Polycystic Ovary Syndrome (PCOS)
Polycystic ovary syndrome is a heteroge collection of signs and symptoms that gathered together form a spectrum of a disorder with a mild presentations in some and a severe disturbance of reproductive endocrine and metabolic function in others.
In 2003 the joint European society of Human Reproduction and Embryology/ American Society for Reproductive Medicine (EHSHRE/ ASRM) agreed on a refined definition of PCOS.
Presence of two of the three criteria constituted PCOS.
- Oligo and or anovulation
- Hyperandrogenism(Clinical and or Bio-chemical)
- Polycystic ovaries (with exclusion of other etiologies)
The morphology of the polycystic ovary has been defined as an ovary with 12 or more follicies measuring 2-9 mm or an ovarium volume > 10cm³.
Hyperandogenism may be determined by clinical or biochemical parameters. Clinical manifestations are hirsutism, alopecia and acne. Hirsutism is a subjective diagnosis and few practioners use scoring methods. Hirsuitism is more prevalent in Mediteranean, South East Asian and Middle Eastern countries. Acne after adolescence may be an indicator for PCOS and many patients may first see a dermatologist.
Total Testosterone – Increased
Free Testosterone – Increased
The spectrum of clinical manifestations of PCOS
- Hyperandrogenism (acne/hirsuitism/ alopecia not virillisation)
- Menstrual distrubance
- Asymptomatic, with polycystic ovaries on ultrasound scan.
- Fasting Insulin (not routinely measure)
- Impaired glucose tolerance test (GTT done in obese patients)
- Increased Androgens (Testosterone + Androsteredione)
- Increased LG (usually normal /FSH)
The alpha and Beta subunits have two H linked glycosylation sites. Oligosacerhoids form 30% of the molecule.
Human hcG differs from LH by having a single additional C terminal peptide and may circulate at concentrations of 1% of LH. Bioactive LH is found in excess in PCOS patients and may be a better marker than FSH LH ratios.
The genetic variant of LH(VLH) has a higher biological activity than wild type of LH. Abnormality inhibin secretion have been implicated in the pathogenesis of PCOS, Hyper secretion of inhibin B by the ovary suppresses FSH.
Hyperinsulinemia: IN PCOS the major defect is a decrease in insulin sensitivity secondary to a post binding abnormality in insulin receptor mediated signal transduction. There is also a decrease in the insulin responsiveness. The decrease in insulin sensitivity is independent of obesity, metabolic abnormalities, body fat topography and sex hormone levels.
However rather than BMI it is the body fat distribution that is important. Visceral obesity with increased waist – hip ratio increases insulin resistance. Insulin acts through multiple sites to increase androgen production.
- Increased insulin resistance increases circulating androgens.
- Excess insulin binds to IGF 1 receptors and enhances the theca cell androgen production.
- Excess insulin decreases the synthesis of SHBG in the liver thereby increasing free T.
- Excess insulin inhibits hepatic secretion of insulin like growth factor protein (IGB P – 1) leading to increased bioavailability of IGF 1 and 2.
- Insulin may increase cytochrome P450 17 alpha enzyme activity thereby increasing androgens.
Insulin resistance is defined as a reduced glucose response to a given amount of insulin and may occur secondary to resistance at the insulin receptor, decreased hepatic clearance of insulin and or increased pancreatic sensitivity.
Obese+ non obese PCOS women are more insulin resistant and this is independent of obesity. Pancreatic B cell dysfunction is responsible for this insulin resistance. Phosphorylation causes insulin receptor substrates IRS 1-4 to promote glucose uptake via the trans membrane glucose transporter (GLU T4). Tyrosine phosphorylation increases tyrosine kinan activity of the insulin receptor whereas seine phosphorylation inhibits it and it appears that 50% of women with PCOS have excess syrine phosphosylation which inhibits normal signaling thus affecting glucose haemostasis. Serine phosphosylation also increases P450c 17 activity androgen synthesis.
Genetics in PCOS:
The familial clustering of PCOS seen in clinical practice shows that there is a genetic component in PCOS. No clear cut mode of inheritance has been identified but both AD and X linked mode has been proposed.
CYP 11 a gene
ACC 1 polymorphism of β FSH gene
The variations in these expressions may explain the hetrogencity of PCOS.
Long term Sequalae:
- Diabetes Mellitus:
PCOS contributes to 20% of impaired glucose tolerance and 40% type 2 diabetes. Long term metabolic abnormalities are related to reduced sensitivity to insulin.
- Cardiovascular Risk:Dislipidaemia – decreased HDL
Increased triglyceridesare the factors for CVD. Subclinical and clinical atherosclerotic changes do occur at a greater rate in PCOS but is apparent in the perimenopausal age.
- Endometrial cancer: Breast cancer, ovarian cancer.
Data supporting gynaecological cancers and PCOS are mostly inferential. Ultrasound scan is a good screening tool and endometrial thickness < 4mm is rarely associated with endometrial cancer.
Management of PCOS:
The management of the PCOS is symptom oriented.
Diet and exercises are the key to symptom control. Weight loss (5-10%) of existing weight improves endocrine profiles.
- Combination of cypretrone Acetate 0.3mg with Ethinyl Estradiol 30mcg marketed as Dianette 35 is the best.
- The best oral contraceptive for women with PCOS is marked as Yasmin. This contains EE 30 msg with a new progesterone drospirenone (5mg) Drospirenone is derived from 17α spironolactone. It increases SHBG leveles 3 to 4 fold and works as an antimeneralo corticoid so may help weight loss. It cannot be used in women with renal disease or hyperkalaemia. It can increase thromboembolism.
- Progestins alone/ Cypreterone
- GnRh a alone
- Antiandrogen therapy
- Spitonolactone – is a diuretic and aldosterone antogonist and binds with androgen receptors with 67% affinity to DHT. It can inhibit ovarian and adrenal stereoidgenesis and inhibit 5 α reductase activity.
25-100mg twice a day.
- Flutamide – Non steroidal antiandrogen
250mg per day
Risk of teratogenecity is present.
Therefore contraception is advised.
- Finasteride – Inhibits both form of 5α reductase
1 mg per day
- Physical methods include depilatory
Creams, electrolysis + laser therapy.
Treatment of Acne:
- Topical benzoyl peroxide 5% or Tretinoin
The aim is to provide regular menstrual cycles.
- Diet and exercises aid weight loss of 5-10%
- Insulin sensitizing drugs – Metformin can regularize cycles in 50% of cases.
- Cyclical EE with Cypreterone acetate Diane 35.
- Cyclical EE with drosperinone.
- Cyclical progesterone only
10 mg Medroxy Progesterone daily for 10 days every month.
Management of Infertility
- Weight loss
- Clomiphene citrate
50-100mg Day 2-6 spontaneous or induced bleeding.
Start with 50mg/ day each cycle.
There is no advantage in using a dose greater than 100mg/ day.
There is no evidence that higher dose increases ovulation or pregnancy rate.
A course of 3-6 cycles is sufficient to know whether CC will work.
80% women ovulate with cc
40% achieve a pregnancy with cc
Those who do not ovulate with cc are called clomiphene resistant. Failure to conceive despite ovulation is called clomiphene failure.
The reasons of prengancy failure may be:
- The antiestrogenic effects of cc on the cervical mucus and endometrium. Minimum 8mm endometrial thickness should be present to achieve a pregnancy.
Multiple pregnancy rate with cc is about 11% and miscarriage rate is 23.6%.
There is no increased risk of congenital abnormalities with cc.
They do not posses the antiestrogenic effect of clomiphene citrate. Used as 2.5-5mg. Currently its use is banned in India.
- Conventional treatment with step up FSH injections 75 i u daily resulted in 34% pregnancy rate and severe OHSS in 4%.
A further study by Track et al produced a cumulative pregnancy rate of 82% but had unacceptable high rates of OHSS and multiple pregnancy.
This is due to extreme sensitivity of the polycystic way which contains twice the quantity of antral follicles.
- Chronic low dose of FSH was designed to reduce the complications due to multifolicular development.
Low starting dose for 14 days with small incremental doses when necessary at intervals of not less than 7 days until monofollicular development occurs. Usually 37.5 iv daily.The chronic low dose protocol yielded 70% uniovulatory cycles with pregnancy rates of 40% in patients and 20% per cycle.OHSS and multiple pregnancy rate was < 6%.
- Step down protocol.
Starting dose of 150 iu and decreasing the dose by 0.5 ampule after follicle reaches 10mm and by same amount every 3 days if follicular growth continued. A comparison of this regimen with the classic step up demonstrated a monofollicular growth rate of 88% in step down to 56% in step up protocol. In a French multicenter study comparing step up and step down protocol it was show that step up regimen was superior.
- Gonadotrophin Release Hormone Agonists GnRh a
Its use in IVF cycles is undisputed. GnRha eliminates premature lutenisation. However its use in PCOS will exacerbate the problem of multifollicular development and increased cycle cancellation, OHSS and multiple pregnancy.
Antagonists suppress gonadotrophin release within a few hours, have no flare effects and gonadal function resumes a few hours without lag effect.
GnRh antagonist could be given in a single or multiple dose when the leading follicle is 13-14 mm. This will theoretically present premature luteinisation. It will shorten cycle treatment, less gonadotrophin usage and less OHSS and multiple pregnancy.
This is an oral bignamide which decreases insulin levels and as a result, circulating androgens are reduced. It enhances peripheral utilization of glucose and inhibits its synthesis in the liver.
It acts on the post receptor levels and stimulates insulin mediated glucose disposal.
Dose used 500mg twice daily or 850mg thrice daily if tolerated.
Combination of cc with Metformin has markedly improved ovulation and pregnancy rates.
A Cochrane review has confirmed a beneficial effect of metformin improving rates of ovulation when compared to placebo; and also in improving both rates of ovulation and pregnancy used with cc compared with cc alone.
It has a role after 3-6 cycles of failure of clomiphene citrate when you want to assess the pelvic cavity.
Serum LH and testosterone levels decrease at the ovarian level and this helps to enhance pregnancy rate both with and without gonadotrophin therapy.
The other advantage is that it reduces the amount of gonadotrophins required to achieve ovulation and decreases multifollicular development.
Only 4-5 punctures should be made to prevent premature ovarian failure.
Pregancy rates of 70-80% can be reached.
Cumulative pregnancy rates are lower than with gonadotrophins alone at s6 months but reach similar levels after 12 months.
The production of androstenedione + 17α hydroxy prog was found to be increased. There was no increase with ACTH injection – which excluded a significant role of adrenal androgen production. This indicates that hyperandrogenemia is ovarian in origin.
Hyperandrogenism in the ovary is caused by
- Excess LH
- Excess insulin
- Excess IGF1
Intra ovarian changes in PCOS:
- Ovary contains a complete insulin like growth factor system (IGF 1 and IGF 2) receptors that modulate LH stimulated androgen synthesis.
- IGF 1 stimulates the expression of LH receptors thereby amplifying action of LH.
LH acts on granulose cells in the presence of insulin leading to premature lutenisation, maturational arrest and excess androgen production.
Hypothalamic Pituitary ovarian Axis
Serum LH concentration is significantly elevated in PCOS patients (in the absence of LH surge or menopause transition). Excess LH is associated with reduced chance of conception. However the altered FSH/ LH ratio is no longer required or useful in the diagnosis of PCOS.
GnRh stimulates production of both FSH and LH from the gonadotroph in a pulsatile manner. When pulsalitiy is low FSH is produced when pulsatility is rapid LH secretion predominates.
The action of GnRh is modulated at the pituitary, the sensitivity of which varies the menstrual cycle in synchrony with E2 levels. In early follicular phase E2 levels are low, as E2 level rises with follicular development it potentiates GnRh responsiveness increasing GnRh receptors. The arcuate nucleus in the hypothalamis acts as a transducer for neuronal cells into endocrine signals. However it appears that hypothalamic dysfunction does not contribute to excess LH. It suggests that increased LH involves a perturbation of ovarian pituitary feedback.
LH exists in multiple forms.
Pregnenolone is converted to DHEA by α 2 step along delta 5 pathway, the conversion catalysed by cytochrome P450 c 17α which is dependent on trophic hormones. There is a school of thought that believes that the adrenal and ovary share a defect in the activity of the 17α hydroxylase and cytochrome P450 enyme system. When this sytem is induced there may be excess production of 17 hydroxy progesterone and conversion to androgens. This forms the substrate to convert to oestrones. Oestrones perturb gonadotrophin secretion. A certain amount of intra – ovarian androgen are essential for normal follicular growth. If the synthesis of androgens is in excess poor follicular maturation and increased follicular atresia occurs.
|Insulin via IR receptors||CRH|
|Insulin via IGF 1 receptors||TGFβ|
In 1990 Rosenfield et al suggested that derangement of P 450 17α activity played a central role in excess androgen production. Androgen excess is usually prevented by the down regulatory mechanism of LH and IGF. This coordination is lost in PCOS. This is mainly due to the dysregulation of P450 17α. Also the Hyperandrogenemia in PCOS is predominantly ovarian in origin.
This has been confirmed by suppressing androgen secretion form from adrenals by dexamethasone injection and then measuring androstenedione and 17α hydroxy progesterone by stimulating its production by a single injection of GnRha.
Androstenedine is produced from cholestrol under influence of LH in the ovary and ACTH in the adrenal gland.
|STAR||Side chain cleavage|
|PREGNENOLONE||17α HYDROXY||17, 20||DHEA|
|PROGESTERONE||DELTA 4||17 HYDROXY||ANDROSTENEDIONE|
|17 HYDROXY PROGESTERONE||NE|
|21 Hydroxylase||21 hydroxylase + 17 β hydroxy steroid delydrogenase|
|11β hydroxylase||11β hydroxylase||5 α reduction|
The initial step in the bio synthesis of all steroid hormone is the conversion of cholesterol to pregnenolone, by α 2 stage process involving cholesterol side chain cleavage enzyme and acute steroidogenic regulatory protein.
|DM||Impaired GTT||Impaired Fasting Glycaemia|
|FBMS mmol/ L||≥ 7.0||< 7.0||≥ 6.1 and < 7.0|
|2 hours||≥ 11.11||≥ 7.8 and 11.1||< 7.8|
|Action||Refer to diabetic clinic.||Dietary advice check FBS annually||Dietary advice check FBS annually|
Clinically women can be hirsute, have acne and alopecia, although the presence of the latter two in isolation is not so common.
The measurement of total testosterone is usually sufficient. A value of > 4.8 nml/L makes it necessary to exclude CAH or Cushings syndrome.
The ovary and adrenal cortex share the bulk of steroid biosynthesis pathways by making equal contributions to the circulating concentrations of androstenedione and testosterone in a normal premenopausal woman.
Both glands secrete androstenedione more than T.
50% of T is derived from peripheral metabolism of androstenedione.
Androgen production in the ovary is the theca interna of the ovarian follicle while adrenal androgens are produced by the zone fasciculata of the adrenal gland.
5.Decreased SHBG (results in increased free androgen index)
6.Increased Estradiol (not measured routinely)
Investigations for PCOS:
|TEST||NORMAL RANGE||ADDITIONAL POINTS|
|Pelvic Ultrasound||To assess ovarian morphology and endometrial thickness.||TAS (unmarried) TVS(married)|
|Testosterone(T)||0.5-3.5nmol/L||A total T value is adequate for general screening. If total T>5nm/L measure other androgens to exclude other causes of hyperandrogenism like CAH or adrenal tumours.|
|SHBG||16-119nmol/L||Insulin suppresses SHBG, resulting in high FAI in the presence of normal T.|
|Free Androgen Index (FAI) T x 100/ SHBG||< 5||The measurement SHBG is not a routine practice and will not affect management.|
|Estradiol||Measurements unhelpful in diagnosis.||Estrogenisation is confirmed by endometrial thickness.|
|LH||2-10 iu/1||Best measured during D1-3 of menstrual bleed.|
|Prolactin||< 500 mu/L|
|Fasting insulin||< 30 mu/L||Not routinely measured
Insulin resistance is measured.