Download Polycystic Ovary Syndrome: Pearls, Pitfalls and Advances in 2010

Polycystic Ovary
Syndrome: What Every
Internist Needs to Know!
By George Sarka MD,MPH,CPH,FACP,FACR,FACPM
DrPH Candidate in Public Health,UCLA
Associate Clinical Professor of Medicine, UCLA
Medical Historian and Lecturer
Member of the American Osler Society
Vice President of the California Neurology Society (2013-2015)
California Neurology Society Director-South (2012-2015)
Immediate Past Governor of the ACP, Southern CA, Region II(2008-2012)
Past President of the LA Neurological Society(2006-2009)
Past President-Elect of LACMA-District 1(2006-2008)
Staff Physician/Multispecialist at the Klotz SHC at CSUN
Staff Rheumatologist at CSMC
Diplomate in Rheumatology, Sports Medicine, Internal Medicine, Neurology, Headache
Medicine, Geriatrics, Emergency Medicine, Occupational Medicine, Public Health/
General Preventive Medicine via ABPM, Public Health via NBPHE and Hypertension
Drug Company Affiliations
• I have no drug company affiliations
germane to this lecture.
Objectives
• Describe the basic pathophysiology and the role
for early intervention
• Choose evidence-based treatment options for
patients seeking fertility and non-fertility care
• Avoid the metabolic and reproductive
complications of PCOS
• Encourage parents and patients to discuss
PCOS to ensure early diagnosis and treatment
taking into consideration age, ethnicity and other
culturally-related aspects
Case Presentation
• Patient FH is a 25 year old female with
type II DM x 2 years here for transference
of care.
• Patient was diagnosed with type II DM
with elevated FBS over 200 and HgbA1C
of 11.0. Patient has been obese most of
her life with BMIs around 35 to 39 in the
last 5 years.
Case Presentation continued
• Patient was put on a diabetic diet,
metformin and now glipizide with
HgbA1Cs around 7.0.
• She has a yearly ophthalmology exam the
latest of which as been normal.
• ROS is essentially non contributory.
• LMP 2 weeks ago
• Family Hx: Both parents have type II DM,
hyperlipidemia and are obese.
Case Presentation continued
• Physical Exam was significant for the following:
– BP of 145/85
– BMI of 39
– Pustular, papular and cystic acne on face and back
– Some hair thinning
– Hyperpigmented areas in the neck and axillae
Case Presentation continued
Diagnoses?
Case Presentation continued
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Type II DM
Obesity
Elevated BP—r/o Hypertension
Menstrual Irregularities
Acne
Alopecia
Acanthosis negricans
Case Presentation continued
• What do you order at this time?
– CBC
– FBS and 2 hour post prandial or HgbA1C
– Chem panel
– Lipid Panel
– U/A
– Spot urine for microalbuminuria
– Gynecological exam
– TSH, Prolactin, Free and Total Testosterone, DHEAs, 17Hydroxyprogesterone
– Some may get fasting insulin level
– Consider an Ultrasound of the pelvis to look at the endometrium
and ovaries
Final Diagnoses
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Type II DM
Obesity
Elevated BP—r/o Hypertension
Hyperlipidemia
NASH
PCOS
– Menstrual Irregularities
– Acne
– Alopecia
– Acanthosis negricans
PreLecture Quiz
(The 64,000 Dollar Question)
• What is the most common endocrinopathy in a
woman of reproductive age?
• A. Diabetes Type I
• B. Diabetes Type II
• C. Hyperthyroidism
• D. Polycystic Ovary Syndrome
• E. Hypothyroidism secondary to Hashimoto’s
Thyroiditis
• F. Hypothalamic Amenorrhea
Answer
• Polycystic Ovary Syndrome
(5% to 10% of the female
population)
PCOS AKAs
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Polycystic Ovarian Syndrome,
Functional Ovarian Hyperandrogenism,
Chronic Hyperandrogenic Anovulation,
Ovarian Hyperandrogenic Dysfunction,
Hirsutism-Anovulation Syndrome,
Stein Leventhal Syndrome,
PCO,
PCOD,
Polycystic Ovaries,
Sclerocystic ovary,
Stein’s Syndrome.
Polycystic Ovary Syndrome
• Although PCOS is associated with
hyperandrogenism and infertility early in
life, it is a harbinger of a lifelong
condition that can lead to serious
sequelae such as diabetes mellitus,
hyperlipidemia, endometrial
hyperplasia/carcinoma, central
obesity, sleep apnea, etc.
• I will review the pathophysiology,Dx and
treatment of this condition.
PCOS-INTRODUCTION
• PCOS is not merely a reproductive disorder but
an endocrinological disorder affecting women in
their reproductive years.
• Although hyperandrogenism and infertility
that PCOS causes are distressing to young
women, its metabolic sequelae eventually
plague the individual in terms of morbidity
and mortality.
PCOS-INTRODUCTION
• It is crucial to diagnose PCOS early in its
course.
• It is imperative not only to recognize it
but also to delay or arrest its metabolic
sequelae.
• Additionally, screening for the expected
complications may allow for proper and
timely management of these conditions.
Why Should Physicians Know
about PCOS?
The Dx of PCOS implies that a woman is at increased risk
for the following:
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Infertility
Dysfunctional Bleeding
Endometrial Carcinoma
Obesity
Obstructive Sleep Apnea
Type 2 Diabetes
Dyslipidemia
HTN
Possibly Cardiovascular Disease
Her Sisters, Daughters and other close Female Relatives may
also be a risk
 She may require lifelong therapy and find that her access to
healthcare coverage is limited.
Historical Aspects of PCOS
• Vallisneri gave the first histological description of
the polycystic ovary, 1721
• Sclerocystic changes in the ovary described by
Chereau, 1844
• Class description of a bearded women with DM,
Achard/Thiers 1921
Historical Aspects of PCOS
• 1935-Stein and Leventhal described the features
of 7 hirsute, amenorrheic women based on the
characteristic ovarian morphology from
histological specimens taken at wedge resection
of the ovaries
• Paper on 75 women who underwent bilateral
wedge resections, nearly 90% of whom began to
have spontaneous menstrual cycles and 65% of
those seeking fertility conceived(Stein,Cohen
and Elson 1948)
Historical Aspects of PCOS
• Laparotomy and wedge biopsy became
the mainstay of both diagnosis and
treatment (Goldzieher and Green l962)
• The next diagnostic milestone occurred
in the late l960s and early l970s with
derangements in the hypothalamicpituitary axis. Endocrinological criteria
were used for the diagnosis such as
elevated LH/FSH ratios
Historical Aspects of PCOS
• Pelvic Ultrasound in the l970s and l980s(first
abdominal sonography and, later, vaginal
sonography) complicated the diagnosis—
PCO/PCOS
• 1990 NIH criteria established for PCOS
• 2003 ESHRE/ASRM(Rotterdam,Netherlands)
consensus definition of PCOS which now
included the possibility of using polycystic
ovaries as part of the Dx
• 2006 Task Force Appointed by the Androgen
Excess Society
• Today’s Picture
Summary of the Historical
Aspects
• In 1935, Stein and Leventhal described 7
women with bilateral enlarged PCO,
amenorrhea or irregular menses, infertility and
masculinizing features.
• This seminal paper introduced clinicians to the
concept of reproductive endocrinopathies.
• Nearly 70 years later, as with most syndromic
illness, the parameters for defining PCOS
remain vague or subjective.
Definition of PCOS
• There is no universally accepted
definition for PCOS!
Definition of PCOS
1990 US NIH Consensus Conference: 2
minimal criteria
1. Menstrual Irregularity due to oligo- or
anovulation
2. Clinical or biochemical hyperandrogenism
a.Hirsutism,Acne,Male Pattern Baldness
b.Elevated Serum Androgen Levels
3. Above not attributable to other causes
Definition of PCOS
• No laboratory evidence required for Dx
• No radiologic evidence required for Dx( in the
North America)
• Ovarian appearance not pathognomic
• Insulin resistance not included in diagnostic
criteria
• Excludes women with other known causes of
hyperandrogenism; Diagnosis of exclusion
• Clinical heterogeneity
2003
ESHRE/ASRM(Rotterdam,Netherlands)
Consensus on the Dx of PCOS
•
Requires the presence of two out of
the following three criteria:
1. Oligo- and/or Anovulation
2. Hyperandrogenism (clinical and/or
biochemical)
3. Polycystic Ovaries, with the exclusion
of other etiologies
Task Force Appointed by the
Androgen Excess Society 2006
• Reviewed all available data and recommended a
new evidence-based definition.(J Clin Endocrinol
Metab.2006 Aug 29)
• The Task Force identified 4 key clinical features
of PCOS:
1.Ovulatory and Menstrual Dysfunction
2.Hyperandrogenism
3.Hirsutism, Acne and Androgenic Alopecia
4.Polycystic Ovaries
Plus the exclusion of other disorders of androgen
PCOS-Epidemiology
• PCOS affects 5% to 10% of women of reproductive
age which approximately 4 million individuals
• It’s prevalence among infertile women is 15% to
20%.
• It is the most common endocrine disorder of women in
this age group.
• It is often seen in the student health population and
general medical practice but most often diagnosed
when a women presents with infertility
PCOS- Economic Cost to
Health Care
“We estimated the mean annual cost of the initial
evaluation to be $93 million (2.1% of total costs), that of
hormonally treating menstrual dysfunction/abnormal
uterine bleeding to be $1.35 billion (31.0% of total), that
of providing infertility care to be $533 million (12.2% of
total), that of PCOS-associated diabetes to be $1.77
billion (40.5% of total), and that of treating hirsutism to
be $622 million (14.2% of total).”
*Azziz, R. et al., Health Care-Related Economic Burden of the Polycystic Ovary
Syndrome during the Reproductive Life Span, J Clin Endocrinol Metab, August
2005, 90(8):4650–4658.
PCOS- Economic Cost to
Health Care
Conclusions: “The total cost of evaluating and providing
care to reproductive-aged PCOS women in the United
States is $4.36 billion. Because the cost of the
diagnostic evaluation accounted for a relatively minor
part of the total costs (approximately 2%), more
widespread and liberal screening for the disorder
appears be a cost-effective strategy, leading to earlier
diagnosis and intervention and possibly the amelioration
and prevention of serious sequelae.”
*Azziz, R. et al., Health Care-Related Economic Burden of the Polycystic Ovary
Syndrome during the Reproductive Life Span, J Clin Endocrinol Metab, August
2005, 90(8):4650–4658.
PCOS-Epidemiology
• PCOS accounts for 95% of cases of
hyperandrogenism
• PCOS is responsible for over 20% of all
cases of amenorrhea
• PCOS is responsible for up to 75% of all
cases of anovulatory infertility.
Question: Are There Advantages
in Having PCOS?
• With a syndrome affecting 5% to 10% of
women, what would selective advantage
of having such a gene?
• With time, a syndrome deleterious to one’s
health would be deleted from the gene
pool.
Advantages of Having PCOS
• Enhanced Survival of the species via the
following
• 1. retaining calories and storing adipose
tissue, especially important in times of
famine, wintertime
• 2. pregnancy issue
• 3. less likely to develop osteopenia,
osteoporosis—less fractures
Genetics of PCOS
• Complex Genetic Trait Disorder.
• While the precise mode of inheritance is
still uncertain, a familial basis for the
syndrome is well established and it is
not uncommon to find a mother or sister
with l or more symptoms of PCOS.
What is the Male Homologue to
PCOS in Women?
• In families with PCOS, males with balding
before the age of 30.
Pathogenesis
• Remains unclear
• Complex Genetic Disorder
• Ovarian Genetic Trait that interacts with
other congenital or cellular environment
factors
• Dysregulation of Steroidogenesis
• ?Centrality of Insulin Resistance
The Etiology of PCOS
• A genetic disorder of ovarian androgen
secretion
• Etiology of PCOS is hotly debated
• Most agree that the ovary, rather
than the adrenal is the principal
source of excess androgen
production.
PCOS-MAJOR CRITERIA
• 1.CHRONIC ANOVULATION-Oligo-and/or
Anovulation
• 2.CLINICAL and/or BIOCHEMICAL SIGNS
OF ANGROGEN EXCESS:
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Hirsutism
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Acne
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Alopecia
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Menstrual Disturbance
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Infertility
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Virilization
• 3.EXCLUSION OF OTHER CAUSES OF
ANDROGEN EXCESS
PCOS-MINOR CRITERIA
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INSULIN RESISTANCE
ONSET AT PUBERTY
ELEVATED LH:FSH RATIO (>2.5-3)
ULTRASONOGRAPHIC EVIDENCE OF
POLYCYSTIC OVARIES
Source of Image:http://fcionline.com/fertility/infertility-diagnosis-services/pcos
A classic reference indicating the prevalence of various presenting clinical symptoms and complaints among a large cohort of women with PCOS ( N
= 1089) culled from 187 previously published papers (46). The frequency is still relevant to today’s population of women with PCOS.
Source of Image: http://www.endotext.org/female/female6/female6.html
What Defines
Irregular Menses?
Menses
• Irregular Menses are defined as being
less than 21 days or greater than 35
days.
• Women with PCOS typically have
prolonged(>35 days) cycles.
• Both decreased menstrual cycle regularity
and dysfunctional uterine bleeding are
clinical consequences of chronic
anovulation.
Menstrual Dysfunction in PCOS
• Erratic menstruation secondary to
anovulation
• Increased risk of endometrial
hyperplasia/carcinoma
• Prolonged amenorrhea associated with
endometrial atrophy
• Menstrual disturbances in PCOS
classically have a peripubertal onset
• PCOS patients generally do no have
premenstrual or pain during
ovulation
Ovulatory and Menstrual
Dysfunction per the Task Force of
the AES 2006
• 75% of patients have clinically evident
menstrual dysfunction, and 20% have a
history of apparent eumenorrhea.
• In women with hirsutism and
eumenorrhea, anovulation can be
confirmed by measuring serum
progesterone during days 20 through 24 of
the cycle.
Clinical Hyperandrogenism
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Hirsutism
Acne
Seborrhea
Male-pattern Balding
Increased Muscle Mass
Deepening Voice
Clitoromegaly
Hirsutism
• Definition
• How does it differ from hypertrichosis?
• Ferriman-Gallwey Model Scoring System for
the severity of hirsutism
• Hirsutism is from Latin hirsutus = shaggy, hairy
Hirsutism
• Defined as excess terminal (thick pigmented)
body hair in a male distribution and is commonly
noted on the upper lip, around the breast nipples
and along the linea alba of the lower abdomen.
• Ferriman-Gallwey Model Scoring System for
severity of hirsutism
Hirsutism and PCOS
• Most women with hirsutism of gradual
onset, with or without menstrual cycle
irregularity, have polycystic ovaries.
• More serious pathology is usually obvious
on clinical history and examination alone
and tends to be associated with a gross
elevation of circulating testosterone.
Hypertrichosis
• Increased in total body hair
• Rare condition that usually reflects an
adverse effect of a drug such as:
1.phenytoin
2.penicillamine
3.diazoxide
4.minoxidil
5.cyclosporine
6.streptomycin
7.hexachlorbenzene
Hypertrichosis
• Also occurs in patients with systemic illnesses
such as the following:
1.hypothyroidism
2.anorexia nervosa
3.malnutrition
4.porphyria
5.dermatomyositis
• Sometimes occurs idiopathically
Ferriman-Gallway Scoring
System for Hirsutism
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1.Upper Lip
2.Chin
3.Chest
4.Upper Back
5.Lower Back
6.Upper Abdomen
7.Upper Arm
8.Forearm
9.Thigh /Leg
Differential Dx of Hirsutism
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PCOS
Idiopathic
Hyperthecosis
Late Onset CAH
Cushing’s Syndrome
Androgen-secreting tumors of adrenal
Acromegaly
Iatrogenic-Testosterone,Danazol,
Anabolic Steroids
Lab Evaluations to Consider
for Hirsutism
• Investigations to consider for hirsutism in women
Free and TotalTestosterone - The only investigation needed in
most cases;
Gonadotrophins - Luteinising hormone concentration is greater
than follicle stimulating hormone in polycystic ovary syndrome—
not consistant
Prolactin - Raised in patients with prolactinomas and taking
certain medications
17-hydroxyprogesterone - Raised in congenital adrenal
hyperplasia
Dehydroepiandrostenedione acetate - Raised in adrenal tumours
Thyroid function tests
Dermatological
Manifestations of PCOS
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Hirsutism
Acne
Androgenic Alopecia
Seborrhea
Acanthosis Nigricans
Acne
• Acne is seen in approximately one-third
or more of PCOS patients(Task Force
of the AES in 2006— 15% to 25%)
• A majority of women with severe or
resistant acne have PCOS
• Androgen excess has also been
associated with more severe acne
Acne
•
•
Primarily affects the face, less often,
the back and chest.
Lesions are grouped into
non-inflammatory-open/closed comedones
inflammatory (papules,pustules,nodules,cysts)
•
Rx-to be discussed
Androgenic Alopecia
• Progressive, non-scarring,patterned loss
of scalp terminal hairs.
• Requires hereditary predisposition/
sufficient androgens.
• Commonly underdiagnosed.
• Incidence is 8%, an underestimation
Androgenic Alopecia
• Clinical features
1.diffuse hair loss over the crown, with
preservation of the frontal hair line;
2.widening of the hair parting is an early sign
of androgenic alopecia.
Acanthosis Nigricans
• Mucocutaneous eruption characterized by
hyperkeratosis, papillomatosis and increased
pigmentation.
• Occurs in up to 5% of women.
• Occurs in the axillae, nape of neck, under the
breast and the flexures.
• The variety associated with PCOS is benign
acanthosis nigricans.
Other Signs in PCOS
• Increased Muscle Mass
• Voice Changes (Deepening Voice)
• Clitoromegaly
*Note, all above are rare in PCOS
The Metabolic Syndrome and
PCOS
• The prevalence of metabolic syndrome in
women with PCOS is approximately 4346%.*
*Third report of the National Cholesterol Education Program. Expert panel on the detection,
evaluation and treatment of high blood cholesterol in adults. Final report. Circulation 106,
3143-3421 (2002).
Insulin Resistance
• Insulin resistance is commonly, though not
universally, found in PCOS, with
prevalence being estimated in 50-70% of
cases.(*)
*Vigil P, Contreras P, Alvarado JL, Godoy A, Salgado A, Cortes ME. Evidence of
subpopulations with different levels of insulin resistance in women with polycystic ovary
syndrome. Hum. Reprod. 22(11), 2974-2980 (2007).
More about PCOS and Insulin
Resistance
• PCOS is associated with peripheral insulin
resistance and hyperinsulinemia, and
obesity amplifies the degrees of both
abnormalities.
Adiponectin and PCOS
• Insulin resistance in PCOS has been
associated with adiponectin, a hormone
secreted by adipocytes that regulates lipid
metabolism and glucose levels.
• Both lean and obese women with PCOS
have lower adiponectin levels than
women without PCOS.
Obesity in PCOS
• Obesity, seen in approximately 60% of
cases, amplifies the severity of PCOS
presentation.*
• The prevalence of obesity varies
according to geographic location: it is
greater in the USA than in other places.**
*Legro RS, Castracane VD, Kauffman RP. Detecting insulin resistance in polycystic ovary
syndrome: purpose and pitfalls. Obstet. Gynecol. Survey 59, 141-154 (2004).
**Carmina E, Legro RS, Stamets K, Lowell J, Lobo RA. Difference in body weight between
American and Italian women with polycystic ovary syndrome: influence of the diet. Hum.
Reprod. 18(11), 2289-2293 (2003).
Impaired Glucose Tolerance
and Diabetes Mellitus
• Of obese women with PCOS, 10% have
undiagnosed diabetes and 35% have
impaired glucose tolerance.*
*Dunaif A. Insulin resistance and polycystic ovary syndrome: mechanisms and implications for
atherogenesis. Endocr. Rev. 18, 774-800 (1997).
Lipid Profiles and PCOS
• Almost 70% of patients with PCOS have
an abnormal lipid profile and high
triglycerides and low high-density
lipoprotein (HDL) cholesterol are often
found. *
*Legro RS, Kunselman AR, Dunaif A. Prevalence and predictors of dyslipidemia in women with
polycystic ovary syndrome. Am. J. Med. 111, 607-613 (2001).
Long Term Risks
Associated with PCOS
Source of Image: Teede, Helena j. et al., Assessment and management of polycystic ovary syndrome: summary
of an evidence-based guideline, Med J Aust 2011; 195 (6): S69.
“Risk of Coronary Artery Disease in Mothers of Women with PCOS”
Kai I Cheang, John E Nestler and Walter Futterweit
The Endocrine Society's 89th Annual Meeting
Abstract presented in Toronto June 4th 2007
•
Among the 270 women with PCOS, 60 had mothers with probable PCOS
while 210 mothers did not meet the PCOS criteria.
• Complete cardiovascular history was successfully obtained from 39 PCOS
mothers and 75 normal mothers.
• The mean age of PCOS mothers at the time of survey did not differ from
that of non-PCOS mothers (58.6 + 1.3 vs. 58.6 + 0.7, respectively).
• Including only those mothers whose cardiovascular histories were available,
13 of 39 (33.3%) PCOS mothers had CAD compared with 1 of 75 (1.3%)
normal mothers (p<0.0001).
• Eight of 39 (20.5%) PCOS mothers had suffered an MI compared with 1 of
75 (1.3%) normal mothers (p<0.0001).
• Notably, all PCOS mothers who had an MI were 65 years old or younger at
the time of their incident MI.
Conclusion: PCOS mothers of women with PCOS are at a higher risk of
CAD events compared with non-PCOS mothers, and MI appears to
occur at an earlier than expected age in PCOS mothers.
Polycystic Ovary Syndrome and Cardiovascular Disease: Premature
Association?
Richard S. Legro
Endocrine Reviews June 1, 2003; 24 (3): 302-312
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Women with polycystic ovary syndrome (PCOS) are often assumed, a priori, to be at increased
risk for cardiovascular disease (CVD), given the high prevalence of the metabolic syndrome X
among them.
There is, however, no single definition of PCOS, and for that reason a comparison of studies that
have analyzed its association with CVD is compromised from the start.
Long-term studies of well characterized women with PCOS are lacking, and the link to primary
cardiovascular events such as stroke or myocardial infarction remains more speculative than
substantive.
Epidemiological studies that have focused on isolated signs and stigmata of PCOS, such as
polycystic ovaries, hyperandrogenism, or chronic anovulation, have found mixed results.
There are studies that suggest a slight increase in cardiovascular events in women with polycystic
ovaries, with perhaps stronger evidence between an increased risk of cardiovascular events in
women with menstrual irregularity.
However, there is little evidence for an association between hyperandrogenism per se and
cardiovascular events.
Furthermore, there are less data to substantiate an increased risk of events in women with PCOS
identified on the basis of a combination of signs and symptoms, such as hyperandrogenic chronic
anovulation.
The existing data suggest that PCOS may adversely affect or accelerate the development
of an adverse cardiovascular risk profile, and even of subclinical signs of atherosclerosis,
but it does not appear to lower the age of clinical presentation to a premenopausal age
group.
Future studies to identify the risk of cardiovascular events in women with PCOS will benefit from
clear and extensive phenotyping of PCOS abnormalities at baseline, from a prospective design,
from larger sample sizes, and from longer follow-up.
Cardiovascular Risk in PCOS
• Several studies using intima media
thickness as a surrogate for
cardiovascular risk evaluation have
shown potential increased
cardiovascular risk in women with
PCOS.*
*
*
*
Talbot EO, Guzick DS, Sutton-Tyrrell K et al. Evidence for association between polycystic ovary syndrome
and premature carotid atherosclerosis in middle-aged women. Arterioscler. Thromb. Vasc. Biol. 20, 24142421 (2000).
Vryonidou A, Papatheodorou A, Tauridou A et al. Association of hyperandrogenism and metabolic
phenotype with carotid intima-media thickness in young women with polycystic ovary syndrome. J. Clin.
Endocrinol. Metab. 90, 2740-2746 (2005).
Luque-Ramirez M, Mendieta-Azcona C, Alvarez-Blasco F, Escobar-Morreale HF. Androgen excess is
associated with increased carotid intima-media thickness observed in young women with polycystic
ovary syndrome. Hum. Reprod. 22, 3197-3203 (2007).
Coronary Artery Calcification
and PCOS
• A similar study using coronary artery
calcification as risk stratification has
shown increased risk in patients with
PCOS.*
*
Christian R, Dumesic DA, Behrenbeck T, Oberg AL, Sheedy PF, Fitzparick LA. Prevalence and
predictors of coronary artery calcification in women with polycystic ovary syndrome. J.
Clin. Endocrinol. Metab. 88, 2562-2568 (2003).
Sleep Apnea and Other Sleep
Disorders
• Multiple groups have documented an increased
risk for sleep apnea and other sleep disorders
including increased daytime somnolence, such
as sleep disordered breathing in women with
PCOS.
• This is surprising as sleep apnea is relatively
uncommon in women, especially
premenopausal women.
Body Image and Quality of Life in
PCOS Patients
• There is little study of the
psychopathology of women defined as
having PCOS in literature
• PCOS disease-specific questionnaire
known as the PCOSQ has been
developed to study the above questions.
• Obesity and infertility cause the greatest
degree of stress
Body Image and Quality of Life in
PCOS Patients
• Both anorexia nervosa and bulimia
have been linked with PCOS(etiological
link?)
• Many conditions co-exist with PCOS such
as pelvic pain, depression and altered
mood but it is unclear where there is a
casual or causal association.
Pregnancy in PCOS
• Increased risk of Pregnancy-related
Hypertension
• Increased risk of Pregnancy-related
Diabetes
• Increased risk for Miscarriages
Morphology of the Polycystic
Ovary
• Ovary with 12 or more follicles*
measuring 2-9 mm in diameter and/or
• Increased ovarian volume(>10 cubic
centimeters)
• *Note that the follicles are usually
peripheral in location.
Imaging
• Ultrasound is the imaging modality of choice
• Polycystic ovaries are enlarged and rounder
than normal with increased stromal echogenicity
• There are numerous small cysts, less than 5mm,
that line up on the periphery, in a “string-ofpearls” appearance
• Ultrasonographic criteria for establishing the
diagnosis of PCOS are 10 or more cysts that are
2-8 mm in diameter and are peripherally
arranged around an echodense stroma
Ovarian Morphology on Pelvic
Ultrasound
• Ovarian pattern is both insufficient and
unnecessary to make the diagnosis of PCOS per
NIH Conference on PCOS criteria of l990
• However, it has been considered necessary to
redefine PCOS and include with it an
appropriate definition of the polycystic ovary per
2003 ESHRE/ASRM criteria
Polycystic Ovaries per the Task
Force by AES 2006
• 75% of patients have polycystic ovaries detected
by transvaginal ultrasonography, although the
false-positive rate is high (approximately 25% of
women in the general population have the same
ovarian morphology).
• The Dx of polycystic ovaries should not be
based merely on a “polycystic” or “multicystic”
appearance.
• At least 1 ovary should have a volume of
>10cm3 (mL), or there should be >= 12
follicles measuring 2 to 9 mm in diameter.
Additional Use for Pelvic
Ultrasound
• To check the endometrium for
hyperplasia and carcinoma
The Pathophysiology of PCOS
• The pathophysiology of PCOS, although
still not entirely clear, is mainly due to the
hormone imbalance caused by both
hyperandrogenism and hyperinsulinemia,
which are also effects of PCOS.
Source of Image: http://fcionline.com/fertility/infertility-diagnosis-services/pcos
Figure 1 Pathophysiological role of hyperandrogenism and the insulin resistancehyperinsulinemic state in determining the PCOS phenotype.
Pasquali R , Gambineri A Eur J Endocrinol 2006;154:763775
© 2006 Society of the European Journal of Endocrinology
PCOS and Infertility
•
•
•
•
Menstrual Irregularity
Ovaries Contain Small Cysts
Cysts Produce Hormone Imbalance
Good chance of Pregnancy with IVF
Laboratory Testing for PCOS is
to Exclude Other Causes
• Total or Free Testosterone—r/o androgensecreting tumor
• DHEAs—r/o androgen-secreting tumor of the
adrenal gland
• Morning 17-hydroxyprogesterone—r/o lateonset CAH
• 24-Hr urine for cortisol and creatinine—r/o
Cushing’s Syndrome
• Prolactin—r/o hyperprolactinemia
• TSH,(T4/T3 if indicated)—r/o hyper-or
hypothryoidism
PCOS-Laboratory Evaluation
• Hyperandrogenemia: 60% to 80% of
patients have increased circulating
androgen levels, primarily free
testosterone.
• This cannot be the sole diagnostic
criterion, because 20% to 40% of
patients with PCOS have normal
androgen levels and assays are
NORTORIOUSLY INACCURATE.
Testosterone
• Total Testosterone levels below 150
ng/dl usually exclude ovarian and adrenal
tumors and ovarian hyperthecosis
• Serum free testosterone concentrations
are disproportionately higher than the
total concentration in PCOS
DHEA-S
• DHEA-S are normal to slightly
increased in most female patients
with androgen excess
• DHEA-S levels about 700 to 800ug/dl
in young females may suggest the
presence of adrenal tumor
• DHEA-S secretion begins to fall after
the age of 30; Measurements must be
interpreted to age-specific normal
ranges
DHEA-S
• Low DHEA-S does not r/o tumors with
100% sensitivity
• Low levels have been reported in a few
women with adrenal CA due to the lack
of sulfating activity within the tumor
PCOS-Laboratory Evaluation
• Although not essential to the diagnosis,
insulin resistance is common and may affect
treatment decisions.
• Therefore, a fasting blood glucose, 2-hr oral
tolerance test, glycated Hgb and fasting
insulin levels can be measured for
hyperinsulinemia.
• Additionally, a fasting lipid panel should also
be done to r/o hyperlipidemia.
Lab in PCOS
• One may see the following:
– Increased free testosterone/N testosterone,
increased androstenedione
– Increased DHEA-S, DHEA
– Increased LH, normal FH; Inc. LH/FSH
– Increased estradiol, estrone
– Increased fasting insulin
– Increased insulin resistance
– Decreased SHBG
– Mildly elevated prolactin
– Increased AST,ALT in pts with NASH
Summary for Dx of PCOS
1. Hx and Physical
2. Pelvic Ultrasound(Transvaginal is best);
Endometrial thickness should always be
assessed to exclude significant endometrial
pathology.
3. Hormone Assays(to exclude other mimickers
of PCOS)
4. Glucose Testing; 2 Hour Post Prandial
5. Lipid Status (to check Total Cholesterol, HDL
and Triglyceride Levels)
6. Other investigations
7. Exclusion of other conditions that may mimic
PCOS
Differential Dx in PCOS
• Congenital Adrenal Hyperplasia
• Androgen-Secreting Ovarian or Adrenal
Tumors
• Idiopathic Hyperandrogenism
• Idiopathic Hirsutism
• Syndromes of Severe Insulin Resistance
• Hyperprolactinomia
• Thyroid Abnormalities
• Cushing’s Syndrome
• Androgenic Anabolic Steroid Usage
• Other Medications Usage :Danazol,
Phenothiazines, Corticotropin or ACTH
analogues, ?Valproate
Late Onset Congenital Adrenal
Hyperplasia
• 21-Hyrpoxylase deficiency
• 11B-Hydroxylase deficiency
• 3B-Hydroxysteroid dehydrogenase
deficiency
PCOS-Treatment
• 1930’s— Ovarian Wedge Resection
• Traditional Treatment—aimed at the clinical
features and dependent on the ones most
bothersome to the patient.
• Response to therapy is slow, 6-9 months
• Rx of acne,hirsutism and menstrual irregulaties
when fertility is not an issue requires a
concentrated effort on many fronts.
PCOS Treatment-Key Points
• Nonpharmacologic measures are universally
recommended.
– These measures include the following(Lifestyle
Measures):
• A) Diet including seeing a dietician who is
knowledgeable in PCOS
• B) Exercise
• C) Weight Reduction if the patient is obese or insulinresistant.
Lifestyle Modification and
Weight Loss in PCOS
• Risk modification and symptom relief (e.g.,
restoration of ovulatory cycles) has clearly
been achieved with lifestyle modification
and weight loss.*
• All strategies for weight loss, including
surgery, need to be explored in PCOS
patients.
*Norman RJ, Noakes M, Wu R, Davies MJ, Moran L, Wang XJ. Improving reproductive
performance in overweight/obese women with effective weight management. Hum. Reprod.
Update 10, 267-280 (2004).
Lifestyle Modification and
Weight Loss in PCOS
• For example, the combination of weightreducing medications and group
lifestyle modification was shown to be
more effective than either alone, in a
group of obese adults.*
*Wadden
TA, Berkowitz R, Womble LG et al. Randomized trial of lifestyle modification and
pharmacotherapy for obesity. N. Engl. J. Med. 353, 2111-2120 (2005).
Lifestyle Modification and
Weight Loss in PCOS
• Bariatric surgery as treatment for obesity
is highly relevant to the PCOS population,
and has been shown to reverse much of
the metabolic, as well as the reproductive,
problems in these patients, including
hirsutism.*
*Escobar-Morreale HF, Botella-Carretero JI, Alvarez-Blasco F, Sancho J, San Millan JL. The
polycystic ovary syndrome association with morbid obesity may resolve after weight loss
induced by bariatric surgery. J. Clin. Endocrinol. Metab. 90, 6364-6369 (2005).
*Eid GM, Cottam DR, Velcu et al. Effective treatment of polycystic ovarian syndrome with Rouxen-Y gastric bypass. Surg. Obes. Relat. Dis. 1(2), 77-80 (2005).
Lifestyle Modification and
Weight Loss in PCOS
• In a study of morbidly obese PCOS
women, weight loss was paralleled by a
decrease in hirsutism score, testosterone
and dehydroepiandrosterone sulfate;
amelioration of insulin resistance occurred
and ovulatory cycles were also restored.*
*
Escobar-Morreale HF, Botella-Carretero JI, Alvarez-Blasco F, Sancho J, San Millan JL. The
polycystic ovary syndrome association with morbid obesity may resolve after weight loss
induced by bariatric surgery. J. Clin. Endocrinol. Metab. 90, 6364-6369 (2005).
Lifestyle Modification and
Weight Loss in PCOS
• In addition to these benefits, bariatric
surgery for severe obesity has been
associated with a decreased overall
mortality.*
*Sjostrom
L, Narbro K, Sjostrom CD et al. Effects of bariatric surgery on mortality in Swedish
obese subjects. N. Engl. J. Med. 357, 741-52 (2007).
PCOS Treatment-Key Points
•
Pharmacologic treatments include the
following:




oral contraceptives
antiandrogen drugs (usually spironolactone)
insulin sensitizers
?statins.
OCPs and PCOS
• One of the most commonly used
medications in PCOS patients are OCPs.
• In addition to their androgen-lowering
effects, it is likely that they protect the
endometrium against hyperplasia and
cancer (as they do in the general
population) and may also reduce the
incidence of functional follicular
ovarian cysts, as shown in the general
population.
PCOS Treatment-Key Points
• When using BCPS to regulate the
menstrual cycle, it is best to work with the
gynecologist.
• Avoid Norgestrel and Levonorgestrel
because of their risk of increased
hirsutism.
PCOS Treatment-Key Points
Spironolactone: For Hirsutism
 Oral aldosterone antagonist with antiandrogenic
properties
 Dosage 50mg to 200mg/day in divided dosages
 Potential Side Effects: menstrual irregularities,
breast tenderness, GI disturbances, HA, dizziness
and hyperkalemia.
 Should be given with BCPs because of the above
and the risk of teratogenicity
Metformin and PCOS
• While the long-term benefits have not
been extensively documented, use of
insulin-lowering and -sensitizing
medications, such as metformin, would be
advisable, although they are unapproved
for such use in the USA.
Metformin and PCOS
• A recent, uncontrolled, retrospective,
observational study, showing that longterm treatment with metformin delays
or prevents the development of
impaired glucose tolerance and
diabetes in women with PCOS, is
certainly in keeping with this concept.*
* Sharma ST,Wickham III EP, Nestler JE. Changes in glucose tolerance with metformin
treatment in polycystic ovary syndrome: a retrospective analysis. Endo. Prac. 13(4), 373379 (2007).
Metformin and PCOS
• Another study showed decreased weight
and systolic blood pressure as well as
increased HDL in metformin-treated
women with PCOS.* In this study,
metformin was also shown to increase
insulin sensitivity and lower testosterone in
obese but not nonobese PCOS women.
* Trolle B, Flyvbjerg A, Kesmodel U, Lauszus FF. Efficacy of metformin in obese and non-obese
women with polycystic ovary syndrome: a randomized, double-blinded, placebo-controlled,
cross-over trial. Hum. Reprod. 22(11), 2967-2973 (2007).
When Fertility is Desired
• BCPs and antiandrogens cannot be used
–
–
–
–
Sometimes weight loss helps
Insulin sensitizers, especially metformin.
Thiazolidinediones(not studied, ?risks)
Fertility Drugs-clomiphene citrate, aromatase
inhibitors, glucocorticoids, gonadotropin therapy
– Laparoscopic Ovarian diathermy
– In vitro fertilization/embryo transfer
Nonsystemic Hair Removal
• Mechanical Means: bleaching,plucking, waxing,
shaving, depilatory creams, electrolysis and
laser therapy.
• Laser therapy requires long-term Rx; most
successful in women of light skin,dark hair
• Eflornithine(Vaniqa), a topical agent, interferes
with an enzyme in the hair follicle and slows hair
growth. Takes 6-8 wks to work but the hair will
reappear after stopping treatment.
PCOS and Menopause
• Very few studies have focused on this age group
• Fewer studies have longitudinally tracked the
natural history over the vital transition time
between 45 to 55 year of age.
• Serum testosterone is maintained in the
menopausal years, while DHEAS declines,
reflecting diminished adrenal androgen
production.
PCOS and Menopause
• Hirsutism after menopause— probably
increases since the polycystic theca
spontaneously hypersecretes androgen.
• In clinical terms, hirsute women with
PCOS may experience post-menopausal
hirsutism more often than average and
may need continuing anti-androgen
cover into the sixth decade of life.
PCOS, Menopause and
Osteoporosis
• Studies are lacking but is felt that patient with
PCOS are less likely to have
osteopenia/osteoporosis.
• Obesity, hyperandrogenemia, hyperinsulinemia,
and possibly hyperestrogenemia—the critical
dimensions through which PCOS may positively
influence bone mass—are not observed in every
PCOS subject.
PCOS, Menopause and
Osteoporosis
• Future regarding this issue:
• Comparisons of bone density and fracture
rates among normal postmenopausal women
and postmenopausal women with PCOS will
ultimately determine the relative protective
influence of androgen excess on the later-life
risk of osteoporosis and its deleterious health
outcomes.
Types of Physicians/Ancillary
Professionals Involved with PCOS
•
•
•
•
•
•
Internist
•
Family Practitioner
•
General Practitioner
•
Pediatrician
•
Obstetrician/Gynecologist •
Fertility/Reproductive
•
Specialist
•
• Dermatologist
• Dietician
• Endocrinologist
Gastroenterologist/Hepatologist
Neurologist/Pulmonologist
Cardiologist
Oncologist
Surgeon(Bariatric Surgery)
Radiologist
Psychiatrist
Who Should Manage PCOS?
• PCOS has evolved out of the purview of the
reproductive specialist and gynecologist.
• PCOS is probably best managed by an
internist, family practitioner or
endocrinologist with the assistance of
subspecialists including gynecologists,
fertility specialist, dermatologists and in the
long run, cardiologists and oncologists as
indicated.
PCOS-Key Points
• PCOS is the most common cause of anovulatory
infertility.
• PCOS is one of the commonest endocrinopathies
to affect women(5-10%).
• PCOS probably represents a spectrum of disease
with variable presentations.
• Is important to diagnose PCOS because of the
potential long-term consequences.
• Early diagnosis may delay or possible prevent
some of sequelae associated with PCOS.
• Further research is necessary in this syndrome.
Why is PCOS unfamiliar to
most Clinicians?
• 1. Poorly taught if it all, in medical
school
• 2. PCOS probably represents a
spectrum of disease and variable
presentations which may be elusive
to the generalist or specialist.
• 3. There is no definitive lab test or
noninvasive procedure to make the
diagnosis.
Why is PCOS unfamiliar to most
Clinicians?
• 4. PCOS has traditionally fallen in the realm
of the gynecologist when in reality, this
syndrome should involve several different
types of physicians.
• 5. There is no financial advantage for drug
companies to promote this syndrome since
most medications used to treat this
syndrome are generic.
• 6. There is not prominent spokeswomen with
PCOS for the media.
• 7. And thus, the purpose of my lecture!
September is PCOS Awareness Month
References
•
•
•
•
•
•
Azziz, R. et al., Health Care-Related Economic Burden of the Polycystic Ovary
Syndrome during the Reproductive Life Span, J Clin Endocrinol Metab, August 2005,
90(8):4650–4658.
Badaway, A., Elnashar, A,. Treatment options for polycystic ovary syndrome,
International Journal of Women’s Health 2011;3:25-35
Boomsma CM, Fauser BC, Macklon NS. Pregnancy complications in women with
polycystic ovary syndrome, Semin Reprod Med 2008, 26 (1), 72–84.
Eid GM, Cottam DR, Velcu et al. Effective treatment of polycystic ovarian syndrome
with Roux-en-Y gastric bypass. Surg. Obes. Relat. Dis. 1(2), 77-80 (2005).
Escobar-Morreale HF, Botella-Carretero JI, Alvarez-Blasco F, Sancho J, San Millan
JL. The polycystic ovary syndrome association with morbid obesity may resolve after
weight loss induced by bariatric surgery. J. Clin. Endocrinol. Metab. 90, 6364-6369
(2005).
Goldenberg N, Glueck C. Medical therapy in women with polycystic ovarian
syndrome before and during pregnancy and lactation, Minerva Ginecol 2008, 60 (1),
63–75.
References continued
•
•
•
•
•
•
•
Norman RJ, Noakes M, Wu R, Davies MJ, Moran L, Wang XJ. Improving
reproductive performance in overweight/obese women with effective weight
management. Hum. Reprod. Update 10, 267-280 (2004).
Pasquali, R., Gambineri, A., Insulin-sensitizing agents in polycystic ovary syndrome,
European Journal of Endocrinology June 1, 2006; 154:763-775.
Sjostrom L, Narbro K, Sjostrom CD et al. Effects of bariatric surgery on mortality in
Swedish obese subjects. N. Engl. J. Med. 357, 741-52 (2007).
Teede, Helena j. et al., Assessment and management of polycystic ovary syndrome:
summary of an evidence-based guideline, Med J Aust 2011; 195 (6): S65-S112.
Trolle B, Flyvbjerg A, Kesmodel U, Lauszus FF. Efficacy of metformin in obese and
non-obese women with polycystic ovary syndrome: a randomized, double-blinded,
placebo-controlled, cross-over trial. Hum. Reprod. 22(11), 2967-2973 (2007).
Vigil P, Contreras P, Alvarado JL, Godoy A, Salgado A, Cortes ME. Evidence of
subpopulations with different levels of insulin resistance in women with polycystic
ovary syndrome. Hum. Reprod. 22(11), 2974-2980 (2007).
Vryonidou A, Papatheodorou A, Tauridou A et al. Association of hyperandrogenism
and metabolic phenotype with carotid intima-media thickness in young women with
polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 90, 2740-2746 (2005).
Books on the PCOS
• Androgen Excess Disorders in Women:PCOS
and Other Disorders, by
Azziz,Nestler,Dewailly, Humana Press, 2006
• PCOS, by Balen,Conway,Homburg,Lego,
Taylor & Francis Publishers, 2005
• PCOS, by Chang,Heindel, Dunaif, Marcel
Dekker, Inc. 2002
• PCOS, by Roy Homburg, Martin Dunitz, 2001
• PCOS, by Gabor T.Kovac, Cambridge
University Press, 2000
• PCOS the Hidden Epidemic,by S.
Thatcher,Perspectives Press, 2000
Patient Support Groups
• PCOSA-Polycystic Ovarian Syndrome
Association, Inc.(Patient Support
Group)
Telephone: 877-775-PCOS
Mail: P.O.Box 7007, Rosemont, Il 60018
Email:[email protected]
Internet:www.pcosupport.org
Androgen Excess and PCOS
Society
• Email—http://www.ae-society.org/
• The Androgen Excess and PCOS Society is an
international organization dedicated to promoting
knowledge, and original clinical and basic research, in
every aspect of androgen excess disorders, including:
 Polycystic Ovary Syndrome
 Adrenal Hyperplasia: Congenital (CAH) | Adrenal
Hyperplasia: Non-classic (late onset)
 Idiopathic Hirsutism
 Premature Adrenarche
Post Lecture Quiz Question #1
Criteria used in the diagnosis of PCOS
include all of the following except?
a.
b.
c.
d.
Menstrual Irregularities
Hyperandrogenism
Cystic Changes in the Kidney and Liver
Exclusion of Other Diseases
Post Lecture Quiz Question #2
Which of the following is false concerning
PCOS?
a. Women with PCOS have an increased rate
of infertility
b. Women with PCOS have an increased rate
of spontaneous abortion
c. PCOS affects about 5-10% of
premenopausal women
d. The lack of hirsutism rules out PCOS
Post Lecture Quiz Question #3
Findings associated with PCOS include all
except which of the following?
a. Fatty Infiltration of the Liver
b. Keratosis Pilaris
c. Obesity
d. Acanthosis Nigricans
e. Acne
Post Lecture Quiz Question #4
Long-Term Sequelae associated with PCOS
include all of the following except?
a.
b.
c.
d.
Type I Diabetes Mellitus
Type II Diabetes Mellitus
Dyslipidemia
Endometrial Carcinoma
Post Lecture Quiz Question #5
The Differential Dx of Hyperandrogenic
Anovulation includes all except:
a.
b.
c.
d.
e.
Autoimmune/Connective Tissue Disease
PCOS
Cushing’s Syndrome
Congenital Adrenal Hyperplasia
Androgen-secreting Ovarian or Adrenal
Tumors
Answer to Questions
1. C-Cystic changes in the kidney and liver
2. D-The lack of hirsutism rules out PCOS
3. B-Keratosis Pilaris
4. A-Type 1 Diabetes Mellitus
5. A-Autoimmune/Connective Tissue
Disease