Endocrine System Flashcards
4 types of endocrine signalling
Classical
Neuroendocrine
Paracrine
Autocrine
Classical endocrine signalling
Endocrine cell releases hormone, which is transported in the blood to the target cell, initiating a response
Neuroendocrine signalling
Neuroendocrine cell releases neurohormone, which is transported in the blood to the target cell, initiating a response
Autocrine signalling
Endocrine cell releases hormone, which diffuses through interstitial fluid and acts on the releasing cell, initiating a response
Paracrine signalling
Endocrine cell releases hormone, which diffuses through interstitial fluid and acts on a nearby cell, initiating a response
What does the forebrain develop into?
The telencephalon which becomes the cerebrum
The diencephalon which becomes the thalamus and hypothalamus
What does the midbrain develop into?
The mesencephalon, which becomes the midbrain of the brainstem
What does the hindbrain develop into?
The metencephalon which becomes the pons and the cerebellum
The myelencephalon which becomes the medulla
Describe the development of the pituitary gland
At week 3 of development, the embryo contains neuroectoderm and oral ectoderm. The neuroectoderm develops into the neurohypophyseal bud and the oral ectoderm develops into the hypophyseal pouch. During the fetal period, these pinch off, becoming the posterior pituitary and the anterior pituitary, respectively.
Neuroectoderm —> neurohypophyseal bud —> PP
Oral ectoderm —> hypophyseal pouch —> AP
Hormonal feedback control of the hypothalamus and anterior pituitary
Stimulus excites hypothalamus which releases GnRH
GnRH excites AP to release LH and FSH
LH and FSH act on the gonads to release estradiol and the hypothalamus to prevent further GnRH release
Estradiol acts on a) the target tissue, b) the AP to prevent further LH/FSH release and c) the hypothalamus to prevent further GnRH release
Anterior boundary of the hypothalamus
Anterior commissure and lamina terminalis
Posterior boundary of the hypothalamus
Mamillary bodies and midbrain
Superior boundary of the hypothalamus
Thalamus
Hormones released from the AP
ACTH FSH LH TSH Prolactin Growth hormone
Hormones released from the PP
ADH
Oxytocin
Hormones released from the hypothalamus
TRH GnRH CRH Dopamine GHRH Somatostatin PRF
Also Oxytocin + ADH, which are then stored in the PP for later release
Median eminence
Highly vascular part of the brain that hormones are released into
Hypophyseal portal system
Large vessels that spiral around the infundibulum of the pituitary to reach the AP (allows carrying of hormones from hypothalamus to AP)
Histological differentiation between AP and PP
PP contains mainly non-myelinated axonal processes (also some capillaries) which don’t pick up H&E stain very well, so it appears light pink. AP contains many hormone release cells which do pick up stain, so it appears dark pink.
Acidophil
Chromophil in the AP (stains pink with H&E)
Releases GH and mammotrophs
Basophil
Chromophil in the AP (stains purple with H&E)
Releases ACTH, TSH, LH and FSH
Name a somatotroph
GH
Name a thyrotroph
TSH
Name a gonadotroph
LH or FSH
Name a corticotroph
ACTH
Name a lactotroph
Prolactin
Where are the cell bodies of the neurosecretory PP cells located?
In the hypothalamus
ACTH release and action
CRH from hypothalamus travels through hypophyseal portal system to AP where ACTH is released. Acts on adrenal cortex of adrenal glands to produce glucocorticoids.
TSH release and action
TRH from hypothalamus travels through hypophyseal portal system to AP where TSH is released. Acts on thyroid gland to release thyroid hormones.
GH release and action
GHRH from hypothalamus travels through hypophyseal portal system to AP where GH is released. Acts on liver to produce somatomedins which act on bone, muscle and other tissues.
Prolactin release and action
PRF from hypothalamus travels through hypophyseal portal system to AP where prolactin is released. Acts on mammary glands.
FSH and LH release and action
GnRH from hypothalamus travels through hypophyseal portal system to AP where LH and FSH are released. Act on testes to release inhibin and testosterone and ovaries to release estrogen, progesterone and inhibin.
Oxytocin release and action
Sensory stimulation causes direct release of oxytocin from PP which acts on uterine smooth muscle and mammary glands in females and smooth muscle in vas deferens and the prostate gland in males.
ADH release and action
Osmoreceptor stimulation causes direct release of ADH from PP which act on the kidneys to concentrate urine in the loop of Henle.
Growth hormone feedback
GHRH from hypothalamus acts on AP to release GH which acts on epithelia, adipose tissue and the liver. In the liver, somatomedins are released, which stimulates the growth on skeletal muscle, cartilage and other tissues, but also negatively feeds back to inhibit GHRH in the hypothalamus and positively feeds back to stimulate GHIH in the hypothalamus, both of which prevent further GH release from the AP.
Prolactin feedback
Non-pregnant state: Prolactin secretion acts on neuroendocrine cells to secrete dopamine, which inhibits prolactin secretion.
Pregnancy and after birth: Placental lactogen, a placental polypeptide hormone produced during pregnancy to supply additional energy to the fetus, bypasses normal prolactin feedback to inhibit dopamine. Prolactin secretion is increased; before birth, this normally feeds back to increase dopamine. After birth, addition of suckling stimulus is thought to cause PRF release from hypothalamus, increasing prolactin secretion.
HPG axis (ovary)
GnRH released from hypothalamus which travels through hypophyseal portal system to AP, released LH and FSH. These act on the ovaries to produce estrogen which inhibits suprachiasmic nucleus of the hypothalamus. This inhibits further GnRH release.
GnRH signal transduction
Hypothalamus releases GnRH, which travels through hypophyseal portal capillaries to the gonadotroph cell. GnRH binds GPCR, causing PLC release. PLC is cleaved by PIP2 to produce IP3 and DAG. IP3 causes calcium release and DAG causes PKC release. Ca+2 and PKC increases LH and FSH synthesis and secretion from the gonadotroph into the circulation.
In thecal cells or Leydig cells in the gonads, LH binds GPCRs, causing adenylate cyclase to be cleaved into cAMP which activates PKA. The GPCR also activates PLC, which produces DAG and IP3, producing PKC and Ca+2 respectively. PKA + PKC + Ca+2 causes oogenesis, spermatogenesis and steroidogenesis.
In granulosa cells or Sertoli cells in the gonads, FSH binds GPCRs, activating adenylate cyclase, then cAMP, then PKA, contributing to oogenesis, spermatogenesis and steroidogenesis.
Kallmann syndrome
GnRH deficiency leading to: Delayed puberty Amenorrhoea Anosmia/hyposmia Myopia and other eye problems Coeliac disease and type II diabetes common comorbidities
Estrogen feedback on GnRH neuronal network
LH and FSH act on ovary to induce ovulation. Developing follicles produce estrogen which feeds back on the pituitary and GnRH neurons (positively and negatively). After ovulation, corpus luteum produces progesterone, which negatively feeds back to pituitary and GnRH neurons.
Estrogen signalling in GnRH neurons
Estrogen released into synapse, then diffuses through channels on cell membrane, inducing Ca+2. Also converts ERbeta to ERK via CAMKII and PKA signalling. ERK + Ca+2 activate TF CREB.
What is Kisspeptin key for?
Puberty initiation
Oogenesis
Formation and development of ovum
Oogonium
Mitosis leads to primary oocyte
Meiosis – arrest in prophase I
Primary oocyte
Meiosis I completed leads to first polar body
Meiosis – arrest in metaphase II leads to secondary oocyte
Fertilisation by sperm leads to completion of meiosis II
Second polar body and mature ovum follows
Why do fallopian tubes need to be free?
Need to move and pick up oocytes during ovulation
Surrounding support cells of oocyte
Granulosa cells
When has a human female developed all her oocytes by?
6 months gestational age –about 7 million
This drops to 1 million around birth and 300,000 around puberty
Follicle
Oocyte + granulosa cells
Located near the surface of the ovary in the cortex
When does meiosis halt?
In fetal development, end of prophase, just prior to metaphase 1
In follicular development, metaphase II, waiting for fertilisation to occur
Follicular wave
Multiple follicles recruited in a cycle even though only 1 (normally) will be ovulated
Ovarian cycle
Following puberty, waves of follicles become activated (85 days from activation to antrum formation)
During the follicular phase, one follicle will dominate in growth
Atresia
Process by which dominant follicle reduces the growth of other follicles and causes them to die
Primordial follicle
Single layer of flattened granulosa cells surrounding oocyte
Stromal cells round the outside
Primary follicle
Single layer of cuboidal granulosa cells
Secondary follicle
Multiple layers of granulosa cells now expressing FSH receptors and producing estrogen, inhibin and AMH
No antrum
Theca cells expressing LH receptors surrounding granulosa cells – produce androgens
Highly vascularised tissue on outside
Tertiary follicle
Antrum formation containing follicular fluid Theca interna (endocrine) and theca externa (structural) layers
Zona pellucida
Made up on ZP1, ZP2 and ZP3
ZP1 present only in primordial follicles
ZP2 and ZP3 added to activated follicles
Important for filtering normal sperm and the polyspermy block
Theca interna
Internal endocrine layer of cells surrounding tertiary occytes producing androgens
Theca externa
External structural layer of fibroblasts and longitudinal cells surrounding tertiary oocytes
AMH
Anti-mullerian hormone
Suppressed follicular recruitment and development
Corpus luteum
Remnants of the follicle left over after ovulation, including granulosa and theca cells
Releases progesterone and estrogen and degrades over the course of a few months
Endocrine control of the ovarian cycle
Estrogen begins to rise around day 6, peaks around day 12 and feeds back to the hypothalamus and pituitary to stimulate LH release
FSH peaks at day 12, then slowly declines
LH surges just after day 12, then rapidly declines
Progesterone begins to rise around day 14 and peaks around day 22 to promote pregnancy
Inhibin
Produced by granulosa cells. Negatively feeds back to pituitary to regulate FSH
Hyperthermic phase
Around day 21/22 of the cycle, progesterone release slightly increases the basal body temperature following ovulation
Regions of the fallopian tube (proximal to distal)
Isthmus
Ampulla
Infundibulum
Fimbrae
Structure of fallopian tube
Epithelial lining – ciliated, secretory and responsive to steroids
Muscular coat (inner circular, outer longitudinal)
Serosal coat
Effect of estrogen in the fallopian tubes
Increases cilia
Increases secretory activity
Increases muscular activity
Effect of progesterone in the fallopian tubes
Decreases muscular activity
Decreases cilia but increases beat frequency after estrogen priming
Decreases volume of secretions
Luminal volume of non-pregnant uterus
10 mL
Luminal volume of pregnant uterus
5 L (baby, amniotic fluid and placenta) More if twins etc.
Growth of uterus
Initially controlled by estrogen and progesterone (therefore ectopic pregnancies show same initial growth)
Largely due to stretching of existing cells rather than proliferation which allows involution of uterus after birth
Cells go from 50 microns in length to 400–600 microns
Uterine positions
Anteverted (most common)
Anteflexed
Retroflexed
Retroverted (25%)
Uterine layers
Serosa/perimetrium Muscular myometrium (90%) Inner endometrium
Structures present in the uterine wall
Endometrium contains simple columnar epithelium, uterine glands, functional layer and basilar layer, which is continuous with the myometrium
Which part of the uterine wall changes over the course of the menstrual cycle?
The functional layer
Decidua
Thin layer of tissue that comes away with the placenta when baby delivered at term
Decidual reaction
Stroma of endometrium become oedematous
Fibroblasts of stroma become large and lay down glycogen (energy source)
Spontaneously occurs at the end of menstruation in humans
Spiral arteries
Arteries in the uterus are coiled up so they can expand during pregnancy and don’t have to rely on rapid growth
Crucial to survival of fetus
During menses, the spiral artery terminal segments are lost along with the rest of the functional layer –the rest of the artery undergoes spasm to prevent exsanguination
Exsanguination
The loss of blood to a degree sufficient to cause death.
Phases of the menstrual cycle
Stratum Basalis: Menstrual phase – day 1 - 7 Preovulatory phase – day 7 - 14 Ovulation – day 14 Postovulatory phase – day 14 - 28 Stratum Functionalis: Menstruation Proliferative/follicular phase Secretory/luteal phase
Histology of mid-proliferative stage
Stromal oedema and mitotic figures present
Histology of early luteal phase
Tortuous glands, basal vaculotation and glandular secretions present
Basal vaculotation
Gaps between basal membrane of epithelium and densely stained cytoplasm
Histology of late luteal phase
Tortuous glands still present but no basal vaculotation
Leukocyte infiltration begins
Histology of decidual reaction
Polagonal, pale staining cells
Role of estrogen in the uterus
Epithelial and stromal cell proliferation Stromal oedema Glandular secretions Estrogen priming Myometrial activity
Estrogen priming
Synthesis of intracellular progesterone receptors
Role of progesterone in the uterus
Thick glandular secretions in the luteal phase
Stromal cell proliferation
Inhibits myometrial activity
How do we know that the decidual reaction is not required for implantation?
Ectopic pregnancy – most common in the fallopian tubes, especially when there is a loss of ciliary activity or contraction
Endometriosis
Ectopic endometrium (6–10% of women) Causes chronic pelvic pain and is associated with infertility, especially when found on ovaries or in fallopian tubes
Three major theories of endometriosis
Retrograde menstruation
Transport of epithelial cells via blood or lymphatics
Growth of endometrial-like tissue from stem cells
Cervical mucus change throughout cycle
Changes in volume, viscosity and threadability
Spinnbarkeit
Stretchy mucus indicating fertile time – receptive to sperm
Induced by estrogen and stopped by progesterone
Endocervix structure
Columnar epithelium
Glands and crypts
Fibrous stroma and few smooth muscle cells
Ectocervix structure
Stratified squamous epithelium
Endocrinology of testes
Exocrine gland – secretes spermatozoa
Endocrine gland – secretes testosterone mainly
Types of cells in the testes
Gonocytes Spermatogonia Sertoli Leydig Myoid
Gonocytes
Primitive germ cells that become spermatogonia
Only present up to minipuberty
Spermatogonia
Germ cells
Pre-sperm cells that replicate by mitosis
Sertoli cells
Epithelial cells lining the lumen of seminiferous tubules that help developing sperm cells
Increase in number during minipuberty
Leydig cells
Interstitial cells that produce androgen
Myoid cells
Contractile cells of the testes
Germ cell origin
Primordial germ cells either become sperm of oocytes
First seen around 3-4 weeks post-conception in the yolk sac of the extraembryonic tissues then migrate to the gonadal ridges
PGCs that wander away from the correct path of migration should be eliminated by apoptosis
Migration of primordial germ cells
PGCs follow fine enteric nerves and are supposed to stop at the testes but sometimes develop ectopically, where they can develop into oocytes
Could be origin of germ cell tumours outside testes
Production of testosterone in males
Produced by Leydig cells
After 14 weeks, production is LH and hCG dependent
Minipuberty
2 months postpartum producing a peak in testosterone of 2–3 ng/mL
Why is minipuberty important?
Masculinises neonatal brain
Promotes Sertoli cell proliferation – this doesn’t occur after minipuberty
Promotes gonocyte differentiation
What cells create the blood–testis barrier?
Sertoli cells
Role of Sertoli cells
Nourish spermatogonia
Resorb excess cytoplasm
Produce seminiferous tubule fluid
Maintain spermatogonial stem cell niche
Blood–testis barrier
Important for fertility and the prevention of antisperm antibody production
Formed at puberty, so after this Sertoli cells cannot proliferate
Testes descent
1) Transabdominal phase (10–15 weeks)
2) Inguinoscrotal phase (25–35 weeks) – androgen driven
Testes form in the gonadal ridges in the lumbar region suspended between the caudal and gubernaculum ligaments. As the testes grow, the gubernaculum does not elongate and the caudal ligament regresses.
INSL-3 (from Leydig cells) causes migration of the gubernaculum towards and dilation of the inguinal canal, dragging testes down
Cryptorchidism
Failure for testes to descend
Most self-correct within 3 months but can be surgically corrected with orchidopexy
Cryptorchidism complications
Infertility due to excess temperature
Testicular cancer
Breast-fed infants less likely to remain cryptorchid
Maldescent
Improper or incomplete testes descent – can end up in abdomen, perineum or thigh
3 phases to spermatogenesis
Mitosis
Meiosis
Cytodifferentiation
Spermatogenesis
At puberty, PGCs reactivated and become spermatogonial stem cells which divide via mitosis – 1 daughter cell differentiates into spermatogonium and 1 stays undifferentiated to maintain stem cell population
Spermatogonia move between Sertoli cells to adluminal compartment of seminiferous tubules, where they are called primary spermatocytes and undergo meiosis
At the end of meiosis I, called secondary spermatocytes
At the end of meiosis II, called spermatids
Spermatids go through spermiogenesis to differentiate their shape and become spermatozoa
Spermiogenesis
Round spermatids differentiate and become spermatozoa
Unnecessary cytoplasm is shed as the residual body
Sperm move into lumen of seminiferous tubule
Androgen-dependent
Hormonal control of spermatogenesis
Hypothalamus produces GnRH which induces LH and FSH release from AP
LH acts on Leydig cells to produce testosterone, which acts on Sertoli cells to nourish sperm
FSH acts on Sertoli cells to produce androgen binding protein
Testosterone + androgen binding protein produces DHT which allows secondary sexual characteristic development
Sertoli cells produce insulin which inhibit further FSH release
Testosterone negatively feeds back to AP and hypothalamus
Spermatogenic wave
The time taken for a sperm to be produced from a germ cell in human males in 64 days – about 16 days between successive waves
Epididymis
Comma shaped organ running posterior and superior to testes
Efferent tubules of the rete testis drain into the head of the epididymis
Sperm spend 10–14 days passing through epididymis where they are concentrated and gain motility
Rete testis
Series of collecting ducts in the hilum of the testes that carries sperm from the seminiferous tubules to the efferent ducts
Vas deferens
Major site of sperm storage in men – mainly in ampulla, an enlarged, folded and crypt-filled region near the prostate
Consists of inner longitudinal, middle circular and outer longitudinal muscle layers
Seminal vesicles
Highly folded tubular glands that secrete an alkaline fluid containing fructose – energy source for sperm
Produces semenogelin
Semenogelin
Zinc binding protein produced by seminal vesicles that causes clotting immediately after ejaculation
Ejaculatory duct
Tube created when the excretory duct of the seminal vesicle joins with the vas deferens
Prostate gland secretions
Milky coloured, slightly acidic fluid containing PSA, which breaks down the seminal coagulum
Prostate gland zones
Central – surrounds the urethra, no cancer
Peripheral – surrounds central zone, often cancer
Transition – surrounds proximal prostatic urethra, BPH
Anterior – fibromuscular, aglandular
Penis
Two corpus cavernosa which relax and fill with blood
One corpus spongiosum containing the urethra
Basic erection process
1) Parasympathetic nerve activity causes ACh release
2) ACh induces NO release by endothelial cells of the corpora
3) NO induces cGMO production which causes vasodilation
4) Corpora relax and engorge with blood
5) Venous outflow reduced, increasing erection
Sildenafil/viagra mechanism
Blocks type V phosphodiesterase, preventing cGMP breakdown
Vasodilation increased
Note: not useful if erectile dysfunction due to PSNS damage
Semen constituents
30% prostatic fluid
10% sperm
60% seminal vesicle fluid
Normally 2–5 mL, containing 20 million sperm per mL
