Week 1 Flashcards
What does the urogenital tract originate from?
Intermediate mesoderm
What are the 3 sets of kidney-like structures during development?
Pronephros, mesonephros and metanephros
Where does the pronephros develop?
Cervical region
Where does the mesonephros develop?
Abdominal region
Where does the metanephros develop?
Pelvic region
How do the kidney structures develop?
In a cranial to caudal, and chronological sequence
What is the pronephros?
7-10 solid cell groups in the cervical region, which is rudimentary and non-function. It regresses by week 4
What is the mesonephros derived from?
Intermediate mesoderm from the upper thoracic and upper lumbar segments
When does the mesonephros form?
In week 4, after regression of the pronephros, the first excretory tubules of the mesonephros appear
What forms with the mesonephros, and why is it significant?
The mesonephric duct, which contributes supporting cells to the genital ridge
When does the metanephros appear, and when is it function?
Appears in week 5 and is functional by week 11
What 2 parts makes up the metanephros?
Ureteric bud, and metanephric cap
What structures make the definitive kidney?
The metanephric cap, becoming associated with the ureteric duct
When does urine production begin?
Early in gestation
What is the cloaca?
A posterior orifice that serves as the only opening for the intestinal, reproductive and urinary tracts at early stages
What is the ureteric bud?
A protrusion from the mesonephric duct, that allows urine drainage from the developing kidney
What is the allantois?
A sac like structure involved in nutrition and excretion, formed by an invagination of the hindgut
What is the urachus?
A duct between the bladder and yolk sac. It forms the allantois at 5-7 weeks
What does the cloaca develop from?
Hindgut (endodermal lining)
What divides the cloaca by fusion with the cloaca membrane?
The urorectal septum
What does the division of the cloacal membrane form?
The anterior urogenital sinus and the posterior rectal/anal canal
What does the anterior urogenital sinus form?
The bladder, along with caudal parts of the mesonephric duct
What is the origin of the trigone?
Mesonephric ducts
What does the bladder lining develop from?
Endoderm
What is the first stage of genital duct development?
The indifferent stage
Describe the indifferent stage of genital duct development
2 pairs of genital ducts develop in weeks 5-6; the paramesonephric ducts which form laterally to the mesonephric ducts
What is the function of the mesonephric ducts?
They drain urine from the mesonephric kidney, and play and essential role is the development of the male reproductive system
What is formed from the mesonephric ducts, and under the influence of what hormone?
Under the influence of testosterone, the mesonephric ducts form the ductus deferens and ejaculatory duct when the mesonephros vanishes
What happens to the mesonephric ducts in females?
Almost completely disappears (leaves a few non-functional remnants)
Describe the development of the paramesonephric ducts in females?
- Develop lateral to the gonads, and mesonephric ducts
- Form funnel shaped cranial ends which open into the peritoneal cavity
- Migrate caudally, parallel to the mesonephric ducts until they reach the future pelvic region
- Approach each other in the midline, cranial portion forms the uterine tubes, caudal portion fuse to form the uterovaginal promordium (uterus and superior vagina)
What happens to paramesonephric ducts in males?
The hormones anti-mullerian hormone (AMH), made by the Sertoli cells of the testes, causes the paramesonephric ducts to degenerate
When do gonads initially appear, and what do they look like?
Gonads appear as a pair of longitudinal ridges at week 5
What are genital ridges?
A mesoderm structure, projecting into the coelomic cavity (gonadic precursors)
Describe initial gonadal development:
Primordial germ cells originate in yolk sac and move to the genital ridge via dorsal mesentery, forming the primitive gonad
What is the importance of primordial germ cell migration?
If PGCs don’t arrive into the gonadal ridge by week 6, then the ridges develop no further
What do primordial germ cells form?
A ‘cord-like’ structure- primitive sex cords
What is the testis determining factor SRY?
Sex determining region of the Y chromosome
What does the SRY act on?
Somatic cells to cause proliferation of sex cords
What happens during male gonad differentiation?
Sex cords become horseshoe shaped, and cords break up into tubules. Leydig cells being to produce testosterone and Sertoli cells produce anti-mullerian hormone. Dense CT forms (Tunica Albuginae) which separates the cords from surface epithelium
What links to form the ductus deferens?
The rete testis and the mesonephric duct
What is the active signal for female development?
Wnt 4 (ovary determining gene)
What happens when primordial germ cells reach genital ridges in females?
PGCs divide by mitosis, to form pool of oogonia. They enter meiotic arrest at 4th month of gestation becoming “oocytes”. Oocytes become associated with follicular cells (primordial follicles)
When does development of external genitalia begin?
Week 3 after fertilisation
What is the initial stage of development of external genitalia?
A pair of cloacal folds develop around cloacal membrane, and join to form the genital tubercle at the cranial end
How are the cloacal folds subdivided?
Urethral folds in front, form labia minor in the female, anal folds behind, genital swellings then appear on either side of the urethral folds, form scrotal swellings in males and labia majora in females
How does the urethra develop?
From the middle pelvic part of the urogenital sinus. In males, androgens from fatal testis cause genital tubercle to elongate into phallus. Phallus pulls urethral folds forwards, and they form lateral walls of urethral groove and close over urethral plate to form penile urethra. Terminal part of male urethra comes from surface ectoderm
How to the male accessory glands develop?
Prostate develops as outgrowths from the prostatic urethra. The bulbourtheral glands develop as outgrowths from the penile urethra
How does the lower part of the vagina develop?
Two outgrowths form urogenital sinus- sinovaginal bulbs- fuse to form a vaginal plate, and hollows to form a cavity
How are hormones classified?
Steroid or peptide
How can receptors for steroid and peptide hormones be divided?
Present on cell surface or intracellular and interact with lipophilic hormones
What are steroid hormones derived from?
Enzymatic modification of cholesterol
What are peptide hormones synthesised from?
Amino acids
Where are the steroid hormones synthesised?
Gonads, adrenal glands and placenta
Where in the cells does the synthesis of steroid hormones occur?
Smooth ER and mitochondria
What are circulating estranges a mix of?
Estrone and Estrdiol
Where is oestrone secreted from?
Ovary or converted from androstenedione
Where is estradiol produced?
Ovaries, derived by direct synthesis in developing follicles or through conversion of oestrone
Where are androgens produced in females?
The ovaries, adrenal cortex and adrenal gland (COME BACK TO THIS)
How are progesterones produced?
Synthesised from cholesterol via pregnenolone, in the corpus luteum of the ovary, the adrenal gland and in the placenta during pregnancy
What is the function of progesterone?
Endometrial development (smooth muscle control), maintenance of pregnancy (placenta) and mammary gland development
What is congenital adrenal hyperplasia?
21-hydroxase deficiency, causing ambiguous genitalia, precocious (early) puberty, anovulation and hirsutism
What is aromatase deficiency?
Prevents oestrogen synthesis- ambiguous genitalia
What is aromatase excess?
Excessive conversion of androgens to oestrogens (feminisation of male genitalia)
How is female reproduction regulated?
By interacties between the hypothalamic-pituitary-ovarian axis and the uterus. The hypothalamus secretes GnRH which stimulates the anterior pituitary to release follicle stimulating hormone (FSH) and luteinising hormone (LH)
What secretes GnRH?
Neurosecretory cells produce gonadotrophin releasing hormone
What is GnRH?
10 amino acid peptide with short half life
What does GnRH act on?
GnRH receptor within anterior pituitary which stimulates release of gonadotrophins
What happens to the anterior pituitary under influence of GnRH?
Anterior pituitary secretes peptide hormones (FSH, LH) which act on ovary
What happens in the ovaries under the influence of peptide hormones?
Levels of FSH and LH trigger follicle maturation and regulate steroid hormone production in the ovary. These hormones act on target tissues in the reproductive tract
Describe FSH action
Initiates recruitment of follicle and supports growth of follicle, especially the granulosa cells
Describe LH action
Supports theca cells. Receptors expressed on maturing follicle. LH surge triggers ovulation
What are the stages of the menstrual cycle?
When thinking about ovarian function, the MC can by defined as a pre-ovulatory follicular phase and post-ovulatory luteal phase
What are the corresponding phases of the MC in the endometrium termed?
Proliferative and secretory phases
What does the menstrual phase represent?
The time of menstruation
Describe the follicular phase
Varies in length (10-14 days). Characterised by growth of dominant follicle.
Describe the development of the primary follicle
Cells (stromal) surrounding oocyte signal (BMPs) oocyte development from primordial follicle to primary follicle. Follicular cells proliferate and surround oocyte
Describe the development of the secondary follicle
FSH secretion increase slightly, stimulating further growth of recruited follicles. Circulating LH levels increase slowly, beginning 1 to 2 days after the increase in FSH. Theca cells develop- follicle gains an independent blood supply. Granulosa cells develop FSH, oestrogen and androgen receptors
What differentiates a secondary follicle from primary?
Fluid filled antrum
What do developing follicles produce?
Hormone inhibin, which inhibits FSH secretion but not LH secretion.
Describe negative feedback in the follicular phase
High enough progesterone and oestrogen inhibit the hypothalamus and anterior pituitary secretion of FSH
What happens when oestrogen levels from the ovary get high enough?
Positive feedback on hypothalamus and anterior pituitary to release LH
What are the uterine changes in response to hormones in proliferative phase?
Oestrogens from the ovary act on the endometrium causing thickening of stroma, elongation of uterine glands and growth of spiral arteries
How does ovulation occur (hormones)?
Towards the end of the proliferative phase, rising oestrogens increase responsiveness of pituitary to GnRH, and surge in hypothalamic secretion of GnRH. Estradiol peaks and progesterone levels begin to increase, high levels of estradiol trigger LH secretion by gonadotropes. Stored LH is release in massive amounts, usually over 86 to 48 hrs with a smaller increase in FSH.
How does ovulation occur?
The LH surge stimulates enemies that initiate breakdown of the follicle wall and release of mature oocyte within about 16 to 32 hrs. The LH surge also triggers completion of the first meiotic division of the oocyte within about 36hrs of ovulation
How long does the luteal phase last?
It averages 14 days
Where does the corpus luteum form from?
The follicle
What does the corpus luteum secrete?
Mainly progesterone, which peaks at 6-8 days after ovulation, and some oestrogen
What is the action of progesterone in the luteal phase?
It stimulates development of the secretory endometrium
What causes levels of LH and FSH to decrease?
High levels of circulating estradiol, progesterone and inhibin
What happens to estradiol and progesterone levels late in the luteal phase?
They decrease
What happens to the corpus luteum if implantation occurs?
The corpus luteum does not degenerate, but remains and is supported by human chorionic gonadotropin, produced by the developing embyro
What causes menstruation?
Inhibin directly inhibits the secretion of gonadotrophins, especially FSH, although LH is also decreased. This results in the regression of the corpus luteum, and a reduction in the secretion of progesterone. Leukocyte infiltration of the endometrium occurs. Spiral arteries supplying the superficial endometrium are constricted, and blood stasis occurs in these arteries. The tissue dies, and is eventually washed away when pressure in the arteries increases so much it causes blood to flow again.
Describe the hormonal effects on the vagina during the phases of menstruation
In the early follicular phase, oestrogen is low- vaginal epithelium is thin and pale. Oestrogen increases at the late follicular phase, and squamous cells mature, causing epithelial thickening. In the luteal phase, mature squamous cells are shed as cellular debris
Describe the hormonal effects on the cervix during the phases of menstruation
In the late follicular phase, oestrogen levels decrease: there is increases cervical vascularity and water mucus, which allows spermatic passage. External os opens slightly and fills with mucus. In the luteal phase, progesterone levels increase: this thickens cervical mucus, and reduces elasticity
What is hormonal contraception made up of?
Hormonal contraception can be a combination of oestrogens and progestins, or continuous progestin therapy
How do hormonal contraceptions enter their effect?
Largely through selective inhibition of pituitary function resulting in inhibitor of ovulation
What are some examples of hormonal excess in female reproductive endocrinology?
Polycystic ovarian syndrome, granulosa cell tumour and teratoma
What are some examples of hormonal deficiency in female reproductive endocrinology?
Hypogonadism, Turner’s snydrome, Klinefelter’s syndrome, Kallmann’s syndrome (GnRH deficiency) and hypopituitarism
What are some examples of hormonal hypersensitivity in female reproductive endocrinology?
Hirsutism (excess hair)
What are some examples of hormonal resistance in female reproductive endocrinology?
Testicular feminisation syndromes, Reifenstein’s syndrome and 5alpha reductase type 2 deficiency syndrome
Describe polycystic ovarian syndrome
Common endocrine abnormality, clinical presentation- infertility (no ovulation, lack of menses (increased androgens), weight gain, hirsutism, acne), complex hormonal imbalance (LH/FSH secretion is ‘out of balance’, no negative feedback- leads to elevated LH:FSH ratio (>2:1 diagnostic), increased LH levels leads to increased androgen production
Describe hormonal levels in the follicular phase:
Progesterone production is low, and oestrogen is rising due to conversion of androgens to oestrogens via aromatase (from granulosa cells)
How do the secondary follicles develop?
Recruited follicles increase production of estradiol via conversion of androgens produced in the theca interna into oestrogens by the granulosa cells- aromatase. This stimulates LH and FSH synthesis but inhibits their secretion. FSH levels decrease. FSH and LH levels diverge party because estradiol inhibits FSH secretion more than LH secretion. Developing follicles produce the hormone inhibin, which inhibits FSH secretion but not LH secretion. Levels of oestrogen, particularly estradiol, increase exponentially
What are the functions of the testes?
Secretion of testosterone, and spermatogenesis
Describe testicular structure:
Sperminiferous tubules (contain germ cells and sertoli cells in wall), interstitial tissue, leydig cells
What cell structure is between cytoplasmic arms of Sertoli cells?
Tight junctions
What is spermatogenesis?
Process by which immature sperm cells proliferate and differentiate into mature sperm
What are the stages of spermatogenesis?
Proliferation, meiosis, spermiogenesis (germ cells develop into motile mature sperm)
How long does spermatogenesis take?
6-8 days, starts at puberty
What is involved in the proliferation stage of spermatogenesis?
Germ cells (spermatogonia) have 3 types Adark, Apale and B. Apale cells undergo 2 mitotic divisions to become B cells, and undergo another mitotic division and then go through meiosis. This takes place in the basement membrane
What happens to B spermatogonium in meiosis?
B spcyte to resting primary spermatocyte to leptotene spcyte, to zygotene spcyte, to pachytene spcyte, to diplotene spcyte to secondary spcyte to round spermatid tp spermiogenesis
When do spermatocytes move off the basement membrane?
At leptotene, spermactocytes move off the basement membrane through the blood testis barrier
What happens in spermatogenesis?
This is a cell differentiation process: nuclear condensation, acrosome forms from golgi, tail develops from centriole, cytoplasm re-distributes and mictochondira re-arrange in middle piece
What structures differentiate spermatozoa from other cells?
Essentially a nucleus with a tail. Head: nucleus with compacted and inactive DNA, and is surrounded by the acrosome (enzyme for penetrating the egg). Mid-piece contains many mitochondria which generate power. Tail generate movement
How is male reproduction controlled?
The hypothalamus secretes GnRH, causing the release of LH and FSH into the blood. These hormones stimulate testis growth and function. Testes release inhibit and androgen which have negative feedback roles and turn off hypothalamus
Describe the endocrine control of the testis:
FSH stimulates Sertoli cell function (and thereby spermatogenesis). LH stimulates Leydig cells to secrete testosterone. Test stimulates Sertoli cells (and peritubular myoid cells). Test secreted into the blood acts to maintain androgen-dependent structures (e.g. Prostate, SV) and stimulates sex-drive in the male
What is the effect of FSH on spermatogenesis?
FSH stimulates spermatogonial proliferation
What is the effect of androgen on spermatogenesis?
FSH and testosterone stimulate spermatogonial differentiation to spermatocytes. Critically, testosterone is essential for passage of spermatocytes through meiosis. Testosterone stimulates spermiogenesis.
What is the function of the epididymus?
It induces sperm maturation. Non-motile, non-fertile sperm enter at the head and then become fertile and motile as they travel down the epididymus. The tail acts as a sperm storage area
What are endocrine disruptors?
Exogenous (natural or man-made) chemicals which disrupt normal endocrine function, due to their similar structure to endogenous hormones
How do endocrine disruptors work?
- Mimic hormone biological activity by binding to receptor and activating it (agonistic)
- too much hormone activity
- activity at inappropriate time
- Bind to receptor so preventing binding of the natural hormone (antagonistic)
- prevents normal hormone action
- Interfere with metabolic processes in body
- affects synthesis or breakdown of natural hormones
What reproductive problems can endocrine disruptors cause?
Reduced fertility, developmental abnormalities, menstrual problems, early puberty, brain/behavioural problems, cancers
What is particularly sensitive to endocrine disruptor effects?
The developing foetus
What are phthalates?
Man-made chemicals, which soften and increase flexibility of polyvinyl chloride plastics. Some phthalates may pose a risk to human development, especially for males.
What happened to rat exposed to phthalates in utero?
Foetus:
Major reduction in testosterone and insulin-like 3 production by Leydig cells. Abnormal testis development and decreased germ cell numbers and delayed differentiation.
Postnatally:
Cryptorchidism, hypospadias, infertility and germ cell cancer
What is testicular dysgenesis syndrome (TDS)?
Cryptorchidism, hypospadias, infertility and germ cell cancer occurring together are known as TDS. Some symptoms of TDS are not seen until adult life.
Why is testicular dysgenesis syndrome called TDS?
All symptoms are due to altered foetal testis development.
What are some examples of endocrine disruptors?
Phthalates, diethylstilbestrol (DES) (caused abnormal reproductive development and vaginal cancer) and maternal smoking during pregnancy
How does maternal smoking act as an endocrine disruptor?
Cigarettes contain a complex mixture of chemicals and EDs. It is the largest preventable cause of adverse foetal outcomes (20% of women still smoke during pregnancy).
Why is the blood-testis barrier important?
To protect developing spermatozoa from destruction by an auto-immune response
What cells are responsible for the maintenance of the blood-testis barrier?
Sertoli cells
