eek 5 Flashcards
range of normal menstrual cycle? menses length
21-35days
3-8days
when does ovulation usually occur in normal menstrual cycle? how much blood is normally lost?
day 14
30ml
what is menarche
when periods start
what are the three stages of ovarian cycle?
follicular, ovulation, luteal
what are the oestrogen levels when follicular stage begins/why does it occur?
low (oestrogen)
what stimulates follicle to develop?
Anterior pituitary secretes FSH and LH [stimulation follicle to develop]
what happens in development of follicle/follicular stage?
- A leading follicle develops
- Granulosa cells around egg enlarge, releasing estrogen
- This causes this uterine lining to thicken
[BASICALLY:During this phase, the ovarian follicles mature and get ready to release an egg]
what are the stages of the uterine cycle?
menses, proliferative, secretory
why does ovulation occur?
Happens at the peak of follicular growth in response to LH surge
what happens in ovulation?
[BASICALLY:second phase of the ovarian cycle in which a mature egg is released from the ovarian follicles into the oviduct]
- levels of estradiol reduce
- massive LH peak (positive feedback mechanism due to prolonged exposure to estradoil)
- proteolytic enzymes and prostaglandins are activated, → digestion of the follicle wall collagen → Follicle ruptures, releasing ova into the Fallopian tubes.
what is the luteal phase?
final phase of the ovarian cycle and it corresponds to the secretory phase of the uterine cycle; the lining of uterus gets thicker to prepare for a possible pregnancy
what is a corpus luteum?
It is the remains of the ovarian follicle that has released a mature ovum during a previous ovulation.
what does the corpus luteum do?
produce high levels of progesterone (peak at 1 week post-ovulation)
what happens to the corpus luteum
if pregnant - embryo will release hormones to preserve corpus luteum
if non-pregnant - stops progesterone, decays, uterine lining detaches, expelled by menstruation
what is expelled in menstruation? how long does this take?
Tissue, blood, unfertilized egg all discharged
Can take from 3-7 days
what is the HPO (hypothalamus-pituitary-ovary axis) hormones?
GnRH (Gonadotropin-releasing hormone) stimulates follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from ant pit.
what part of the hypothalamus is responsible for producing GnRH?
Arcuate nucleus
there are two parts of the ovary (outer cortex and inner medulla), which contains follicles?
outer cortex
what attaches the ovaries tot the pelvic wall?
the IP ligament [suspensory ligament of the ovary, also infundibulopelvic ligament]
what is the endometrium? what increases its thickness?
basal layer and superfuical layer of uterus (thickens in response to oestrogen)
what cause the endometrium to slough off?
Lack of hCG and progesterone
what is GnRH?
- gonadotropin releasing hormone
- is a deca peptide hormones
how many types of GnRH are there? which important?
3 types of GnRH hormone
GnRH 1 is responsible for the reproductive function (released in pulsatile manner, t1/2=2-4mins)
what is FSH?
- follicle-stimulating hormone
- glycoprotein, t1/2 - hours
why is FSH important?
responsible for recruiting the dominant follicle
It is also responsible for granulosa cell growth and activates aromatase activity (precursor to oestrogen)
what does LH do?
- Acts on the theca cells
- Uptake of cholesterol
- Androgens to oestrogens
what does oestrogen do?
Acts synergistically with FSH
Induces FSH and LH receptors
where are inhibins found?
[Local peptide] in the follicular fluid
what do inhibins do?
-ve feed back on pituitary FSH secretion
Locally enhances LH-induced androstenedione production
where are activins found? what do they do?
Found in follicular fluid
Stimulates FSH induced estrogen production
what are the tubular components of the testes?
sertoli cells
germ cells
what are the interstitial components of the testes
Leydig cells
Capillaries
what is the function of sertoli cells? how do they do this?
to support germ cells in development
in sperm maturation, excess cytoplasm and materials in the cells are “eaten up” by Sertoli cells,
what is the function of germ cells?
to mature into sperm
[Spermatogonia → 1° Spermatocytes
→2° Spermatocytes
→Spermatids (Early to Elongated)
→Testicular spermatozoa]
what occurs in the maturation of sperm?
formation of acrosome from Golgi(digestive enzymes) - outer shell for ovum
formation of flagellum from centriole - tail for motility
why is egg bigger than ovum? (what does it contain that sperm doesn’t )
yolk proteins ribosomes t-RNA m-RNA protective chemicals
(cytoplasm and organelles necessary for cell division and growth to begin)
site of fertilisation?
ampulla of the fallopian tube
what are pre-fertilisation events that occur in women?
thinner cervical mucus
fibril end comes into contact with ovary and peristalsis brings egg to ampulla
what is Capacitation
functional maturation of the spermatozoon
necessary for acrosome reaction (enzyme to penetrate egg)
process of fertilisation
chemotaxis, release of acrosomal enzymes, binding of sperm, passage through extracellular envelope, fusion of pronuclei
chemotaxis in fertilisation
Around the egg there are specific receptors that produces exocytosis and acrosome reaction
what triggers please of acrosomal enzymes?
Zona pellucida ZP3 [when sperm comes in contact with egg]
what occurs in the binding of sperm in fertilisation?
corona radiata (part of ovum) broken through (aided by flagellum), bona reaction then occurs preventing polyspermy
how is polyspermy avoided?
fast block (NA+ influx changes membrane potential)
slow block (kinase stimulation has many effects, e.g.: inc calcium)
what occurs in egg activation?
Dramatic increase in the levels of free intracellular Ca2+ ions in the egg shortly after the sperm makes contact with the egg’s plasma membrane
Act as second messengers to initiate changes
what does sperm penetration do?
- inc Ca2+
- triggers egg to complete meiosis
- triggers cytoplasmic rearrangement
- sharp inc in protein synthesis and general metabolism
fusion of nuclei in fertilisation
final stage of fertilisation; haploid sperm and egg fuse for diploid zygote
where is oestrogen produced in the body?
ovaries, adrenal glands and fatty tissue
how is oestrogen made?
aromatase acts on steroid precursors creating estradiol
why do fat men get ED?
inc fat means inc oestrogen and this decreases testosterone = ED (also neurological/vascular problems at higher risk)
what is Oligomenorrhea
reduction in frequency of periods to less than 9/year
what is Primary amenorrhea
failure of menarche by the age of 16 years
what is Secondary amenorrhea
cessation of periods for >6 months in an individual who has previously menstruated
what are causes of amenorrhea?
physiological,
primary and secondary amenorrhea
what are physiological causes of amenorrhea?
Pregnancy
Post-menopausal
causes of Primary amenorrhea
Consider congenital problems (Turner’s syndrome, Kallman’s syndrome), anatomical problem
causes of secondary amenorrhea?
Ovarian problem: PCOS, Premature Ovarian Failure
Uterine problem: uterine adhesions
Hypothalamic Dysfunction: weight loss, over exercise, stress, infiltrative
Pituitary: high PRL, hypopituitarism
Hx of amenhorrhea
Symptoms of oestrogen deficiency (flushing, libido, dyspareunia)
Hypothalamic problem: exercise, weight loss, stress
Features of PCOS/androgen excess : hirsutism/acne
Anosmia ?Kallman’s
Symptoms of hypopituitarism/pituitary tumour including galactorrhea
?Drugs associated with hyperprolactinemia
Examination of amenorrhea
Body habitus ?Turners
Visual fields/anosmia
Breast development
Hirsutism/acne/androgen excess
investigating oligo/amenorrhea (necessary )
- LH, FSH, Oestradiol
- Thyroid function, Prolactin
what additions investigation can be done for oligo/amenorrhea
Ovarian ultrasound +/- endometrial thickness
Testosterone if hirsutism
Pituitary function tests + MRI pituitary if hypothalamic pituitary probems suspected
Karyotype if primary amenorrhea or features of Turner’s syndrome
what is female hypogonadism identified by?
low levels of oestrogen
why when body is under stress (phycological, anorexia, exercise…) do periods stop?
body stops GnRH (as doesn’t want to get pregnant when not well)
a low estradiol and low FSH/LH diagnose what?
secondary hypogondism
a low estradiol and high FSH/LH diagnose what?
primary hypogonadism (ovaries have packed up)
where is cholesterol converted to oestrogen?
in the ovaries (primarily) - deficiency leads to amenhorrea
what is primary hypogonadism also known as?
hypergonadotrophic hypogonadism
what is secondary hypogonadism also known as?
hypogonadotrophic hypogonadism
commonest cause of primary hypogonadism
premature ovarian failure
commonest causes of secondary hypogonadism?
high PRL, hypopituitarism (primary pit or hypothalmic problem)
what is premature ovarian failure (POF) classified as?
loss of normal function of your ovaries before age 40(early menopause)
what is POF
Amenorrhea, oestrogen deficiency and elevated gonadotrophins occuring < 40years of age, as a result of loss of ovarian function
how is POF diagnosed?
FSH >30 on 2 separate occasions > 1 month apart
causes of POF
- Chromosomal abnormalities (e.g. Turner’s syndrome, Fragile X)
- Gene mutations (e.g. FSH receptor/LH receptor)
- Autoimmune disease (e.g. association with Addison’s, thyroid, APS1/2)
- Iatrogenic (radiotherapy/chemotherapy)
what is Secondary Hypogonadism?
Hypogonadism as a result of hypothalamic or pituitary disease
Characterised by low oestradiol with low/normal LH/FSH
causes of Secondary Hypogonadism?
Hypothalamic problem:
Functional hypothalamic disorders
Kallman’s syndrome
Idiopathic hypogonadotrophic hypogonadism (IHH)
Pituitary problems
Miscellaneous:
Prader-Willi
Haemachromatosis
functional hypothalamic amenorrhea (factors affecting)
Weight change
Stress
Exercise
Anabolic steroids Systemic illness Iatrogenic (surgery/radiotherapy) Recreational drugs Head Trauma Infiltrative disorders e.g sarcoidosis
what is Idiopathic hypogonadotrophic hypogonadism (IHH)?
Identified by absent or delayed sexual development associated with inappropriate low levels of gonadotrophin and sex hormone levels in absence of anatomical / functional defects of hypothalamic-pituitary gonadal axis
features of Idiopathic hypogonadotrophic hypogonadism (IHH)?
inability to activate pulsatile GnRH
-hypogonadism, e.g: reduced or absent puberty, low libido, infertility,
hats the role of kisspeptin in regulation of GnRH?
the ligand for KISS1R – ‘Kisspeptin’ - is a potent stimulator of GnRH secretion
what is Kallman’s syndrome?
A genetic disorder characterised by a loss of GnRH secretion + anosmia or hyposmia; rest of pituitary function normal
how is kallman’s syndrome diagnosed?
clinical diagnosis of exclusion (MRI normal as is only absence of olfactory bulbs); FHx association.
what is difference between klaxon’s syndrome and IHH?
kallamans is a form of HH (has smell deficit)
pituitary dysfunction investigations relating to
loss of LH/FSH stimulation
hyperprolactinemia
causes of loss of LH/FSH (pituitary dysfunction )
Non-functioning pituitary macroadenoma (pressure effects lead to hypopituitarism)
Empty Sella
Pituitary infarction
cause of hyperprolactinemia
Prolactinomas Other pituitary pathology Drugs (anti-psynchotics, dopamine antagonists) Hypothyroidism Idiopathic
what are the ovarian causes of amenorrhea?
PCOS
ovarian failure (high gonadotrophins)
congenital problem
what are the criteria for diagnosing PCOS?
normal oestrogen levels
2/3: menstrual irregularity, Hyperandrogenism (hirsutism, elevated free testosterone)
Polycystic ovaries
what congenital problems can cause amenorrhea?
(Absence of Uterus, Vaginal atresia)
Turner Syndrome, Testicular feminisation, congenital adrenal hyperplasia (late onset CAH)
what is hirsutism?
excess hair; usually used when referring to women with male pattern hair distribution
why does hirsutism occur?
Caused by androgen excess at the hair follicle:
- Due to excess circulating androgen
- Due to increased peripheral conversion at the hair follicle
what does PCOS stand for?
Polycystic Ovarian Syndrome
causes of hirsutism?
PCOS (commonest)
Familial, idiopathic, non-classical congenial adrenal hyperplasia
adrenal/ovarian tumour
what are signs of worrying hirsutism? what is cause?
short Hx, sign of virilisation,
due to Adrenal or Ovarian Tumour
what is congenital adrenal hyperplasia (CAH)?
CAH is an inherited group of disorders characterized by a deficiency in one of the enzymes necessary for cortisol synthesis
what are most CADs due to? genetics and PC?
90% due to 21α-hydroxylase deficiency, autosomal recessive with varied clinical presentation
what are the two type of CAH? what is the difference?
classic CAH - typically diagnosed in infancy (e.g. virilisation/salt-wasting)
non-classic CAH - partial 21α-hydroxylase deficiency, Presents in adolescence/aduthood with hirsutism, menstrual distrbance, infertility due to anovulation
what is turner’s syndrome?
45X0
investigation of CAH [due to 21-OH deficiency] results
Increased 17-OH progesterone esp after ACTH stimulation
Synacthen test
androgen-secrting tumours PC
rapid symptoms - virlisation, high testosterone levels
androgen-secrting tumours investigation
MRI adrenals and ovaries will demonstrate tumours > 1cm
PCOS treatment
metformin (high BMI)
oral contraceptive pill (regulates cycle, decreases ovarian androgens)
Anti-androgens (cyproterone acetate)
local anti-androgens (efflornithine cream)
cosmesis (laser phototherapy/electrolysis)
treatment for late onset CAH?
Low dose glucocorticoid to suppress ACTH drive
turner’s syndrome genetics
severe or mosaicism possible (only affects women, infertile)
turner’s syndrome PC
short stature, webbed neck, shield chest with wide spaced nipples, underdeveloped breasts, Cubitus values, no menstruation
turner’s syndrome PC in paediatrics
Short Stature
Failure to progress through puberty:
-Normal adrenarche (pubic hair development)
-Breast development – depends when ovaries fail. May have no breast development
- 30% have some pubertal development
turner’s syndrome PC in adults
Primary or secondary amenorrhea
Infertility
problems with CVS, GI and other
CVS:Coarctation of the aorta
Bicuspid aortic valve
Hypoplastic left heart
GI:Bleed (vascular malformation)
Increased Crohns/UC
Other: lymphoedema, AI hypothyroidism, osteoporosis, scoliois, otitis media, renal abnormalities
rarer causes of amenorrhea
XX gonadal dysgenesis: absent ovaries but no chromosomal abnormality
Testicular feminisation/Androgen insensitivity syndrome: Genetically XY Male (with testes), but in the complete form, phenotypically female (pseudohermaphrodites)
male hypogonadism PC
not enough testosterone
delayed puberty, reduced body hair and beard, enlarged breasts, loss of muscle, and sexual difficulties.
what are the two types of male hypogonadism? what biochemical results seen?
Primary hypogonadism:
Low testosterone with high LH/FSH= Acquired and congenital causes
Secondary hypogonadism:
Low testosterone with inappropriate low LH/FSH = Pituitary /Hypothalamic disease
causes of primary male hypogonadism?
kleinfelter’s, y-chromosome micro deletions, Undescended testicles, Hemochromatosis, Injury to the testicles/torsion, cancer treatment (irradition/chemo), orchitis (mumps)
causes of secondary male hypogonadism?
hyperprolactinamiea, IHH (Kallmann syndrome). Pituitary disorders/damage. prader-willi syndrome, Inflammatory disease. medications, obesity
Hx of male hypogonadism
Symptoms:
Sexual function (libido, erections, ejaculation)
Age of puberty, shaving frequency etc
Fertility
Symptoms of pituitary disease
Duration of symptoms/features (permanent vs acquired)
Other relevant history (trauma, infection, chemo/radiotherapy etc)
Signs
Staging of puberty (secondary sexual characteristics)
Testicular volume
Visual fields / other pituitary disease
investigating hypogonadism in men
testosterone low, then measure LH/FSH. (high=primary and low=secondary hypogonadism)
what is kleinfelter’s syndrome?
XXY (most common congenital form of primary hypogonadism)
clinical features of kleinfelters?
Reduced testicular volume Gynaecomastia Eunuchoidism (intellectual dysfucntion in 40%) (azoospermia)
investigating kleinfelters
Low testosterone, high LH/FSH (elevated SHBG/oestradiol)
do Karytope: 47 XXY (or mosaicism)
treatment of hypogonadism
consider testosterone replacement (young men)
[does not restore fertility]
testosterone replacement pros
Improved sexual function
Bone health improved (BMD)
reduce fat and inc strength
testosterone replacement cons
CVS risk
secondary hypogonadism: generally case by and how is diagnosed?
Hypogonadism as a result of hypothalamic or pituitary dysfunction
Low 9am testosterone, low normal LH/FSH
causes of secondary hypogonadism
congenital = IHH (inc kallman’s) + CAD
functional = exercise, weight change, stress, systemic illness
Infiltrative disorders – sarcoid, haemachromatosis,
Cranial irradiation / trauma
Drugs (e.g. anabolic steroids, opiates)
Hyperprolactinaemia
Hypothalamic or Pituitary tumours / surgery
Prader-Willi syndrome
what is Gynaecomastia caused by?
Increased oestrogen action on breast tissue
causes of Gynaecomastia
Physiological
Drugs: Oestrogens, testosterone, spironolactone, digoxin +many more
Hypogonadism
Tumours; Oestrogen/androgen testicular or adrenal origin; hCG secreting (e.g. germinoma)
Endocrine disorders (e.g. thyrotoxicosis, Cushings)
Systemic illness
Hereditary disorders
Hx of Gynaecomastia
Duration of symptoms Pain? Symptoms of hypogonadism Symptoms of systemic disease History of recreational drugs / alcohol
exam of gynaecomastia
Breast tissue vs fat Unilateral/symmetrical Any hard irregular nodules Examination of testes ?tumour General examination (e.g. ?liver disease)
investigations and imaging of gynaecomastia
investigations = Testosterone, LH, FSH, Oestradiol, Prolactin, AFP, HCG, LFTs, SHBG
imaging = Breast imaging
Testicular/adrenal imaging
treatment of gynaecomastia
Reassurance in majortiy of cases
Address underlying cause (e.g. remove causative drugs)
Surgery (cosmetic)
Medication (e.g. anti-oestrogens)
what is infertility classed as?
failure to achieve a clinical pregnancy after 12 months of more of regular unprotected sexual intercourse (in absence of known reason) in a couple who have never had a child (WHO definition)
what are the two types of infertility?
Either primary (couple never conceived) or secondary (couple previously conceived, although pregnancy may not have been successful e.g. miscarriage or ectopic pregnancy)
factors affecting a woman’s fertility
<30, previous pregnancy, short time trying to conceive, intercourse around ovulation. BMI of 18.5-30kg/m2, non-smokering partners, no recreational drugs, limited caffeine.
