LECTURE 24: Polycystic Ovary Syndrome

Dr. G. Vilches| May 20, 2021

There have been separate efforts to establish the

OUTLINE:
I. INTRODUCTION
II. CRITERIA FOR DIAGNOSIS
III. PHENOTYPE
IV. PCOS IN ADOLESCENT
V. PATHOPHYSIOLOGY
VI. MODALITIES OF PCOS
VII. SEQUELAE OF PCOS
VIII. MANAGEMENT
IX. TREATMENT OF ADOLESCENT PCOS
X. SUMMARY
XI. REFERENCES
XII. APPENDIX
Important Add. Notes Book Power point
Bold » ß ₪ of 3 major criteria which include:
POLYCYSTIC OVARIAN SYNDROME
• The most common endocrine disorder in reproductive-
aged women.
• It is a very complex endocrine condition making its
diagnosis difficult and challenging for gynecologists
• It has reproductive, metabolic, psychological and
dermatologic features which require management by a
multidisciplinary team
BACKGROUND:
• This condition was first introduced in 1935 by 2 American
gynecologists, Irving F. Stein, Sr. and Michael L.
Leventhal, who described this syndrome in 7 women
who were amenorrheic, hirsute, and with enlarged
polycystic ovaries (4 of whom were obese) .
• The condition was termed Stein Leventhal syndrome for
women with these clinical features, and the term was
used for more than 50 years until it was changed to
polycystic ovary syndrome (PCOS).
• Stein and Leventhal then speculated that the thickened
ovarian capsule prevented the follicles from reaching and
escaping from the surface of the ovary during ovulation.
So their mode of management at that time was bilateral
ovarian wedge resection which involved removal of one-
half to three-fourths of each ovary. This resulted in
resumption of regular menses in all 7 and 2 even became
pregnant after the procedure.
CRITERIA FOR DIAGNOSIS OF PCOS
The presentation of PCOS is widely variable. Patients
may complain of oligomenorrhea/amenorrhea, infertility,
obesity, hirsutism, endometrial cancer, an diabetes.
diagnostic criteria for PCOS.
1. The first was a consensus made by the National Institutes
for Health (NIH) convened in 1990. It concluded that the
major criteria for Dx of PCOS (in order of importance)
were
a. menstrual dysfunction
b. clinical and/or biochemical hyperandrogenism.
2. The second was a conference co-sponsored by European
Society for Human Reproduction and Embryology ESHRE
and American Society for Reproductive Medicine ASRM
convened in Rotterdam, The Netherlands, in 2003. It
concluded that Dx of PCOS should be based on at least 2
a. oligo-/anovulation
b. clinical or biochemical signs of
hyperandrogenism
c. finding of polycystic ovaries (by ultrasound).
This is known as the Rotterdam criteria and is
considered the most popular and the one that is
used at present.
3. The third was a task force appointed by the Androgen
Excess Society (AES) in 2006 which considered
hyperandrogenism as an important feature, concluding
that dx of PCOS requires
a. hyperandrogenism (clinical and/or
biochemical hyperandrogenism)
b. ovarian dysfunction (oligo/anovulation), or
c. presence of polycystic ovaries on UTZ.
4. NIH Evidence-Based Methodology Workshop on
Polycystic Ovary Syndrome convened again in December
2012 an evidence-based methodology workshop on
polycystic ovary disease. It concluded that the Rotterdam
criteria should be adopted because of its familiarity but
didn’t believe that it is the ideal because of its
limitations. It also suggested that the name PCOS be
given a more appropriate name that would reflect the
complex nature of this syndrome and its implications for
women’s reproductive and metabolic health.
» When making the diagnosis of PCOS, you should
always exclude other disorders that present similarly to
PCOS like non-classic congenital adrenal hyperplasia,
thyroid disorder, hyperprolactinemia, androgen-
secreting tumors, or Cushing syndrome.

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 LECTURE 24: Polycystic Ovary Syndrome
Dr. G. Vilches| May 20, 2021
INITIAL DIAGNOSTIC EVALUATION
History:
• Menstrual history - age of menarche, frequency of
menses
• Development of signs of androgen excess – hirsutism,
acne and alopecia
• Family history of PCOS (mother or sister)
P.E.
• Signs of hyperandrogenism
• Features that would help rule out other
endocrinopathies
DIAGNOSTIC TESTS
• Pregnancy test – to rule out pregnancy in women who
present with amenorrhea, or if bleeding is sec to
pregnancy
• Serum TSH; prolactin –to r/o other causes of anovulation
like hyperprolactinemia and hypothyroidism
• Serum androgen levels: free testosterone index and
free androgen index are the more sensitive markers of
biochemical hyperandrogenemia
• Total testosterone is not a sensitive marker of androgen
excess, but may be useful if an androgen-secreting
neoplasm is suspected. Total testosterone is usually 2-
fold increased in androgen-secreting tumors.
Androstenedione and DHEA-S also have limited role in
the Dx of PCOS. You should be aware that a reliable
assessment of biochemical hyperandrogenism is not
possible if patient is on contraception. Consider
withdrawal for ≥3 months prior testing and give non-
hormonal contraceptive in the meantime.
• In the presence of oligomenorrhea or amenorrhea,
measurement of serum FSH and estradiol are helpful to
r/o ovarian insufficiency or hypogonadotropic
hypogonadism.
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• LH, FSH to see if there’s elevation of LH levels and
increased LH:FSH ratio. Not a requirement for Dx of PCOS
due to its inconsistency.
• Pelvic utz to determine if patient satisfies the criteria for
polycystic ovarian morphology when only menstrual
irregularity or hyperandrogenism is present. Helps to
determine the phenotype, TO R/O ovarian tumors
• 2-hr 75-g OGTT (to screen for glucose intolerance
/T2DM). Women with PCOS should be rescreened every
3-5 years or more often as indicated. (Endocrine Society
and the AE-PCOS Society)
• Lipid profile (screen for dyslipidemia – HDL, LDL and
triglycerides) – to rule out metabolic syndrome
• 17-hydroxyprogesterone level to r/o non classic
congenital adrenal hyperplasia
• Endometrial biopsy (to r/o endometrial
hyperplasia/endometrial malignancy) especially in
overweight or obese patients
ROTTERDAM CRITERIA
1. MENSTRUAL IRREGULARITY
• 1st and most common criterion
• Menstrual dysfunction occurs in approximately 50%-
90% of women with PCOS due to anovulation and
usually presents as:
o oligomenorrhea (cycles >35 days, or
frequency of <6-8 episodes per year), or
o amenorrhea (absence of menstruation of 6
months or longer)
Menstrual Irregularity Present Definition
✓ irregular cycles are considered normal during the 1st
year postmenarche
✓ menstrual cycles are considered irregular if it occurs
<1 to >3 years postmenarche if in the interval is <21
days or >35 days
✓ irregular if it occurs >3yrs to perimenopause with
<21 days or >35 days interval, or if<8 cycles occur
per year
✓ irregular if at >1 year postmenarche, cycles occur at
a frequency of >90 days for any one cycle
✓ if still amenorrheic by age 15, or >3 years after
thelarche.
Menstrual irregularity is the best correlate of having
insulin resistance in women with PCOS.
2. HYPERANDROGENISM (CLINICAL OR BIOCHEMICAL)
Clinical Biochemical
Hirsutism Hyperandrogenemia
Acne
Alopecia
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Dr. G. Vilches| May 20, 2021
• often considered to be the cardinal feature of PCOS.
Androgen excess may come from the ovaries,
adrenals, or periphery. It is implicated in
contributing to the abnormalities in LH secretion,
weight gain, and adipose deposition, and the
metabolic derangements of PCOS.
A. HIRSUTISM
• One of the clinical features of androgen excess and
the most common is HIRSUTISM. This occurs when
there is increased serum androgen levels.
• Hirsutism is the growth of excessive hair in a male
type pattern caused by the conversion of vellus hair
to terminal hair under androgen effect on the
pilosebacous unit. It is present in 60-90% of women
with PCOS. (Committee of ASRM, 2016)
• Presence or absence of hirsutism depends on
whether androgens are converted peripherally by
5α-reductase to the more potent
Dihydroxytestosterone (DHT), as reflected by
increased circulating levels of 3α-diol-G (3 alpha-
Androstanediol glucuronide). This is a good marker
of androgen action in peripheral tissues.
• Modified Ferriman-Gallwey scale (see appendix)
o Used to asses hirsutism
o to quantify the amount of hair growth on
various androgen dependent body areas.
o 9 key anatomic sites that are sensitive to
androgens. The original scale used 11 body
areas – lip, chin, chest, upper back, lower
back, upper abd, lower abd, upper arms,
forearms X, thighs, legs X. )
» However, race and ethnicity play a significant part
in hirsutism.
• Each area is rated from 0 (no terminal hair)- to 4
(maximal growth of terminal hair/ frankly virile). A
score of 8 or more indicates the presence of
androgen excess. <8 is still considered a normal
variant.
» In some literature, a score of <8 is normal variant.
8-15 mild, >15 moderate to severe.
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B. ACNE
• Acne which is present in approximately 20%-40% of
women with PCOS. This is due to increased sebum
production that cause breakouts on areas such as
the face, chest, and upper back. PCOS-associated
acne often is resistant to standard treatment.
C. ANDROGENIC ALOPECIA
• It is characterized by thinning of the scalp hair in a
male distribution pattern (hair thinning over the
crown of the scalp with retention of the frontal hair
line).
• This is due to the gradual conversion of terminal hair
to vellus hair resulting from high testosterone levels.
It occurs in approximately in 40%-70% of women
with PCOS.
Ludwig scale is recommended in assessing severity of
alopecia.
• Grade I: Perceptible thinning of the hair on the
crown, limited in the front by a line situated 1-3 cm
behind the frontal hairline
• Grade II: Pronounced rarefaction of the hair on the
crown within the area seen in Grade I.
• Grade III: Full baldness (total denudation) within the
area seen in Grades I and II.
As the attending physician, you should be aware of the
potential negative psychosocial impact of the skin
manifestations of PCOS.
D. HYPERANDROGENEMIA
• If there is no clinical evidence of hyperandrogenism
• This is reflected by elevation of serum androgen
levels (free or total testosterone levels,
androstenedione or DHEA-S)
» In PCOS, there is also decreased hepatic production of
SHBG (sex hormone binding globulin) that’s why you
have an increase in free testosterone which is the active
form (Futterweit, 2007). Increased free testosterone
levels are found in approximately 70% of women with
PCOS.
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Dr. G. Vilches| May 20, 2021

» Testosterone is produced primarily from the ovary, and inhibit both aromatase activity and FSH
and DHEA-S is produced by the adrenal glands. induction of LH receptors on granulosa cells, thereby
» Total testosterone levels can indicate the severity of impeding or preventing progressive follicular
the androgen excess (Practice Committee of the ASRM, development.
2006). • Granulosa cells obtained from polycystic ovaries are
» DHEA-S is increased in approximately 25%-35% of not functionally impaired. They are sensitive to FSH
and insulin-like growth factors and produce
women with PCOS.
estrogen, but cannot generate and maintain the
estrogenic follicular milieu required to achieve more
3. POLYCYSTIC OVARIES ON UTZ
advanced stages of development.
• any one ovary with 12 or more cystic follicles having
• Ultrasound is now not recommended in diagnosis in
a diameter of 2-8 mm, or an ovarian volume of >10
those within 8 years of menarche.
cu. mm as documented by transvaginal or
transrectal UTZ in the absence of a dominant follicle • Polycystic ovaries alone are not sufficient for a
is sufficient. And these follicles are usually diagnosis of PCOS because polycystic ovaries are
peripherally located around a dense stroma. found in approximately 20%-30% of young women
(Azziz et al., 2009). PCOS clinicians and researchers
• Others find that the stromal/peripheral area ratio is
are debating a name change for PCOS because of
the most important diagnostic criterion and
overemphasis on polycystic ovaries, which are not
correlates well with androgen status of the woman.
the cause of PCOS (Azziz, 2014). -Polycystic ovaries
• A polycystic-appearing ovary is not pathognomonic
result from a functional derangement in follicular
of PCOS though, and presence of PCO alone does not
development induced or sustained by increased
give the diagnosis of PCOS.
intraovarian androgen levels as a consequence of
» The characteristic polycystic ovary develops when chronic anovulation, whatever the cause.
a chronic anovulatory state persists for a sufficient
length of time.
» 1.4.1 CCR Ultrasound should not be used for the
diagnosis of PCOS in those with a gynaecological age of <
» new follicular growth continues but arrests long 8 years (< 8 years after menarche), due to the high
before full maturation is achieved, resulting in
incidence of multi-follicular ovaries in this life stage.
multiple small follicular cysts surrounded by
hyperplastic theca cells, which often become
» 1.4.4 CCR Using endovaginal ultrasound transducers
with a frequency bandwidth that includes 8MHz, the
luteinized due to increased LH stimulation. Atretic
threshold for PCOM should be on either ovary, a follicle
follicles ultimately contribute to an expanding
number per ovary of ≥ 20 and/or an ovarian volume ≥
ovarian stroma that increases in volume over time,
10ml, ensuring no corpora lutea, cysts or dominant
further increasing the cellular mass producing
follicles are present.
androgens, in yet another self-propagating cycle that
predisposes to chronic anovulation. » Pre-antral follicles→Failure of LH surge→Leading to
failure of Ovulation
» But why are there polycystic ovaries?
• 1- Normally, an orderly follicular development
ultimately leads to the emergence at monthly
intervals of a dominant follicle that releases an
oocyte, but this does not occur routinely in patients
with PCOS. Development of the follicle is only to its
initial growth stage. As a consequence, the ovarian
cortex becomes populated with numerous small
follicles, or “cysts,” in these patients.
• 2-This effect may also be induced in the ovaries of
women who are exposed to persistently elevated
androgen levels. High local androgen concentrations
contribute to the polycystic morphogenesis of the
• ovaries, via conversion to more potent 5a-reduced
androgens, which cannot be aromatized to estrogen

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 LECTURE 24: Polycystic Ovary Syndrome
Dr. G. Vilches| May 20, 2021

PHENOTYPES approach is preferred so it’s not done if not sexually active

Although the syndrome is named after the clinical feature of and if not acceptable to the individual.
polycystic ovaries, it is not a prerequisite in the Dx of the
condition. The Dx of PCOS is based on the presence of all 3 or PATHOPHYSIOLOGY OF PCOS
a minimum of 2 of the clinical features as shown in the • (see appendix) The exact etiology of PCOS is still not
diagram after ruling out other causes of hyperandrogenism. completely understood but some believe that some
CRITERIA: women have genetic predisposition to PCOS (presence
✓ Androgen excess of susceptibility genes, loci at 2p16.3, 2p21, and 9q
✓ ovulatory dysfunction 33.3, involving the LH/human chorionic
✓ polycystic ovarian morphology gonadotropin (hCG) receptor, a thyroid adenoma
Since the Rotterdam criteria only requires a minimum of 2
locus, and DENND1A, potentially affecting function
criteria for the Dx of PCOS, there are 4 possible phenotypes
of the endoplasmic reticulum) and environmental
1. Phenotype A (frank/classic polycystic ovary PCOS) – all 3
factors may be involved as well.
criteria are present; associated with increased CV risk
• These factors cause hypothalamic dysfunction so that
2. Phenotype B (classic non-polycystic ovary PCOS) –
there is an increase in the amplitude and pulsatility of
anovulation with hyperandrogenism
GnRH release resulting in increased LH pulse frequency
3. Phenotype C (ovulatory PCOS) - hyperandrogenism with
resulting in turn in inappropriately increased LH levels
polycystic ovaries, but ovulatory; has less metabolic and
but not of FSH (normal or low).
CV risks, but still with subfertility problems
• The decrease in FSH levels results from the increase in
4. Phenotype D (mild PCOS) - irregular cycles, polycystic
GnRH pulse frequency, the negative feedback effects of
ovaries in the absence of hyperandrogenism
chronically elevated estrone concentrations (derived
from peripheral aromatization of increased
PCOS IN ADOLESCENT
androstenedione), and normal or modestly increased
» The Dx of PCOS in a teenager is challenging and should be
levels of inhibin B (derived from small follicles).
made with caution.
• So that there is an increase of LH:FSH ratio of 3 or more.
2013 GUIDELINE • In the presence of insulin resistance, there is
compensatory hyperinsulinemia. Insulin acts
• 3 Rotterdam criteria should be present
synergistically with LH to increase androgen production.
• Dx is made only 3 years postmenarche.
• LH enhances theca cell androgen production while insulin
» This is made so because during the first few years
decreases hepatic production of SHBG thereby increasing
postmenarche, findings of polycystic ovaries and
the level of the active form of androgens.
menstrual irregularities are very common as part of
• Elevated androgens will now cause the cutaneous signs
pubertal transition. Hence, these features may still be
of PCOS such as hirsutism, acne or androgenic alopecia.
considered as normal development.
• Hyperandrogenism can also cause dyslipidemia, central
obesity and predispose patient to metabolic
INTERNATIONAL EVIDENCE-BASED GUIDELINE FOR THE
syndrome,and cardiovascular disease. Insulin resistance
ASSESSMENT, DIAGNOSIS AND MANAGEMENT OF PCOS
(IR) can also lead to T2DM.
2018
• Another consequence of androgen excess is that it
• both hyperandrogenism and irregular cycles be present,
inhibits antral follicle development. Together with the
with ultrasound NOT indicated due to overlap with
relative decrease in FSH, the follicles tend to grow all at
normal reproductive physiology.
the same time but not one becomes the dominant
• Ultrasound is now NOT recommended in diagnosis in
follicle. This results in the polycystic ovarian morphology
those within 8 years of menarche but are considered at
seen on ultrasound.
risk for PCOS and re-assessment is recommended.
• There is also anovulation due to absence of the Graafian
follicle, so there is increased level of estrogen produced
» Adolescent females have cystic ovaries under normal by the follicles that stimulates marked proliferative
conditions, so an ultrasound will not lead to a definitive
changes and thickening of the endometrium.
diagnosis. Therefore, pelvic ultrasound is not critical for
• When the endometrium becomes thick enough, the
diagnosis in adolescents. And besides, the transvaginal
upper portions becomes depleted of blood supply and

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Dr. G. Vilches| May 20, 2021
this results in irregular shedding of the endometrium
causing menstrual irregularity.
• And also when unopposed estrogen (no progesterone
from anovulation) stimulation becomes chronic, women
with PCOS are at risk for endometrial hyperplasia or
endometrial cancer.
• Another consequence of anovulation is failure to release
an ovum for fertilization resulting in subfertility or
infertility.
MODALITIES IN PCOS
INSULIN RESISTANCE
• It is present in 85% of patients with PCOS, including 95%
of obese and 65% of lean affected women.
• Insulin sensitivity is decreased by an average of 35-40%
in women with PCOS resulting in compensatory
hyperinsulinemia (a condition wherein there is a need for
a larger than the usual amount of insulin to transport
glucose into cells for energy).
Results in compensatory hyperinsulinemia
• high levels of these do not bind to the insulin
receptors but to receptors for IGF-1 (insulin-like
growth factor-1) which are significantly homologous
structurally to insulin receptors.
• These IGF-1 and IGF-1 binding proteins are
produced by the granulosa cells and these IGF-1 can
enhance LH stimulation and production of
androgens by the theca cells in women with PCOS.
• hyperinsulinemia can arrest follicular growth which
contributes to anovulation (less production of
estradiol which promotes follicular development)
• hyperinsulinemia also alters the GnRH pulse
secretion pattern, suppresses the SHBG, and
potentiates ovarian androgen production in women
with PCOS.
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ACANTHOSIS NIGRICANS
• Velvety plaques on nape and intertriginous area
resulting from Epidermal hyperkeratosis.
• Increased insulin activates insulin-like growth factor
receptors particularly IGF-1 leading to keratinocyte
and dermal fibroblast proliferation.
• Found in 30% of all hyperandrogenic women and in
50% of hyperandrogenic women with PCOS
WEIGHT GAIN/ OBESITY
• major predictor of abnormal metabolic findings and risk
for cardiovascular disease.
• Obesity increases hyperandrogenism, hirsutism,
infertility, and pregnancy complications both
independently and by exacerbating PCOS.
• In general populations, obesity and IR further increase
type 2 diabetes mellitus (DM2) and CVD. Likewise, in
PCOS patient with obesity worsens the IR and
exacerbates reproductive and metabolic features.
• So practically, all Sx of PCOS worsen with increasing
weight.
ABDOMINAL OR CENTRAL OBESITY
• aggravates the degree of IR and compensatory
hyperinsulinemia, hence, it appears to be strongly
associated with metabolic complications, like T2DM,
VISCERAL FAT
• CVD, metabolic syndrome. more active
metabolically than subcutaneous fat
• more sensitive to lipolysis and releases more FFA
• produces a number of cytokines involved in IR (TNF-
alpha, interleukin-6, leptin, resistin)
» Increase in visceral fat and abdominal fat correlated with IR
and metabolic dysfunction. So that lifestyle management is
really important and should be maintained lifelong.
Underweight < 18.5
Normal 18.5 - 22.9
Overweight 23 - 24.9
Obese I 25 - 29.9
Obese II >/= 30
METABOLIC SYNDROME
• prevalence of 60% among women with PCOS aged 20-39
years old
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• The Dx is based on adult treatment panel III criteria
• The Endocrine Society and the AE-PCOS Society highly
recommend that all women with PCOS should be
screened for CVD risk factors including family history,
cigarette smoking, glucose intolerance or diabetes,
hypertension, dyslipidemia, obstructive sleep apnea, and
obesity, especially central obesity (Legro et al.,
2013; Wild et al., 2010).
• (3 out of 5)
Waist circumference ≥ 88 cm (Non-Asian)
≥ 80 cm (Asian)
HDL < 50 mg/dL
• This can subsequently trigger the development of
endometrial hyperplasia and ultimately endometrial
cancer.
» Studies show that women with PCOS have a 2- to 3-
fold increased risk of developing endometrial cancer
even with weight control. It should be emphasized that
PCOS has other multiple risk factors for endometrial
cancer – aside chronic anovulation, there is centripetal
obesity and DM.
OVARIAN CANCER
• 2.5x increased risk.

Triglycerides ≥ 150 mg/dL BREAST CANCER

• 2-4x increased risk
BP ≥ 130/ ≥ 85 mmHg

FBS >100 mg/dL » Risks for endometrial and ovarian cancers can be brought
down with Oral Contraceptive use (for about 5 years)

TYPE 2 DIABETES MELLITUS

» Metformin has inhibitory effects in various cancers (esp for
endometrial & breast cancer)
• 2- to 3-fold higher in women with PCOS. It is driven
by IR which is worsened by obesity and menstrual
irregularity. QUALITY OF LIFE ISSUES
• Since there is a high conversion rate in women with
• There is poor QOL among women with PCOS and this
PCOS from euglycemia to impaired glucose
may be related to being overweight or obese, having
tolerance, and 54% conversion rate from impaired
irregular cycles, decreased fertility or infertility, and skin
glucose tolerance to frank diabetes, it is important to
concerns like hirsutism, acne and alopecia.
screen these patients for diabetes using 75-g OGTT
• Studies also showed a 4-fold increase in the prevalence
(oral glucose tolerance test).
of depression.
• HbA1C is NOT recommended for screening but it is
• Interventions: weight loss, change in lifestyle and various
useful in following up patients under treatment.
treatments are able to improve quality of life.
CARDIOVASCULAR DISEASE (CVD)
SEQUELAE OF PCOS
• multiple risk factors
Summary of the sequelae of PCOS.
o IDyslipidemia
o Hypertension Abnormal uterine bleeding
o Diabetes Cutaneous manifestations- hirsutism, acne, alopecia
o Obesity Infertility
Obesity
INFERTILITY Metabolic syndrome
• due to anovulation; no mature oocyte is periodically Cardiovascular disease
released so there is no ovum to fertilize Type II diabetes mellitus
• It may also be due to amenorrhea due to atrophy of Non-alcoholic fatty liver disease
the endometrium from high levels of androgen Pregnancy complications
Depression
Obstructive sleep apnea
CANCER Endometrial cancer
ENDOMETRIAL CANCER
• begin at a younger age because of long-term
anovulation and unopposed estrogen stimulation of the
endometrium.

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» PCOS is a lifelong disease. It is presented with a continuum
spectrum of symptoms and is connected with significant
cardiometabolic risk.
During the early age, there will be more reproductive
problems, but when the woman becomes older, more of the
metabolic problems may occur.
So mgt requires a multidisciplinary approach.
It is imperative to remember that the treatment of PCOS
changes throughout age and should be guided by
symptomatology. Early detection of long-term morbidities
through appropriate screening tests constitutes an essential
part of the management of this condition.
Ovarian aging: PCOS and Menopause
» As women age, ovaries decrease in size and androgen
levels decrease, so phenotype of PCOS may change or
disappear.
It has also been observed and documented that women with
PCOS with irregular menstrual cycle when younger, become
more regular and ovulatory as they age.
• As women enter menopause, hirsutism, if present
before Hirsutism may still be prevalent, if present
before menopause
• Persistence of metabolic issues
MANAGEMENT
❖ Optimal treatment regimen for PCOS is still unknown
» Treatment of PCOS is individualized and is directed to the
specific complaint.
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GOALS:
1. Restore regular menstruation, and prevent
endometrial hyperplasia and endometrial cancer
2. Restore or improve fertility
3. Treat hirsutism, acne and alopecia
4. Prevent long-term health risks—T2DM, insulin
resistance, CVD, metabolic disease, endometrial hyperplasia,
endometrial cancer
❖ For restoration of regular menstrual cycles (for
those not wanting to conceive)
➢ COCs or Combined oral contraceptives - first-
line treatment
o Regulate menstrual cycles
o Progestin component inhibits
endometrial proliferation, preventing
hyperplasia
» Another more important use of COCs is to
cause regular endometrial shedding (due to
progesterone component) thereby preventing
long-term consequences of anovulation which
are endometrial hyperplasia or cancer due to
unopposed estrogen endometrial stimulation.
➢ Cyclic progestins
o Started from Day 14 for 12-14 days
o Drosperinone, Dienogest
➢ GnRH analogues
o For refractory bleeding
❖ For treatment of signs of androgen excess
Combined oral contraceptives (COC)
- Can mitigate hyperandrogenism
Mechanisms:
- Progesterone component -> decrease LH
- Estrogen component -> increase hepatic production
of SHBG -> decrease free testosterone
- Inhibit 5α-reductase- > decrease conversion of
testosterone to active DHT -> decrease circulating
androgen
❖ For Treatment of hirsutism and acne:
» OCP – remains the first-line mgt for hirsutism; can be used
for those patients with menstrual irregularity and hirsutism or
acne. But first you have to screen for contraindications to OC
use. If there is, you may use Metformin. This can also be
combined with an anti-androgen.
Estrogen component inhibits the activity of the
hypothalamic–pituitary–gonadal axis, reducing ovarian
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androgen production as well as increasing the sex hormone- Veet - Common active ingredients are salts of thioglycolic
binding globulin levels. acid and thiolactic acids. These compounds break the
=Response to endocrine therapy takes at least 3-6 months in disulfide bonds in keratin and also hydrolyze the hair so that
concordance with hair growth cycle. it is easily removed.

Cyclic anti-androgenic progestins may also be used like

drosperinone and dienogest. ❖ For alopecia
- COC
Progesterone - anti-androgen
- slows the midcycle pulses of LH (and GnRH). - spironolactone
- may also improve insulin sensitivity and lipid profiles - minoxidil
in patients with PCOS. » Rogaine - brand of minoxidil
Anti-androgens In androgenetic alopecia, the anagen phase is shortened and
Androgen receptor antagonist - competitive antagonists of a progressive miniaturization of hair follicles occurs,
the androgen receptor eventually leading to hair loss. Although the mechanism is
- Spironolactone - an effective, off-label, add-on still not understood, minoxidil stimulates anagen phase and
treatment for hirsutism, acne, and alopecia because promotes hair growth.
of its antiandrogen effects
- Cyproterone acetate ❖ For infertility
- Flutamide First-line therapy Ovulation induction is the
simplest and least
Mechanism of action: expensive infertility
competes with androgens for androgen receptors therapy
inhibits interaction of DHT with its intracellular receptor Clomiphene citrate +/-
increases the metabolic clearance of testosterone Metformin
inhibits androgen production letrozole (aromatase
inhibitor) - currently
considered first-line drug
5α-reductase inhibitor
for ovulation induction
- Finasteride
o blocks conversion of testosterone to the Second-line therapy Gonadotropins
more potent DHT (dihydrotestosterone). Laparoscopic ovarian
drilling
Insulin sensitizers Third-line therapy in-vitro fertilization (IVF)
- Metformin
o Indirectly minimize effects of androgen
excess by improving insulin resistance and
➢ Clomiphene citrate
signs of hyperandrogenism. though it has
Dose:
limited benefit compared to anti-estrogens
50 mg OD initially starting on Day 5 for 5 days
and OCPs
Increase daily dose by 50 mg with each cycle If still
Mechanical methods unsuccessful at a daily dose of 150 mg, use
alternative medications
- depilating creams containing eflornithine
- It is a selective estrogen receptor modulator which has been
- shaving
the mainstay of ovulation induction for PCOS. It inhibits
- waxing
estrogen binding (estrogen agonist and antagonist activity)
- electrolysis
which stimulates the hypothalamus to release GnRH which
- lasers
further stimulates the pituitary to produce FSH to induce
» Eflornithine when added to laser tx is superior to using ovarian follicular development.
laser alone. Eflornithine works by blocking the enzyme -results in 30% successful pregnancies; however, 20% of
ornithine decarboxylase (ODC) that stimulates hair growth. these pregnancies result in spontaneous abortions or
(Vaniqa, Eflora) stillbirths.

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 LECTURE 24: Polycystic Ovary Syndrome
Dr. G. Vilches| May 20, 2021
-pregnancy needs to be excluded prior to ovulation induction
-Tubal patency testing should be considered prior to
ovulation induction in women with PCOS where there is
suspected tubal infertility.
Adverse effects: may include ovarian enlargement, ovarian
hyperstimulation syndrome, multiple pregnancies, hot
flashes, and gastrointestinal distention, bloating, and
discomfort
➢ Clomiphene citrate + Metformin - increased
ovulation rates but does not significantly improve
live birth rate over that of CC alone.
Aromatase inhibitor
Ex. Letrozole
Dose: 2.5 mg daily
Anti-estrogenic
Reduce up to 98% of estrogen levels
» This drug is principally a treatment for breast cancer in
postmenopausal women but more recently it has been used
off-label for ovulation induction and is being made the first-
line therapy for women with PCOS and anovulatory infertility.
As an aromatase inhibitor, it increases release of GnRH and
pituitary gonadotropins through an estrogen antagonist
effect. it lowers estrogen production by 98%. So, if estrogen
is low, it will give a negative feedback to the hypothalamus to
secrete GnRH which will in turn stimulate the pituitary to
secrete adequate FSH needed for development of mature
follicle, and subsequent ovulation. It is given at a dose of 2.5
mg daily
»ACOG recently recommended letrozole as first-line therapy
for ovulation induction in women with PCOS because of the
higher live birth rates compared to clomiphene when given
alone
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➢ Gonadotropins - If clomiphene-resistant with
anovulatory and no other infertility factors
- like FSH and human menopausal gonadotropin
as 2nd line pharmacological agents which can
also be used to induce ovulation.
➢ Ovarian drilling - lower rate of hyperstimulation
therefore less multiple births; disadv- adhesion
formation and damage to ovarian reserve (lose more
ovarian tissue). Incidence of ovulation 70%,
pregnancy rate 40%
» The old way of managing hyperandrogenism was doing
ovarian wedge resection.
Ovarian wedge resection results in sustained decrease in
androgen levels that precedes return of ovulatory cycles. The
success of the procedure correlates with the amount of
androgen-producing stromal tissue that is removed.
However, laparoscopic ovarian “drilling” using electrosurgical
needle or laser have replaced the classical wedge resection
which achieved similar results.
Bilateral ovarian cautery -> decrease serum androgen levels
by nearly 50% in women with PCOS
➢ In-vitro fertilization (IVF) ± Intra-cytoplasmic sperm
injection (ICSI)
- hCG – given at lowest dose to trigger final
oocyte maturation and reduce incidence of
OHSS (ovarian hyperstimulation syndrome)
❖ For obesity
Weight loss
- Diet
- Exercise
- Bariatric surgery
» Obesity is prevalent in 50-80% of women with PCOS. There
was higher live birth rates with ovulation induction in women
with BMI <30 kg/sq m compared to those >35. Mainstay
treatment is Lifestyle intervention (exercise and diet) which
significantly improved live birth rates.
Importance of lifestyle modification should be stressed for
those who are obese. Promote weight loss with calorie-
restricted diet and exercise . Studies showed that weight loss
is one of the most effective approach for managing insulin
abnormalities, irregular menses and central obesity.
It decreased testosterone levels, and improved hirsutism and
insulin resistance. Some women who lost 5-10% of their
body weight had their periods become regular.
Bariatric surgery is reserved for those who are morbidly
obese.
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 LECTURE 24: Polycystic Ovary Syndrome
Dr. G. Vilches| May 20, 2021

Like metformin, troglitazone may affect hyperandrogenism by

Inositol should currently be considered an experimental
therapy in PCOS, with emerging evidence on efficacy
highlighting the need for further research
- reduce blood triglyceride levels
- improve insulin function
- lower blood pressure
- promote ovulation in women with PCOS
1) reducing pituitary gonadotropin secretion; 2) reducing
ovarian androgen secretion; 3) reducing adrenal androgen
secretion; and 4) increasing plasma levels of SHBG.
It is suggested that the inositols MI (myo-inositol) and DCI (D-
chiro inositol) can reduce insulin resistance, improve ovarian
function, and reduce androgen levels in women with PCOS

❖ For hyperinsulinemia/ IR - As insulin resistance is a TREATMENT FOR ADOLESCENTS WITH PCOS

common feature of PCOS, the use of insulin
sensitizing agents, particularly metformin, for Lifestyle modification
treatment of anovulatory infertility is physiologically - diet and exercise
reasonable.
- These are the insulin-lowering agents that may COC – for menstrual irregularity, hirsutism and acne
be used for hyperinsulinemia
Metformin – for glucose intolerance
Metformin - Impede hepatic glucose
production ➢ Goals of treatment for adolescents with PCOS are to
- Increase peripheral insulin improve quality of life and prevent long-term health
sensitivity outcomes.
Dose: 1,500 mg/day Treatment is primarily symptomatic and directed at the major
clinical manifestations which are:
Diazoxide Lowers circulating insulin Abnormal uterine bleeding – Menstrual irregularity or
levels excessive bleeding
Troglitazone Enhance insulin effects at ●Cutaneous hyperandrogenism – Primarily hirsutism and
peripheral target sites (A/E:
persistent acne
liver toxicity)
●Obesity and insulin resistance
Inositol Reduce insulin resistance,
improve ovarian function, First-line treatment of the comorbidities of obesity and
and reduce androgen levels insulin resistance is lifestyle modification with calorie
restriction and increased exercise.
Cyclic Combined oral contraceptives (COC) are the preferred
Metformin acts by impeding hepatic glucose production and first-line medical treatment because they reliably improve
increasing the peripheral insulin sensitivity. It can be used to both the menstrual abnormality and signs of
treat and prevent progression to NIDDM in PCOS women. hyperandrogenism.

Dioxazide lowers circulating insulin levels. Diazoxide directly

suppresses plasma insulin. Its mechanism of action is via -
adrenergic stimulation of pancreatic -islet cells. 100 mg
diazoxide/d for 10 d
In women with PCOS and insulin resistance, the reduction of
hyperinsulinemia that is produced by troglitazone improves
the hyperandrogenism that characterizes PCOS, restoring
ovulation.
Troglitazone is an oral antidiabetic drugs that act by
enhancing insulin effects at peripheral target sites. In March
2000, troglitazone was withdrawn from the market due to
liver toxicity. 400 mg troglitazone/d, free T dropped 25–35%
and SHBG increased by 25–66%
Metformin in conjunction with behavior modification is
indicated for glucose intolerance and weight reduction.
Lifestyle modifications remain first-line management of
overweight and obese adolescents with PCOS. Combined oral
contraceptives (COC) are first line pharmacotherapy for
management of menstrual irregularity and acne, and
metformin is superior to COCs for weight reduction and
improved dysglycemia. COCs and metformin have similar
effects on hirsutism, but often need to be paired with other
treatment modalities to achieve further improvement of
cutaneous symptoms.

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 LECTURE 24: Polycystic Ovary Syndrome
Dr. G. Vilches| May 20, 2021

SUMMARY:

• PCOS is the most common endocrine disorder in

women of reproductive age.
• It is a lifelong disease which can be managed and
controlled, but no cure.
• The syndrome is characterized by signs and
symptoms of androgen excess and ovarian
dysfunction and has varied phenotypes.
• Its underlying pathophysiology is still not completely
understood.
• It is associated with many co-morbidities and has a
number of long-term metabolic and other
consequences, hence should be managed by a
multidisciplinary team.
• Therapy remains focused on managing symptoms
and reducing long-term health risks.

END OF TRANSCRIPTION
REFERENCES
● Comprehensive Gynecology 7th edition
● Dr. Vilches’ ppt

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 LECTURE 24: Polycystic Ovary Syndrome
Dr. G. Vilches| May 20, 2021

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