Transcript 1. Polycystic ovary syndrome

Prof. Yousef Gadmour
Al- Fateh university
Al- Jalla Maternity Hospital
Tripoli - Libya
Polycystic ovarian syndrome
Definition :
It is a clinical syndrome characterized by presence of
polycystic ovary and symptoms such as
:
1. Infertility .
2. Hirsutism.
3. Oligo-amenorrhoea.
4. Obesity.
5. Dysfunctional uterine bleeding.
6. Verilisation.
7. Hyperprolactinaemia.
Incidence
- It is the Commonest endocrinal gynecologic
disorder
- About 2% of general population.
- 4-10% based on clinical, biochemical and
u/s criteria.
- 10-20% based on U/s only.
- 30% of infertility.
- 90% of Hirsutism with regular cycle.
- 87% of case of oligomenorrhea.
- 82% of cases with recurrent miscarriage.
Pathology:
The ovaries are enlarged and show :
1. Numerous small cystic follicles ( usually 2-8 mm in
diameter and peripherally placed ) .
2. Thickened white ovarian capsule .
3. Theca cell hyperplasia ( due to increased LH ).
4. Granulosa cell atresia ( due to low FSH ) .
The cystic follicles and increased ovarian stroma
can be demonstrated by ultrasound .
Endocrine abnormalities : (
cont.) – ovarian androgens excretion
1. Androgens
(testosterone and androstenedione )is commonly
increased but the adrenal (dehydroepiandrosteronesulfate) is also involved in up to 40% of cases.
2.
3.
Sex hormone binding globulin (SHBG) levels are
reduced This result in an increase in unbound (and
therefore active ) androgen and oestradiol levels.
Insulin – women with PCOS are hypre-insulinaemic but
are insulin-resistant.
( Hyper-insulinaemia
levels of SHBG)
(? PC0S mechanism )
Pathogenesis :
connective Tissue
Androstenedione
Oestradiol
Oestrone
( ov.& adrenal )
Obesity
Insulin
SHBG
Free Oestradiol
DUB
Free Oestradiol
FSH
LH
Granulosa cell atresia
No LH surge
No ovulation
Theca cell hyperplasia
5 α-reductase
Hirsutism
+ Virilization
DHT
Androgens
High Follicular phase LH concentrations
have been found to be associate with:
• Poor oocytes quality
• Reduced rate of fertilization
• Reduced pregnancy rate
• Increase incidence of miscarriage
Diagnosis of PCOS
• Oligoamenorrhea or amenorrhea and subfertility.
• Symptoms of androgen excess.
 U /S (Adams criteria) : 1-Many follicles 8-10
2-Follicles <10mm diameter
3-Thickened white capsule
4-Hyperechogenic stroma
 Biochemical :↑LH in 40% of cases (LH/FSH>2)
↑serum testosterone in 30% of cases
serum prolactin in 40% of cases
Management
Principals of management :
• Confirm diagnosis and identify category.
• Identify and manage concurrent illness.
• Identify and manage patient needs.
There are numerous options for successful PCO
management – medical / surgical
Preprocedural Considerations
• Endometrial Neoplasia
• Insulin Resistance
• Metabolic Syndrome
• Weight loss
Endometrial Neoplasia
• Chronic anovulation associated with PCOS
may lead to endometrial hyperplasia and
sometimes to frank endometrial cancer
(Meier and Schenker,1996).
• Endometrial biopsy is indicated in all women
with H/O long term unopposed estrogen
exposure and in those where endometrial
thickness is greater than 12mm.
Insulin Resistance (IR)
• IR is defined as reduced glucose response to a given
amount of insulin.
• It occurs in 80% of obese women and 30 to40% of
women with normal wt. with PCOS .
• Peripheral target tissue insulin resistance can be due
to decreased no of peripheral insulin receptors,
decreased insulin binding or a post receptor failure.
• In PCOS it is caused by the post receptor defect due
to excessive serine phosphorylation of beta chain of
insulin receptor and of adrenal and ovarian
cytochrome P450c enzyme . This enzyme is a rate
limiting step in androgen biosynthesis thus leading to
hyperandrogenemia .
Increased
Serine
phosphorylation
Decreased
glucose
transport
Hyperinsulinemia
P450c 17
&17,20 lyase
activity
Adrenals :
Increased
DHEAS
Ovaries :
Increased
Androstenedione&
testosterone
Diagnostic criteria for metabolic
syndrome
Diagnosis is made when 3 or more of
these risk criteria are met :
1.
2.
3.
4.
5.
↑ Glucose ≥ 6.1 mmol/l
Waist circumference ≥ 88 cm.
↓ HDL-C≤ 1.3 mmol/l
↑BP ≥ 130 / ≥ 85 mm Hg
↑TG ≥ 1.7 mmol/l
(Shroff et al.,2007)
Weight Loss
• Weight loss has advantage of being effective
and cheap with no side effects and should be
the first line of treatment .
• Weight loss improves endocrine profile
and ovulation and subsequent healthy
pregnancy (decreasing insulin and
androgens and increasing SHBG ).
• Weight loss has been shown to improve the
outcome of all forms of infertility treatments,
including IVF (Clark et al.,1998).
Various treatment modalities
Pharmacological Treatment
CC
Gonadotropin
Hyperinsulinemia?
hMG
Insulin sensitizer
uFSH
GnRH-analogs
HP-FSH
rec-FSH
A. Medical Treatment
• Infertility is treated by increasing the rate
of ovulation, in part by reducing insulin
drive through exercise and weight loss .
• Ovarian stimulation is used for those
patients who do not ovulate, despite
loosing weight by different drugs and
different protocols.
Medical Treatment (cont.)
• Treat Hyperprolactinaemia with
Bromocriptine.
• Glucocorticoids for adrenal hyperplasia .
( 0.25mg Dexamethasone at night )
• COC pills or POP for dysfunctional uterine
bleeding and to reduce the risk of
endometrial carcinoma .
Insulin sensitizing drugs
Metformin
•
Action :
-inhibit hepatic glucose production.
-enhance sensitivity of peripheral tissues to insulin
-↓ insulin secretion.
•  Ovarian hyperstimulation in gonadotrophin
therapy
• RCT- clomiphene -resistant pts., use of metformin
& CC produced significant improvement
B. Surgical treatment modalities
Surgical Treatment
Cauterization
( laser, electric )
Wedge resection
Methods of Ovarian Surgery For
Ovulation Induction In PCOS
• Laparoscopic Techniques of Ovarian Surgery
(LOS)
Laparoscopic Ovarian Drilling (LOD) :
Diathermy / LASER.
• Transvaginal Techniques of Ovarian Surgery
(TVOS)
1) Transvaginal mini-laparoscopy (Fertiloscopy)
2) Transvaginal ultrasound (TVS)-guided ovarian
drilling.
Indications
I. Ovulation induction: in the following cases:
a) C.C resistant PCO:
Defined as failure to ovulate on a dose of 100 mg,
for 5 days (recently in 3 cycles, in contrast to 6
cycles in the past ) or
failure to ovulate on incremental doses of CC(50-150mg).
b) C.C failure PCO:
Defined when pregnancy does not occur despite of
regular ovulation on C.C for 6-9 cycles.
c) C.C pregnancy failure:
Defined as failure to maintain pregnancy conceived
with C.C.
Indications( cont.)
II. Other potential indications:
1.
2.
3.
LH hypersecretion.
Patient cannot follow treatment regularly.
Prevention of long term morbidity in PCOS
patient.
4. Menstrual irregularity in PCOS patient.
5. Acne and hirsutism resistant to treatment
in
PCOS patient.
Mechanism of action Of LOS
1. Drainage of atretic follicles with high
(Androgen+ inhibin) content.
2. Destruction of ovarian stroma that
produce androgen.
3.LOS → Postoperative ↑ of FSH →↑Intrafollicular aromatase activity
1,2,3 →
↓Intra-follicular androgenic environment →
remove intraovarian block to follicular
maturation that precedes ovulation.
Mechanism of action Of LOS
(CONT.)
4.Surgical trauma to the ovary :
• Production of non steroidal factors →
Restore hypothalamo-pitutary-ovarian
function.
• Production of ovarian growth factors{IGF1}→ Sensitize ovary to circulating FSH.
Risks:
1-Adhesion formation,
2-Potential surgical risks (bleeding and infection)
3-Anesthesia risks,
4-Premature ovarian failure (theoretical
complication)
Technique Of LOS
Utero-ovarian ligament
is grasped by atrumatic
forceps moving the ovary
(towards anterior
abdominal wall& in
front of the uterus).
LASER versus electrocautery
for LOS:
Electrocautery IS superior why?
1) Less coast &easy application.
2) Achieve higher ovulation and pregnancy
rate.
3) Less surface injury than CO2 LASER →
Surface adhesion.
4} Effect of diathermy may last longer than
the effect of LASER .
Results
• Short term results:
– In responders ovulation occur within 2-4 wk,&
menstruation within 4-6 wks.
– Ovulation rate: 50-90%.(Patient with high LH
level respond better to LOS).
– Cumulative Pregnancy &Live birth
rates:76%-64% respectively.
• Long term results:
Improvement in reproductive performance is
sustained for many years. (49% Of women
conceived within the 1st year after LOS)
Conclusions
• Obesity plays a central role in development
of PCOS leading to Hyperinsulinemia in
susceptible individuals.
This Hyperinsulinemia may alter androgen
metabolism via a variety of mechanisms,
the net result of which Hyperandrogenism.
Conclusions
• The management of patients with PCOS
depends upon the individual patient’s
complaints.
• Hyperandrogenism is optimally dealt with
by reducing insulin drive to the ovary, such
as exercise and reducing diet
Hirsutism
Definition
Excessive and inappropriate growth of
facial and body hair .
Causes
1. Endocrine- PCOS; adrenal
hyperplasia/Cushing's syndrome;
hypothyroidism; acromegaly .
2. Androgen-secreting tumours of adrenal or
ovary .
3. Drugs- phenytoin , diazoxide , danazol ,
corticosteroids .
4. Idiopathic .
Investigation
1. Check serum testosterone – if < 5 nmol /l no further
investigation .If > 5 nmol/l repeat and check
urinary steroids in 24 hour sample.
2. Check serum LH and FSH . An elevated LH
suggests PCOS .
3. Pelvic ultrasound will demonstrate polycystic
ovaries.
4. Check thyroid function .
5. Measure serum 17-hydroxyprogesterone if
congenital adrenal hyperplasia is suspected .
If levels are high consider ACTH stimulation
and dexamethasone suppression tests .
6. If urinary cortisol is elevated investigate for
Cushing's syndrome .
7. If adrenal tumor is suspected carry out CT
scans and consider direct catherisation of
adrenal veins or surgical exploration .
Treatment
This will depend on the cause.
Sympathetic handling and reassurance
are necessary at all times.
1. Polycystic ovary syndrome
Induce ovulation if infertility is also a problem.
combined oesrogen/progestogen pill to suppress
androgen production. Response to treatment is slow
at best. It may be 6 months to a year before any
reduction in hirsutism is seen.
Cyproterone acetate is an anti-androgen with
progestogenic activity.
Pregnancy must be avoided during its use.
It is therefore best used cyclically (day 5-15) in
combination with ethinyl Oestradiol (day 5-26) which
not only helps to inhibit ovulation but also increases
SHBG concentrations.
This lowers the levels of free androgens.
2. Adrenal hyperplasia
This is the only situation in which corticosteroid
treatment – remove after localisation.
3. Androgen – producing tumours
Remove after localisation.
4. Idiopathic hirsutism
This may be due to end – organ hypersensitivity.
There may be some response to the
oesrogen/progestogen pill or spironolactone
and electrolysis is useful cosmetically.