Diagnosis and treatment of PCOS

SPOTLIGHT
Copyrighted and permission granted by Ezyhealth Media Pte Ltd
Polycystic
Ovaries
Diagnosis and treatment of PCOS
by Dr Seng Shay Way
Dr Seng Shay Way
is a Consultant
Obstetrician and
Gynaecologist at the
Raffles Fertility Centre
in Raffles Hospital. Dr
Seng graduated from
the Royal College
of Surgeons in
Ireland. He pursued
his internship and
subsequently obstetrics and gynaecology training
at TTSH and KKH, before being admitted
to the Royal College of Obstetricians and
Gynaecologists in London. Dr Seng is a MOHcertified reproductive specialist with expertise
and knowledge from over 15 years of experience
in teaching and in the treatment of reproductive
disorders and infertility. He served as an
executive council member in the Obstetrical and
Gynaecological Society of Singapore (OGSS)
from 2001 to 2003 and is currently a member
of OGSS. His main research interests are in
polycystic ovary syndrome (PCOS), recurrent
miscarriages, the use of antagonist in IVF cycles,
endometriosis treatments and surgery. He has
undergone training in gynaecological surgery
including abdominal laparoscopy, with emphasis
on fertility treatment and preservation.
www.medicalgrapevineasia.com
P
olycystic ovary syndrome (PCOS) is a complex, heterogeneous
disorder of uncertain aetiology and is thought to be one of the leading
causes of female subfertility and the most frequent endocrine problem
in women of reproductive age.1
Currently, there is no consensus on the causes of PCOS but there
is strong evidence that it can be classified as a genetic disease. This is
observed in familial clustering of cases, with greater concordance in
monozygotic compared to dizygotic twins and heritability of endocrine and
metabolic features of PCOS.2-4 Recent data also suggest that the genetic
variant maybe inherited in an autosomal dominant fashion with high
genetic penetrance but variable expressivity in females.3-5 The genetic
variant(s) can be inherited from either the father or the mother, and can be
passed along to both sons (who may be asymptomatic carriers or may have
symptoms such as early baldness and/or excessive hair) and daughters,
who will show signs of PCOS.5
Clinical Signs and Symptoms
PCOS produces symptoms in approximately 5% to 10% of women of
reproductive age (12 to 45 years old). The symptoms of PCOS may begin in
adolescence with menstrual irregularities, or a woman may not know she
has PCOS until later in life when symptoms and/or infertility occur. Women
of all ethnicities may be affected.
PCOS includes a heterogeneous collection of signs and symptoms with
varying degrees of severity in affecting the reproductive, endocrine and
MG Singapore JAN-FEB 2013
35
SPOTLIGHT
Copyrighted and permission granted by Ezyhealth Media Pte Ltd
Currently, there is no consensus
on the causes of PCOS but there
is strong evidence that it can be
classified as a genetic disease. This
is observed in familial clustering of
cases, with greater concordance in
monozygotic compared to dizygotic
twins and heritability of endocrine
and metabolic features of PCOS.2-4
Frequency
Oligomenorrhea
29% to 52%
Amenorrhea
19% to 51%
Hirsutism
64% to 69%
Obesity
35% to 41%
Acne
27% to 35%
Alopecia
3% to 6%
Acanthosis nigricans
<1% to 3%
Infertility
20% to 74%
Elevated Serum LH
40% to 51%
Elevated testosterone 29% to 50%
Table 1. Clinical signs and symptoms
associated with PCOS7
metabolic function. The classic triad
of the disorder includes hirsutism,
menstrual dysfunction, and obesity.
Some common symptoms of PCOS
include:
greater proportion of clinicians worldwide accepts and uses the Rotterdam
criteria published in 2003 or the National Institute of Health criteria (1990)
for recognising PCOS.
In 1990, a consensus workshop sponsored by the NIH/NICHD suggested
that a patient has PCOS if she has all of the following:8
• Menstrual disorders – PCOS
mostly produces oligomenorrhea
or amenorrhea, but other types
of menstrual disorders may also
occur.1
• Infertility – this generally
results directly from chronic
anovulation.1
• Hyperandrogenism – the most
common signs are acne and
hirsutism (male pattern of hair
growth), but it may produce
hypermenorrhea (very frequent
menstrual periods) or other
menstrual disorders.1
• Metabolic syndrome – this
appears as a tendency towards
central obesity and other
symptoms associated with
insulin resistance.1 Serum insulin, insulin resistance and
homocysteine levels are higher in
women with PCOS.6
• Oligoovulation
• Signs of androgen excess (clinical or biochemical). Androgen excess
can be tested by measuring total and free testosterone levels. Other
androgens, such as DHEA-S, may be normal or slightly above the normal
range in patients with polycystic ovarian syndrome (PCOS), while levels
of sex hormone–binding globulin (SHBG) are usually low in patients with
PCOS. Androstenedione levels are also elevated in women with PCOS.
• Other entities are excluded that would cause polycystic ovaries.
Diagnosis
Even though PCOS was described
primarily in 1935 by Stein and
Leventhal, to date we are lacking
the commonly accepted agreement
in the issue of diagnosis of this
syndrome. Contemporarily, a
36
Symptoms
MG Singapore JAN-FEB 2013
In 2003, a PCOS diagnosis consensus workshop sponsored by ESHRE/
ASRM in Rotterdam indicated PCOS to be present if any two out of the
following three criteria are met and other entities are excluded that would
cause these:1,9,10
• Oligoovulation and/or anovulation
• Excess androgen activity (clinical or biochemical). Androgen excess
can be tested by measuring total and free testosterone levels. Other
androgens, such as DHEA-S, may be normal or slightly above the normal
range in patients with polycystic ovarian syndrome (PCOS) while levels
of sex hormone–binding globulin (SHBG) are usually low in patients with
PCOS. Androstenedione levels are also elevated in women with PCOS.
• Polycystic ovaries
(by gynaecologic ultrasound or any other imaging modalities) with
at least one of the following criteria should be present to establish
polycystic ovaries: either 12 or more follicles measuring 2mm to 9mm in
diameter, or increased ovarian volume (>10cm3).11
Some other blood tests are suggestive but not diagnostic.
• The ratio of LH (luteinising hormone) to FSH (follicle stimulating
hormone), when measured in international units, is greater than 1:1
(sometimes more than 3:1),18 as tested on Day 3 of the menstrual cycle.
www.medicalgrapevineasia.com
SPOTLIGHT
Copyrighted and permission granted by Ezyhealth Media Pte Ltd
The pattern is not very specific and was present in less than 50% in
one study.12
Other assessments for associated conditions or risks:
• Fasting biochemical screen and lipid profile13
• Two-hour oral glucose tolerance test (GTT) in patients with risk factors
(obesity, family history, history of gestational diabetes)1 may indicate
impaired glucose tolerance (insulin resistance) in 15% to 33% of women
with PCOS.13 Fifty to eighty percent of PCOS patients may have insulin
resistance at some level.1
• Thyroid function tests
• Pregnancy test
• Prolactin levels
• Endometrial sampling if there is prolonged amenorrhea or ultrasound
evidence of endometrial hyperplasia.
Differential Diagnosis
Other causes of irregular or absent menstruation and hirsutism, such
as hypothyroidism, congenital adrenal hyperplasia (21-hydroxylase
deficiency), Cushing's syndrome, hyperprolactinaemia, androgen
secreting neoplasms, and other pituitary or adrenal disorders, should be
investigated.1,13
Figure 1. Ultrasound pictures of
polycystic ovaries
Management
Medical treatment of PCOS is tailored to the patient's needs and goals.
These can be broadly classified into five categories:
• Lowering of insulin levels
• Restoration of fertility
• Treatment of hirsutism or acne
• Restoration of regular menstruation, and prevention of endometrial
hyperplasia and endometrial cancer
• Psychological stress of PCOS
In each of these categories, there is considerable debate as to the
optimal treatment. One of the major reasons for this is the lack of large
scale evidence-based clinical trials comparing the different treatments.
General interventions that help to reduce weight or insulin resistance can
be beneficial for all these aims, because they address what is believed to be
the underlying cause.
Diet
Where PCOS is associated with overweight or obesity, successful weight
loss is the most effective method of restoring normal ovulation and
menstruation, but many women find it very difficult to achieve and sustain
significant weight loss. Low-carbohydrate diets and sustained regular
exercise14 may help. Some experts recommend a low GI diet in which a
significant part of total carbohydrates are obtained from fruit, vegetables
and whole grain sources.15 Vitamin D deficiency may play some role in
the development of the metabolic syndrome,14 so treatment of any such
deficiency is indicated.
Medications
Reducing insulin resistance by improving insulin sensitivity through
www.medicalgrapevineasia.com
medications such as metformin,
and thiazolidinedione (glitazones),
has been a promising approach,
and initial studies seemed to
show effectiveness.14,16 However,
subsequent reviews in 2008 and
2009 have noted that randomised
control trials have, in general, not
shown the promise suggested by
the early observational studies.17
Infertility
Not all women with PCOS have
difficulty becoming pregnant.
For those who do, anovulation or
infrequent ovulation is a common
cause. Other factors include
changed levels of gonadotropins,
hyperandrogenaemia and
hyperinsulinaemia.18 Like women
without PCOS, women with PCOS
who are ovulating may be infertile
due to other causes, such as tubal
blockages, endometriosis or uterine
fibroids.
For overweight, anovulatory
women with PCOS, weight loss
MG Singapore JAN-FEB 2013
37
SPOTLIGHT
Copyrighted and permission granted by Ezyhealth Media Pte Ltd
Where PCOS is associated with
overweight or obesity, successful
weight loss is the most effective
method of restoring normal ovulation
and menstruation, but many women
find it very difficult to achieve and
sustain significant weight loss.
and diet adjustments, especially
to reduce the intake of simple
carbohydrates, are associated with
resumption of natural ovulation.
For those who, after weight
loss, are still anovulatory or for
anovulatory lean women, then the
ovulation-inducing medications
clomiphene citrate14 and FSH are
the principal treatments used to
promote ovulation. Previously,
the anti-diabetes medication
metformin was the recommended
treatment for anovulation, but
it appears less effective than
clomiphene.
For patients who do not
respond to clomiphene, diet
and lifestyle modification,
there are options available,
including assisted reproductive
technology (ART) procedures
such as controlled ovarian
hyperstimulation with folliclestimulating hormone (FSH)
injections followed by in-vitro
fertilisation (IVF).
Though surgery is not
commonly performed, the
polycystic ovaries can be treated
with a laparoscopic procedure
called "ovarian drilling”, which
often results in either resumption
of spontaneous ovulation14 or
ovulation after adjuvant treatment
with clomiphene or FSH. There
are, however, concerns about
38
MG Singapore JAN-FEB 2013
the long-term effects of ovarian
drilling on ovarian function.14
Hirsutism and Acne
When appropriate, a standard
oral contraceptive pill (OCP) is
frequently effective in reducing
hirsutism.14 A common choice
of OCP is one that contains a
progestogen with anti-androgen
effects that block the action of
male hormones that are believed
to contribute to acne and the
growth of unwanted facial and
body hair. OCP containing
cyproterone acetate or drospirenone are common locally available
contraceptive pills that are effective. On the other hand, progestogens
such as norgestrel and levonorgestrel should be avoided due to their
androgenic effects.14
Other drugs with anti-androgen effects include flutamide19 and
spironolactone,14 which can give some improvement in hirsutism.
Metformin can reduce hirsutism, perhaps by reducing insulin
resistance, and is often used if there are other features such as insulin
resistance, diabetes or obesity that should also benefit from metformin.
Eflornithine is a drug which is applied to the skin in cream form,
and acts directly on the hair follicles to inhibit hair growth. It is usually
applied to the face.14 Medications that reduce acne by indirect hormonal
effects also include ergot dopamine agonists such as bromocriptine.
5-alpha reductase inhibitors may also be used. They work by blocking
the conversion of testosterone to dihydrotestosterone.
Although these agents have shown significant efficacy in clinical
trials (for oral contraceptives, in 60% to 100% of individuals14), the
reduction in hair growth may not be enough to eliminate the social
embarrassment of hirsutism, or the inconvenience of plucking or
shaving. It is usually worth trying other drug treatments if one does
not work, but drug treatments do not work well for all individuals. For
removal of facial hairs, electrolysis or laser treatments are – at least for
some – faster and more efficient alternatives than the above mentioned
medical therapies.
Menstrual Irregularity and Endometrial Hyperplasia
If fertility is not the primary aim, then menstruation can usually
be regulated with a contraceptive pill.14 The purpose of regulating
menstruation is essentially for the woman's convenience and perhaps
her sense of well-being. There is no medical requirement for regular
periods, so long as they occur sufficiently often.
If a regular menstrual cycle is not desired, then therapy for an
irregular cycle is not necessarily required – most experts consider
that if a menstrual bleed occurs at least every three months, then the
endometrium is being shed sufficiently often to prevent an increased
risk of endometrial abnormalities or cancer.20 If menstruation occurs
less often or not at all, some form of progestogen replacement is
www.medicalgrapevineasia.com
SPOTLIGHT
Copyrighted and permission granted by Ezyhealth Media Pte Ltd
recommended. Some women prefer a uterine progestogen device
such as the intrauterine system or the progestin implant, which
provides simultaneous contraception and endometrial protection
for years. An alternative is oral progestogen taken at intervals (e.g.
every three months) to induce a predictable menstrual bleeding.12
Psychological Stress of PCOS
In addition, as PCOS appears to cause significant emotional distress,
these stresses can come in the form of frustration from fertility
treatment, physical stress of acne and hirsutism or stress of long
term risk. It is recommended that clinicians discuss emotional
aspects of PCOS with patients and refer for appropriate support
where necessary and in accordance with patient preference.21
Long Term Risks
Women with PCOS are at risk for the following:
• Endometrial hyperplasia and endometrial cancer due to lack
of progesterone resulting in prolonged stimulation of uterine
cells by estrogen.22 It is not clear if this risk is directly due to the
syndrome or from the associated obesity, hyperinsulinaemia, and
hyperandrogenism.
• Insulin resistance/type 2 diabetes.22 A review published in 2010
concluded that women with PCOS had an elevated prevalence of
insulin resistance and type 2 diabetes, even when controlling for
body mass index (BMI). PCOS also makes a woman, particularly if
obese, prone to gestational diabetes.22
• High blood pressure, particularly if obese and/or during
pregnancy22
• Depression/depression with anxiety
• Dyslipidaemia22 – disorders of lipid metabolism — cholesterol
and triglycerides. PCOS patients show decreased removal of
atherosclerosis-inducing remnants, seemingly independent of
insulin resistance/type 2 diabetes.
• Cardiovascular disease,22 with a meta-analysis estimating a
two-fold risk of arterial disease for women with PCOS relative to
women without PCOS, independent of BMI.22
• Weight gain/obesity22
• Miscarriage23
• Sleep apnoea, particularly if obesity is present22
• Non-alcoholic fatty liver disease, again particularly if obesity is
present22
Conclusion
In general, PCOS is a very complex condition that may require a
multidisciplinary team to manage. Although there is no cure for
PCOS, most women can control the symptoms with just lifestyle and
dietary changes. It is also important to recognise the potential long
term condition as early diagnosis and intervention may reduce the
risk of some of these complications, such as type 2 diabetes, stroke
and heart disease12, and promote long-term health.
www.medicalgrapevineasia.com
References
1H Teede; A Deeks; L Moran (30 June 2010). "Polycystic ovary
syndrome: a complex condition with psychological, reproductive
and metabolic manifestations that impacts on health across the
lifespan". BMC Medicine (BioMedCentral) 8: 41. doi:10.1186/17417015-8-41. Retrieved 14 November 2011
2Page 836 (Section: Polycystic ovary syndrome) in: Fauser, B. C. J.
M.; Diedrich, K.; Bouchard, P.; Dominguez, F.; Matzuk, M.; Franks,
S.; Hamamah, S.; Simon, C. et al. (2011). "Contemporary genetic
technologies and female reproduction". Human Reproduction
Update 17 (6): 829–847. doi:10.1093/humupd/dmr033.
PMC 3191938. PMID 21896560. edit
3Legro RS; Strauss JF (September 2002). "Molecular progress in
infertility: polycystic ovary syndrome". Fertility and Sterility 78 (3):
569–576. doi:10.1016/S0015-0282(02)03275-2. PMID 12215335.
4Diamanti-Kandarakis E; Kandarakis H, Legro RS (August 2006). "The
role of genes and environment in the etiology of PCOS". Endocrine
30 (1): 19–26. doi:10.1385/ENDO:30:1:19. PMID 17185788.
5Crosignani PG, Nicolosi AE (2001). "Polycystic ovarian disease:
heritability and heterogeneity". Hum. Reprod. Update 7 (1): 3–7.
doi:10.1093/humupd/7.1.3. PMID 11212071.
6Nafiye Y, Sevtap K, Muammer D, Emre O, Senol K, Leyla M
(April 2010). "The effect of serum and intrafollicular insulin
resistance parameters and homocysteine levels of nonobese,
nonhyperandrogenemic polycystic ovary syndrome patients
on in vitro fertilization outcome". Fertil. Steril. 93 (6): 1864–9.
doi:10.1016/j.fertnstert.2008.12.024. PMID 19171332.
7Martha Finn; Lucy Bowyer; Sandra Carr; Vivienne O'Connor (20
January 2005). Women's Health: A Core Curriculum. Elsevier
Australia. pp. 24–. ISBN 978-0-7295-3736-0. Retrieved 5
September 2012
8Richard Scott Lucidi (25 October 2011). "Polycystic Ovarian
Syndrome". eMedicine. Retrieved 19 November 2011.
9The Rotterdam ESHRE/ASRM-sponsored PCOS consensus
workshop group (2004). "Revised 2003 consensus on diagnostic
criteria and long-term health risks related to polycystic ovary
syndrome (PCOS)". Human Reproduction 19 (1): 41–47. doi:10.1093/
humrep/deh098. PMID 14688154. Retrieved 14 November 2011.
10Azziz R (March 2006). "Diagnosis of Polycystic Ovarian Syndrome:
The Rotterdam Criteria Are Premature". Journal of Clinical
Endocrinology & Metabolism 91 (3): 781–785. doi:10.1210/jc.20052153. PMID 16418211.
11"Ultrasound assessment of the polycystic ovary: international
consensus definitions". Human Reproduction Update 9 (6):
505–514. 2003. Retrieved 10 October 2012.
12Banaszewska B, Spaczyński RZ, Pelesz M, Pawelczyk L (2003).
"Incidence of elevated LH/FSH ratio in polycystic ovary syndrome
women with normo- and hyperinsulinemia". Rocz. Akad. Med.
Bialymst. 48: 131–4. PMID 14737959
13"Polycystic Ovarian Syndrome Workup". eMedicine. 25 October
2011. Retrieved 19 November 2011.
14"Polycystic Ovarian Syndrome Treatment & Management".
eMedicine. 25 October 2011. Retrieved 19 November 2011.
15Marsh K, Brand-Miller J (August 2005). "The optimal diet for
women with polycystic ovary syndrome?". Br. J. Nutr. 94 (2):
154–65. doi:10.1079/BJN20051475. PMID 16115348.
16Lord JM, Flight IHK, Norman RJ (2003). "Metformin in polycystic
ovary syndrome: systematic review and meta-analysis". BMJ
327 (7421): 951–3. doi:10.1136/bmj.327.7421.951. PMC 259161.
PMID 14576245.
17Leeman L, Acharya U (August 2009). "The use of metformin in
the management of polycystic ovary syndrome and associated
anovulatory infertility: the current evidence". J Obstet Gynaecol 29
(6): 467–72.
18Qiao, J.; Feng, H. L. (2010). "Extra- and intra-ovarian factors in
polycystic ovary syndrome: impact on oocyte maturation and
embryo developmental competence". Human Reproduction Update
17 (1): 17
19"Polycystic ovary syndrome – Treatment". United Kingdom:
National Health Service. 17 October 2011. Retrieved 19 November
2011.
20"What are the health risks of PCOS?". Verity – PCOS Charity.
Verity. 2011. Retrieved 21 November 2011.
21Veltman-Verhulst, S. M.; Boivin, J.; Eijkemans, M. J. C.; Fauser,
B. J. C. M. (2012). "Emotional distress is a common risk in
women with polycystic ovary syndrome: A systematic review and
meta-analysis of 28 studies". Human Reproduction Update 18 (6):
638–651.
22Mayo Clinic Staff (4 April 2011). "Polycystic Ovary Syndrome –
All". MayoClinic.com. Mayo Clinic. Retrieved 15 November 2011
23Boomsma CM, Fauser BC, Macklon NS (2008). "Pregnancy
complications in women with polycystic ovary syndrome".
Semin. Reprod. Med. 26 (1): 72–84. doi:10.1055/s-2007-992927.
PMID 18181085.
MG Singapore JAN-FEB 2013
39