secrete milk, stored in lumens

**Mammary tubules**: Collect milk from alveoli

**Mammary ducts**: Formed by joining tubules of each lobe

**Lactiferous ducts**: Several ducts form wider **mammary ampulla** → **lactiferous ducts** → **nipple**

**Function**: Secrete **milk** for breastfeeding (activated post-delivery by hormones)

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GAMETOGENESIS

**Gametogenesis** = Formation of gametes (sperms and ova) by **meiotic division** of germ cells.

SPERMATOGENESIS (Sperm Formation)

**Definition**: Process of formation of mature male gametes (sperms) from immature germ cells in seminiferous tubules; begins at **puberty** and continues **lifelong**.

**Hormonal initiation**:

At puberty: **↑ GnRH** (gonadotropin-releasing hormone, from hypothalamus)

GnRH → Anterior pituitary → ↑ **LH (Luteinising Hormone)** and ↑ **FSH (Follicle Stimulating Hormone)**

**LH** acts on **Leydig cells** → synthesis of **androgens** (testosterone) → stimulates spermatogenesis

**FSH** acts on **Sertoli cells** → secretion of factors facilitating **spermiogenesis**

**Stages of spermatogenesis**:

1. **Mitotic proliferation phase**:

**Spermatogonia** (diploid, 2n=46) at seminiferous tubule wall

Mitotic division → increase in number

Some spermatogonia → **Primary spermatocytes** (diploid, 2n=46)

2. **Meiotic phase**:

**Primary spermatocyte** (2n) → **First meiotic division (Reduction division)**

Produces two **Secondary spermatocytes** (haploid, n=23 each)

Each **Secondary spermatocyte** → **Second meiotic division**

Produces four **Spermatids** (haploid, n=23 each)

All four spermatids are **equal in size**

3. **Spermiogenesis** (Transformation phase):

**Spermatids** → **Spermatozoa (mature sperms)**

Nucleus condenses

Golgi apparatus → **Acrosome** formation (at anterior end)

Centrioles → **Flagellum (tail)** formation

Mitochondria concentrate in **middle piece**

Excess cytoplasm removed

Sperm heads **embed in Sertoli cells**

4. **Spermiation**:

Mature sperms released from Sertoli cells

Enter seminiferous tubule lumen

Transport to epididymis via rete testis and vasa efferentia

**Duration**: Entire process from spermatogonium to mature sperm ≈ **74 days**

**Output**: One spermatogonium → Four functional sperms (unlike oogenesis)

Sperm Structure and Functions

**Structure** (Figure 2.6):

**Head**:

Contains **elongated haploid nucleus** (n=23)

Covered anteriorly by **acrosome** (cap-like structure)

**Acrosome enzymes**: Help penetrate **zona pellucida** of ovum during fertilisation

**Neck**:

Connects head to middle piece

Contains **centrioles** (organise microtubules for flagellum)

**Middle piece**:

Contains **numerous mitochondria**

Mitochondria produce **ATP** for energy

Energy required for **tail motility**

**Tail (Flagellum)**:

Long filamentous structure

Whipping motion propels sperm

Essential for **swimming** through female reproductive tract

**Plasma membrane**: Envelops entire sperm body; plays role in fusion with ovum

**Fertility parameters** (WHO standards):

**Sperm count**: 200–300 million sperms per ejaculate

**Morphology**: ≥60% normal shape and size required

**Motility**: ≥40% show vigorous forward movement

**Viability**: Most sperms must be alive

Transport and Maturation of Sperms

Sperms released from seminiferous tubules are **immature and immotile**

**Epididymis**: Sperms spend **12–20 days** here

Sperms **mature** (acquire motility)

Sperms **stored** until ejaculation

**Vas deferens**: Transports mature sperms

**Seminal vesicle secretions**: Rich in **fructose** (energy source)

**Prostate secretions**: Slightly alkaline, helps neutralise vaginal acidity

**Bulbourethral secretions**: **Lubricating mucus**

**Semen** = Sperms + Seminal plasma (secretions of accessory glands)

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OOGENESIS (Ovum Formation)

**Definition**: Process of formation of female gamete (ovum) from oogonia; **cyclic**, **unequal divisions**, occurs only during reproductive years (puberty to menopause).

**Timing and initiation**:

Begins during **embryonic development** (fetal stage)

Initiated at birth: each ovary contains **couple of million primary oocytes**

**NO new oogonia added after birth** (unlike continuous spermatogenesis)

Activated at **puberty** (one follicle per menstrual cycle)

**Ceases at menopause** (age ~50 years)

**Stages of oogenesis**:

**1. Proliferation phase (Fetal life)**:

**Oogonia** (diploid, 2n) in fetal ovary

Mitotic divisions → increase in oogonia numbers

Couple of million oogonia present at birth

No mitosis after birth

**2. Growth and maturation phase (Birth to puberty)**:

**Primary oocyte** (2n, arrested in **Prophase I** of meiosis I)

Surrounded by single layer of **granulosa cells** → **Primary follicle**

Large number of follicles **degenerate** (atresia) from birth to puberty

At puberty: Only **60,000–80,000 primary follicles** remain (from millions at birth)

**3. Follicular development (Puberty onwards, cyclically)**:

**a) Primary follicle**:

Primary oocyte surrounded by **single layer of granulosa cells**

Oocyte remains arrested in **Prophase I**

**b) Secondary follicle**:

Primary oocyte surrounded by **multiple layers of granulosa cells**

**Theca layer** develops around granulosa (theca interna and externa)

Oocyte still arrested in Prophase I

**c) Tertiary follicle (Antral follicle)**:

Appearance of **antrum** (fluid-filled cavity) among granulosa cells

Theca organized into **theca interna** (inner, vascularized) and **theca externa** (outer)

**Primary oocyte completes First Meiotic Division** (MI):

**Unequal division** (due to eccentric spindle)

Forms **Secondary oocyte** (large, haploid, n=23) retaining most **nutrient-rich cytoplasm**

Forms **First polar body** (tiny, haploid, n=23) with little cytoplasm — **degenerates** (mostly)

Secondary oocyte **arrested in Metaphase II** (will complete only if fertilised)

**d) Mature Graafian follicle**:

Tertiary follicle with fully grown secondary oocyte

Secondary oocyte surrounded by **zona pellucida** (transparent membrane, secreted by oocyte)

Antrum enlarged, follicle bulges from ovary surface

**4. Ovulation**:

**Graafian follicle ruptures** due to **LH surge** (mid-cycle)

**Secondary oocyte** (not yet mature ovum) released

Surrounded by **zona pellucida** and some **granulosa cells**

Transported into fallopian tube by **fimbriae**

**5. Completion of meiosis II (only if fertilised)**:

Secondary oocyte **arrests in Metaphase II** until sperm fertilisation

Upon sperm penetration: **Second Meiotic Division** (MII) completed

Forms **mature ovum (ootid)** (haploid, n=23) with most cytoplasm

Forms **Second polar body** (tiny, haploid) — degenerates

**Timeline of oogenesis**: **Birth to ovulation** = **10–50+ years** (very long)

Key Differences: Spermatogenesis vs Oogenesis

| Feature | Spermatogenesis | Oogenesis |

|---------|-----------------|-----------|

| **Location** | Seminiferous tubules | Ovary (follicles) |

| **Initiation** | Puberty | Embryonic development (fetal) |

| **Timing** | Continuous, lifelong | Cyclic, puberty to menopause |

| **Number** | Continuous supply, millions per day | Fixed pool (millions at birth → ~400 released in lifetime) |

| **Division type** | **Equal divisions** | **Unequal divisions** |

| **Output** | 4 equal, functional sperms | 1 functional ovum + 2–3 polar bodies (non-functional) |

| **Meiosis completion** | Before release (mature sperm ejaculated) | MI at puberty; MII only if fertilised |

| **Hormones** | LH, FSH, androgens (continuous) | LH, FSH, estrogen, progesterone (cyclic) |

| **Duration** | ~74 days | 10–50+ years |

| **Cytoplasm** | Relatively equal in all products | Unequal; ovum gets most nutrients |

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MENSTRUAL CYCLE

**Menstrual cycle** = Reproductive cycle in female primates (monkeys, apes, humans); cyclical series of events in ovaries and uterus; average **28–29 days**.

**Terminology**:

**Menarche**: First menstruation (onset at puberty, age 12–13 years)

**Menopause**: Cessation of menstruation (age ~50 years)

**Reproductive phase**: Period between menarche and menopause with cyclic menstruation

Phases of Menstrual Cycle

**1. MENSTRUAL PHASE (Days 1–5)**

**Duration**: 3–5 days

**Events**:

**Breakdown of endometrial lining** (due to low progesterone after corpus luteum degeneration)

**Shedding of endometrial tissue and blood** → **Menstrual flow** (menses)

Bleeding lasts **3–5 days**

Loss of blood: ~50 mL (up to 80 mL in some cases)

**Hormonal status**:

**Progesterone levels**: Very low (corpus luteum degenerating)

**Estrogen levels**: Low

**GnRH, LH, FSH**: Begin to increase towards end of menstrual phase

**Uterine changes**:

Endometrium is **thin** (after shedding)

Marked vasodilation and tissue necrosis

**Ovarian status**: Follicles are **small and dormant**

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**2. FOLLICULAR PHASE (Days 1/6–13, overlaps with menstruation initially)**

**Duration**: ~6–13 days (sometimes extends to day 1 of cycle)

**Events**:

**In Ovary**:

**↑ FSH** (from pituitary) stimulates growth of primary follicles

Primary follicles develop into **secondary and tertiary follicles**

**Granulosa and theca cells** of growing follicles secrete **estrogen** (estradiol)

**Estrogen levels gradually increase** throughout follicular phase

Follicle that matures fastest becomes **dominant follicle** (becomes Graafian follicle by day 13)

Other follicles undergo **atresia** (degeneration)

**In Uterus**:

Endometrium undergoes **proliferation** (thickening and re-vascularization) due to ↑ estrogen

Endometrial glands increase in size and number

Blood vessels become more prominent

**Cervical mucus** becomes **watery, thin, alkaline** (facilitates sperm entry)

**Hormonal changes**:

**FSH**: High initially, then declines as negative feedback of estrogen increases

**Estrogen**: ↑ gradually, reaches pre-ovulatory peak by day 13

**LH**: Gradually increases (positive feedback from ↑ estrogen)

**Progesterone**: Very low

**Ovulatory signal**: **↑ Estrogen** → **Positive feedback** → **LH surge** triggers ovulation

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**3. OVULATORY PHASE (Day 14, very brief)**

**Duration**: Usually day 14 (but varies 12–16 days depending on cycle length)

**Events**:

**LH surge** occurs (~24–36 hours before ovulation)

Rapid ↑ in **LH concentration** (peaks mid-cycle)

**Graafian follicle ruptures** due to enzymatic breakdown of follicle wall

**Secondary oocyte** released from ovary (called **ovulation**)

Secondary oocyte surrounded by **zona pellucida** and corona radiata (granulosa cells)

Transported into **fallopian tube** by **fimbriae**

**FSH also surges** (along with LH) but LH surge is more pronounced

**Timing significance**:

Ovulation is **only fertile event** in menstrual cycle

Secondary oocyte viable in fallopian tube for **12–24 hours** (some sources say 24–48 hours)

Sperms viable in female tract for **48–72 hours** (up to 5 days)

**Fertile window**: 3–5 days before ovulation to 24 hours after (due to sperm and ovum viability overlap)

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**4. LUTEAL PHASE (Days 15–28)**

**Duration**: ~14 days (more constant than follicular phase)

**Events**:

**In Ovary**:

**Corpus luteum formation**: Remaining follicle cells (granulosa + theca) transform into **corpus luteum** (yellow body)

**Corpus luteum secretes large amounts of progesterone** and some estrogen

**Progesterone levels ↑ steadily**, peak around day 21

**Estrogen levels ↑ moderately** from corpus luteum

Corpus luteum is functional for **~14 days**

**In Uterus**:

**Endometrium reaches maximum thickness** and vascularity

Endometrial glands **maximally developed** and secretory (preparing for implantation)

**Cervical mucus** becomes **thick, viscous, acidic** (blocks sperm entry)

Uterus ready for **implantation** of fertilised ovum

**Hormonal status**:

**Progesterone**: ↑↑ (essential for endometrial maintenance and implantation)

**Estrogen**: Moderate (from corpus luteum)

**LH and FSH**: Low (inhibited by negative feedback of progesterone and estrogen)

**If fertilisation occurs**:

**hCG (human Chorionic Gonadotropin)** secreted by **embryo/trophoblast**

hCG maintains **corpus luteum** (if absent, would degenerate)

**Progesterone secretion continues** → Endometrium maintained

**NO menstruation** → Pregnancy continues

Eventually placenta takes over progesterone production

**If fertilisation does NOT occur**:

**Corpus luteum degenerates** after 14 days (unless hCG present)

**Progesterone and estrogen levels ↓↓ sharply**

Low progesterone → **Endometrial breakdown** → Menstruation

**New menstrual cycle begins** (Day 1 = start of menstruation)

Hormonal Regulation of Menstrual Cycle

**GnRH-Pituitary-Ovarian Axis**:

**Hypothalamus** releases **GnRH** (pulsatile manner)

**Anterior pituitary** releases **FSH and LH**

**FSH** → Follicular growth and estrogen secretion

**LH** → Ovulation and corpus luteum formation

**Ovarian hormones** (estrogen, progesterone) exert **negative feedback** (days 1–13) and **positive feedback** (day 13–14) on pituitary and hypothalamus

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FERTILISATION AND IMPLANTATION

Fertilisation

**Definition**: Process of **fusion of sperm with ovum** to form **diploid zygote**; occurs in **ampulla of fallopian tube**.

**Prerequisites for fertilisation**:

1. **Simultaneous transport** of ovum and sperms to ampulla

2. **Sperm capacitation**: Sperms undergo physiological changes in female tract (removal of glycoproteins from surface) — essential for fertility

3. **Ovum transport**: Ovum collected by fimbriae, transported by **cilia and peristalsis** of fallopian tube

4. **Sperm transport**: Sperms swim through cervix, uterus into fallopian tube; **chemotaxis** towards ovum

**Why fertilisation doesn't always occur**:

Not all copulations result in simultaneous presence of ovum and viable sperms in ampulla

Ovum has limited viability (12–24 hours)

Sperms must be deposited appropriately

Female tract conditions must be favourable

Process of Fertilisation

**Step 1: Sperm-Zona pellucida interaction**:

Sperm approaches **secondary oocyte** surrounded by **zona pellucida** (transparent glycoprotein layer)

Sperm comes into contact with zona pellucida

**Zona pellucida receptors** bind to sperm surface proteins

**Step 2: Acrosome reaction**:

Contact with zona pellucida triggers **acrosome reaction**

**Acrosomal enzymes** (acrosin, hyaluronidase) released

Enzymes **digest zona pellucida** → hole formation

Sperm penetrates through zona

**Step 3: Block to polyspermy** (crucial):

Entry of **first sperm induces cortical reaction** in oocyte

**Cortical granules** release their contents into perivitelline space

Zona pellucida becomes **impermeable** to additional sperms

**Prevention of polyspermy** (fusion with multiple sperms — would be lethal)

Ensures **only one sperm** fertilises ovum

**Step 4: Completion of Meiosis II**:

Sperm entry triggers completion of **Second Meiotic Division (MII)** in secondary oocyte

**Unequal division**: Forms **mature ovum** (large, haploid, n=23) + **second polar body** (tiny, degenerates)

**Step 5: Nuclear fusion (Syngamy)**:

**Male pronucleus** (nucleus of sperm, n=23) and **female pronucleus** (nucleus of mature ovum, n=23) fuse

Forms **diploid zygote** (2n=46)

**All chromosomes from mother and father combined**

Zygote contains **23 pairs of chromosomes** (22 pairs autosomes + 1 pair sex chromosomes)

**Sex determination at fertilisation**:

Female gamete always carries **X chromosome** (n=23, including one X)

Male gametes: **50% carry X chromosome**, **50% carry Y chromosome**

**X sperm + X ovum** → **XX (Female)**

**Y sperm + X ovum** → **XY (Male)**

**Sex of baby determined by father** (type of sperm that fertilises ovum)

Sex predetermined at fertilisation itself

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Post-Fertilisation Development

**Cleavage** (mitotic divisions):

Zygote undergoes **mitotic cell divisions** as it moves through fallopian tube towards uterus

**Cleavage** = rapid mitotic divisions without significant cell growth

Divisions produce **blastomeres** (daughter cells)

**2-cell stage**, **4-cell stage**, **8-cell stage**, **16-cell stage** → **morula**

**Morula** (Mulberry stage):

Embryo with **8–16 blastomeres**

Solid ball of cells

Forms as early as day 3 after fertilisation

Name derived from resemblance to mulberry

**Blastocyst**:

Formed by day 5–6 after fertilisation as embryo enters uterus

**Hollow structure** with two cell populations:

**Trophoblast**: Outer layer of cells; gives rise to **placenta and membranes**

**Inner cell mass (Embryoblast)**: Inner group of cells attached to trophoblast; gives rise to **embryo proper**

**Blastocoel**: Fluid-filled cavity inside blastocyst

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Implantation

**Definition**: Attachment and embedding of **blastocyst into endometrium** (uterine lining); occurs **6–12 days** after fertilisation.

**Synchronisation required**:

Blastocyst must reach uterus at correct time (day 5–6)

**Uterine endometrium must be in luteal phase** (progesterone-dominated, receptive)

Window of implantation: Days 6–10 after ovulation (days 20–24 of menstrual cycle)

**Process of implantation**:

**1. Apposition** (Day 6–7):

Blastocyst comes in contact with endometrium

**Trophoblast cells** in contact with endometrial epithelium

**2. Adhesion** (Day 7–8):

Cells of trophoblast **adhere firmly** to endometrial epithelium

**Cell surface adhesion molecules** involved

**3. Invasion/Embedding** (Day 8–12):

**Trophoblast cells** secrete **enzymes** (protease, collagenase)

Enzymes digest endometrial tissue

**Trophoblast invades** endometrial stroma

Blastocyst **embeds itself** into endometrium

Endometrial tissue grows over the blastocyst (buried)

**After implantation**:

**Inner cell mass** differentiates into **three germ layers** (ectoderm, mesoderm, endoderm) — begins embryonic development

**Trophoblast** begins formation of **extraembryonic membranes** and **placenta**

**Conceptus** (embryo + membranes + placenta) develops

Progesterone production continues → No menstruation

**Failure of implantation causes**:

Luteal phase defect

Uterine abnormalities

Improper endometrial development

Faulty blastocyst quality

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PREGNANCY AND EMBRYONIC DEVELOPMENT

Early Embryonic Development

**Bilaminar disc** (Week 2):

Inner cell mass differentiates into **epiblast** and **hypoblast**

Forms **primary yolk sac**

**Trilaminar disc** (Week 3 — Gastrulation):

**Gastrulation** begins: formation of three germ layers

**Primitive streak** appears in epiblast

Three germ layers form:

**Ectoderm** (outer): Forms nervous system, skin epidermis, hair

**Mesoderm** (middle): Forms muscle, bone, blood, reproductive organs

**Endoderm** (inner): Forms lining of GI tract, respiratory system, liver, pancreas

**Week 4–8 — Organogenesis**:

Organs begin formation from germ layers

**Heartbeat** begins (week 4)

**Brain and spinal cord** development begins

**Limb buds** appear (week 5)

By end of week 8: All major organs formed; structure recognizable as "mini human"

**Embryonic period** ends at week 8

**Week 9–12 — Fetal period begins**:

Embryo now called **fetus**

Organs continue to mature and differentiate

Size: ~10 cm at 12 weeks

Extraembryonic Membranes and Placenta

**Four extraemb