WEEK 8 Flashcards
What is infertility?
in a medical sense, it’s used to describe people who have difficulties (or may find it impossible) to have children naturally.
How big a problem is infertility?
- approx 1 in 6 couples may have difficulty conceiving
- the no. of infertile couples is about 5%
What are the causes of infertility?
- Factors affecting a woman’s fertility:
- abnormal ovulation (polycystic ovary syndrome, early menopause)
- blockage of fallopian tubes
- age - Factors affecting a man’s fertility:
- low sperm count/quality
- damage to testicles and/or failure to ejaculate
What are the various methods to treat infertility (Assisted reproductive technologies)? (HINT: there’s 5)
- intrauterine insemination (IUI)
- in vitro fertilisation (IVF)
- IVF with intracytoplasmic sperm injection (ICSI)
- use of donor sperm/eggs
- surrogacy
What are the steps involved in IVF?
- Egg production stimulated by hormone therapy = suppress (GnRH agonist) then stimulate (FSH) then maturation (hCG)
- Eggs retrieved from ovary e.g. ultrasound-guided transvaginal aspiration, or laparoscopy
- Sperm sample provided
- Eggs and sperm combined for fertilisation - use ICSI if necessary; leave in incubator and check after 16-30hrs
- Fertilised eggs introduced into uterus - transfer after 2-6 days; use USS; use progesterone for luteal phase support
What are the risks associated with IVF? (HINT: there’s 3)
- Ovarian hyperstimulation syndrome
- can occur thanks to superovulation in response to the drugs - Transferral of several embryos => multiple births
- recommendation is for single embryo transfer - Welfare of the child
- 1990: the need for a father
- 2008: the need for supportive parenting (allowing single women and same sex couples)
What are the guidelines for IVF in Scotland?
- LESS THAN 40 yrs: 3 cycles of IVF
- infertility with appropriate cause of any duration OR
- unexplained infertility of 2 yrs (heterosex couples)
- unexplained fertility following 6-8 cycles of donor insemination (same sex couples) - 40-42 yrs: 1 cycle of IVF
- no IVF before
- No evidence of low ovarian reserve
- Discussion of implications of IVF and pregnancy at this age
What are the major statistics for IVF in the UK?
What is the HFEA? What is their role?
26.5% of IVF treatments, using own fresh eggs, successful
- 2/3 women were under 37
- 6/10 IVF cycles were privately
- 1 cycle costs about £3500
HFEA = human fertilisation and embryology authority
- a regulator and information provider
- regulates treatment (inspect and license clinics) and research (licenses for human embryo research)
What are the ethical issues surrounding IVF with regards to ACCESS TO IVF?
- heterosexual couples
- homosexual couples
- NHS GGC v. public case in 2009; at first GGC said no, but then overturned decision - single women
- case of Elizabeth Pearce; using sperm bought from US, and IVF funded by NHS
What are the ethical issues surrounding IVF with regards to the GAMETES?
- FROZEN - how long and what happens in the event of death
- DONATED
- is it okay to pay donors?
- should there be a limit to no. children created?
- Should children be able to find out their biological parents? (since 2005, change in law and now they can)
What are the ethical issues surrounding IVF with regards to the EMBRYOS?
- they are graded (use immediately, freeze, discard, or research)
- how many should be made?
- how many should be implanted?
- what do we do with spares?
What are the ethical issues surrounding IVF with regards to the REPRODUCTIVE TOURISM?
- cost
- waiting lists
- avoid legal restrictions
What is IVF with mitochondrial replacement?
“3 parent IVF”
- technique which allows those at risk of passing on certain mitochondrial conditions to avoid that risk
- pro nuclear transfer or maternal spindle transfer
What are the 4 considerations identified in IVF with mitochondrial replacement?
- modification of embryos and changing the germ-line
- implications for identity and the status of the mitochondria donor
- general views on the permissibility of techniques
- licensing models and further regulatory
What is (i) partial surrogacy (ii) full surrogacy?
(i) surrogate mother inseminates herself with commissioning father’s sperm
(ii) IVF (commissioning couple’s egg and sperm mixed in vitro and then transferred)
In surrogacy; who is the legal mother from birth? What are the 2 key reports for surrogacy?
The surrogate mother
- Brazier report and Warnock report.
Where is cholesterol distributed within the body?
- Membrane lipid (is a regulator of membrane fluidity)
- In plasma associated with apoproteins, triacylglycerols and phospholipids in various type of micellular structures called lipoproteins
- Cytosolic lipid droplets as cholesterol esters (mainly in steroid-secreting endocrine cells)
How is cholesterol made? What is the rate limiting step?
The liver synthesises cholesterol, de novo from acetyl CoA in a multi-step process that occurs in the SER and cytosol
- the rate limiting step is the conversion of 3-hydroxy-3-methylglutaryl (HMG-CoA) to mevalonate by HMG-CoA reductase
What are the 4 major steroid hormone classes?
- glucocorticoids
- mineralocorticoids
- oestrogens
- progestins
What are the 3 main physiological roles of cholesterol?
- Component of cell (plasma) membranes
- decrease membrane fluidity and decreases physical permeability to charged/polar compounds associated with the formation of lipid rafts - Precursor for the production of bile salts
- uptake of fats and fat-soluble vitamins in the GI - Precursor for all steroid hormones
- glucocorticoids, mineralocorticoids and sex steroids
Where are the major sites of steroid hormone biosynthesis?
Adrenal cortex - z.glomerulosa = aldosterone - z.fasciculata = cortisol - z.reticularis = cortisol and androgens Gonads - leydig cells in testes = androgens - thecal/granulosa cells = estrogens and progestins
What is the structure of cholesterol?
Cyclopentano-perhydro-phenanthrene nucleus
8-carbon aliphatic side chain
What is lecithin?
Phosphatidylcholine
The cholesterol needed as the starting material in the synthesis of steroid hormones comes from what 2 sources?
Approx 80% is taken up as LDL particles via receptor mediated endocytosis
- the cell synthesises the remaining cholesterol de novo from acetyl CoA.
Describe the anatomy of the adrenal gland.
Sits upon each kidney and comprises of two glands - the cortex and the medulla
- the outermost layer contains the glomerulosa cells that secrete aldosterone, and the 2 inner layers of cortex (fasciculata and reticularis) synthesise cortisol and sex steroids
- the blood supply enters the cortex in the subcapsular region and flows through anastomotic capillary beds while coursing through both the cortex and the medulla
- medulla contains chromaffin cells which secrete epinephrine and a small amount of norephrine
Describe the anatomy of the adrenal gland.
Sits upon each kidney and comprises of two glands - the cortex and the medulla
- the outermost layer contains the glomerulosa cells that secrete aldosterone, and the 2 inner layers of cortex (fasciculata and reticularis) synthesise cortisol and sex steroids
- the blood supply enters the cortex in the subcapsular region and flows through anastomotic capillary beds while coursing through both the cortex and the medulla
- medulla contains chromaffin cells which secrete epinephrine and a small amount of norephrine
Describe receptors on Leydig- and Sertoli-cell.
LEYDIG has receptors for LH - which increases testosterone synthesis
SERTOLI has receptors for FSH - which promotes synthesis of androgen-binding protein (ABP), aromatase, growth factors and inhibin
Describe the crosstalk which occurs between Leydig- and Sertoli-cell.
- the leydig cells make testosterone, which acts on sertoli cells
- sertoli cells convert some of testosterone to estradiol which can act on leydig cells
- sertoli cells also generate growth factors which act on leydig cells
What does the final steroid product(s) of the ovaries depend on?
Different phases of the menstrual cycle
- during follicular phase the major product of the follicle is estradiol, whereas during the luteal phase the major products of the corpus luteum are the progestins, although estradiol synthesis is still substantial
What happens in the follicular phase? What can theca-lutein and granulosa-lutein cells produce?
LH primes the theca cells to convert cholesterol to androstenedione diffuses to the granulosa cell, whose aromatase activity has been stimulated
What happens in the follicular phase?
LH primes the theca cells to convert cholesterol to androstenedione. Because the theca cell lacks aromatase, it can’t generate estradiol from this androstenedione. Instead, the androstenedione diffuses to the granulosa cell, whose aromatase activity has been stimulated by FSH. The aormatase converts the androstenedione to estradiol
What happens in the luteal phase?
The vascularization of the corpus luteum makes LDL available to the granulosa-lutein cells
What can theca-lutein and granulosa-lutein cells produce?
Progesterone
= the major product of the corpus luteum
What is the fundamental reproductive unit?
single ovarian follicle
- composed of one germ cell (oocyte), surrounded by endocrine cells
What is Menarche? What factors determine age at puberty?
Menarche = beginning of menstrual cycles (11-13yrs)
- genetics, nutrition, geographic location, exposure to light, body composition, fat deposition, exercise
What is Menarche? What factors determine age at puberty?
Menarche = beginning of menstrual cycles (11-13yrs)
- genetics, nutrition, geographic location, exposure to light, body composition, fat deposition, exercise
What are the 3 phases to the ovarian cycle?
- Follicular phase: av 15 days (range 9-23 days)
- Ovulatory phase: 1-3 days (and culminated with ovulation)
- Luteal phase 13days (less variable than follicular)
What are the 3 phases of the endometrial cycle?
menstruation, proliferative and secretory phases
What are the functions of the ovary? (HINT: there’s 4)
- Oogenesis (production of gametes during foetal period)
- Maturation of oocyte
- Expulsion of mature oocyte (ovulation)
- Secretion of female sex steroid hormones and peptide hormone inhibin
What is oogenesis?
The steps/processes a developing egg (oocyte) goes through to differentiate into a mature egg (ovum)
- it involves completion of meiosis which occurs at the time of fertilisation
What is oogonia produced by? When does prophase of 1st meiosis begin and what does it become?
by mitotic division
- 8 to 10 wks of gestation
- becomes primary oocyte surrounded by pre-granulosa cells, called primordial follicle
Define (i) mitosis (ii) meiosis.
(i) process of cell division which results in 2 genetically identical daughter cells developing from a single parent cell
(ii) division of a germ cell involving 2 fissions of the nucleus and giving rise to 4 gametes, or sex cells, each possessing half the no. of chromosomes of the original cell
When does the 1st phase of oogenesis occur? Describe the steps involved.
During foetal life
- oogonia develop in the embryonic yolk sac 3 wks post conception (pc)
- migrate to ovary, colonise cortex, undergo mitosis
- at 8-10 wks, meiosis begins
- millions of oocytes degenerate before birth and the remaining are arrested in meiotic prophase until last oocytes are ovulate (for up to 50 yrs - post menopause)
When does the 2nd phase of oogenesis occur? Describe the steps involved.
At ovulation
- meiosis resumes (stimulated by LH) and the first division is completed and haploid nuclei separate to form 2 cells
- cytoplasm is unequally shared forming a large secondary oocyte and a polar body
- meiosis arrests again at metaphase II and the secondary oocyte is ovulated
- 2nd division of meiosis is only completed in those oocytes that are fertilised
Describe the fate of female germ cells (oocytes).
First observed in the embryonic yolk sac and then migrate to developing ovaries, proliferate and reach max numbers before birth
(i) In females when does mitotic proliferation of oogonia occur? (ii) In males when do spermatogonia proliferate?
(i) prior to birth
(ii) only after puberty
(i) In females, what does meiotic division of oocyte produce? (ii) In males what does meiotic divisions of primary spermatocyte produce?
(i) one mature ovum
(ii) 4 mature spermatozoa
(i) In females, when is second meiotic division completed? (ii) In males, when do the products of meiosis (spermatids) undergo substantial differentiation?
(i) only upon fertilisation
(ii) in the maturing process
Where do eggs exist in ovaries?
In structures known as follicles
What are the 5 steps involved in the formation of a mature follicle?
- Primordial follicle = single layer of granulosa cells around oocyte
- Oocyte increases, multiple layers of granulosa cells, and separation of oocyte from granulosa cells by thick layer of material (zona pellucida)
- BUT cytoplasmic processes cross the zona pellucida and form gap junctions with oocyte and nutrients and chemical messengers are passed to oocyte
- Follicle grows by mitosis of granulosa cells and some differentiate to become theca
- Antrum begins to form from amongst granulosa cells from fluid they secrete
What are single follicles (primordial)? What do they secrete?
Most numerous follicles at any time
- oocyte nucleus is in meiotic prophase
- single layer of follicular cells (granulosa cells)
SECRETE anti-Mullerian hormone (AMH)
- levels reflect the ovarian follicular reserve and therefore can be measured to assess ovarian ageing
What are medium follicles (primary)? How many do females have in their body? Why are they important?
At puberty, have 300,000 oocytes. May experience 450 cycles but may lose approx 650 per cycle
- throughout life, cohorts of small follicles recruited to begin a period of slow growth
- follicular (granulosa) cells divide forming 3 layers around oocyte
- growth independent of hormones
How long does it take to reach 3 layers of follicular cells?
85 days (3 cycles)
What does FSH stimulate rapid development of?
Medium follicles over 14 days - this leads to either ovulation or atresia
- zona pellucida (egg shell) develops and enclosing oocyte and masking its antigens
- rapid mitotic division in follicular cells forms many layers
- antrum develops and fills with fluid
What does LH activate?
The theca interna to synthesise androstenedione, the precursor for estradiol 17 beta synthesis by granulosa cells
Describe the (i) initial and (ii) final growth of follicular development. (HINT: state whether dependent/independent and how long stage takes)
(i) independent of hormones and takes 85 days
(ii) dependent on FSH and takes 10-14 days
What are the 4 chemical mechanisms of ovulation?
- LH SURGE: induces prostaglandin endoperoxidase synthase in granulosa cells
- FSH (some LH): stimulates release of plasminogen activator from granulosa cells (converts plasminogen to plasmin)
- Prostaglandins E and F: release lysosomal enyzmes that digest follicular wall
- Stigma: forms on surface of follicle, balloons out, forms vesicle and ruptures so the oocyte is expelled. Facilitated by intrafollicular pressure and contraction of smooth muscle in theca
How is Corpus luteum formed?
Mature follicle discharges its antral fluid and egg
- collapses around antrum and undergoes rapid transformation
Granulosa cells enlarge, and form gland-like structures ie CORPUS LUTEUM
What does CL secrete?
oestrogen
progesterone
inhibin
If no egg development, when does CL development reach maximum?
Within approx 10 days
- and rapidly degenerates by apoptosis
What are the 2 pathways for cholesterol metabolism?
Exogenous
- gut to plasma to liver, liver transports bile to gut
Endogenous
- other tissues to plasma to liver, which transfers VLDL to plasma - LDL in other tissues
What is the side-chain cleavage enzyme is also known as ?
20,22 desmolase
What happens if the synthesis of cortisol is prevented by any one of several dysfunctional enzymes? Give an example.
Other steroid products might be produced in excess
- a block in the 21 alpha-hydroxylase will diminish production of both cortisol and aldosterone and increase production of sex steroids
- certain of these pathways are shared in the biosynthesis of the androgen as well as estrogens
How many different P-450 enzymes are identified in the human genome?
57
How many pathways are there from pregnenolone to testosterone? What is the preferred pathway in the human testis?
4 possible pathways
- pregnenolone to androstenediol, followed by oxidation of the A ring to testosterone
- some of these pathways are shared in the biosynthesis of the glucocorticoids, mineralocorticoids and estrogens
How does the ovary differ from the testis? (HINT: what does it contain??)
It contains aromatase, which converts androgens to oestrogens (testosterone to estradiol)
What are the 2 types of cells in the ovary for steroid synthesis?
Theca cells
Granulosa cells
What are the (i) anterior pituitary gonadotropins (ii) gonadal sex hormones?
(i) LH and FSH
(ii) oestrogen and progesterone
What is the function of (i) FSH (ii) LH?
(I) increases in early part of follicular phase, then steadily decreases throughout remainder of cycle EXCEPT small midcycle break
(ii) constant during most of follicular phase, then large midcycle increase (LH surge) peaking about 18h before ovulation. Then rapid decrease with further slow decline during the luteal phase
What is the function of (i) oestrogen (ii) progesterone (iii) inhibin?
(i) Low and stable for 1st week, increases rapidly in 2nd weeks, starts to decline before LH peak. Then second increase due to corpus luteum in last few days of cycle
(ii) low level due to ovary release during follicular phase with small increase just before ovulation. Soon after ovulation, large increase due to CL release, then similar pattern to oestrogen
(iii) similar to oestrogen i.e. increases in later follicular phase, remains high during luteal phase, decreases as corpus luteum degenerates
What are the feedback effects of the ovarian hormone oestrogen?
Oestrogen, in low plasma concentrations, causes anterior pituitary to secrete less FSH & LH in response to GnRH and may inhibit the hypothalamic neurons that secrete GnRH.
RESULT: -ve feedback inhibition of FSH & LH secretion during the early and middle follicular phase.
What are the feedback effects of the ovarian hormone inhibin?
Inhibin acts on the pituitary to inhibit the secretion of FSH.
RESULT: -ve feedback inhibition of FSH secretion throughout the cycle.
What does oestrogen do when increasing dramatically? What does this result in?
Causes anterior pituitary cells to secrete more LH and FSH in response to RnRH
- can also stimulate hypothalamic neurons which secrete GnRH
RESULT = +ve feedback stimulation of LH surge, which triggers ovulation
What does high plasma concentrations of progesterone (in presence of oestrogen) do? What does this result in?
Inhibits hypothalamic neurons that secrete GnRH
RESULT = -ve feedback inhibition of FSH and LH secretion and prevention of LH surges during the luteal phase and pregnancy
Describe the journey/ function of FSH. What are granulosa cells similar to?
Concentration of FSH in blood rises to max during follicular phase of menstrual cycle
- in first week of follicular phase it stimulates growth of medium sized follicles
- granulosa cells of ovary express FSH receptors during follicular phase of the menstrual cycle
- granulosa cells are homologous to Sertoli cells of testis
Describe Luteinising hormone (LH). What are theca cells similar to?
Levels of LH vary during follicular and secretory phases of menstrual cycle
- during secretory: stimulates steroid hormone synthesis by corpus luteum
- 12hrs before ovulation, LH rises dramatically. this is stimulated by increasing rate of secretion of oestrodiol-17-beta
- theca cells are similar to Leydig cells in males
What is the function of (i) thecal cells (ii) granulosa cells?
(i) stimulated by LH to synthesise androstenedione
* * Andostenedione diffuses across BM**
(ii) stimulated by FSH to convert androstenedione to oestrodiol-17-beta
(i) what causes the LH surge? (ii) What does an increased plasma LH trigger? (iii) How are actions of LH mediated?
(i) dominant follicle secretes large amounts of oestrogen which acts on posterior pituitary => LH surge
(ii) triggers ovulation and formation of corpus luteum
(iii) via granulosa cells
How is secretion of oestrogens regulated?
By interrelated feedback loops
Mid-cycle shift from -ve to +ve feedback
- caused by upregulation of receptors (e.g. HnRH in ant pituitary) when oestrogen levels increased
- results in LH and FSH surge prior to ovulation
What is the effects of LH surge on ovarian function? (HINT: theres 5 points)
- The primary oocyte completes 1st meiotic division and undergoes cytoplasmic changes, prepare ovum for implantation (should fetrilisation occur). LH effects mediated by mediators from granulosa cells in response to LH
- Antrum size and blood flow to follicle increase markedly
- Granulosa cells begin releasing progesterone and decreasing oestrogen cycle, hence midcycle decrease in plasma oestrogen conc. and small rise in plasma progesterone just b4 ovulation
- Enzymes and PGs (granulosa cells) breakdown follicular-ovarian membranes. Weakened membranes rupture, oocyte and surrounding granulosa carried into surface of ovary
- Remaining granulosa cells of ruptured follicle (+theca cells) are transformed into corpus luteum, begins to release progesterone and oestrogen.
What are the 7 functions of granulosa cells
- nourish oocyte
- secrete chemical messengers which influence oocyte and theca cells
- secrete antral fluid
- site of action for oestrogen and FSH in control of the follicle development during early and middle follicular phases
- express aromatase, which converts androgen (from theca cells) to oestrogen
- secrete inhibin, which inhibits FSH secretion via action on pituitary
- site of action for LH induction of changes in oocyte and follicle culminating in ovulation and formation of CL
What occurs in the luteal phase? What happens if there is NO implantation?
Suppression of LH and FSH If no implantation: - hCG (human chorionic gonadtropin) doesn't appear in blood - CL dies - progesterone and oestrogen decrease - menstruation occurs and next MC begins
What are the essential controllers for MC?
Hypothalamus and anterior pituitary
BUT
events in ovary are the real sources of timing of the cycle
What occurs when there is enough oestrogen from the ovary?
LH surge induced
- > ovulation
- > when CL degenerates, decrease (oestrogen/progesterone) secretion
- > FSH and LH increase enough for new follicle growth
What occurs if progesterone remains high?
Levels of FSH and LH suppressed and ovulation not occur
e. g. occurs in pregnancy
- hCG produced by placenta maintains CL which continues to secrete progesterone
What are the effects of oestrogen? (HINT: there’s 11)
STIMULATES:
- growth of ovary and follicles
- growth of smooth muscle and proliferation of epithelial linings of repro tract
- external genitalia growth
- breast growth, ducts and fat deposition during puberty
- female body config development puberty - narrow shoulders, broad hips, fat deposit on hips and breasts
- fluid secretion from lipid (sebum)-producing glands (anti acne effect)
- bone growth and ultimate cessation of growth - protects against osteoporosis
- vascular effects
- feedback effects on hypothalamus and ant pituitary
- prolactin secretion but inhibits is milk action on breasts
- protects against atherosclerosis by effects on plasma cholesterol, BVs and clotting
What are the 8 effects of progesterone?
- converts oestrogen-primed endometrium to an actively secreting tissue suitable for implantation of embryo
- induces thick, sticky cervical mucus
- decreases contractions of fallopian tubes and endometrium
- decreases proliferation of vaginal epithelial cells
- stimulates breast growth, particularly glandular tissue
- inhibits milk-inducing effects of prolactin
- has feedback effects on hypothalamus and ant pituitary
- increases body temp
For OESTROGEN (i) what is it produced by? (ii) What does it cause (iii) what is its systemic effects?
(i) ovary
(ii) increases motility of uterine tube and causes proliferation of endometrium
(iii) development of secondary sexual characteristics
For PROGESTERONE (i) what is it produced by? (ii) What does it cause (iii) what is its systemic effects?
(i) ovary
(ii) causes secretory activity in endometrium
(iii) viscous cervical mucus
What causes the bleeding during of the menstrual phase?
Epithelial lining of uterus (endometrium) degenerates
it is part of ovarian follicular phase
What happens during the proliferative phase of the menstrual cycle?
Menstrual flow ceases and endometrium thickens under the influence of oestrogen (growth of underlying myometrium also occurs)
- synthesis of receptors for progesterone in endometrial cells also occurs
- lasts for about 10 days till ovulation and is part of ovarian follicular phase
Describe the histology during the proliferative phase. What is it dominated by?
Dominated by estradiol 17-beta
- repair of lining epithelium
- proliferation and thickening of stroma
- simple test tube shaped glands
- induction of synthesis of intracellular receptors for progesterone (primes uterus for later progesterone secretion)
- contractility and excitability of myometrium increases
What is the proliferative phase of the uterine cycle simultaneous with?
The follicular phase of the ovarian cycle
Describe the secretory phase.
Begins soon after ovulation, endometrium increases secretory activity under influence of progesterone
- endometrial glands become coiled, filled w. glycogen, BVs more numerous, enzymes accumulate in glands and connective tissue (this makes endometrium hospitable enviro for implantation and nourishment of developing embryo)
What does the secretory phase of uterine cycle coincide with?
The ovarian luteal phase
Describe the histology during the secretory phase. What is it dominated by?
Dominated by progesterone
- proliferation/thickening of stroma
- spiral arteries develop alongside complex, hacksaw shaped glands
- secretion in glands is rich in glycoprotein sugars and AA’s
- enlargement of myometrial cells but depressed overall excitability
What causes the ischaemic phase? Describe the histology of this phase.
Loss of steroid support
- constriction of spiral arteries
- ischaemia and collapse of endometrium
- separation of basal and functional layers
- functional layer shed as menstrual bleeding increases in neutrophils
What are the menstrual cycle major events during DAYS 1-5?
Oestrogen and progesterone low as previous corpus luteum is regressing therefore…
- endometrial lining sloughs
- secretion of FSH and LH released from inhibition and their plasma conc increase
- therefore several growing follicles are stimulated to mature
What are the menstrual cycle major events during DAY 7?
a single follicle (usually) becomes dominant
What are the menstrual cycle major events during DAYS 7 - 12?
- plasma oestrogen increases bcoz of secretion by dominant follicle therefore endometrium is stimulated to proliferate
- LH and FSH decrease due to oestrogen and inhibin negative feedback therefore degeneration (atresia) of non-dominant follicles occurs
What are the menstrual cycle major events during DAYS 12 - 13?
LH surge is induced by increasing plasma oestrogen, therefore…
- oocyte induced to complete its first meiotic division and undergo cytoplasmic maturation
- follicle stimulated to secrete digestive enzymes and PGs
What are the menstrual cycle major events during DAY 14?
ovulation mediated by follicular enzymes and PGs
What are the menstrual cycle major events during DAYS 15 - 25?
Corpus luteum forms and (under influence of low but adequate LH levels) secretes oestrogen and progesterone, increasing their plasma conc, therefore…
- secretory endometrium develops
- secretion of FSH and LH inhibited so that no new follicles develop
What are the menstrual cycle major events during DAYS 25 -28?
Corpus luteum degenerates (if implantation of conceptus doesn’t occur), therefore…
- plasma oestrogen and progesterone conc decrease so that endometrium beings to slough at conclusion of day 28 and a new cycle begins
Define (i) meno (ii) oligomenorrhoea (iii) metrorrhagia.
(i) menstruation
(ii) infrequent light periods
(iii) irregular bleeding
What is the main cause of dysmenorrhoea? What can this lead to?
Main cause = overproduction of PGs produced by endometrium in response to decrease in plasma oestrogen and progesterone
(PGs affect smooth muscle elsewere so pt may also experience N/V, headache)
- leads to excessive uterine contractions
What are the (i) causes (ii) effects of amenorrhoea (no periods)?
(i) PRIMARY:
- anatomical/congenital abnormality (underdevelopment or absence of uterus/vagina)
- genetic (Turner’s syndrome)
SECONDARY: pregnancy, lactation, exercise/nutrition, menopause, POS, latrogenic
(ii) Oestrogen deficiency symptoms (hot flushes, vaginal dryness)
Loss of bone mineralisation (reduction in peak bone mass attained, osteopenia/oesteoporosis
What are the characteristics of polycystic ovary syndrome? (HINT: there’s 6)
- hyperandrogenemia
- oligomenorrhea
- obesity (depends on ethnicity)
- hirsutism
- infertility
- enlarged cystic ovaries
What is the biochemical spectrum of PCOS? (HINT: there’s 4)
- elevated oestrogen from peripheral aromatase, or low from anovulation
- elevated free testosterone
- insulin resistance
- elevated anti Mullerian hormone
What therapy is used for PCOS?
Directed to relevant part of clinical spectrum:
- weight control
- cycle regulation e.g. contraceptive pill
- anti androgen therapy e.g. cyproterone acetate
- cosmetic hair removal
- ovulation induction
Describe Prolactin; (i) where is it synthesised and released? (ii) What is it controlled by? (iii) What modulates its secretion?
(i) anterior pituitary gland
(ii) hypothalamic prolactin inhib factor (PIF) which is shown to be dopamine (stress inhibits dopamine release which allows prolactin to rise) and reaches pituitary via blood supply
(iii) dopamine carried from neurosecretory cells in arcuate nucleus via hypophyseal portal system to ant pituitary where modulates prolactin secretion
What does hyperprolactinaemia result in? (HINT: there’s 2 things)
- inhibit FSH and LH leading to secondary amenorrhea
2. inappropriate lactation, libido loss
What does a pituitary tumour cause? How are they treated?
If blood supply to pituitary constricted, prevents PIF reaching ant pituitary. Pituitary tumours (macroadenoma) may constrict blood supply to pituitary and w/out PIF prolactin levels rise
Surgical approach via nasal cavity and sphenoid air sinus
What causes menopause? How can symptoms be treated?
Exhaustion of primordial follicles. Lack of follicular development leads to low oestrogen and elevated FSH owing to lack of -ve feedback
- symptoms treated with oestrogen replacement … HRT
What is POF? What tends to cause POF?
Premature Ovarian Failure - when menopause occurs in women at age 40
- idiopathic, autoimmune disorders, genetic disorders such as fragile X, chemo, radiation
What cells do pituitary tumours affect with regards to prolactin? What are they treated with?
Prolactinomas
- these secrete excessive prolactin and treated with dopamine agonist BROMOCRIPTINE or CABERGOLINE to relieve amenorrhoea and shrink tumour
Define sex determination? What is the process of sex differentiation?
Determination = The initiation of the male differentiation pathway by SRY
Differentiation - process by which male and females become structurally and functionally dissimilar
With sexual differentiation, what causes female differentiation?
If the developing testes (or ovaries) are removed
- the development of sexually differentiated gonads drives further sexual differentiation of reproductive tracts
- specialised structures of female repro tracts are needed to nurture the growing embryo and infant after birth
How many genes does the Y chromosome encode?
About 48 genes involved in skeletal growth, tooth development and a few for testes development
-it has a regulatory gene which controls testes development genes on X so indirectly controls testes formation
What is SRY?
(Sex determining region of the Y chromosome)
- it encodes a DNA binding protein (transcription factor) that regulates expression of genes on other chromosomes responsible for testes differentiation
The testes and ovaries form which 2 distinct cell types?
1, somatic mesenchyme
2. primordial germ cells
What is the genital ridge formed by?
Proliferation of surface epithelium and condensation of mesenchyme forming sex cords
Describe the role of primordial germ cells (PGCs) in gonadal differentiation.
Originate from epiblast and first identifiable at approx 2 wks in wall of yolk sac
- approx 10 PGCs appear but undergo mitotic divisions en route to genital ridge (2000 arrive)
- they migrate into genital ridge, driven by chemotaxis
- by 6wks they invade the genital ridges and become surrounded by primitive medullary sex cords
What happens if migration of PGCs fails to enter the genital ridge? What is the function of PGCs?
The gonads do not develop
- the PGCs have an inductive influence on development of the gonad into ovaries and testes but no role in driving sexual dimorphism
Describe gonadal differentiation in MALES.
Under SRY gene influence, primitive sex cords proliferate and penetrate medulla forming testis cords
- the cords become looped and contact w. ingrowing mesonephric tubule called Rete testis and PGCs reside in developing testis cords
- mesodermal cells become sertoli cells in cords and mesenchyme tissue in interstitial spaces develops into Leydig cells and starts to secrete testosterone by wk8
- testosterone then influences development of genital ducts and external genitalia
- by 20wks testis cords are horseshoe shaped, made of germ cells and Sertoli cells
Describe gonadal differentiation in FEMALES.
- due to absence of Y leads to degeneration of primitive sex cords (7th wk onwards)
- second set of cords form from mesenchyme (cortical cords) and by 12 wks these form distinct cell clusters around germ cells
- cells proliferate and surround each oogonium (germ cell) with epithelial layer of follicular cells, forming primordial follicles
- germ cells are required for formation of ovarian follicles
How are the genital ducts formed?
A 7-8 wks embryos acquire dual ductal systems that’re precursors to male and female internal genitalia
- wolffian (mesonephric) ducts give rise to male genital ductal system and Mullerian (paramesonephric) ducts give rise to female genital ductal system
- development path taken depends on hormones secreted by developing testes - not the ovary
Describe the development of the male internal genitalia.
- SRY acts in conjunction with other transcription factors (SOX9 and SF-1) to stimulate the differentiation of Sertoli and Leydig cells
- Sertoli then express anti-Mullerian hormone (AMH) which leads to regression of Mullerian ducts and prevents development of female structures
- Leydig cells start secreting testosterone which supports the development of Wolffian ducts and leads to virilisation
Describe the development of the female internal genitalia.
- absence of hormones means Wolffian ducts degenerate and Mullerian develop forming fallopian tubes
- WNT4 up-regulates DAX1, which inhibits the functions of SOX9, preventing male programme
- WNT4 also regulates the expression of other genes responsible for ovarian differentiation (most target genes haven’t been identified)
- oestrogen stimulates mullerian ducts to develop into female internal genitalia
(i) What forms the lower vagina? (ii) what forms the vaginal plate (iii) When is vaginal outgrowth complete?
(i) paramesonephric tubercle (a region called the sinovaginal bulbs)
(ii) 2 evaginations grow out from the pelvic side and proliferate
(iii) by 20 weeks and it expands around the end of the nucleus
What happens in females to the (i) medullary (ii) cortical cords?
(i) degenerate
(ii) develop
What happens in males to the (i) medullary (ii) cortical cords?
(i) develop
(ii) degenerate
What does development of the external genitalia depend upon?
The presence or absence of androgens
- in males androgens are present and in females they are not
What is Turner’s syndrome? How many people does it affect? What occurs?
45, XO affects 1 in 2-5 thousand female births
- oocytes degenerate since two “X” chromosomes needed for full ovarian development…streak ovary
- deficiency in ovarian steroids => lack of 2ndary sex characteristics and infertility
- short stature, webbed neck and skeletal deformities
- infertile, amenorrhoea
What is Klinefelter’s syndrome?
47, XXY
- develop male phenotype
- low testosterone but high oestrogen
- incomplete virilisation and breast enlargement
- small testes with decreased spermatogonia
- infertile
Describe Pseudohermaphroditism, a sexual disorder differentiation (DSD).
- have gonads appropriate to genotype but external genitalia of opposite sex
- abnormality in endocrine signalling between gonads and developing tissues
- one such syndrome is AIS (previousl called etsticular feminisation syndrome) with 46 XY karyotyoe
Describe Androgen-Insensitivity Syndrome, a sexual disorder differentiation (DSD).
Testes intially normal but tissues lack/have dysfunctional androgen receptor so unable to respond to testosterone
- Wolffian ducts degenerate w/out support of androgens (unable to sense the signal)
- testes secrete normal amounts of AMH so female ducts degenerate, NO DUCTs at all
- female external genitalia develops but have undescended testes (these are pre cancerous, usually need to get them removed)
Describe Congenital Adrenal Hyperplasia, a sexual disorder differentiation (DSD).
Genotype = XX and ovaries develop but feta adrenals are overactive
- secrete large amounts of steroid hormones, some of which have androgenic action
- causes development of Wolffian ducts and formation of male external genitalia
- no AMH is secreted so female ducts persist, therefore 2 ductal systems present
When the testis migrates from the posterior abdominal wall to anterior into the scrotum, what does it take with it?
- the vas deferens, the testicular vessels and a peritoneal pouch (processus vaginalis) which after birth should lie as a closed potential space around the testis (tunica vaginalis)
When the layers of the abdominal wall are drawn along with the testis what does; (i) the 3 layers of spermatic fascia form? (ii) what does transversalis fascia become? (iii) the parietal peritoneum do?
(i) forms the spermatic cord
(ii) continues as internal spermatic fascia
(iii) loops down the developing spermatic cord as the processus and tunica vaginalis
With regards to the testis, (i) what do the transversus abdominis and internal oblique combine to form? (ii) What does the external oblique form?
(i) the cremasteric (middle layer) fascia and muscle
(ii) external spermatic fascia
Name the (i) 3 arteries (ii) 3 tubes (iii) 3 nerves which are within the spermatic cord.
(i) 1. testicular artery (from Ao @ L2) and pampiniform plexus
2. artery to vas (from inf vesical)
3. cremasteric artery and vein (from inf epigastric to supply cremasteric fascia and muscle)
(ii) 1. vas
2. lymph from testis (to para-aortic nodes)
3. processus vaginalis (obliterated tube) - which may or may not close off and lead to cysts/hydrocele
(iii) 1. genital branch of genitofemoral to supply cremaster muscle
2. sympathetic (efferent and afferent to testis) - derived from lesser splanchnic nerve T10 and 11
3. Ilio-inguinal (L1) to medial thigh
What is the function of the scrotum?
It suspends the testes outside the body, with the left lower than the right
What is the scrotum lined by? Describe in detail.
Lined by fascial layers which are the same as those which form the spermatic cord
- the layers surround and invest the testis and combine in midline to form scrotal septum
What is dartos fascia?
A combination of Colles’ perineal fascia and Dartos muscle
What is the (i) nerve (ii) blood and (iii) lymph supply of the scrotum?
(i) ANT 1/3 = ilio-inguinal, genitofemoral
POST 2/3 = S2,3 via scrotal branches of perineal branches of pudendal nerve
(ii)ANT 1/3 = deep and superficial ext pudendal of femoral
POST 2/3 = branches of int pudendal branch of int iliac posteriorly
Venous drainage mirrors arterial: external pudendal to great saphenous anterior and int pudendal posterior
(iii) Superficial inguinal nodes
Where does sperm go before it reaches the epididymis?
Pass from the tubules to the rete testis in its mediastinum, then via efferent ductules to the epididymis
Where do the testes lie? What is their function?
in the scrotum, with the left lower than the right
- oblique, upper pole ant-lat, lower pole post-med
- they produce sperm and testosterone
What is the epididymis?
is post-lat and has a head body, and tail becoming vas
What are the clinical problems of scrotal pain?
Appendix testis (hyatid of Morgagni), paramesonephric
Appendix epididymis, mesonephric
Torsion, rotate on pedicle (necrose)
What is the significance of the tough capsule of tunica albuginea?
It maintains internal pressure to help transport of sperm
Each testis has a series of coats or tunics. Describe them. (HINT: there’s 3)
- Vaginalis w. visceral and parietal layers, potential space for movement of testis (hydrocele); sinus of epididymis
- Albuginea, tough, fibrous (int pressure to help sperm transport) forms mediastinum and septae
- Vasculosa w. branches of testicular vessels
What is the blood, lymph and nerve supply of the testes?
Testicular artery (Ao L2) - plus anastomosis with cremasteric artery and artery to vas
- testicular vein starts as pampiniform plexus (varicocele) which coalesces in inguinal canal to form testicular veins; left drains to L. renal, R. to IVC
- lymph = para-aortic nodes
- nerves = symp T10,11 (peri-umbilical)
Describe the vas deferens, explain its location/route it takes in the body.
- thick-walled cord like tube that carries sperm from testis and epididymis
- lies post to testis (medial to epididymis), leaves scrotum + passes throguh abdo wall w/in spermatic cord in inguinal canal.
- emerges into abdo lateral to inf epigastric artery, then lies on lateral wall of pelvis medial to pelvic vessels; before turning medially to pass anteromedial to ureter and join w. duct from seminal vesicle to form ejaculatory duct that passes through prostate and into urethra
What is the blood supply of the vas deferens?
From the artery to the vas
- usually inf vesicle
Where are the seminal vesicles located? What is their function?
Left and right - lie just above prostate gland sandwiched between bladder and rectum
- they secrete seminal fluid to nourish sperm
Q on urethra
-
What are the 2 major compartments of the testes? What is the significance of these compartments?
- SEMINIFEROUS TUBULES
- approx 250m total length
- developing germ cells
- Sertoli cells - INTERSTITIAL SPACES
- Leydig cells (synthesise androgens)
- blood and lymph vessels
Both compartments separate “Blood-testis barrier”
- prevents immune reaction to spermatozoa and separates fluids of different composition
The production of mature spermatozoa from undifferentiated germ cells (PGC) occurs in 3 stages, what are the 3 stages?
- Mitotic proliferation
- Meiotic (reduction) division
- Cell modelling (spermiogenesis)
When does the first division to release of spermatozoa occur?
74 days
How does spermatogenesis occur timewise?
In waves, every 16 days
What happens at the end of sperm differentiation? (HINT: there’s 3 things)
- cytoplasmic links are broken
- spermatozoa released into tubule lumen
- sperm virtually immobile
During sperm maturation, what does the fluid secreted by Sertoli cells do?
It flushes developing spermatids from seminiferous tubules, through the rete testis into the epididymis
- capacity for motility by time they reach tail of epididymis
- motility suppressed by epididymal fluid
What is capacitation? When does it occur? What is the process?
oocytes will not fertilise with sperm until they have undergone capacitation
- normally occurs in female repro tract w/in 2-6hrs
- glycoprotein coat gained in epididymis is stripped resulting in hyperactivation (increased flagellar beats) and the head acquires the capacity to initiate the acrosome reaction
What is sub-fertility?
-
What is (i) oligozoospermia (ii) azoospermia (iii) asthenozoospermia (iv) teratozoospermia (v) antisperm antibodies?
(i) low sperm count (less than 20x10^6/ml)
(ii) absence of sperm in the ejaculate
(iii) low sperm motility (less than 50% moving)
(iv) high proportion of abnormally-shaped sperm
(v) abnormal immune response to sperm
What 4 hormones do testes synthesise?
- Testosterone (steroid) by Leydig cells
- in some tissues do not exert direct effects, but are conevrted to dihydrotestosterone or oestrogens - Oestrogens (steroid) by Sertoli and Leydig cells
- Inhibins (polypeptides) by sertoli cells - feedback loop to control hormone levels
- Oxytocin (polypeptide) by Leydig cells - contraction of smooth muscle of genital tract
What is the role of testosterone?
Essential for spermatogeensis
- if production prevented spermatogenesis caeses
- blocked when primary spermatocytes enter meiotic prophase
- if blood [testosterone] is low then fewer stem cells will begin cell division but the whole process will still take 74 days
What is the role of the pituitary gland and hypothalamus?
Ant pituitary controls testicular function by secreting the gonadotrophins from the gonadotroph cells
- pituitary gonadotrophins in turn are controlled by the hypothalamus, which secretes GnRH
What is secretion of hormones by the hypothalamus, ant pituitary and testes regulated by?
Complex feedback loops
What hormones are produced in the ANTERIOR pituitary gland?
- Gonadotrophs
- basophilic cells secrete LH and FSH (glycoproteins)
- most cells secrete one or other but some secrete both - Lactotrophs
- acidophilic cells secrete prolactin (polypeptide)
What hormones are produced in the POSTERIOR pituitary gland?
Neurosecretory neurones
- secrete arginine vasopressin (AVP) and oxytocin (peptides)
How is gonadotrophin secretion controlled?
LH and FSH secretion is controlled by GnRH which is released into the portal blood in pulses every hour
- it must be pulsatile or it is ineffective
What does (i) high or (ii) low GnRH pulse amplitude and frequency stimulate?
(i) stimulates LH synthesis and secretion
(ii) stimulates FSH synthesis and secretion
What is the importance of LH? What happens if LH secretion is too low?
Leydig cells in testes have receptors for LH
- stimulates synthesis and secretion of testosterone
- if LH secretion is too low, testosterone is low and spermatogenesis halts
What is FSH needed for? What cells does it act upon?
Required for maximum sperm production and acts on Sertoli cells
What is the functions of FSH on sertoli cells? (HINT: there’s 7)
- increases RNA and protein synthesis
- increases energy metabolism
- increased inhibin secretion
- increased cAMP
- increased ABP secretion
- increased fluid secretion
- increased androgen receptors (=> increased FSH receptors)
What is the (i) false pelvis (ii) true pelvis?
(i) posterior abdo wall, iliacus covering iliac bones
(ii) inferior to arcuate lines on iliac bones, equivalent to the pelvic brim or pelvic inlet
What lines the pelvic lateral wall?
Obturator internus
What is the perineum? What does it contain?
Diamond shaped pudendal region below the pelvic floor which contains genitalia and urethra anteriorly, and the anal canal and ischioanal fossae posteriorly
What compartments is the perineum divided into? What causes this compartmentation?
Deep and superficial
- by perineal membrane
What makes up the pelvic brim/inlet?
pubic symphysis and crest; superior pubic ramus or pectineal line; to arcuate line of hilum; to SI joint, sacral ala and promontory (S1)
What makes up the pelvic outlet?
pubic symphysis and ischiopubic ramus to ischial tuberosity; to sacrotuberous ligament and sacrum and coccyx (hugely important in childbirth)
How does the female pelvis differ from males? Why is this?
- female pelvis must accommodate childbirth so it is lighter, more rounded and wider, with an oval inlet
- male pelvis is heavier with a heart shaped inlet and an outlet narrowed by a more acute sub-pubic angle and encroached upon by the ischial spines
Where do the sacrospinous and sacrotuberous ligaments lie? What is their function?
SACROSPINOUS: from ischial spine to adjacent sacrum and coccyx
SACROTUBEROUS: from ileum, sacrum and coccyx to ischial tuberosity
- they enclose the greater and lesser sciatic foramina
Describe and explain what muscles make up the pelvic walls.
- PIRIFORMIS from sacrum to greater trochanter forms posterior pelvic wall and divides the greater sciatic foramen
- OBTURATOR INTERNUS from obturator memrbane and adjacent bone, passing to greater trochanter, forms, the lateral pelvic wall with its oevrlying obturator fascia that gives origin to pelvic floor muscle (levator ani)
What is levator ani divided into?
- Iliococcygeus (supplied by direct branches from S3,4)
- Pubo-coccygeus, subdivided into pubo -rectalis (post), -vaginalis or prostaticus, -urethralis (anteriorly around UG opening) also suppled by direct branches from S3,4
The levator ani forms a bowl or funnel beneath which is the perineum. Why is said ‘bowl’ hugely important?
For support of the viscera and maintenance of urinary and faecal continence
- weakness may cause incontinence and prolapse
What do each side of the levator ani do when they meet in the midline?
They form the Anococcygeal raphe (body and ligament) and Perineal body or Central tendon of perineum just ant to anal canal and posterior to the vagina in females
What is the function of the levator ani muscles?
- support pelvic viscera
- makes recto-anal angle more acute aiding rectal continence
- augments ext anal and urethral sphincters
- forms a vaginal sphincter
Where are obturator lymph nodes found?
on the lateral pelvic walls, alongside the obturator NVB
What is the somatic nerve supply of the pelvis?
Ventral rami of spinal nerves L4,5 S1-4 emerging from anterior sacral foramina to form lumbosacral nerve
Pudendal nerve S2-4 to pelvic floor and voluntary sphincters
Plus direct branches from S3 and 4 to pelvic floor muscles
What is the route the pudendal nerve takes in the pelvis?
Passes out of the greater sciatic foramen and into the buttock
- nerve then curves posterior to ischial spine, sacrospinous ligament and coccygeus to run forwards into the perineum, below levator ani
What is the autonomic nerve supply of the pelvis?
Sympathetic trunks bilateral and extending into the pelvis to give Sacral Splanchnics
- superior hypogastric sending branches to the pelvic plexuses
What is the pelvic (inf hypogastric) plexus?
- derived from superior hypogastric plexus that descends over sacrum and is from the pre-aortic plexus therefore essentially carrying fibres from the lesser and least splanchnic nerves T10,11,12
- it is ‘boosted’ by the sacral splanchnics and is afferent and efferent
What are the pelvic splanchnics? Describe them.
- are afferent and efferent parasymp fibres derived from S2-4
- they join the pelvic plexus, which is now BOOTH parasymp (cholinergic) and sympathetic (adrenergic)
What is the pelvic plexus susceptible to?
Surgical injury
Describe the internal iliac artery, what does it branch from? what does it divide into? what does it supply?
- branches from common iliac opposite SI joint at level of L5 disc
- divides into anterior and posterior trunks
- supplies buttocks and medial thigh, posterior pelvic and abdominal walls, pelvic viscera and the perineum
- its gluteal branches contribute to important anastomoses around the hip that may form a collateral circulation for the lower limb
Describe the internal iliac vein, what does it drain? where does it drain into?
- drains equivalent areas to artery and joins ext iliac to form common iliac, that meets its opposite number to form the IVC
- most pelvic viscera have an extensive venous plexus that drains to the int iliac or int pudendal vein
What is the anal canal a site of?
porto-systemic anastomosis
Where is the bladder located within the body?
anteriorly in the pelvis
- immediately behind the pubic bones in the midline and sits on pelvic floor
What are the surfaces of the bladder?
(Postero)-Superior
Infero-lateral x2
Base (trigone)
Describe the bladder neck, ensuring to mention differences in the neck between males and females.
- lies 3-4cm behind the pubic symphysis
- males have a preprostatic internal sphincter to prevent semen backflowing into bladder
- females, the neck is above the pelvic floor so that the pressure of pelvic organs (as well as levator ani) contribute to urinary continence
What supports the bladder? (HINT: thickening of fasica - ligaments)
Fibromuscular and fascial condensations from bladder, prostate and urethra to pubis, lateral pelvic walls, rectum and sacrum support the bladder e.g. puboprostatic (male) and pubovesical (female) ligaments
In males, what relations are found (i) superior and at the (ii) base of the bladder?
(i) peritoneum, ileum, sigmoid (on mesenteries)
(ii) restrovesical pouch and septum, rectum, vas deferens, seminal vesicle
What is the vascular supply of the bladder?
ARTERIES: supplied by arteries to adjacent organs - int iliac, ant. trunk, sup and inf. vesical (inf vesical replaced by vaginal in female)
VEINS: plexus on inferolateral surface of bladder and drains to int iliac. May also drain to prostatic plexus (which then goes to int iliac but may communicate with int vertebral venous plexus)
What is the (i) lymph drainage (ii) nerve supply of the bladder?
(i) 3 plexuses - mucosa, muscle, serosa. Mainly to nodes on ext iliac artery
(ii) from anterior part of pelvic plexus that passes rectum to reach bladder
- detrusor has profuse, mainly PS supply S2,3,4 pelvic splanchnic nerves
- symp to preprostatic sphincter as well as some to detrusor derived from T12, L1, 2 then via pelvic plexus
What can injury to the bladder and urethra (in a particular way) lead to?
urinary extravasation “trapped’ by Scarpa’s and Colles’ perineal fascia
- limits spread of urine and bruising to lower abdo, upper thighs, penis and scrotum but no further posteriorly as Colles’ perineal fascia fuses to Perineal body
Describe the preprostatic urethra.
1-1.5 cm from bladder =to upper aspect of verumontanum (colliculus seminalis)
- surrounded by genital, preprostatic or internal sphincter; plus smooth muscle from bladder wall that passes into urethra and also into prostate
Describe the prostatic part of the male urethra.
closer to the anterior aspect of the prostate and emerges anterior to the apex
What is the function of the prostate? What does it look like? Name the surfaces of the prostate.
Genital function rather than urinary
- slightly acidic seminal secretion: acid phosphatase, amylase, PSA, fibrinolysin
- fibromuscular and glandular, upside down pyramid in tough capsule and supported by puboprostatic ligaments
- base, apex, posterior suface next to Denonvillier’s fascia and rectum, anterior surface to pubic symphysis and arch, 2 inferolateral surfaces to pelvic floor
Describe the (i) lobes (ii) zones of the prostate.
(i) lobes only in foetus, 2 lateral and a median may be described in adult. Anterior part of gland is fibromuscular only
(ii) 1. TRANSITION 5% around urethra, anterior to ejaculatory ducts (BPH)
2. CENTRAL 25% behind transition, contains ejaculatory ducts
3. PERIPHERAL 70% around transition and central (Carcinoma)
Where are the seminal vesicles located? What are their function? How/what forms the ejaculatory duct?
- lie just above prostate gland, sandwiched between bladder and rectum. Secrete seminal fluid to nourish sperm
- dilated ampullary end of vas unites with duct from seminal vesicle to form the ejaculatory duct which passes through the prostate to enter the urethra
What is the arterial supply of the prostate and urethra? (Note if any differences in gender)
MALE: prostate gland and prox urethra = inferior vesical
FEMALE: urethra = vaginal and internal pudendal
What is the venous supply of the prostate and urethra? (Note if any differences in gender)
MALE: urethra and prostate = vesical and prostatic plexuses which drain to int.iliac. There are communications w. valveless veins of vertebral plexuses facilitating tumour spread
FEMALE: urethra = veins equivalent to arterial supply => vaginal and int. pudendal veins
What is the (i) lymphatic drainage (ii) nerve supply of the proximal urethra and prostate?
(i) mainly to internal iliac nodes
(ii) derived from S2,3,4
- pudendal nerve and its perineal branches (somatic m&s)
- p’symp pelvic splanchnics to pelvic plexus (afferent+efferent)
- symp from L1,2 via superior hypogastric plexus to pelvic plexus (a+e)
Explain in detail the storage of urine. Ensuring to explain the autonomic stretch reflex (and when it prevails)
- detrusor essentially under PS control, which is counteracted via sympathetics to allow bladder musculature to relax so bladder fills w/out any increase in tension
- when full, stretch receptors send signals via PS pelvic splanchnics to S2,3,4 where they trigger reflexes in PS efferents to cause detrusor contraction = autonomic stretch reflex
- prevails in untrained infant so that the bladder empties automatically when full
How is it that we in adults prevent the autonomic stretch reflex occurring and hence not being incontinent?
- with training, afferents (sensory) ascend up SC to trigger cortical inhibition in frontal lobe which superimposes cortical control on micturition centre in ponse that in turn usually controls preganglionic, parasymp neurones at S2,3,4
How is it, when in an appropriate place, that we are able to empty our bladders by micturition?
1y neurones stimulate 2y neurones in bladder wall ganglia => detrusor contraction
- simultaneous relaxation of ext.urethral sphincter via pudendal nerve (S2,3,4) and contraction of abdo wall
- sensation of urine in the urethra maintains the relfex
What can result in us returning to the automatic, infant reflex (when bladder empties immediately when full)?
- cord transection above S2
- loss of cortical control following CVA
What happens if the sacral segments 2,3,4 are destroyed?
detrusor is paralysed and the bladder distends until there is overflow incontinence
What is the sperm like in the seminiferous tubules? Where does it go?
- it is in a large volume of fluid
- washes sperm into rete testis, vasa efferentia and epididymis
What happens if the vasa efferentia (efferent ductules) are blocked?
seminiferous tubules and testis swell
How long does it take sperm to travel through vasa efferentia and epididymis?
6 to 12 days
What are the changes to the following to sperm in epididymis; (i) conc. (ii) sperm modelling (iii) metabolism (iv) motility (v) membrane?
(i) 1-fold (5x10^7/ml enter 5x10^9 leaving)
(ii) nuclear condensation and acrosome shaping completed. Cytoplasmic droplet shed
(iii) increased dependence on ext.fructose for glycolytic energy
little oxidative metabolsim
increased intracellular pH
(iv) increased disulphide bridges between proteins in outer dense fibres of tail
[cAMP] rises in tail
acquires capacity for forward movement
(v) composition of various components change
Where is seminal fluid formed mainly? What is its function? What can it be exploited by?
- formed in accessory glands
- provides nutrients etc to protect spermatozoa
- exploited by infectious agents e.g. Hep B, HIV
What is the (i) conc. (ii) main source of spermatozoa in the ejaculate?
(i) 50 - 150/nl
(ii) testes
What is the (i) conc. (ii) main source and (iii) function of fructose in the ejaculate?
(i) 8 - 37 mM
(ii) seminal vesicle and ampulla
(iii) anaerobic energy metabolism
What is the (i) conc. (ii) main source and (iii) function of inositol in the ejaculate?
(i) 1 - 3 mM
(ii) testes and epididymis
(iii) osmotic blast
What is the (i) conc. (ii) main source and (iii) function of citric acid in the ejaculate?
(I) 5 - 73 mM
(ii) prostate
(iii) Ca2+ chelator - depresses semen coagulation
What is the (i) conc. (ii) main source and (iii) function of glycerylphosphorylcholine in the ejaculate?
(i) 2 - 3 mM
(ii) epididymis
(iii) used a source of choline in phospholipid metabolism
What is the (i) main source (ii) function of acid phosphatase in the ejaculate?
(i) prostate
(ii) cleaves choline from glycerophosphorylcholine
For the penis to introduce semen into the female genital tract, what must it be like? What does this involve?
It must be turgid
- haemodynamic changes that involve the corpora cavernosa
What are the ways in which arousal in the male can be produced?
- Erotic psychological stimuli (e.g. visual, olfactory)
- Tactile stimuli at level of the brain
- Tactile stimuli can also mediate local spinal reflexes
What is the function of (i) sympathetic (ii) parasympathetic activity on the penis?
(i) lower thoracic and lumbar spinal segments, maintains flaccidity
(ii) control centre in sacral spinal segments, increased activity produces turgidity
What mediates the erection reflex? Describe what occurs for the erection reflex to occur.
- erection centre in sacral spinal cord
- dilation of arterioles to c. cavernosa and c. spongiosum
- closing of arteriovenous shunts that normally bypass the c.cavernosa
- probably also occlusion of veins draining penis
How does parasympathetic stimulus cause relaxation of vascular smooth muscle?
- p’symp action involves ACh acting on vascular endothelial cells
- indirectly triggers release of NO
- NO causes relaxation of vascular smooth muscle
What are the 4 reasons for failure to obtain an erection?
- mechanical damage to c.cavernosa
- obstruction of arteries to the penis
- drugs that block p’symp actions
- physiological factors
What nerve supply mediates ejaculation? What are the 2 phases of ejaculation? Describe them.
- sympathetic mediated with ejaculatory centre in lower thoracic and lumbar SC, signals to ducts of genital tract and to bulbocavernosus muscle at base of penis
1. EMISSION PHASE - smooth muscle contraction in walls of genital tract and expels semen into urethral bulb
2. EXPULSION PHASE - rhythmic contractions of penis and bulbocavernosus muscle to eject semen in spurts
note that ejaculation is normally followed by a refractory phase of 10 mins to an hour
Describe the composition of ejaculate.
It is not uniform
- first component = prostate which is rich in acid phosphatase and citric acid
- second component = vas deferens which is rich in spermatozoa
- third component = seminal vesicle which is rich in fructose
What are 3 frequent disorders of the prostate?
Benign prostatic hyperplasia
Carcinoma
Prostatitis
What is benign nodular hyperplasia?
COMMON
- non neoplastic as it associated with hormone imbalance
- nodular hyperplasia of glands and stroma but is not premalignant
- obstructs urine flow, is associated with infection and is treatable
Describe benign prostatic hyperplasia; what is it? what does it cause? what does it involve?
- involves transition zone of prostate plus peri-urethral glands
- nodules of glands and stroma
- compress and elongate urethra
- involvement of peri-urethral zone interferes with urethral sphincter
- causes urinary retention; acute = painful, chronic = painless, more gradual
What are the various complications of BPH?
- bilateral hydronephrosis
- bilateral hydroureter
- infection, renal failure, calculi, septicaemia
- muscular hypertrophy of bladder
- bladder diverticulum
- trabeculation
- compression of urethra
- nodular enlargement of prostate gland
What is a precursor for prostate carcinoma?
prostatic intraepithelial neoplasia
How do you classify the spread of a prostate carcinoma?
GLEASON SCORE - differentiation and distribution
Stage TN
- direct, via lymphatics or via blood
What does a pt with a prostate carcinoma present with?
- urinary symptoms
- incidental finding on rectal examination
- bone metastases
- lymph node metastases
What are the challenges of prostate carcinoma?
Latent
In situ
Indolent - treat less aggressive, more conservative or not at all
Aggressive
Screening - high PSA tends to be associated with metastatic prostatic disease UNLESS you have prostatitis
- low PSA may be inflammation, infection, prostatic cancer
- normal PSA you might still have prostatic cancer
How is a prostate carcinoma diagnosed?
- imaging (USS, MRI, isotope bone scan)
- cytoscopy
- biochem PSA
- haematology (bone marrow involvement)
- biopsy
What treatment is used for prostate carcinoma? (HINT: there’s 5)
- Oestrogens
- GnRH analogues
- Orchidectomy
- Radiotherapy
- Radical prostatectomy
What are 2 types of congenital malformations of the penis and scrotum?
Hypospadias - urethral opening on inf. aspect
Epispadias - often accompanied by abnormal development of bladder
What are the 2 types of tumours of the penis and scrotum? Describe them both.
- Bowen’s disease (non-invasive intraepithelial carcinoma)
- occurs anywhere on penis, erythematous patch, keratotic surface, raised red plaque - Invasive squamous cell carcinoma
- rare in UK, HPV, glans penis or inner aspect of prepuce, nodule or plaque
- metastasises to inguinal nodes
What are the 2 types of inflammation and infection you can get of the penis and scrotum?
Phimosis
Paraphimosis
Who are people at high risk of developing carcinoma of the scrotum? What is it like? What can it result in/spread to?
1755 percival potts
- chimney sweeps and arsenic workers
- nodular ulcerated mass
- causes squamous cell carcinoma to inguinal nodes, possible ulceration
What are the possible problems that can arise in the urethra?
- Obstruction
- congential valves (rare in men)
- rupture
- stricture - Urethitis
- gonococcal or non gonococcal - Rupture
- Tumours
- warts or transitional cell carcinoma
What are the symptoms/signs of gonococcal urethitis?
It is common, painful everytime you pass urine, pus may come out of penis
- prostatitis
- epididymitis
- acute urethitis and later urethral stricture
Where does lymph of superficial testes drain to?
Para aortic lymph nodes
What are the various types of testicular lesions?
- Developmental and Cystic lesions
- undescended testis (cryptorchidism)
- hydrocoele or haematocoele - Orchitis
- mumps orchitis
- idiopathic granulomatous orchitis
- syphillic orchitis - Testicular tumours
Who do testicular tumours tend to affect? What is a predisposing factor?
- young men (commonest tumours under 35) and old men
- undescended testis = predisposing (x10 risk)
What are the 3 main types of testicular tumours? What is their incidence
Teratoma 32%
Seminoma 40%
Lymphoma 7% (typically older men)
How do testicular tumours present?
- painless unilateral enlargement
- secondary hydrocoele
- symptoms from metastases
- retroperitoneal mass
- gynaecomastia
What is a seminoma tumour? Describe its origin, peak incidence and types.
- commonest testicular tumour
- germ cell origin
- peak incidence 30 to 50
- types = classical, spermatocytic, anaplastic or combined
What is a teratoma tumour? Describe its origin, incidence, types and useful markers.
- germ cell origin
- peak = 20 - 30 yrs
- more aggressive than seminoma (almost always malignant)
- types = differentiated, intermediate, undifferentiated, trophoblastic
- beta-hCG and alpha-fetoprotein = useful markers
What is a useful tumour marker for teratomas?
AFP
- shows if you have a recurring disease
What are 4 types of non-germ cell tumours?
- malignant lymphoma (elderly men)
- leydig cell tumour (may produce androgens)
- sertoli cell tumour
- metastatic tumours
What are the causes of male infertility?
- Endocrine disorders
- GnRH deficiency
- oestrogen excess - Testicular lesions e.g.
- cryptorchidism
- abnormal spermatogenesis - Post-testicular lesions
- obstruction of efferent ducts
What are any problems that can arise within the epididymis and spermatic cord?
- congenital abnormalities
- epididymal cysts and spermatocoeles
- varicocoele
- torsion of spermatic cord and testis
- inflammatory lesions (epididymo-orchitis)
- Tumours (rare)
