Disorders of Ovulation Flashcards
Introduction
Whenever you measure any of the female hormone (LH, FSH, progesterone) , you need to know where in the menstrual cycle you are taking the blood test.
- There is normally a preovulatory surge in LH and FSH
- you can see Estradiol levels rising and the falling just before the preovulatory surge and then have a secondary rise in the luteal phase of the cycle. Estradiol is one of three estrogen hormones naturally produced in the body.
- you can see that the progesterone levels are low in the follicular phase of the cycle and then provided the cycle has been ovulatory and the corpus luteum has been formed, progesterone levels peak because they are produced by the corpus luteum and you can see along the bottom a reminder that alongside the menstrual cycle is the endometrial cycle with the proliferative phase followed by the secretory phase.
Central mediator: kisspeptin
- The discovery of kisspeptin has helped us to understand the regulation of Gonadal axis
- kisspeptin is A GnRH secretagogue (promotes the secretion of GnRH): so its right at the apex of the reproductive axis in the hypothalamus
- These KISS1 neurons are highly responsive to oestrogen and they mediate both the positive and negative central feedback of sex steroids on GnRH production.
kisspeptin is very important in mediating the Metabolic influences on reproduction
–mediated by leptin via the kisspeptin system
–also important in terms of the permissive effect on puberty & reproduction
Diagnosis of ovulation
Clinical: Take a history from the woman.
- the best predictor of ovulation is regular menstruation usually 28 days
- (check not on hormonal contraception)
- i.e an oral contraceptive may make you bleed but its not a period
- some women experience mid cycle pain at ovulation
- other women notice that their vaginal discharge alters (increased mucus post-ovulation)
-Ovulation pain (leakage of follicle fluid at the time of ovulation irritates the peritoneum and causes pain.
Diagnosis of ovulation
1. Biochemistry: Day 21 progesterone blood test (7 days before start of next menstrual period). If cycle 28 days then take blood on Day 21. If cycle longer then take blood 7 days before expected usual period eg Day 28 if cycle 35 days long.
2. LH detection kits: urinary kits bought over the counter. LH detection kits used from Day 10 daily. Once the LH surge is detected then ovulation occurs 24-36 hours later.
3. Transvaginal pelvic ultrasound done from Day 10, alternate days to demonstrate the developing follicle size and Corpus Luteum. The follicle grows daily and usually at 20-24mm size ovulation occurs, post ovulation you can visualize the corpus luteum as it looks different to a follicle. The endometrium post ovulation is usually >12mm thi
*not Basal Body Temperature, cervical mucus change, vaginal epithelium changes nor endometrial biopsies
Amenorrhoea
- lack of a period for more than 6 months
•Primary Amenorrhoea - never had a period (never went through menarche)
•Secondary Amenorrhoea -has menstruated before
Oligomenorrhoea
irregular periods
•usually occurring more than 6 weeks apart
Causes of Ovulation problems
1. Hypothalamus (lack of GnRH)
•GnRH deficiency and this can be a gentic condition called (Kallmann’s syndrome) and some patients with Kallmann’s syndrome because of the way the neurons develop in the olfactory bulb, also have anosmia
–may be associated with anosmia (loss of smell)
• more commonly you may get a condition called ‘Functional’ hypothalamic amenorrhoea
-functional meaning that there is no structural abnormality, if you image the hypothalamus, it looks normal. this is seen in people following extreme weight loss and can be stress related, excessive exercise , people with eating disorder like anorexia nervosa/bulimia
Causes of Ovulation problems
2. Pituitary (lack of FSH and LH)
-this can cause ovulation problems i.e in people with;
- pituitary tumours (prolactinoma orother tumours)
- or post pituitary surgery /radiotherapy
Causes of Ovulation problems
3. Ovary
•Premature ovarian insufficiency. this may include;
–Chromosomal abnormalities eg Turner syndrome
–Autoimmune causes
–Iatrogenic causes
•Surgery/chemotherapy that mya be cytotoxic/radiotherapy
Causes of Ovulation problems
4. Hyperandrogenism
-An imbalance with an excess amount of male hormones
–Polycystic ovarian syndrome: commonest cause
–Congenital adrenal hyperplasia
HIRSUTISM
Excess body hair in a male pattern distribution i.e
‘Androgen-dependent’ hair growth.
- This is different from people being generally hairy throughout their body which is independent of androgens and is sometimes called Hypertrichosis
- In this people there is both Familial / racial hair growth effects on hair growth and this is not the same as HIRSUTISM.
Differential diagnosis of hirsutism
1 • vast majority 95% is PCOS or ‘idiopathic hirsutism’ (no clear endocrine cause for it)
2 • much rarer causes 1% is Non-classical congenital adrenal hyperplasia (CAH)
3• <1% Cushing’s syndrome
4.• <1% Adrenal / ovarian tumour which over produces androgenic hormones
*Prevalence of polycystic ovarian syndrome: 5-10% women!
WHEN TO WORRY
1•Sudden onset of severe symptoms of hirsutism
2•Virilisation (the development of male physical characteristics)
–Frontal balding
–Deepening of voice
–Male-type muscle mass
–Clitoromegaly (abnormal enlargement of the clitoris. )
3. we will also investigate if we think the patient might have Possible Cushing’s syndrome (high cortisol)
Clinical Features of PCOS ( Polycystic ovarian syndrome
(PCOS)
-Hyperandrogenism –Hirsutism, acne
-. Chronic oligomenorrhoea / amenorrhoea
–
- sparse irregular menstrual period which can cause a problem with fertility
- It is associated with Obesity (but 25% of women with PCOS are “lean”)
ELEMENTS IN THE DIAGNOSIS OF PCOS
There are 3 overlapping ways of diagnosing the condition;
- Androgen excess
- (this can be manifested clinically through Hirsutism)
- Acne (can be manifested clinically by measuring the levels of testosterone) - Oligo/Anuovulation- the sparse menstrual periods.
- The cystic appearance of the ovaries.
USS appearance of Polycystic Ovaries
- If you do a scan of a woman with PCOS, they may or may not have polycystic ovaries
- You must reassure patients that this is not an ovarian cyst which is something different
- The things you can see around the ovaries looking like pearls are immature follicles which have all come to the surface at the same time. whereas, you will just have one follicle becoming dominant prior to ovulation.
- not all women with PCOS will have this ultrasound scan appearance
- because a transvaginal test is invasive, it not always the necessary test to do to diagnose PCOS if you have clinical and biochemical grounds to make the diagnosis.
> 10 subcapsular follicules 2-8 mm in diameter, arranged around a thickened ovarian stroma
This is not the same as a cyst; Not cysts – definition of cyst is a mass > 3cms. Wrong name for the condition! Should be poly small follicles disease!
Hormonal abnormalities in PCOS
Not in everybody but frequently you will see;
- Raised baseline LH and normal FSH levels. Ratio LH:FSH 3:1
- Raised androgens and free testosterone
- Reduced Sex Hormone Binding Globin (SHBG)
_*Oestrogen usually normal_
Sex Hormone Binding Globulin
- Produced by the liver
- Binds testosterone and oestradiol
•If testosterone bound - not converted to active component dihydrotestosterone ie not “free” when a hormone is bound, its not active or free.
- SHBG is increased by oestrogens. i.e women on the pill will have high levels of SHBG.
- SHBG decreased by testosterone thus releasing more free testosterone.
Origin of PCOS
- not fully understood.
- there is a hypothesis that something happens in utero, some sort of programming resulting in both a metabolic and endocrine disorder
- so a tendency to insulin resistance and central weight gain as well as a tendency to a high LH secretion with hyper androgenemia and anovulation.
- its a topic for ongoing research and not yet fully understood.
We are sure that there is a link between insulin resistance and the metabolic syndrome and polycystic ovarian syndrome
- The features of PCOS can be associated with obesity and certainly exacerbated by obesity
- the exact mechanisms for this are not yet understood.
- high levels of insulin in someone who is resistant to insulin can reduce levels of SHBG resulting in more free testosterone
TURNER SYNDROME
-Turner syndrome is a syndrome, it’s not just primary ovarian insufficient , it has other associations. they include;
1. Short stature
•Consider GH treatment. although they are not deficient in growth hormone, giving them GH in childhood can result in some value centimetres of growth in later life.
2. Cardiovascular system
- Coarctation of aorta
- Bicuspid aortic valve
- Aortic dissection
- Hypertension (adults)
*This is screened for using cardiac MRI and Echocardiogram
3. Renal
•Congenital abnormalities
4. Metabolic syndrome
-type 2 DM, weight gain.
5. Hypothyroidism
6. Ears / hearing problems
7. Osteoporosis (lack HRT)
ADRENAL STEROID SYNTHESIS
Within the adrenal cortex, there is a complex network of pathways to synthesise all the various steroid hormones and each step is mediated by a different enzyme.
- you can see that from cholesterol, we can make aldosterone (mineralocorticoid), cotisone (the glucocorticoid), and also adrenal androgens.
- The predominant and most active androgen is testosterone, which is produced by the male testes. The other androgens, which support the functions of testosterone, are produced mainly by the adrenal cortex—the outer portion of the adrenal glands—and only in relatively small quantities.
- The ovaries, which produce a woman’s eggs, are the main source of estrogen from your body. Your adrenal glands, located at the top of each kidney, make small amounts of this hormone, so does fat tissue
Congenital adrenal hyperplasia (CAH)
-There are enlarged adrenal glands present at birth
•disorders of cortisol biosynthesis
–Carrier frequency 1 : 60. common
–Most patients are compound heterozygotes, they inherit 2 different genetic defects. so 2 different mutations on different alleles from each of their parent.
-This disease may be caused by a number of enzyme insufficiency in the adrenal corticosteroid pathway.
•95% CAH cases caused by 21-hydroxylase deficiency which helps in making aldosterone and cortisol.
–This results in Cortisol deficiency
–May have aldosterone deficiency
–but an Androgen excess because it rarely affects androgen synthesis.
–It is quite variable and it Depends on degree of enzyme deficiency
*Low levels of cortisol stimulates the pituitary to release more ACTH which stimulates the adrenal gland to continually proliferate and this is what causes enlargement/hyperplasia of the adrenal gland.
21-HYDROXYLASE DEFICIENCY
-21-HYDROXYLASE DEFICIENCY (in blue)
-Causes Defect in cortisol biosynthesis
- raised CRH / ACTH (lack of negative feedback)
-drives excess adrenal androgen production
Diagnosis: we measure 17-hydroxyprogesterone which come just before the road block and it normally very high.
Can confirm with Synacthen test
