57. Reproduction Flashcards
Which cells within the testes does LH stimulate and what does it make these cells produce?
Leydig Cells –> they are stimulated to produce testosterone
Which cells within the testes does FSH stimulate and what does it makes these cells produce?
Sertoli cells (in the seminiferous tuules) –> they are stimulated to produce sperm and inhibin A and B
What does inhibin inhibit?
Pituitary FSH secretion
What are the three phases of the menstrual cycle?
Follicular Phase Ovulation Luteal Phase
What does LH stimulate in the ovaries?
Oestradiol and progesterone production
What does FSH stimulate in the ovaries?
Follicular development and inhibin production
What effect does oestrogen have on the HPG axis in the follicular phase of the menstrual cycle?
It has a negative feedback effect – inhibits FSH and LH
What does the leading follicle develop into by around day 10?
Graffian Follicle
Once oestrogen reaches a certain level it switches to positive feedback. How does it do this?
It increases the GnRH secretion It increases LH sensitivity to GnRH
Define infertility.
Inability to conceive after 1 year of regular unprotected sex
What is primary gonadal failure and what effects does it have on the HPG axis?
It is a problem with the gonads The testes/ovaries don’t produce enough testosterone/oestrogen so there is no negative feedback on the HPG axis meaning that you get high GnRH, high LH and high FSH.
Describe the levels of the different hormones in the HPG axis in the case of hypothalamic/pituitary disease causing infertility.
Low GnRH Low FSH Low LH
State some of the clinical features of male hypogonadism.
Loss of libido Impotence Small testes Decreased muscle bulk Osteoporosis (testosterone has anabolic action in the bone)
State 5 causes of male hypogonadism.
Hypopituitarism Kallmann’s Syndrome (anosmia + low GnRH) Illness/underweight Hyperprolactinaemia Androgen receptor deficiency (RARE)
State some congenital and acquired causes of primary gonadal disease.
Congenital: Klinefelter’s Syndrome (XXY) Acquired: Testicular torsion, chemotherapy
What are the main investigations for male hypogonadism?
LH, FSH and testosterone (if all are low –> MRI to check pituitary problem) Prolactin Sperm count (azoospermia – absence of sperm in ejaculate; oligospermia – reduced number of sperm in ejaculate) Chromosomal analysis (check for Klinefelter’s)
What is given to all patients with hypogonadism?
Testosterone to increase muscle bulk and protect against osteoporosis
How do you restore fertility in someone with hypothalamic/pituitary disease?
Subcutaneous gonadotrophin injections – stimulates testosterone release
What is the treatment for hyperprolactinaemia?
Dopamine agonists – bromocriptine and cabergoline Pituitary surgery (though this is rarely used because medicine normally works well)
State some endogenous sites of production of androgens.
Interstitial leydig cells in the testes Adrenal cortex Ovaries Placenta Tumours
What are the main actions of testosterone?
Development of the male genital tract Maintains fertility in adulthood Control of secondary sexual characteristics Anabolic effects (muscle, bone)
Testosterone is heavily plasma protein bound and it can be converted to other hormones in various tissues. State two products that testosterone can be converted to and the enzymes responsible for these conversions.
Converted by 5-alpha-reductase to dihydrotestosterone (DHT), which acts on androgen receptors Converted by aromatase to 17-beta-oestradiol, which acts on oestrogen receptors
What type of receptors does DHT and E2 act on?
Nuclear receptors
What are the clinical uses of testosterone?
Lean body mass Muscle size and strength Bone formation and bone mass Libido and potency NOTE: it does NOT restore fertility
What is the difference between primary and secondary amenorrhoea?
Primary Amenorrhoea = failure to develop spontaneous menstruationby the age of 16 years Secondary Amenorrhoea = absence of menstruation for 3 months in a woman who has previously had cycles
What is oligomenorrhoea?
Irregularly long cycles
List some causes of amenorrhoea.
Pregnancy Lactation Ovarian failure: Premature ovarian insufficiency Oophorectomy Chemotherapy Ovarian dysgenesis (Turner’s Syndrome (45 X)) Hypothalamic/pituitary disease Kallmann’s syndrome Low BMI Post-pill amenorrhoea (if you use the pill for a long time and then go off it, it could take a while for the periods to return) Hyperprolactinaemia Androgen excess (gonadal tumour)
State some features of Turner’s syndrome.
Short statue Cubitus valgus (forearm is angled away from the body to a greater degree than normal when fully extended) Gonadal dysgenesis
State some investigations for amenorrhoea.
Pregnancy test LH, FSH and Oestradiol Day 21 Progesterone (this should be high (showing that you’re ovulating) because progesterone rises in the second half of the menstrual cycle) Prolactin Thyroid function test (both hyper- and hypothyroidism can cause problems with the menstrual cycle) Androgens (testosterone, androstenedione, DHEAS) Chromosomal analysis
What are the implications on health of polycystic ovarian syndrome (PCOS)?
Increased cardiovascular risk Insulin resistance (diabetes)
What are the criteria for diagnosing PCOS?
They must have at least 2 of the following: Polycystic ovaries on ultrasound scan Clinical/biochemical signs of androgen excess Oligoovulation/anovulation
What are the clinical features of PCOS?
Hirsuitism Menstrual irregularities Increased BMI
Describe the treatment for PCOS.
METFORMIN – insulin sensitiser CLOMIFENE – anti-oestrogenic effects in the hypothalamo-pituitary axis – binds to oestrogen receptors in the hypothalamus thereby blocking the negative feedback –> increased GnRH and gonadotrophin secretion GONADOTROPHIN THERAPY as part of IVF treatment
What hypothalamic hormone has a stimulatory effect on prolactinrelease?
Thyrotrophin releasing hormone (TRH)
What effect does hyperprolactinaemia have on the HPG axis?
It reduces GnRH pulsatility so that it is released basally all the time rather than in regular pulses It will switch off gonadal function via LH actions on the ovaries and testes
State some causes of hyperprolactinaemia.
Dopamine antagonists (anti-emetics and anti-psychotics) Prolactinoma Stalk compression due to pituitary adenoma (so dopamine can’t get to adenohypophysis) PCOS Hypothyroidism Oestrogens (OCP) Pregnancy Lactation Idiopathic
What are the clinical features of hyperprolactinaemia?
Galactorrhoea Reduced GnRH and gonadotrophin secretion –> HYPOGONADISM Prolactinoma: Visual field defect Headache
Where is tubular fluid reabsorbed and what controls this process?
Rete testis Early epididymis This is under the control of oestrogen
Where do you find oestrogen within the male reproductive tract?
Tubular fluid produced by sertoli cells
What stimulates the release of nutrients and other molecules (e.g. glycoproteins) into the epididymal fluid?
Androgens
What are the roles of these secreted nutrients and molecules?
Provide energy for the impending journey Coat the surface of the spermatozoon (to protect them from the hostile environment)
Within which part of the male reproductive tract is fluid reabsorbed and secretory products put in?
Epididymis
Why is the concentration of sperm in the vas deferens higher than further down the reproductive tract?
Further down the reproductive tract, other fluids and secretory products are added thus diluting the sperm.
Where is a vasectomy performed?
Lower end of the vas deferens
Where is tubular fluid reabsorbed and what controls this process?
Rete testis Early epididymis This is under the control of oestrogen
Where do you find oestrogen within the male reproductive tract?
Tubular fluid produced by sertoli cells
What stimulates the release of nutrients and other molecules (e.g. glycoproteins) into the epididymal fluid?
Androgens
What are the roles of these secreted nutrients and molecules?
Provide energy for the impending journey Coat the surface of the spermatozoon (to protect them from the hostile environment)
Within which part of the male reproductive tract is fluid reabsorbed and secretory products put in?
Epididymis
Why is the concentration of sperm in the vas deferens higher than further down the reproductive tract?
Further down the reproductive tract, other fluids and secretory products are added thus diluting the sperm.
Where is a vasectomy performed?
Lower end of the vas deferens
Which structures contribute to the seminal fluid?
Epididymis/testes (small contribution) Seminal vesicle (2/3) Prostate (1/3)
Why is there fibrinogen and fibrinolytic enzymes in the seminal fluid?
After ejaculation, the semen initially clots and then must be broken down
Describe the capability of the spermatozoa in the seminiferous tubule.
Quiescent and incapable of fertilising an ovum
Describe the capabilities of the spermatozoa in the vas deferens.
Capable of limited movement Limited capability to fertilise an ovum
When do sperm achieve full activity and capability achieved and what is the name given to this process?
Capacitation This occurs within the female reproductive tract
What 3 changes take place in capacitation?
Loss of glycoprotein coat Change in surface membrane characteristics (leading to acrosome reaction when in close proximity to the ovum) Whiplash movements of the tail
What are all these changes dependent on?
Oestrogen Calcium
Describe the acrosome reaction.
Spermatozoon binds to ZP3 glycoprotein on the zona pellucida Once bound to ZP3, progesterone stimulates calcium influx into the spermatozoon This results in a calcium-dependent acrosome reaction This enables an exposed spermatozoon recognition site to bind to ZP2 Once bound to ZP2, the acrosome releases its enzymes allowing penetration of the zona pellucida so that the head of the spermatozoon can enter the ovum
Where does fertilisation normally occur?
Fallopian tube
What does fertilisation result in the expulsion of?
Second polar body
The zonal reaction immediately follows fertilisation. Describe the zonal reaction.
Cortical granules release molecules that degrade the zona pellucida (including ZP3 and ZP2) This prevents further binding of other sperm This is also CALCIUM dependent
Describe how the conceptus receives nutrients before implantation.
Uterine secretions
How long is this free-living phase of the conceptus?
9-10 days
In what stage of the menstrual cycle is all of this occurring?
Luteal phase – oestrogen and progesterone are high
What does the conceptus compact to form?
8-16 cells morula
What are the two parts of the blastocyst?
Inner cell mass – becomes the embryo Trophectoderm – becomes the chorion (which becomes the placenta)
What hormonal change facilitates the transfer of the conceptus to the uterus?
Increasing progesterone: oestrogen ratio
What is a decidua?
Thick layer of modified mucous membrane, which lines the uterus during pregnancy and is shed with afterbirth
What hormone environment is required for implantation?
Progesterone dominance in the presence of oestrogen
State 2 molecules that are of particular importance in implantation. Mention which cells produce these molecules.
Leukaemia inhibitory factor (LIF) Produced by endometrial secretory glands Stimulates adhesion (attachment) of blastocyst to endometrial cells IL-11 Also released from endometrial cells and released into uterine fluid
When the trophoblast cells of the blastocyst invade the underlying uterine stromal tissue, you get a decidualisationreaction. What main changes take place in decidualisation?
Increased vascular permeability in the invasion region, associated with oedema of tissues Localised changes in intracellular composition and progressive sprouting and growth of capillaries
Which chemical factors are involved in decidualisation?
Mainly IL-11 Histamine Certain prostaglandins TGF-beta = promotes angiogenesis
What is the role of hCG and when does it peak?
Peaks at 8 weeks and is particularly important in the first 6 weeks It mimics LH by binding to LH receptors on the corpus luteum and stimulating the production of oestrogen and progesterone NOTE: hCG is produced by trophoblast cells
What change takes place after about 5 weeks?
The role of hormone production is handed over from the corpus luteum to the placenta
Describe how oestrogen and progesterone levels change throughout pregnancy.
Oestrogen and progesterone levels continue to rise through pregnancy with progesterone always being the dominant influence
What is human placental lactogen? Describe its roles.
It is a growth hormone that has prolactin like effects It is important for the growth and development of the foetus
After what point would oophorectomy have no effect on pregnancy and why?
After around 6 weeks (40 days) By this point the placenta would have taken over the role of hormone production so the ovaries are no longer needed
Which steroid precursor tends to be provided by the mother for the foetus?
Pregnenolone
Which androgen is formed by the maternal and foetal adrenals?This is used as a precursor for oestrogen production.
Dehydroepiandrosterone Sulphate (DHEAS)
Which oestrogens are produced by the placenta using DHEAS from the mother and foetus?
Oestradiol Oestrone
These two oestrogens aren’t a good measure of foetal health. Explain why.
These oestrogens are dependent on precursor production from the both the foetal AND maternal adrenals. Therefore, it is not a good measure of foetal health.
What is the main oestrogen of pregnancy? Describe how it is produced.
OESTRIOL DHEAS from the foetal adrenals is conjugated in the foetal liver to form 16-alpha-hydroxy DHEAS 16-alpha-hydroxy DHEAS is then de-conjugated in the placenta and used to produce oestriol
What can be measured to gage the health of the foetus?
Oestriol: oestradiol + oestrone levels Oestriol: total oestrogens
Describe how maternal hormones change in pregnancy.
Most hormones increase in pregnancy (the pituitary gland becomes enlarged) Hormones that increase: Thyrotrophin Corticotrophin Prolactin Growth hormone Iodothyronines Adrenal steroids PTH Hormones that decrease: Gonadotrophins hGH (because placental hGH variant increases towards term) NOTE: hGH = human growth hormone
What biochemical change is required for contraction of the uterus during parturition?
Increase in intracellular calcium concentration
Describe how oestrogen increases the chance of contraction.
Oestrogen binds to oestrogen receptors and triggers the synthesis of prostaglandins within the endometrial cells. Prostaglandins stimulate the release of calcium from intracellular stores. So oestrogen tends to increase the chance of contraction
Describe how oxytocin increases the chance of contraction.
Oxytocin binds to its receptor on the endometrial cell and opens calcium channels, allowing calcium ions to move in from outside
Describe the effect of progesterone on this contraction process.
Progesterone keeps the effects of oestrogen under control Progesterone inhibits oestrogen receptors Progesterone inhibits the production of prostaglandins
What change occurs when the foetus reaches a particular size, which is crucial for contraction to take place?
There is a switch in steroid synthesis from progesterone synthesis to oestrogen synthesis This leads to oestrogen dominance –> prostaglandin production –> calcium release from intracellular stores –> promotion of muscle contraction
What 2 hormones are involved in milk production and milk ejection?
Prolactin – milk production Oxytocin – milk ejection These both have a similar neuroendocrine reflex arc stimulated by suckling
Which structures contribute to the seminal fluid?
Epididymis/testes (small contribution) Seminal vesicle (2/3) Prostate (1/3)
What 2 hormones are involved in milk production and milk ejection?
Prolactin – milk production Oxytocin – milk ejection These both have a similar neuroendocrine reflex arc stimulated by suckling
What change occurs when the foetus reaches a particular size, which is crucial for contraction to take place?
There is a switch in steroid synthesis from progesterone synthesis to oestrogen synthesis This leads to oestrogen dominance –> prostaglandin production –> calcium release from intracellular stores –> promotion of muscle contraction
Describe the effect of progesterone on this contraction process.
Progesterone keeps the effects of oestrogen under control Progesterone inhibits oestrogen receptors Progesterone inhibits the production of prostaglandins
Describe how oxytocin increases the chance of contraction.
Oxytocin binds to its receptor on the endometrial cell and opens calcium channels, allowing calcium ions to move in from outside
Describe how oestrogen increases the chance of contraction.
Oestrogen binds to oestrogen receptors and triggers the synthesis of prostaglandins within the endometrial cells. Prostaglandins stimulate the release of calcium from intracellular stores. So oestrogen tends to increase the chance of contraction
What biochemical change is required for contraction of the uterus during parturition?
Increase in intracellular calcium concentration
Describe how maternal hormones change in pregnancy.
Most hormones increase in pregnancy (the pituitary gland becomes enlarged) Hormones that increase: Thyrotrophin Corticotrophin Prolactin Growth hormone Iodothyronines Adrenal steroids PTH Hormones that decrease: Gonadotrophins hGH (because placental hGH variant increases towards term) NOTE: hGH = human growth hormone
What can be measured to gage the health of the foetus?
Oestriol: oestradiol + oestrone levels Oestriol: total oestrogens
What is the main oestrogen of pregnancy? Describe how it is produced.
OESTRIOL DHEAS from the foetal adrenals is conjugated in the foetal liver to form 16-alpha-hydroxy DHEAS 16-alpha-hydroxy DHEAS is then de-conjugated in the placenta and used to produce oestriol
These two oestrogens aren’t a good measure of foetal health. Explain why.
These oestrogens are dependent on precursor production from the both the foetal AND maternal adrenals. Therefore, it is not a good measure of foetal health.
Which oestrogens are produced by the placenta using DHEAS from the mother and foetus?
Oestradiol Oestrone
Which androgen is formed by the maternal and foetal adrenals?This is used as a precursor for oestrogen production.
Dehydroepiandrosterone Sulphate (DHEAS)
Which steroid precursor tends to be provided by the mother for the foetus?
Pregnenolone
After what point would oophorectomy have no effect on pregnancy and why?
After around 6 weeks (40 days) By this point the placenta would have taken over the role of hormone production so the ovaries are no longer needed
What is human placental lactogen? Describe its roles.
It is a growth hormone that has prolactin like effects It is important for the growth and development of the foetus
Describe how oestrogen and progesterone levels change throughout pregnancy.
Oestrogen and progesterone levels continue to rise through pregnancy with progesterone always being the dominant influence
What change takes place after about 5 weeks?
The role of hormone production is handed over from the corpus luteum to the placenta
What is the role of hCG and when does it peak?
Peaks at 8 weeks and is particularly important in the first 6 weeks It mimics LH by binding to LH receptors on the corpus luteum and stimulating the production of oestrogen and progesterone NOTE: hCG is produced by trophoblast cells
Which chemical factors are involved in decidualisation?
Mainly IL-11 Histamine Certain prostaglandins TGF-beta = promotes angiogenesis
When the trophoblast cells of the blastocyst invade the underlying uterine stromal tissue, you get a decidualisationreaction. What main changes take place in decidualisation?
Increased vascular permeability in the invasion region, associated with oedema of tissues Localised changes in intracellular composition and progressive sprouting and growth of capillaries
State 2 molecules that are of particular importance in implantation. Mention which cells produce these molecules.
Leukaemia inhibitory factor (LIF) Produced by endometrial secretory glands Stimulates adhesion (attachment) of blastocyst to endometrial cells IL-11 Also released from endometrial cells and released into uterine fluid
What hormone environment is required for implantation?
Progesterone dominance in the presence of oestrogen
What is a decidua?
Thick layer of modified mucous membrane, which lines the uterus during pregnancy and is shed with afterbirth
What hormonal change facilitates the transfer of the conceptus to the uterus?
Increasing progesterone: oestrogen ratio
What are the two parts of the blastocyst?
Inner cell mass – becomes the embryo Trophectoderm – becomes the chorion (which becomes the placenta)
What does the conceptus compact to form?
8-16 cells morula
In what stage of the menstrual cycle is all of this occurring?
Luteal phase – oestrogen and progesterone are high
How long is this free-living phase of the conceptus?
9-10 days
Describe how the conceptus receives nutrients before implantation.
Uterine secretions
The zonal reaction immediately follows fertilisation. Describe the zonal reaction.
Cortical granules release molecules that degrade the zona pellucida (including ZP3 and ZP2) This prevents further binding of other sperm This is also CALCIUM dependent
What does fertilisation result in the expulsion of?
Second polar body
Where does fertilisation normally occur?
Fallopian tube
Describe the acrosome reaction.
Spermatozoon binds to ZP3 glycoprotein on the zona pellucida Once bound to ZP3, progesterone stimulates calcium influx into the spermatozoon This results in a calcium-dependent acrosome reaction This enables an exposed spermatozoon recognition site to bind to ZP2 Once bound to ZP2, the acrosome releases its enzymes allowing penetration of the zona pellucida so that the head of the spermatozoon can enter the ovum
What are all these changes dependent on?
Oestrogen Calcium
What 3 changes take place in capacitation?
Loss of glycoprotein coat Change in surface membrane characteristics (leading to acrosome reaction when in close proximity to the ovum) Whiplash movements of the tail
When do sperm achieve full activity and capability achieved and what is the name given to this process?
Capacitation This occurs within the female reproductive tract
Describe the capabilities of the spermatozoa in the vas deferens.
Capable of limited movement Limited capability to fertilise an ovum
Describe the capability of the spermatozoa in the seminiferous tubule.
Quiescent and incapable of fertilising an ovum
Why is there fibrinogen and fibrinolytic enzymes in the seminal fluid?
After ejaculation, the semen initially clots and then must be broken down
What is menopause?
Permanent cessation of menstruation - amenorrhoea for more than 12 months NOTE: usually happens between 45-55 yrs
What is the term given to the period of transition just beforemenopause? Describe this period of transition.
Climacteric period You go from having normal regular cycles and then it becomes a little irregular (oligomenorrhoea) and then it progresses to amenorrhoea.
State some symptoms of menopause.
Hot flushes Urogenital Atrophy (leads to dyspareunia – difficult or painful sexual intercourse) Sleep disturbance Decreased libido Depression Joint pain
What do the ovaries produce that feeds back on the HPG axis?
Oestradiol and Inhibin B
How does this feedback change in menopause?
There is a loss of ovarian follicular activity so you get a decreased production of oestradiol and inhibin This means that there is less negative feedback on the HPG axis
What would you expect the LH and FSH levels of a menopausal woman to be?
High – because of the loss of oestrogen and inhibin production
What are the main complications of menopause?
Osteoporosis (the protective effect of oestrogen on bone is lost) Cardiovascular disease (women are protected against cardiovascular disease before menopause)
What is menopause?
Permanent cessation of menstruation - amenorrhoea for more than 12 months NOTE: usually happens between 45-55 yrs
What is the term given to the period of transition just beforemenopause? Describe this period of transition.
Climacteric period You go from having normal regular cycles and then it becomes a little irregular (oligomenorrhoea) and then it progresses to amenorrhoea.
State some symptoms of menopause.
Hot flushes Urogenital Atrophy (leads to dyspareunia – difficult or painful sexual intercourse) Sleep disturbance Decreased libido Depression Joint pain
What do the ovaries produce that feeds back on the HPG axis?
Oestradiol and Inhibin B
How does this feedback change in menopause?
There is a loss of ovarian follicular activity so you get a decreased production of oestradiol and inhibin This means that there is less negative feedback on the HPG axis
What would you expect the LH and FSH levels of a menopausal woman to be?
High – because of the loss of oestrogen and inhibin production
What are the main complications of menopause?
Osteoporosis (the protective effect of oestrogen on bone is lost) Cardiovascular disease (women are protected against cardiovascular disease before menopause)
What are the risks of giving oestrogen as part of HRT?
Endometrial hyperplasia, which increases the risk of endometrial carcinoma
How is this effect of oestrogen prevented?
You give progesterone as well as oestrogen The progesterone blocks this effect of oestrogen on the endometrium and, hence, prevents endometrial hyperplasia
In which subset of patients would you give oestrogen only HRT?
Patients who have had a hysterectomy There is no uterus so there is no endometrium to stimulate with oestrogen
Describe the 2 different formulations of HRT.
Cyclical – take oestradiol every day and then for the last 12-14 days you take progesterone Combined continuous – take a little oestrogen and progesterone every day
State 4 different types of oestrogen preparations.
Oral oestradiol (1 mg) Oral conjugated equine oestradiol (0.625 mg) Transdermal oestradiol (50 mcg/day) Intravaginal
Describe the absorption and metabolism of oestradiol.
Oestradiol is absorbed well but it is heavily metabolised in the liver (first pass) so the bioavailability is very low. This means that in oral preparations, you must give a high dose of oestradiol.
Name a semi-synthetic oestrogen that’s used in oral contraceptives.
Ethinyl oestradiol The ethinyl group protects the drug from hepatic first pass metabolism.
What is the difference between the types and dose of oestrogen given in HRT compared to the oral contraceptive?
In HRT you are just giving a little bit of oestrogen to prevent the symptoms of menopause. In contraception, you are trying to suppress the HPG axis so you give a more potent type of oestrogen.
State some side-effect/risks of HRT.
Breast cancer Venous thromboembolism Stroke Gallstones
How does HRT affect cardiovascular disease risk?
There is an increased risk of coronary heart disease The timing of exposure is important in terms of cardiovascular disease risk – older patients who are started on HRT have an increased risk of CHD but in younger women there was no increased risk
Name a synthetic prohormone that has oestrogenic, progestogenic and weak androgenic effects.
Tibolone
What is this drug used for and what are the risks?
It reduces the risk of fracture It increases the risk of stroke
What is raloxifene and how does it work?
It is a selective oestrogen receptor modulator (SERM) In bone it has oestrogenic effects and reduces the risk of fracture In breast and uterus it has anti-oestrogenic effects and reduces the risk of breast cancer
What are the problems with raloxifene?
It is associated with an increased risk of fatal stroke and VTE
When would you use the progesterone only pill?
If oestrogen is contraindicated – this is if there is an increased risk of thrombosis (oestrogen has pro-coagulant effects)
What is an important point to remember about when to take the progesterone only pill?
It must be taken at the same time every day
What is the name given to the long-acting intra-uterine progesterone device?
Mirena
What 3 things can you use for emergency (post-coital) contraception?
Copper IUD (affects sperm viability and function and inhibits fertilisation) Levonorgestral (within 72 hours – high dose progesterone) Ulipristal (within 120 hours) Anti-progestin activity Delays ovulation by as much as 5 days Impairs implantation
What is tamoxifen?
Anti-oestrogenic on breast tissue
What is tamoxifen used for?
Treatment of oestrogen-dependent breast tumours and metastatic breast cancers
What is the term given for menopause before the age of 40?
Premature Ovarian Insufficiency
What could POI be caused by?
Autoimmune Surgery Chemotherapy Radiotherapy
What type of oestrogen is in the combined oral contraceptive pill?
Ethinyl oestradiol
What types of progestogen is used in the combined oral contraceptive pill?
Levonorgestral Norethistrone
What other effect do progestogens have that reduces the chance of conception?
It thickens cervical mucus meaning that it is more difficult for sperm to penetrate it
When would you use the progesterone only pill?
If oestrogen is contraindicated – this is if there is an increased risk of thrombosis (oestrogen has pro-coagulant effects)
What is an important point to remember about when to take the progesterone only pill?
It must be taken at the same time every day
What is the name given to the long-acting intra-uterine progesterone device?
Mirena
What 3 things can you use for emergency (post-coital) contraception?
Copper IUD (affects sperm viability and function and inhibits fertilisation) Levonorgestral (within 72 hours – high dose progesterone) Ulipristal (within 120 hours) Anti-progestin activity Delays ovulation by as much as 5 days Impairs implantation
What could POI be caused by?
Autoimmune Surgery Chemotherapy Radiotherapy
What type of oestrogen is in the combined oral contraceptive pill?
Ethinyl oestradiol
What types of progestogen is used in the combined oral contraceptive pill?
Levonorgestral Norethistrone
What other effect do progestogens have that reduces the chance of conception?
It thickens cervical mucus meaning that it is more difficult for sperm to penetrate it
When would you use the progesterone only pill?
If oestrogen is contraindicated – this is if there is an increased risk of thrombosis (oestrogen has pro-coagulant effects)
What 3 things can you use for emergency (post-coital) contraception?
Copper IUD (affects sperm viability and function and inhibits fertilisation) Levonorgestral (within 72 hours – high dose progesterone) Ulipristal (within 120 hours) Anti-progestin activity Delays ovulation by as much as 5 days Impairs implantation
What is the name given to the long-acting intra-uterine progesterone device?
Mirena
What is an important point to remember about when to take the progesterone only pill?
It must be taken at the same time every day
What is the term given to the period of transition just beforemenopause? Describe this period of transition.
Climacteric period You go from having normal regular cycles and then it becomes a little irregular (oligomenorrhoea) and then it progresses to amenorrhoea.
What 3 things can you use for emergency (post-coital) contraception?
Copper IUD (affects sperm viability and function and inhibits fertilisation) Levonorgestral (within 72 hours – high dose progesterone) Ulipristal (within 120 hours) Anti-progestin activity Delays ovulation by as much as 5 days Impairs implantation
What is the name given to the long-acting intra-uterine progesterone device?
Mirena
What is an important point to remember about when to take the progesterone only pill?
It must be taken at the same time every day
When would you use the progesterone only pill?
If oestrogen is contraindicated – this is if there is an increased risk of thrombosis (oestrogen has pro-coagulant effects)
What other effect do progestogens have that reduces the chance of conception?
It thickens cervical mucus meaning that it is more difficult for sperm to penetrate it
What types of progestogen is used in the combined oral contraceptive pill?
Levonorgestral Norethistrone
What type of oestrogen is in the combined oral contraceptive pill?
Ethinyl oestradiol
What could POI be caused by?
Autoimmune Surgery Chemotherapy Radiotherapy
What is the term given for menopause before the age of 40?
Premature Ovarian Insufficiency
What is tamoxifen used for?
Treatment of oestrogen-dependent breast tumours and metastatic breast cancers
What is tamoxifen?
Anti-oestrogenic on breast tissue
What are the problems with raloxifene?
It is associated with an increased risk of fatal stroke and VTE
What is raloxifene and how does it work?
It is a selective oestrogen receptor modulator (SERM) In bone it has oestrogenic effects and reduces the risk of fracture In breast and uterus it has anti-oestrogenic effects and reduces the risk of breast cancer
What is this drug used for and what are the risks?
It reduces the risk of fracture It increases the risk of stroke
Name a synthetic prohormone that has oestrogenic, progestogenic and weak androgenic effects.
Tibolone
How does HRT affect cardiovascular disease risk?
There is an increased risk of coronary heart disease The timing of exposure is important in terms of cardiovascular disease risk – older patients who are started on HRT have an increased risk of CHD but in younger women there was no increased risk
What is the term given for menopause before the age of 40?
Premature Ovarian Insufficiency
What is tamoxifen used for?
Treatment of oestrogen-dependent breast tumours and metastatic breast cancers
What is tamoxifen?
Anti-oestrogenic on breast tissue
State some side-effect/risks of HRT.
Breast cancer Venous thromboembolism Stroke Gallstones
What are the problems with raloxifene?
It is associated with an increased risk of fatal stroke and VTE
What is the difference between the types and dose of oestrogen given in HRT compared to the oral contraceptive?
In HRT you are just giving a little bit of oestrogen to prevent the symptoms of menopause. In contraception, you are trying to suppress the HPG axis so you give a more potent type of oestrogen.
Name a semi-synthetic oestrogen that’s used in oral contraceptives.
Ethinyl oestradiol The ethinyl group protects the drug from hepatic first pass metabolism.
Describe the absorption and metabolism of oestradiol.
Oestradiol is absorbed well but it is heavily metabolised in the liver (first pass) so the bioavailability is very low. This means that in oral preparations, you must give a high dose of oestradiol.
State 4 different types of oestrogen preparations.
Oral oestradiol (1 mg) Oral conjugated equine oestradiol (0.625 mg) Transdermal oestradiol (50 mcg/day) Intravaginal
Describe the 2 different formulations of HRT.
Cyclical – take oestradiol every day and then for the last 12-14 days you take progesterone Combined continuous – take a little oestrogen and progesterone every day
In which subset of patients would you give oestrogen only HRT?
Patients who have had a hysterectomy There is no uterus so there is no endometrium to stimulate with oestrogen
How is this effect of oestrogen prevented?
You give progesterone as well as oestrogen The progesterone blocks this effect of oestrogen on the endometrium and, hence, prevents endometrial hyperplasia
What are the risks of giving oestrogen as part of HRT?
Endometrial hyperplasia, which increases the risk of endometrial carcinoma
What are the main complications of menopause?
Osteoporosis (the protective effect of oestrogen on bone is lost) Cardiovascular disease (women are protected against cardiovascular disease before menopause)
What would you expect the LH and FSH levels of a menopausal woman to be?
High – because of the loss of oestrogen and inhibin production
How does this feedback change in menopause?
There is a loss of ovarian follicular activity so you get a decreased production of oestradiol and inhibin This means that there is less negative feedback on the HPG axis
What do the ovaries produce that feeds back on the HPG axis?
Oestradiol and Inhibin B
State some symptoms of menopause.
Hot flushes Urogenital Atrophy (leads to dyspareunia – difficult or painful sexual intercourse) Sleep disturbance Decreased libido Depression Joint pain
What is the term given to the period of transition just beforemenopause? Describe this period of transition.
Climacteric period You go from having normal regular cycles and then it becomes a little irregular (oligomenorrhoea) and then it progresses to amenorrhoea.
State some symptoms of menopause.
Hot flushes Urogenital Atrophy (leads to dyspareunia – difficult or painful sexual intercourse) Sleep disturbance Decreased libido Depression Joint pain
What do the ovaries produce that feeds back on the HPG axis?
Oestradiol and Inhibin B
How does this feedback change in menopause?
There is a loss of ovarian follicular activity so you get a decreased production of oestradiol and inhibin This means that there is less negative feedback on the HPG axis
What would you expect the LH and FSH levels of a menopausal woman to be?
High – because of the loss of oestrogen and inhibin production
What are the main complications of menopause?
Osteoporosis (the protective effect of oestrogen on bone is lost) Cardiovascular disease (women are protected against cardiovascular disease before menopause)
What are the risks of giving oestrogen as part of HRT?
Endometrial hyperplasia, which increases the risk of endometrial carcinoma
How is this effect of oestrogen prevented?
You give progesterone as well as oestrogen The progesterone blocks this effect of oestrogen on the endometrium and, hence, prevents endometrial hyperplasia
In which subset of patients would you give oestrogen only HRT?
Patients who have had a hysterectomy There is no uterus so there is no endometrium to stimulate with oestrogen
Describe the 2 different formulations of HRT.
Cyclical – take oestradiol every day and then for the last 12-14 days you take progesterone Combined continuous – take a little oestrogen and progesterone every day
What is raloxifene and how does it work?
It is a selective oestrogen receptor modulator (SERM) In bone it has oestrogenic effects and reduces the risk of fracture In breast and uterus it has anti-oestrogenic effects and reduces the risk of breast cancer
What is this drug used for and what are the risks?
It reduces the risk of fracture It increases the risk of stroke
Name a synthetic prohormone that has oestrogenic, progestogenic and weak androgenic effects.
Tibolone
How does HRT affect cardiovascular disease risk?
There is an increased risk of coronary heart disease The timing of exposure is important in terms of cardiovascular disease risk – older patients who are started on HRT have an increased risk of CHD but in younger women there was no increased risk
State some side-effect/risks of HRT.
Breast cancer Venous thromboembolism Stroke Gallstones
What is the difference between the types and dose of oestrogen given in HRT compared to the oral contraceptive?
In HRT you are just giving a little bit of oestrogen to prevent the symptoms of menopause. In contraception, you are trying to suppress the HPG axis so you give a more potent type of oestrogen.
Name a semi-synthetic oestrogen that’s used in oral contraceptives.
Ethinyl oestradiol The ethinyl group protects the drug from hepatic first pass metabolism.
Describe the absorption and metabolism of oestradiol.
Oestradiol is absorbed well but it is heavily metabolised in the liver (first pass) so the bioavailability is very low. This means that in oral preparations, you must give a high dose of oestradiol.
State 4 different types of oestrogen preparations.
Oral oestradiol (1 mg) Oral conjugated equine oestradiol (0.625 mg) Transdermal oestradiol (50 mcg/day) Intravaginal
What is menopause?
Permanent cessation of menstruation - amenorrhoea for more than 12 months NOTE: usually happens between 45-55 yrs
What is menopause?
Permanent cessation of menstruation - amenorrhoea for more than 12 months NOTE: usually happens between 45-55 yrs
What other effect do progestogens have that reduces the chance of conception?
It thickens cervical mucus meaning that it is more difficult for sperm to penetrate it
What types of progestogen is used in the combined oral contraceptive pill?
Levonorgestral Norethistrone
What type of oestrogen is in the combined oral contraceptive pill?
Ethinyl oestradiol
What could POI be caused by?
Autoimmune Surgery Chemotherapy Radiotherapy
What is the term given for menopause before the age of 40?
Premature Ovarian Insufficiency
What is tamoxifen used for?
Treatment of oestrogen-dependent breast tumours and metastatic breast cancers
What is tamoxifen?
Anti-oestrogenic on breast tissue
What are the problems with raloxifene?
It is associated with an increased risk of fatal stroke and VTE
What is raloxifene and how does it work?
It is a selective oestrogen receptor modulator (SERM) In bone it has oestrogenic effects and reduces the risk of fracture In breast and uterus it has anti-oestrogenic effects and reduces the risk of breast cancer
What is this drug used for and what are the risks?
It reduces the risk of fracture It increases the risk of stroke
Name a synthetic prohormone that has oestrogenic, progestogenic and weak androgenic effects.
Tibolone
How does HRT affect cardiovascular disease risk?
There is an increased risk of coronary heart disease The timing of exposure is important in terms of cardiovascular disease risk – older patients who are started on HRT have an increased risk of CHD but in younger women there was no increased risk
State some side-effect/risks of HRT.
Breast cancer Venous thromboembolism Stroke Gallstones
What is the difference between the types and dose of oestrogen given in HRT compared to the oral contraceptive?
In HRT you are just giving a little bit of oestrogen to prevent the symptoms of menopause. In contraception, you are trying to suppress the HPG axis so you give a more potent type of oestrogen.
Name a semi-synthetic oestrogen that’s used in oral contraceptives.
Ethinyl oestradiol The ethinyl group protects the drug from hepatic first pass metabolism.
Describe the absorption and metabolism of oestradiol.
Oestradiol is absorbed well but it is heavily metabolised in the liver (first pass) so the bioavailability is very low. This means that in oral preparations, you must give a high dose of oestradiol.
State 4 different types of oestrogen preparations.
Oral oestradiol (1 mg) Oral conjugated equine oestradiol (0.625 mg) Transdermal oestradiol (50 mcg/day) Intravaginal
Describe the 2 different formulations of HRT.
Cyclical – take oestradiol every day and then for the last 12-14 days you take progesterone Combined continuous – take a little oestrogen and progesterone every day
In which subset of patients would you give oestrogen only HRT?
Patients who have had a hysterectomy There is no uterus so there is no endometrium to stimulate with oestrogen
How is this effect of oestrogen prevented?
You give progesterone as well as oestrogen The progesterone blocks this effect of oestrogen on the endometrium and, hence, prevents endometrial hyperplasia
What are the risks of giving oestrogen as part of HRT?
Endometrial hyperplasia, which increases the risk of endometrial carcinoma
Describe the change in number of oogonia in women throughout life.
Maximum (24 weeks gestation) - 6-7 million Birth - 2 million Puberty - 400,000 300-400 mature eggs released Menopause - 0
What is the process by which oogonia degenerate and die?
Atresia
Describe the steps in spermatogenesis.
Germ cells divide to produce spermatogonia. Spermatogonia remain dormant until puberty where a rise in FSH triggers division of spermatogonia to produce more spermatogonia and primary spermatocytes (still diploid). Primary spermatocytes enter first meiotic division to form secondary oocytes (haploid). Secondary oocytes enter second meiotic division to form spermatids. Spermatids mature into spermatozoa.
What stimulates the spermatogonia to proceed to the next stage and when does this happen?
FSH release during puberty
How long does the process of spermatogenesis take place?
70 days
Describe the steps in oogenesis.
Begin with oogonia from division of germ cells. Oogonia divide mitotically to produce primary oocytes (diploid). Primary oocytes enter the first meiotic division straight away but are halted in prophase of the first meiotic division. The oocytes form a layer of cells around them, forming primordial follicles. These cells remain dormant for 12-50 years. More cells die of atresia. Puberty - release of FSH rescues a group of the dormant cells and they continue development. They complete the first meiotic division around the time of ovulation. If fertilisation takes place, they will complete the second meiotic division to form an ovum.
What is produced after the first meiotic division is complete?
Secondary oocyte + first polar body
What is required to complete the second meiotic division?
Fertilisation
What is produced after the second meiotic division is complete?
Ovum + second polar body
Describe the passage of sperm from production to release.
Sperm is produced in seminiferous tubules. It moves to the rete testis where it is concentrated. It then moves via the vasa efferentia to the epididymis for storage. It is ejected via the vas deferens (which has smooth muscle around it) and then via the urethra.
Describe the structure of seminiferous tubules.
Spermatogonia around the outside Underlying this is a layer of Sertoli cells The lumen of the seminiferous tubule is on the inside
What important cell type lies outside the seminiferous tubules? What do they produce?
Leydig cells - they produce testosterone which is needed for spermatogenesis to take place
How do spermatogonia pass through the Sertoli cell barrier?
They move into the Sertoli cells and are enclosed in the cytoplasm of the Sertoli cells. The Sertoli cells provide structural and metabolic support for the spermatogonia and help them develop. They then enter the lumen.
Describe which receptors are expressed by Sertoli cells and Leydig cells.
Sertoli Cells - FSH receptor and Androgen receptor Leydig Cells - LH receptor
What is inhibin and what cells produce this?
Inhibin inhibits the release of FSH and is produced by Sertoli cells
What is a Graffian follicle?
The maximum size of a maturing follicle
Which steps in steroidogenesis are common to both adrenals and gonads?
The first four steps - pregnenolone –> progesterone –> 17 hydroxyprogesterone –> androstenedione
What enzyme in the testes converts androstenedione to testosterone?
17 hydroxysteroid dehydrogenase
What do the ovaries do to androstenedione and testosterone?
Aromatises androstenedione and testosterone to oestrone, which can then be converted to 17-oestradiol
What are the phases of the ovarian and endometrial cycle?
Ovarian - Follicular –> (ovulation) –> Luteal Endometrial –> Proliferative –> Secretory
What are the effects of oestrogen on the endometrium in the proliferative phase?
Oestrogen increases mitosis, increases progesterone receptors and increases oestrogen receptors. It stimulates thickening of the endometrial lining.
What are the effects of progesterone in the secretory phase?
Progesterone - reduces the proliferation caused by oestrogen and stimulates secretory activity of the uterus to make it a better environment for implantation.
Describe the menstrual cycle.
There is a slightly elevated level of FSH at the start of the cycle. This rescues some of the follicles from dormancy so they continue development. The follicles start producing 17 beta oestradiol which inhibits gonadotrophins (FSH and LH) One follicle becomes dominant - others undergo atresia Eventually oestrogen levels remain high enough for long enough that they switch to a positive feedback effect and stimulate a surge in LH and FSH. Surge in LH stimulates ovulation Empty follicle becomes a corpus luteum and produces 17 beta oestradiol and progesterone, which has a negative feedback effect on gonadotrophins If fertilisation doesn’t take place, oestrogen and progesterone levels fall and negative feedback on FSH and LH decreases so levels rise again.
What other effect does progesterone have on the body?
Increases body temperature
What stage do the follicles develop to in embryonic life?
Pre-antral stage
What is the next step in embryonic life and what is required to stimulate this step?
They develop to early antral follicles - stimulation is FSH If FSH isn’t high enough, they undergo atresia.
What are the two cell types in this follicle? What receptors do they have and what do they do?
Thecal cells (outside of follicle) - LH receptors - produce androgens Granulosa cells (inside of follicle) - FSH receptors - produces oestrogens from progesterone using aromatase enzyme
Name the weak androgen that is produced both in the adrenal glands and in the testes.
Androstenedione
What two reactions can testosterone follow and what do they produce?
Testosterone —> Oestrogen (aromatisation - by the action of aromatase) Testosterone —> Dihydrotestosterone (reduction) Dihydrotestosterone is a more potent androgen that binds to the same androgen receptors as testosterone.
How is testosterone and DHT transported in the blood?
Mainly bound to sex hormone binding globulin (SHBG) Some of it is bound to albumin A small amount is free and bioactive This is in dynamic equilibrium
How is testosterone and DHT transported in the seminiferous tubules?
Bound to androgen binding globulin (ABG)
What are the effects of androgens in the foetus and in adults?
Development of male internal and external genitalia Stimulates general growth Adult - spermatogenesis, pubertal growth spurt, stimulates protein synthesis
Define oestrogen.
Any molecule that induces mitosis in the endometrium.
What is the main oestrogen in the menstrual cycle?
17 beta oestradiol
What is the main oestrogen in pregnancy?
Oestriol
What are the actions of oestrogens?
Stimulate mitosis in the endometrium Increased salt and water reabsorption Increase HDL Causes LH surge Stimulates growth of ductile system in the breast Decreases sebaceous gland secretion
Define progestogen.
Any molecule that induces secretory changes in the endometrium
What are the actions of progestogens?
Stimulates secretory activity in the endometrium and cervix Decrease renal NaCl absorption Growth of alveolar system in breast Increase in body temperature
What hypothalamic hormone stimulates FSH and LH release from the pituitary gland?
Gonadotrophin Releasing Hormone (GnRH)
Which cells in the testes have receptors for FSH and LH?
Sertoli Cells - FSH Leydig Cells - LH
Describe the negative feedback from the testes to hypothalamo-pituitary axis.
Sertoli Cells - produce INHIBIN - negative feedback effect on hypothalamus and pituitary Leydig Cells - produce TESTOSTERONE - negative feedback effect on hypothalamus and pituitary
How do these pathways cause negative feedback?
Decreases the AMPLITUDE of the GnRH pulses.
Describe the local positive feedback loop in the ovaries.
FSH stimulate aromatase and increase conversion of androgens to 17 beta oestradiol. Oestrogen then leaves the granulosa cell and binds to oestrogen receptors on the SAME granulosa cell and further stimulates production of oestrogen.
Rising oestrogen levels has a negative feedback effect on FSH.
Most developing follicles will then undergo atresia and only one follicle remains, the Graffian follicle. What enables this follicle to survive the negative feedback on FSH? The Graffian follicle is no longer FSH-dependent and can survive with it’s own local production of oestrogen. The other cells are FSH-dependent and so undergo atresia when the FSH is removed.
What conditions must be in place for the rising oestrogen concentration switch from negative feedback to positive feedback on gonadotrophins?
Absence of progesterone Oestrogen concentration must be high enough for a minimum of 36 hours
The oestrogen levels in the luteal phase are as high as the levels that triggered ovulation in the follicular phase so why is there no LH surge in the luteal phase?
Presence of progesterone
If fertilisation occurs, high levels of oestrogen and progesterone is needed. What molecule is produced to mimic LH and stimulate further oestrogen and progesterone production?
Human Chorionic Gonadotrophin
If fertilisation does not occur, what happens?
Oestradiol, Progesterone and Inhibin have negative feedback effect on FSH and LH leading to luteolysis and menstruation.
What is the difference between primary and secondary amenorrhoea?
Primary - never had a period Secondary - used to have period but then they stopped
Define infertility.
Woman - inability to get pregnant Man - inability to impregnate
