Reproductive System

• Speed: Nervous system is fast (seconds; action potentials, neurotransmitters); Endocrine system is slower (hormones travel in blood).

• Mechanism: Nervous system acts via synapses and nerve impulses; Endocrine system acts via hormones on distant or local target cells.

Compare the nervous system and endocrine system in terms of speed and mechanism.

• Body fluid composition

• Metabolism

• Muscle contraction

• Glandular secretion

• Immune function

• Growth and reproduction

• Circadian rhythms

What primary physiological processes does the endocrine system regulate to maintain homeostasis?

• Endocrine (circulating): Hormone travels through the blood to a distant target cell with the matching receptor.

• Paracrine: Hormone acts locally on a neighbouring cell.

• Autocrine: Hormone acts back on the same cell that secreted it.

Define the three modes of hormone signalling (Endocrine, Paracrine, Autocrine)

• Peptides/Proteins:

  • Solubility: Water soluble

  • Examples: GnRH, FSH, LH, Oxytocin

  • Mechanism: Bind surface receptors → 2nd messenger cascade (e.g., phosphorylation) → fast-acting

• Steroids:

  • Solubility: Lipid soluble

  • Examples: Androgens, Oestrogens, Progestagens

  • Mechanism: Travel bound to transport proteins → diffuse into cell → bind cytoplasmic/nuclear receptors → alter gene expression → slower-acting

Compare Peptide/Protein hormones and Steroid hormones (Solubility, Examples, Mechanism of action).

Hypothalamus → Releasing/release-inhibiting hormones → Anterior pituitary secretory cells → Pituitary hormone → Target tissue.

What is the general pathway of the Hypothalamic–Pituitary–Target tissue axis?

• Anterior Pituitary: Vascular link via the hypophyseal portal system (direct capillary-to-capillary blood flow).

• Posterior Pituitary: Neural link; stores and releases oxytocin and ADH made directly in the hypothalamus.

How does the hypothalamus communicate with the anterior pituitary vs. the posterior pituitary?

Hypothalamus (GnRH) → Anterior pituitary gonadotrophs (FSH+LH) → Gonads → Sex steroids.

What is the specific hormonal cascade of the HPG axis for reproduction?

• Primary mechanism: Negative feedback (sex steroids feed back to inhibit the hypothalamus and pituitary).

• Exception: Around ovulation, oestrogen briefly switches to positive feedback to trigger the LH surge.

What is the primary regulatory feedback mechanism for the HPG axis, and what is the key exception?

• Main forms: Testosterone (main product) and 5α-dihydrotestosterone (DHT, more potent).

• Male roles: Male sex development, secondary sex characteristics, spermatogenesis, libido, muscle development.

• Female roles: Bone health, libido, muscle (produced in much smaller amounts than in males).

What are the main types and functions of androgens in males and females?

• Oestradiol: Main circulating oestrogen during reproductive life; produced mainly by granulosa cells of the growing follicle.

• Oestrone: Weaker oestrogen; produced by adipose tissue (stromal cells); main circulating oestrogen after menopause and in males.

• Oestriol: Important during pregnancy and labour.

Compare the three main types of oestrogens (Oestradiol, Oestrone, Oestriol).

• Females: Female sex development, secondary sex characteristics, menstrual cycle regulation, and endometrial growth.

• Both sexes: Bone growth and epiphyseal closure (driven by oestrogen in both males and females).

What are the key physiological roles of oestrogens in males and females?

• Primary form: Progesterone.

• Source: Produced by the corpus luteum (and the placenta during pregnancy).

• Roles: Appears only after ovulation; prepares for and maintains pregnancy.

What is the primary progestagen, where is it produced, and what are its key roles?

• Sex determination: Commitment of the bipotential gonad (in the genital ridge) to become a testis or an ovary (driven by presence/absence of the SRY gene).

• Sex differentiation: Hormone-driven development of internal and external genital structures after the gonad has formed.

What is the difference between sex determination and sex differentiation?

• Male (Active):

  • Sertoli cells → Anti-Müllerian Hormone (AMH) → Müllerian duct regresses.

  • Leydig cells → Testosterone → Wolffian duct develops into epididymis, vas deferens, seminal vesicles.

• Female (Passive):

  • No testosterone → Wolffian duct regresses.

  • Absence of AMH → Müllerian duct develops into fallopian tubes, uterus, cervix, and upper vagina.

How do internal genitalia differentiate in male vs. female embryos?

• Genital tubercle: Glans penis (Male) vs. Clitoris (Female).

• Urethral folds: Fuse to form penile shaft (Male) vs. Stay separate as labia minora (Female).

• Labioscrotal swellings: Fuse to form scrotum (Male) vs. Stay separate as labia majora (Female).

How do the embryonic precursors develop into male vs. female external genitalia?

• Cause: Genotypic male (46,XY) with functional testes, but a mutated androgen receptor prevents testosterone from acting.

• Presentation: External genitalia default to a female appearance; often presented as primary amenorrhoea (absence of menstruation) at puberty.

What is Androgen Insensitivity Syndrome (AIS) and how does it manifest?

• First sign: A rise in Luteinising Hormone (LH).

• Cause: Increased secretion of GnRH from the hypothalamus.

• Pattern: Pulses occur mainly at night during sleep in early puberty, expanding to daytime pulses in late puberty.

What is the first endocrine sign of puberty, and what causes it?

1. Breast bud development (~8–13 yrs; driven by oestrogen)

2. Pubic hair development (shortly after)

3. Peak height velocity (~9.5–14.5 yrs; ~2 years before males)

4. Menarche (first menstrual bleed, ~10–16.5 yrs, typically ~12–13)

5. First ovulation (months after menarche; regular cycles take 1–2 years)

What is the normal sequence of puberty events in females?

1. Testicular enlargement (~10–13.5 yrs; first sign, driven by LH/FSH response)

2. Pubic hair development

3. Penis growth

4. Peak height & strength spurt (occurs later and is higher than in females)

5. Spermarche (first spontaneous ejaculation; sperm detectable ~13–14 yrs)

What is the normal sequence of puberty events in males?

• Critical Body Weight Hypothesis: Onset of puberty requires reaching a threshold body weight/fat store (~47 kg), which explains menstrual disruption in low-body-weight individuals (e.g., athletes).

• Secular Trend: Historical drop in age of menarche over ~200 years (from ~17–18 yrs to ~12–13 yrs) due to improved health/nutrition; age of menopause has remained unchanged.

Explain the Critical Body Weight Hypothesis and the Secular Trend regarding puberty.

• Precocious puberty: Signs appearing before age 7 (girls) or age 9 (boys); can be caused by a hypothalamic tumour.

• Delayed puberty: Absence of signs by age 13 (girls) or age 14 (boys); e.g., Kallmann syndrome (GnRH deficiency + loss of smell).

Define precocious puberty and delayed puberty, including age thresholds and primary examples.

• Cause: The ovary running out of functional follicles.

• Age of onset: Typically ages 50–52 (unlike menarche, this timing has not shifted historically).

• Definition: Retrospectively defined as 12 consecutive months without a period (amenorrhoea).

What is the underlying cause, typical age of onset, and formal definition of menopause?

1. Pre-menopause: Regular menstrual cycles.

2. Menopausal transition / Perimenopause: Cycles become irregular; symptoms begin.

3. Menopause: 12 months of amenorrhoea achieved.

4. Post-menopause: Period following menopause.

5. Ovarian senescence: ~1–2 years post-menopause; the ovary essentially stops producing hormones.

What are the 5 sequential phases of the menopausal transition?

• Oestrogen production drops to <101​th of pre-menopausal levels.

• The main remaining oestrogen becomes oestrone (a weaker form), produced via peripheral conversion in adipose tissue stroma.

How do oestrogen levels and primary oestrogen types change during/after menopause?

• Vasomotor: Hot flushes, night sweats.

• Genitourinary: Atrophic changes, vaginal dryness.

• Bone: Increased risk of osteoporosis.

• Behavioural / Psychological: Depression, tension, anxiety, mental confusion, loss of libido.

• Treatment: Menopausal Hormone Therapy (MHT) / Oestrogen replacement.

What are the key symptoms of oestrogen deprivation during menopause across system categories?

• Structure & Dimensions: An elastic muscular tube measuring 7.5–9.0 cm in length that extends from the cervix to the exterior of the body.

• Functions: Serves as a passage for menstrual fluid, receives the penis and holds sperm during intercourse, and forms the lower part of the birth canal.

• Microbiome: Maintains a healthy local environment essential for overall reproductive health and protection against infections.

What are the key details regarding the vagina's structure, functions, and microbiome?

• Dimensions: Small and pear-shaped, weighing 30–40 g.

• Regions:

  1. Fundus: The rounded top portion.

  2. Body: The central main region.

  3. Cervix: Protrudes into the vagina; contains a cervical canal usually plugged with mucus to block sperm and bacteria (except around ovulation).

What are the basic physical dimensions and three main anatomical regions of the uterus?

• Stratum functionalis: The inner layer containing most uterine glands; shed during each menstrual cycle.

• Stratum basalis: The outer, permanent layer attached to the myometrium; regenerates the stratum functionalis after shedding

What are the key structural and functional differences between the two layers of the endometrium?

• Anteflexed: Normal position, present in ~80% of women.

• Retroflexed: Tilted backwards, present in ~20% of women.

• Clinical implications: Can cause pain during menstruation (dysmenorrhea) or intercourse (dyspareunia); usually self-corrects during pregnancy.

How do an anteflexed and a retroflexed uterus differ, and what are the clinical implications of retroflexion?

• Rule: Fundal height (distance in cm from pubic bone to fundus) ≈ gestational age in weeks.

• Larger than expected: Indicates twins, breech position, or gestational diabetes.

• Smaller than expected: Indicates small for gestational age or intrauterine growth restriction (IUGR).

What is McDonald's rule (fundal height), and what do abnormal measurements indicate?

• Regions: Infundibulum (with fimbriae) → Ampulla (typical site of fertilisation) → Isthmus.

• Structure & Transport: Ciliated cells (move oocyte/embryo) + non-ciliated secretory cells (provide a rich nutritive environment with lipids and glycogen) surrounded by smooth muscle. Transport is driven by a combination of ciliary beating and peristalsis.

• Ovulation Mechanism: Fimbriae with beating cilia sweep the released oocyte off the ovarian surface into the tube.

• Ectopic (Tubal) Pregnancy: Embryo implants in the tube instead of the uterus. Risk factors include smoking (impairs ciliary beating), advanced maternal age, and prior tubal damage (e.g., chlamydia, endometriosis).

What are the key anatomical, functional, and clinical characteristics of the uterine (Fallopian) tubes?

• Physical Characteristics: Oval-shaped organs weighing 5–10 g (smaller than testes).

• Histological Regions:

  • Ovarian Cortex: Outer region containing the follicles.

  • Ovarian Medulla: Central region consisting of stroma and steroid-producing cells.

  • Hilum (Hilus): Inner region serving as the entry point for nerves and blood vessels.

What are the key physical characteristics and three histological regions of the ovaries?

• Overview: Follicles arise in the fetal ovary (~several million at 3 months gestation); most undergo atresia, leaving ~400 to be ovulated over a lifetime.

• 1. Primordial Follicle: Oocyte + single layer of flattened (squamous) pre-granulosa cells sitting in cortical nests.

• 2. Primary (Pre-antral) Follicle: Granulosa cells become cuboidal; oocyte secretes the zona pellucida (species-specific sperm binding & polyspermy block); stromal cells condense to form theca.

• 3. Secondary (Antral) Follicle: Driven by FSH. Fluid forms a single antrum. Features corona radiata (inner granulosa attached to zona pellucida), cumulus oophorus (outer granulosa mass), and theca interna/externa (thecal androgens are converted to oestradiol by granulosa cells).

• 4. Mature (Graafian) Follicle: Antrum enlarges; oocyte is suspended in fluid, attached to the follicle wall by a thin granulosa stalk.

• 5. Ovulation: Enzyme/hormone-mediated rupture releases the oocyte + cumulus mass into the Fallopian tube.

• 6. Corpus Luteum: Formed post-ovulation; granulosa cells undergo luteinisation to secrete large amounts of progesterone (+ oestrogen). Lifespan is ~2 weeks unless rescued by hCG.

• 7. Corpus Albicans: White scar tissue left after corpus luteum degenerates; slowly reabsorbed into ovarian stroma as the cycle restarts

What are the key stages and structural features of follicular development (from fetal origin to corpus albicans)?

• Fertile Cycle (Fertilisation Occurs):

  • The embryo's chorion secretes human chorionic gonadotropin (hCG) starting around day 8 post-fertilisation.

  • hCG rescues the corpus luteum from degeneration, maintaining progesterone secretion to sustain the pregnancy.

  • hCG detection in blood/urine forms the basis of home pregnancy tests.

• Futile Cycle (No Fertilisation):

  • The corpus luteum degenerates after ~2 weeks.

  • Hormone levels drop, leading to menstruation, and the cycle restarts.

What happens to the corpus luteum and progesterone levels if fertilisation occurs vs. if it does not ("fertile" vs. "futile" cycle)?

• Average Length: ~28 days (varies considerably between individuals and with age).

• Ovarian Cycle (2 phases):

  • Follicular phase: Day 1 → ovulation. Variable length; shortens with age.

  • Luteal phase: Ovulation → menstruation. Fixed at ~14 days.

• Uterine (Endometrial) Cycle (3 phases): Menstrual, proliferative, and secretory.

What are the basic features and main phases of the female reproductive (menstrual) cycle?

1. Corpus luteum regresses: Oestrogen and progesterone fall, causing FSH to rise due to loss of negative feedback.

2. Follicular growth: Rising FSH stimulates a cohort of ~20–30 follicles to begin developing.

3. Selection of dominant follicle (~Day 6–7): Dominant follicle produces rising oestradiol (others undergo atresia).

4. FSH suppression: Rising oestradiol suppresses FSH and LH via negative feedback, ensuring only one follicle matures.

5. Feedback switch (~Day 12): Oestradiol exceeds a threshold level for ~36 hours, triggering a switch from negative to positive feedback.

6. LH surge: Positive feedback triggers a rise in GnRH, leading to a massive LH surge (and a smaller FSH rise).

7. Ovulation: The LH surge triggers the release of the oocyte.

8. Corpus luteum formation: Corpus luteum develops post-ovulation, leading to rising progesterone.

9. Negative feedback restored: Elevated progesterone inhibits GnRH, dropping FSH and LH back down.

10. Luteal demise: Corpus luteum degenerates if no pregnancy occurs → hormone levels drop → cycle restarts at Step 1.

What are the 10 key hormonal events of the female reproductive (menstrual) cycle in sequential order?

• Menstrual Phase: Shedding of the stratum functionalis driven by low hormone levels (oestrogen and progesterone).

• Proliferative Phase: Oestrogen drives endometrial regrowth and repair following menstruation.

• Secretory Phase: Progesterone (along with oestrogen) converts the endometrium into a glandular, nutrient-secreting tissue prepared for embryo implantation.

What are the three phases of the endometrial (uterine) cycle and their key characteristics?

1. Produce an oocyte.

2. Incubate an embryo.

What are the two primary functions of the female reproductive tract?

• Fertile cycle: Embryo is present → hCG rescues the corpus luteum → pregnancy continues.

• Futile cycle: No embryo is present → corpus luteum degenerates → endometrium is shed → cycle restarts.

What differentiates a fertile cycle from a futile cycle?

The human endometrium becomes too thick to be safely reabsorbed without presenting a significant infection risk, so it is shed instead.

What is one theory for why humans experience menstruation instead of reabsorbing the tissue?

Only in the seminiferous tubules of the testes.

Where does spermatogenesis take place?

• Oogenesis: Oocytes are all made by ~6 months of fetal life (a fixed lifetime supply of ~6–7 million) and decline from then on.

• Spermatogenesis: Starts at puberty and runs continuously for life.

How does the timing and timeline of spermatogenesis differ from oogenesis?

Approximately 300–600 sperm per gram of testis tissue per second (~10,000 sperm/sec or ~600,000 sperm/testis/minute for a 20 g testis).

What is the rate of sperm production in a mature male?

1. Mitotic division

2. Meiotic division

3. Cytodifferentiation (spermiogenesis)

What are the three main phases of spermatogenesis?

• Role: The sperm-precursor lineage undergoing cell division.

• Sequence: Spermatogonia → spermatocytes → spermatids → sperm.

What are spermatogenic (germ) cells and what sequence of development do they follow?

• Role & Location: Large supporting ("nurse") cells located inside the seminiferous tubule in direct contact with developing germ cells; they nurture and support developing sperm.

• Structure & Hormone Response: Tightly joined to each other to form the blood–testis barrier; respond to FSH.

What are Sertoli cells, where are they located, and what key structure do they form?

• Location: Sit outside the seminiferous tubules in the interstitial tissue.

• Function: Respond to LH by producing testosterone.

What are Leydig (interstitial) cells, where are they located, and what hormone do they respond to?

• Location: Basal compartment (on basement membrane).

• Chromosome Number: 2n=46 (diploid).

• Key Events: Reactivated at puberty; divide by mitosis.

What occurs at the Spermatogonial stem cell stage?

• Location: Basal compartment.

• Chromosome Number: 2n=46 (diploid).

• Key Events: Undergo ~6 rounds of mitotic division. One daughter cell remains an undifferentiated stem cell to maintain the stem cell pool, while the other continues dividing/differentiating.

What are the key details of Spermatogonia?

• Location: Move to adluminal compartment (squeeze between adjacent Sertoli cells).

• Chromosome Number: 2n=46 (DNA content doubles).

• Key Events: Undergo meiosis I (a slow process).

What happens to Primary spermatocytes?

• Location: Adluminal compartment.

• Chromosome Number: n=23 (haploid, 2 chromatids each).

• Key Events: Undergo meiosis II very rapidly (rarely seen on histology) to form 4 spermatids.

What are the features of Secondary spermatocytes?

• Location: Adluminal compartment, lumen side.

• Chromosome Number: n=23 (haploid).

• Key Events: Round, normal-looking cells that undergo spermiogenesis (cytodifferentiation).

What are Spermatids (round) and what stage do they undergo?

• Location: Released into the lumen.

• Chromosome Number: n=23 (haploid).

• Key Events: Detach from Sertoli cells and fall into the tubule lumen.

What are Spermatozoa (sperm) and how are they released?

• Basal compartment: Mitotic divisions occur here.

• Adluminal compartment: Meiosis and differentiation occur here (after cells cross the Sertoli cell tight junctions / blood–testis barrier).

In which compartments of the seminiferous tubule do mitosis, meiosis, and differentiation occur?

• Tail: Propulsion for swimming.

• Midpiece: Packed with mitochondria ("engine room") to power propulsion.

• Head: Contains the haploid nucleus (n=23).

• Acrosome: Cap containing receptors (bind zona pellucida/oocyte) and enzymes (digest zona pellucida). Essential for fertilisation.

• Residual Body: Excess cytoplasm shed and phagocytosed by Sertoli cells to streamline the sperm.

What are the key structural adaptations during spermiogenesis and their functions?

• Produced in higher brain centres.

• Regulates the GnRH pulse generator in the hypothalamus (sits "above" GnRH in the control hierarchy).

What role does kisspeptin play in upstream hormonal control of spermatogenesis?

• Release: Secreted in pulses by the hypothalamus; reaching an adequate pulse frequency triggers puberty.

• Target Pathway: Travels via the hypophyseal portal system to gonadotrophs in the anterior pituitary

What is the release pattern of GnRH, how does it trigger puberty, and where does it travel?

• Target Cell: Leydig cells (located outside the seminiferous tubules).

• Main Action: Stimulates testosterone production.

What is the target cell and main action of LH in the male reproductive system?

• Target Cell: Sertoli cells (located inside the seminiferous tubules).

• Main Actions:

  • Stimulates production of androgen-binding protein (ABP).

  • Stimulates production of inhibin.

  • Supports germ cell development.

What is the target cell and main actions of FSH in the male reproductive system?

• Potency: Testosterone is converted to DHT, which is ~2× more potent.

• Secondary Sex Characteristics: Both drive pubic/facial/body hair, voice deepening, male pattern baldness, muscle development, libido, and aggression.

• Role in Spermatogenesis: Testosterone is essential to complete spermatogenesis; without it, the process arrests at meiosis I.

What are the key features and functions of testosterone and dihydrotestosterone (DHT)?

• Potency: Testosterone is converted to DHT, which is ~2× more potent.

• Secondary Sex Characteristics: Both drive pubic/facial/body hair, voice deepening, male pattern baldness, muscle development, libido, and aggression.

• Role in Spermatogenesis: Testosterone is essential to complete spermatogenesis; without it, the process arrests at meiosis I.

What are the key features and functions of testosterone and dihydrotestosterone (DHT)?

• Production: Produced by Sertoli cells in response to FSH.

• Function: Binds and transports lipid-soluble androgens (testosterone, DHT) through the aqueous bloodstream and tubules.

What is Androgen-Binding Protein (ABP), where is it produced, and why is it needed?

• Blood: Carries testosterone throughout the body.

• Seminiferous Tubule Lumen: Maintains a high local concentration of testosterone, which is required to drive the completion of spermatogenesis.

Where is Androgen-Binding Protein (ABP) secreted, and what are its roles in each location?

• Testosterone: Feeds back negatively at both the hypothalamus (↓ GnRH) and the anterior pituitary (↓ FSH and LH).

• Inhibin: Produced by Sertoli cells in response to FSH; feeds back selectively at the pituitary to suppress FSH only.

How do testosterone and inhibin exert negative feedback in the male reproductive system?

Kisspeptin⟶GnRH pulses⟶FSH & LH

↓

Leydig cells (Testosterone) & Sertoli cells (ABP, Inhibin)

↓

Testosterone & Inhibin feed back to restrain GnRH, FSH, and LH

What is the overall sequence of the male HPG axis feedback loop?

Couples, not individuals, are diagnosed as "infertile" clinically, though the underlying pathology is often localized to one partner ("male factor" vs. "female factor" infertility).

How is clinical infertility defined regarding couples vs. individuals?

A normal ejaculate should contain ≥20 million sperm/mL.

What is the WHO reference value for sperm concentration in a normal ejaculate?

• Oligospermia: Reduced sperm count (<20 million/mL).

• Azoospermia: Complete absence of sperm in the ejaculate.

• Asthenozoospermia: Immotile sperm present; unable to swim and fertilize.

What are oligospermia, azoospermia, and asthenozoospermia?

• IVF: Oocyte(s) and ~50,000 motile sperm are placed together in a media droplet under oil in a petri dish; fertilisation occurs "naturally."

• ICSI: A single sperm is picked up via microinjection pipette and injected directly into the oocyte cytoplasm while a holding pipette stabilises the egg.

How do the processes of IVF and ICSI differ?

• IVF: Requires a reasonable number of motile sperm (sperm must swim and penetrate the zona pellucida independently).

• ICSI: Sperm does not need to be motile; it bypasses natural fertilisation barriers entirely.

What are the sperm requirements for IVF vs. ICSI?

• IVF: Ejaculate (can concentrate sperm by washing if count is low, e.g., oligospermia).

• ICSI: Ejaculate OR sperm retrieved directly via testicular biopsy (useful in azoospermia).

Where is sperm sourced for IVF vs. ICSI?