Polikistik Over Sendromu ve İnfertilite /Polycystic Ovary Syndrome

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Polycystic Ovary Syndrome
Synonym: Stein-Leventhal syndrome
Originally described by Doctors Stein and Leventhal in 1935, the cause of this common, poorly understood
syndrome is uncertain. It encompasses a syndrome of polycystic ovaries, in association with systemic
symptoms causing reproductive, metabolic and psychological disturbances. These most commonly present with
infertility, amenorrhoea, acne or hirsutism.
Epidemiology
Polycystic ovaries on ultrasound are very common and can be seen in up to 33% of women of reproductive
age.[1] However, the majority of women with polycystic ovaries do not have features of polycystic ovary
syndrome (PCOS) and do not require intervention. Prevalence figures vary depending on diagnostic criteria used,
but PCOS is thought to affect 5-15% of women of reproductive age.[2]
Pathophysiology[1]
The cause remains unclear but is likely to be multifactorial. The essential changes are:
Excess androgens produced by the theca cells of the ovaries (due either to hyperinsulinaemia or
increased luteinising hormone (LH) levels).
Insulin resistance, ie loss of sensitivity to insulin, resulting in hyperinsulinaemia in many women with
PCOS. Weight gain further increases insulin resistance. Effects of this increase in insulin are:
Increased androgen production through more than one mechanism
Reduced production of sex hormone-binding globulin (SHBG) in the liver. Free testosterone
may subsequently be raised as testosterone is bound to SHBG, even if total testosterone is
normal.
Raised LH levels due to increased production from the anterior pituitary (in around 40% of women with
PCOS).
Raised oestrogen levels in some women, which may lead to a hyperplastic endometrium.
The underlying endocrine disturbance can exist in the absence of polycystic ovaries; affected women may have
classical clinical features, yet biochemically normal androgen levels.
The condition appears to have a genetic link in some cases, as there is familial clustering; however, the gene
involved and mode of inheritance have not yet been identified.[3] [4]
Presentation
The patient often presents in the peripubertal period through to her mid-20s.
Symptoms
These include:
Oligomenorrhoea (defined as <9 periods per year).
Infertility or subfertility.
Acne.
Hirsutism.
Alopecia.
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2. Obesity or difficulty losing weight.
Psychological symptoms - mood swings, depression, anxiety, poor self-esteem.[5]
Sleep apnoea.
Clinical signs
These include:
The presence of hirsutism, (often on the upper lip, chin, around the nipples and in a line beneath the
umbilicus). This occurs in 60% of women with PCOS.[5]
Male-pattern balding, alopecia.
Obesity - this is common (usually central distribution).
Acanthosis nigricans - may be present and is thought to be a sign of insulin resistance.
Occasionally, clitoromegaly, increased muscle mass, deep voice (more usually, these are signs of
more severe hyperandrogenism syndromes).
Diagnostic criteria[6]
Two of the three following criteria are diagnostic of the condition, assuming other causes have been excluded
(Rotterdam criteria):
Polycystic ovaries (either 12 or more peripheral follicles or increased ovarian volume (greater than 10
cm3).
Oligo-ovulation or anovulation.
Clinical and/or biochemical signs of hyperandrogenism.
Differential diagnosis[1]
Thyroid disorder (particularly hypothyroidism).
Hyperprolactinaemia.
Cushing's syndrome.
Acromegaly.
Side-effects of medication (medication causing hirsutism, weight gain or oligomenorrhoea as side-
effects, for example).
Late-onset congenital adrenal hyperplasia (CAH).
Androgen-secreting ovarian or adrenal tumours.
Ovarian hyperthecosis.
If there are signs of virilisation, rapidly progressing hirsutism or high total testosterone level then suspect one of
the latter three. 17-hydroxyprogesterone, measured in the follicular phase, will be raised in CAH. Consider
checking levels even where testosterone is not significantly raised in those with higher risk, such as Ashkenazi
Jews or people with a family history of CAH.
Investigations[1]
Total testosterone: Normal to slightly raised in PCOS.
Free testosterone levels may be raised but if total testosterone is >5 nmol/L, exclude androgen-
secreting tumours and CAH.
Sex hormone-binding globulin. Normal or low in PCOS. This can also be used to calculate the free
androgen index (= 100 times the total testosterone value divided by the sex hormone-binding globulin
value). Free androgen index is usually normal or elevated in PCOS and can be used as an alternative
to measuring free testosterone if this is not locally available.
LH may be elevated, with the LH:follicle-stimulating hormone (FSH) ratio increased (>2), with FSH
normal; however, this is not part of the diagnostic criteria and may be normal. (Remember the oral
contraceptive pill affects levels.) This also helps to exclude premature ovarian insufficiency (LH and
FSH both raised) and hypogonadotropic hypogonadism (LH and FSH reduced).
Ultrasound scan demonstrates characteristic ovaries (the average volume is three times that of
normal ovaries); however, the syndrome can exist without the presence of polycystic ovaries. In
adolescence a scan should be interpreted with caution as follicle counts are higher.
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3. Other blood tests, where indicated from the clinical picture, to exclude other potential causes - eg, TFT
(thyroid dysfunction), 17-hydroxyprogesterone levels (CAH), prolactin (hyperprolactinaemia), DHEA-S
and free androgen index (androgen-secreting tumours), and 24-hour urinary cortisol (Cushing's
syndrome).
Fasting glucose and oral glucose tolerance tests are useful in assessing insulin resistance/diabetes.
Women who are overweight or have other risk factors for diabetes should have an oral glucose
tolerance test on diagnosis of PCOS.[6]
Fasting lipid levels should be checked.
Management
General points[6]
Women diagnosed with PCOS should be informed of the possible long-term risks to health that are associated
with their condition. Associations with obesity, dyslipidaemia and insulin resistance are likely to result in increased
cardiovascular risk. Women should be offered screening for impaired glucose tolerance and diabetes, and
screening for other cardiovascular risk factors. They should also be asked about symptoms of sleep apnoea and
informed this is also a risk.
Women diagnosed with PCOS should be advised on weight control and exercise. Weight loss has been shown
to improve fertility, psychological symptoms and metabolic features (insulin resistance and cardiovascular risks),
even when BMI remains in the high ranges.[5] It has been shown to improve ovulation, pregnancy rates and
outcomes.[7]
It makes sense that a low GI diet would be most beneficial in women with PCOS and there is some evidence for
this.[8] [9] Hypertension should be treated but there is no use for routine use of statins in women with PCOS,
other than normal guidelines for use.[6] [10]
Oligomenorrhoea or amenorrhoea may predispose women to endometrial hyperplasia and cancer. Treatment
which leads to a withdrawal bleed every three or four months should be recommended with cyclical progestogen
or the combined oral contraceptive pill (COCP). Alternatively the intrauterine system (IUS) may be used to
prevent hyperplasia. Ultrasound of the endometrium should be done if withdrawal bleeds do not occur, and
endometrial biopsy if the endometrial thickness is greater than 7-10 mm.
Pharmacological treatment
There is no treatment which reverses the hormonal disturbances of PCOS and treats all clinical features, so
medical management is targeted at individual symptoms and only in association with lifestyle changes.
For women not planning pregnancy
Co-cyprindrol: is licensed for treating hirsutism and acne, although not specifically in PCOS. It is also
used to induce regular endometrial bleeds and thereby reduce the risk of endometrial carcinoma.
COCP: is also used to control menstrual irregularity. If risk factors deem women ineligible,
progestogens may be used to induce bleeds to protect the endometrium (eg, medroxyprogesterone 10
mg daily for 7-10 days every three months). Alternatively the IUS may be used as endometrial
protection.
Metformin: has been increasingly used off-licence for PCOS; however, a Cochrane review showed it
to be less effective than the COCP for menstrual irregularity, hirsutism and acne, and the National
Institute for Health and Care Excellence (NICE) Evidence Summary suggests its side-effects and cost
outweigh its benefits and any, as yet unproven, long-term health benefits.[11] [12] Metformin should not
be initiated in primary care other than for diabetes; women considering metformin should be referred
to secondary care.[1]
Eflornithine: may be used for hirsutism, as can cosmetic treatments (electrolysis, laser, waxing,
bleaching). There is some limited evidence that eflornithine improves the appearance of facial hair in
the short term; however, prescribing may depend on local policy.[13]
Orlistat: can help with weight loss in obese women with PCOS and may improve insulin
sensitivity.[14] [15]
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4. For women wishing to conceive and presenting with infertility
2013 NICE guidelines advise (after weight loss where indicated and a full fertility work-up) women should be
treated with clomifene, metformin or a combination of the two.[7] ACochrane review in 2012, however, found no
benefit in live birth rates from the use of metformin or other insulin-sensitising drugs, although it did improve
numbers of pregnancies.[16]
Clomifene: induces ovulation and has been proven to improve pregnancy rates.[17] It should not be
used for more than six months and, as it is associated with an 11% risk of multiple pregnancy, women
should have ultrasound monitoring during treatment.[7]
Metformin: may be used instead of or together with clomifene to improve pregnancy rates, according
to 2013 NICE guidelines. Women should be warned of the side-effects.
Laparoscopic ovarian drilling or gonadotrophins: are second-line treatments for those who are
resistant to clomifene.
Complications[6]
Infertility. PCOS is the cause of infertility in 75% of women who are infertile due to anovulation.[1]
Oligomenorrhoea or amenorrhoea are known to predispose to endometrial hyperplasia and
endometrial cancer in untreated cases. It is good practice to recommend treatment with progestogens
to induce a withdrawal bleed at least every 3-4 months.
It has been suggested that women with PCOS may have a higher cardiovascular risk than weight-
matched controls, as they have increased cardiovascular risk factors such as obesity,
hyperandrogenism, and hyperinsulinaemia, and a higher prevalence of risk factors such as
hyperlipidaemia, hypertension, the metabolic syndrome and diabetes.[18] There have not yet been
studies which confirm the greater cardiovascular morbidity or mortality. However, there is some
evidence of compromise of endothelial function in women with PCOS, which is an early marker of
cardiovascular disease.[19]
Women presenting with PCOS, particularly if they are obese (BMI greater than 30), have a strong
family history of type 2 diabetes or are over the age of 40 years, are at increased risk of type 2
diabetes and should be offered screening. The risk of diabetes is increased to some degree in women
with PCOS even if they are not overweight. Screening should be with a glucose tolerance test, as
HbA1c has not yet been defined in this situation.
Women diagnosed with PCOS (or their partners) should be asked about snoring and daytime
fatigue/somnolence and informed of the possible risk of sleep apnoea. They should be offered
investigation and treatment when necessary.
Complications in pregnancy
There is a higher risk of gestational diabetes in women with PCOS, which may be more than double.[2] Women
who have been diagnosed as having PCOS before pregnancy (such as those requiring ovulation induction for
conception) should be screened for gestational diabetes at 24-28 weeks of gestation (by oral glucose tolerance
test, with referral to a specialist obstetric diabetic service if abnormalities are detected. Women with PCOS also
have higher risks of preterm birth and pre-eclampsia.
Further reading & references
Moran LJ, Hutchison SK, Norman RJ, et al; Lifestyle changes in women with polycystic ovarysyndrome. Cochrane
Database Syst Rev. 2011 Jul 6;(7):CD007506. doi: 10.1002/14651858.CD007506.pub3.
1. Polycystic ovarysyndrome; NICECKS. February2013 (UKaccess only)
2. Roos N, Kieler H, Sahlin L, et al; Risk of adverse pregnancyoutcomes in women with polycystic ovarysyndrome:
population based cohort study. BMJ. 2011 Oct 13;343:d6309. doi: 10.1136/bmj.d6309.
3. Fauser BC, Diedrich K, Bouchard P, et al; Contemporarygenetic technologies and female reproduction. Hum Reprod
Update. 2011 Nov-Dec;17(6):829-47. doi: 10.1093/humupd/dmr033. Epub 2011 Sep 6.
4. Zhao H, LvY, Li L, et al; Genetic Studies on Polycystic OvarySyndrome. Best Pract Res Clin Obstet Gynaecol. 2016 May19.
pii: S1521-6934(16)30024-4. doi: 10.1016/j.bpobgyn.2016.04.002.
5. Teede H, Deeks A, Moran L; Polycystic ovarysyndrome: a complexcondition with psychological, reproductive and metabolic
manifestations that impacts on health across the lifespan. BMC Med. 2010 Jun 30;8:41. doi: 10.1186/1741-7015-8-41.
6. Long-term Consequences of Polycystic OvarySyndrome; Royal College of Obstetricians and Gynaecologists (November
2014)
7. Fertility-Assessment and treatment for people with fertilityproblems; NICEGuidance (February2013)
8. Marsh KA, Steinbeck KS,Atkinson FS, et al; Effect of a low glycemic indexcompared with a conventional healthydiet on
polycystic ovarysyndrome.Am J Clin Nutr. 2010 Jul;92(1):83-92. doi: 10.3945/ajcn.2010.29261. Epub 2010 May19.
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5. 9. Mehrabani HH, Salehpour S,Amiri Z, et al; Beneficial effects of a high-protein, low-glycemic-load hypocaloric diet in
overweight and obese women with polycystic ovarysyndrome: a randomized controlled intervention study. JAm Coll Nutr.
2012Apr;31(2):117-25.
10. RavalAD, Hunter T, StuckeyB, et al; Statins for women with polycystic ovarysyndrome not activelytrying to conceive.
Cochrane Database Syst Rev. 2011 Oct 5;(10):CD008565. doi: 10.1002/14651858.CD008565.pub2.
11. Costello M, Shrestha B, Eden J, et al; Insulin-sensitising drugs versus the combined oral contraceptive pill for hirsutism,
acne and risk of diabetes, cardiovascular disease, and endometrial cancer in polycystic ovarysyndrome. Cochrane
Database Syst Rev. 2007 Jan 24;(1):CD005552.
12. Polycystic ovarysyndrome: metformin in women not planning pregnancy; NICEEvidence Summary, February2013
13. Hirsutism; NICECKS, December 2014 (UKaccess only)
14. Jayagopal V, Kilpatrick ES, Holding S, et al; Orlistat is as beneficial as metformin in the treatment of polycystic ovarian
syndrome. J Clin Endocrinol Metab. 2005 Feb;90(2):729-33. Epub 2004 Nov9.
15. Ghandi S,AflatoonianA, Tabibnejad N, et al; The effects of metformin or orlistat on obese women with polycystic ovary
syndrome: a prospective randomized open-label study. JAssist Reprod Genet. 2011 Jul;28(7):591-6. doi: 10.1007/s10815-
011-9564-2. Epub 2011Apr 12.
16. Tang T, Lord JM, Norman RJ, et al; Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for
women with polycystic ovarysyndrome, oligo amenorrhoea and subfertility. Cochrane Database Syst Rev. 2012 May
16;5:CD003053. doi: 10.1002/14651858.CD003053.pub5.
17. BalenAH, RutherfordAJ; Managing anovulatoryinfertilityand polycystic ovarysyndrome. BMJ. 2007 Sep 29;335(7621):663-
6.
18. Dokras A; Cardiovascular disease risk factors in polycystic ovarysyndrome. Semin Reprod Med. 2008 Jan;26(1):39-44.
doi: 10.1055/s-2007-992923.
19. Sprung VS,Atkinson G, Cuthbertson DJ, et al; Endothelial function measured using flow-mediated dilation in polycystic
ovarysyndrome: a meta-analysis of the observational studies. Clin Endocrinol (Oxf). 2013 Mar;78(3):438-46. doi:
10.1111/j.1365-2265.2012.04490.x.
Disclaimer:This article is for information only and should not be used for the diagnosis or treatment of medical
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OriginalAuthor:
Dr HayleyWillacy
Current Version:
Dr MaryHarding
Peer Reviewer:
Prof CathyJackson
Document ID:
2628 (v25)
Last Checked:
24/06/2016
Next Review:
23/06/2021
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