Endocrinology of Female Reproduction Flashcards
What is reproduction?
-Genetic material is passed on between generations
-New individuals of a species can be produced
=a result of mixing genes from two individuals
Why is infertility becoming more common?
-Sexually transmitted infections (chlamydia, gonorrhoea= tubular damage to fallopian tubes so eggs cannot be transported)
-Obesity (overweight/ underweight= hormones off-balanced)
-Tobacco (decreased blood flow in penis)
-Increase in age at childbearing
=Infertility now affects 1 in 7 couples (inability to conceive after 1 year of unprotected sex)
=Sub fertility= inability to conceive after 6 months of unprotected sex
Describe male fertility
- Constant fertility from puberty
- 300 million per day from puberty
- Gradual decline with age
Describe female fertility
- Cyclical fertility, 3-5 days a month from puberty
- 7 million follicles in utero declines to 0 at menopause
- 400 follicles are ovulated
How is the ovarian reserve formed?
- Primordial germ cells (precursor to eggs) colonise the gonad
- Numbers expand by mitosis (to 7 million)
- Germ cells enter, and then arrest, in meiosis (form oogonial cysts, interconnected by cytoplasmic bridges)
- Primordial follicles form (granulosa cells wrap oocytes, arrested in diplotene of meiotic prophase 1, only returns at ovulation)
=relies on connections between chromosomes not decaying over time - Folliculogenesis
What is a follicle and how does it progress?
- Reproductive unit of ovary
- Egg/ oocyte surrounded by granulosa cells
1. Primordial= flattened/ squamous single layer granulosa
2. Primary= squamous to cuboidal, layers, glycoprotein layer zona pellucida (secreted by oocyte)
3. Secondary= increased no. granulosa cells, theca layer (stroma cells differentiated)
4. Early-antral follicle= theca differentiated into theca interna (glands, blood vessels) and theca externa (fibrous protective capsule), fluid filled gaps (antral/ follicular, secreted by granulosa cells)
5. Graafian= all fluid gaps coalesced into follicular antrum, pushes oocyte out into one layer granulosa cell (corona radiata)
Describe the hypothalamic/ pituitary/ gonadal axis
-Gonadotrophin-releasing hormone from hypothalamus
-FSH, LH released from anterior pituitary (gonadotrophs)
-Stimulates granulosa cell proliferation and follicle ovulation in the ovaries
=Oestrogens
=Progesterone
=Inhibin
-Negative feedback loop
How are neurosecretory neurones different?
- Synthesise hormones and stores in vesicles
- Released at terminal when there is an impulse
- Posterior pituitary (ADH, oxytocin)
What is oxytocin?
-Oxytocin has major effects on smooth muscle contraction
=milk ejection
=contraction of uterus during childbirth (myometrium)
-Secretion is stimulated in response to stimulation of nipples or uterine distension.
-Oxytocin is used to induce labour
Describe gonadotropin-releasing hormone
-Synthesised by hypothalamic neurons (small), terminate onto portal system
-Pulsatile release
=prevents receptor desensitisation & downregulation
-Responds to ovarian hormonal feedback (oestrogen and progesterone)
What is Kisspeptin?
-Small neuropeptide hormones
=feedback onto GnRH neurone themselves, regulate secretion
=Can receive signals from gonads and integrate signals from all over the body (cortisol from adrenal gland, leptin from body fat, environmental cues= shift workers and air hostesses suffer from infertility)
How do these hormones travel through the blood?
-Water soluble= travel in blood freely
=Target site= diffusion through binding to receptor, cascade through cAMP
=GnRH, FSH, LH
-Lipid soluble
=Travel bound to transport protein
=Freely diffuse into cell passing through cell membrane into nucleus, transcription factor
=Oestrogen and progesterone
What causes follicle activation?
-Gonadotropin regulated growth phase (important at pre-antral follicle and above)
=FSH- antral granulosa cell differentiation, proliferation and function (make oestrogen)
=LH- theca cell androgen production, ovulation (antral expansion as well)
*Gradual decline of primordial follicles not affected by endocrine system
What is Anti-Mullerian hormone?
-Made by granulosa cells
-Absent in primordial follicles but present at later stages
-Inhibitory effect on follicle development (negative feedback on primordial follicles to keep resources for themselves)
-Unaffected by gonadotropins/steroid hormones
=reliable reflection of growing follicles/ how many left
*In males, stops female duct formation in male reproductive tract
Why is only one follicle selected?
-LH receptor
=Oestrogen and FSH induce expression of LH receptor on theca cell
=Most number of LH receptor and in prime position to receive LH hormone= dominant ovulated follicle
What is the relationship between oestrogen and FSH?
-As oestrogen is produced by follicles, has negative feedback effect on FSH production in pituitary
-At a certain threshold, effect reverses so positive effect on FSH secretion from pituitary
-Stimulates LH release from pituitary
=Both stimulate LH receptors on theca cells
Describe follicular rupture
-Wears away at surface of ovary
-Proteases digest areas
-Releases follicular fluid, egg and cumulus complex
=swept into ovary duct and down into the uterus
Describe the Corpus luteum
-Ruptured follicle develops into corpus luteum
=granulosa and theca cells
-Lutein cells – mitochondria, smooth ER, Golgi, lipid droplets, and pigment lutein (yellow colour)
-Luteinisation = progesterone secretion
What happens to the corpus luteum if there is no pregnancy?
-Corpus luteum undergoes luteolysis/ regresses due to lack of hCG (become corpus albicans= scar tissue)
=FSH rises
=progesterone and oestrogen drop
=Endometrium shed
Describe how hormonal contraception works
-Suppresses ovulation via negative feedback of progesterone
=secondary effects on female genital tract (on endometrium)
-Combined pill – oestrogen provides additional feedback & promotes progesterone receptor expression
-During ‘off period’ own HPG axis is awakened
How is breast development linked to the placenta?
- Once placenta is birthed, steroidal block on breast development removed
- Prolactin acts on breast tissue for milk production, blocked by the hormones made by placenta
Describe the anatomy of the breast
-15 to 20 ducts in adult breast tissue
=Alveola make breast milk
=Sacs surrounded by myoepithelial cells (contractile, contract in response to oxytocin)
-Number of alveola increase in puberty in response to oestrogen
How is breast milk made?
-Need suckling!
=nerve impulses sent to the brain to maintain prolactin levels
=depends on strength and how long a baby suckles for
-Prolactin release from anterior pituitary, maintained for a few weeks but needs suckling to be maintained
-Alveoli swell and secrete milk
How is milk released?
-Need suckling!
=nerve impulses sent to the brain
-Boosts oxytocin synthesis & secretion from posterior pituitary
-Myoepithelial cell contraction around alveoli = milk expulsion
-Milk ejection reflex can be conditioned
Why is fertility reduced during lactation?
- Lactation can continue for months
- Menstruation & ovulation re-established by 3-6 months
- ~50% of unprotected nursing mothers fall pregnant during 9 months of lactation
- Negative feedback of prolactin on FSH/LH
Differentials of high LH
- Premature Ovarian Failure
- Polycystic Ovarian Syndrome
- Ashermans syndrome
- Functional Gonadotroph Tumour
Describe Premature Ovarian Failure/Insufficiency
-High LH, high FSH, low E2
-Premature menopause or hypergonadotropic hypogonadism
=flushes, difficulty concentrating, vaginal dryness, night sweats
=Cause are genetic (Turners), Familial, Iatrogenic, autoimmune, infection
-USS small ovaries, no follicles
Describe PCOS
-High LH, normal FSH, normal E2, High testosterone, low SHBG
=weight problems, hirsutism, skin problems, family history, FH diabetes, oligomenorrhoea
-USS polycystic
Describe Ashermans syndrome
-Normal ovulation but no menstruation due to lack of endometrium
=High LH and high E2
=damage can occur after termination of pregnancy or D and C for miscarriage so scarring/ uterine surgery
=cyclical changes and discomfort
-Trans-vaginal USS ovulation= dominant follicle but thin abnormal endometrium
Describe functional gonadotroph tumour
-Very rare
=progressive headache, visual field defect
-LH/FSH not subject to feedback will have large numbers of large follicles (USS multiple large follicular cysts on each ovary)
What are the differentials for high testosterone?
- PCOS
- CAH (congenital adrenal hyperplasia)
- Androgen secreting tumour (ovary or adrenal sites)
- Exogenous testosterone/ steroids
Describe CAH
-Relative block to enzyme that makes cortisol (21-hydroxylase)
=precursors for cortisol build up and are converted into potent androgens
=ACTH high so hyperplasia of adrenal gland
-Incomplete block is late onset, complete is neonate in crisis
=sudden and severe onset
=can be virilised (breasts atrophy, voice deepen, hair loss and clitoromegaly), late menarche, oligomenorrhoea
=image with MRI, CT or USS/ 17-a-OH progesterone (mainly adrenal origin)/ Synacthen test
How do we investigate doping?
-Low LH due to negative feedback
=In doping look for pattern of other androgens and metabolites and they will be different from PCOS where there is a spectrum with several forms of androgen elevated
What are the differentials of low oestradiol?
- Hypogonadotropic hypogonadism
- Hyperprolactinaemia
- Premature Ovarian Failure
- Exogenous hormones
Describe hypogonadotropic hypogonadism
-Low LH, low FSH, low E2, normal PRL
=often symptom free (childlike in hormonal status)
=low body fat in anorexia and over exercise, acute stress and chronic stress (severe illness)
=bone scan and hormones
Describe hyperprolactinaemia
-Low LH, low FSH, Low E2, high prolactin
=galactorrhoea
=bitemporal hemianopia, tunnel vision= microadenoma (MRI)
=drug treatment (antipsychotics and antiemetics are dopamine antagonists)
=hypothyroidism (thyroid function test)
Describe exogenous hormones
=contraceptive depo provera causes prolonged amenorrhoea with low E2
Risk of POF
-Osteoporosis
=Acceleration of heart disease to male levels
Management of POF
-Oestrogen replacement
=combined pill
=donor egg (and primed with oestradiol followed by progesterone)
Management of Ashermans syndrome
- Main treatment for pregnancy
- Hysteroscopy and curettage to break down adhesions and copper coil to hold sides of uterus apart for endometrium to regrow and work normally (remove after 4 months)
Risk of PCOS
-Hormone imbalance exaggerated by weight and insulin resistance
-Associated with metabolic imbalance such that there are higher concentrations of insulin
=more likely to be T2DM
-Thick endometrium
(unopposed E2)= heavy bleed and risk of hyperplasia
Management of PCOS
-Weight loss
-Lowering insulin with metabolic approach (metformin)
-Hormonal treatment
=contraceptive pill
=raise FSH for pregnancy (injections/ clomifene, tamoxifen oestrogen antagonists)- only for 5 days at start
Management of CAH
-Suppress ACTH by low dose glucocorticoids (dexamethasone)
=Replace glucocorticoids and reduce drive to androgens
Management of hypogonadotropic hypogonadism
-Lifestyle modification
-Oestrogen replacement (COCP, sequential HRT)
=headache, nausea, tender breasts so counselling
-Pulsatile GnRH/ LH and FSH injections for pregnancy
Management of hyperprolactinaemia
-Dopamine agonist =shrink microadenoma =bromocriptine (daily) =cabergoline (weekly) -Surgery if pressing on optic chiasma
Examples of anti-oestrogen drugs
- Ovulation induction = clomifene blocks oestrogen receptors at anterior pituitary
- Treat oestrogen sensitive breast cancer = Tamoxifen
- Letrozole can be used for either as aromatase inhibitor
What are the C numbers for hormones?
-Oestrogens C18
-Androgens C19
-Progesterone C21
-Corticosteroids C21
=glucocorticoids (cortisol, prednisolone, dexamethasone)
=mineralocorticoids (aldosterone, fludrocortisone)
