Management of Women with Clomiphene
Citrate
Resistant Polycystic Ovary Syndrome
DR Seyed Mehdi Ahmadi
OB & Gynecologist
Isfahan Fertility & Infertility Center
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.
Increased
Serine
phosphorylation
Decreased
glucose
transport
Hyperinsulinemia
P450c 17
&17,20 lyase
activity
Adrenals :
Increased
DHEAS
Ovaries :
Increased
Androstenedione&
testosterone
Various treatment modalities
Tre Pharmacological
CC
Gonadotropin
Hyperinsulinemia?
hMG
uFSH
HP-FSH
rec-FSH
Insulin sensitizer
GnRH-analogs
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 .
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.
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 .
1) lifestyle modifications :

Weight loss

Caffeine intake

Alcohol consumption

Smoking

Dietary modification

Exercise

Psychosocial stressors
Role of weight loss in PCOS treatment:
Reduce insulin resistance by about 50%
Restore ovulation
Regulate menstrual cycles
Reduce pregnancy complications
Improve fertility
Improve health during pregnancy
Improve the health of a child during pregnancy
Improve emotional health (self-esteem, anxiety, depression)
Reduce risk factors for diabetes and heart disease
PROTOCOLS OF MANAGEMENT IN
ADOLESCENTS

Counselling for weight reduction and life style
modification.

Carbohydrate and fat restricted diet.

Diet restriction and exercise is the sheet anchor
of treatment for overweight.

Low glycemic index diet upto 85% will improve
menstrual cycle regularity and ovulation in about
six months

Even 7% weight reduction may lead to spontaneous
resumption of menses.

Moderate physical activity, 30-60 minutes per day should
be goal of all patient with adolescent PCOS.M.O.A:-

lowers circulating free androgen and insulin levels.

Increases SHBG, thereby decreases level of free
testosterone.
FSH Ovulation Induction Protocol
Increase dose slowly - can be very sensitive
Starting
dose
Scan
d7
Scan
d14
Increase dose
by 50%
25-50iu/day
Scan
d21
Follicle
=16mm
Increase dose
by 50%
hCG
5000u
2) Gonadotrophins :

Ovulation induction with gonadotrophins has been used as a
second line treatment for CC-resistant PCOS women.

Disadvantage : expensive/ requires extensive monitoring /risk
for OHSS & multiple pregnancy .

The high sensitivity of the PCOS to gonadotrophic stimulation is:
they contain twice the number of FSH -sensitive antral follicles
than the normal ovary.

A lowdose,step-up gonadotrophin therapy should be preferred.

Recommended approach is :
begin with a low dose of gonadotrophin, (typically 37.5– 75
IU/day)
increasing after 7 days or more if no follicle >10 mm has yet
emerged, in small increments, at intervals, until evidence of
progressive follicular development is observed.

The maximum required daily dose of FSH/hMG seldom exceeds
225 IU/day.

There is no evidence of a difference between recombinant FSH
(rFSH) and uFSH for ovulation induction in CC- resistant PCOS
women.
3) Laparoscopic Ovarian Drilling

WHO BENEFITS FROMMechanism LEOS
• ?Removalresistant, CC androgen-producing tissueProblems Slim,
Anovulatory ,
• Hazards of laparoscopic surgery & GA (although rare) raised S.LH
• TemporaryEfficacy
• <50% clomiphene-resistant women conceive (ovulation rate 80%+)
• Hormone profile returns to normal
• ?Fewer miscarriages compared to gonadotrophin injection
treatment
3) Laparoscopic Ovarian Drilling
(LOD):

Being as effective as gonadotrophin treatment and is not
associated with an increased risk of multiple pregnancy or
OHSS.

When applied properly, does not seem to compromise the
ovarian reserve in PCOS women.

n economic evaluation has shown that the cost of a live
birth after LOD is approximately one-third lower than the
equivalent cost of gonadotrophin treatment.

Four punctures per ovary using a power setting of 30 W
applied for 5s per puncture.

Unilateral LOD being equally efficacious as bilateral drilling
in inducing ovulation and achieving pregnancy in CC
resistant PCOS patients and may be regarded as a suitable
option with the potential advantage of decreasing the
chances of adhesion formation.

Mechanism :

LOD
drains the ovarian follicles containing a high
concentration of androgens and inhibin
reduction
of blood androgens and blood inhibin
resulting in
an increase of FSH and recovery of the ovulation function .

poor responders to LOD :
-
Women with marked obesity (BMI >35 kg/m2)
-
Marked hyperandrogenism (serum testosterone
concentration >4.5 nmol/l
-
free androgen index (FAI) >15
-
long duration of infertility (>3 years)

Predictor of higher probability of pregnancy : LH levels
>10 IU/l in LOD responders
Technique of Laparoscopic Ovarian
Drilling
4) Insulin-sensitizing drugs :
IMPROVEMENT OF HYPERINSULINEMIA
BY INSULIN SENSITIZERS

Directly sensitizing insulin receptors.

Preventing neoglucogenesis.

Reducing absorption of glucose from intestine.

Increasing hepatic synthesis of SHBG level thereby
reducing the level of bioactive free testosterone
Metformin

Decreases basal hepatic glucose output in patients and
lowers fasting plasma glucose concentration.

It increases the uptake and oxidation of glucose by
adipose tissue as well as lipogenesis.

S/E- diarrhoea, nausea, vomiting ,specially initially. To
avoid them metformin should be taken with meals and the
dose increased gradually. Or SR release formulations are
used once a day 1000 mg SR or 500mg SR twice a day
OTHER DRUGS WHICH CAN BE USED
• Rosiglitazone ,
• Pioglitazone,
• D chiro inositol,
• Myoinositol
• N acetyl cysteine.
• Micronutrients
OTHER DRUGS WHICH CAN BE USED IN
ADDITION TO O.C.P

In cases of failure or where there is clinical or biochemical evidence
of gross hyperandrogenicity or hyperinsulinemia, addition of
metformin is recommended.

Spironolactone- it has antiandrogenic effects in doses 100-200 mg
daily.

Finasteride - a competitive inhibitor of Type-2 5a reductase to treat
hirsutism. Dose 1-5 mg/day.
5) Third-generation aromatase
inhibitors :
Anastrozole, Letrozole, Exemestane
DURING PREGNANCY

RECURRENT MISCARRIAGES 50%

GESTATIONAL DIABETES

PREGNANCY INDUCED HYPERTENSION

INTRAUTERINE GROWTH RETARDATION
6) Oral contraceptives :
Oral contraceptive administration
reduce serum LH, estradiol and androgen levels
improving the ovarian microenvironment
Inhance ovarian response to CC
7) N-acetyl-cysteine :

N-acetyl cysteine (NAC) is the acetylated variant of the amino acid
L-cysteine.

It is an excellent source of sulfhydryl groups and is converted in
vivo into metabolites that stimulate glutathione production,
promote detoxification, and act directly as free-radical
scavengers.

combination of CC and NAC increases ovulation and pregnancy
rates in CC-resistant PCOS patients who also suffer from infertility.

NAC has antiapoptotic effects on the ovary and apoptosis is
definitely responsible for the process of follicular atresia.
Biological activities of N-acetyl cysteine
8) Dexamethasone therapy :
Dexamethasone (after 2 weeks of treatment )
Reduced DHEAS
Reduced Testostrone
Reduced LH levels and the LH/FSH ratio
Inhance ovarian invironment
9) Bromocriptine :
Bromocriptine administration provided no benefit in CC-resistant PCOS
patients with normal prolactin levels.
Bromocriptine administration improve ovarian response in
hyperprolactinemic patients.
Dopaminergic components have control of LH release in PCOS patients
10) IVF/ET or IVM :

If all else fails for the infertile PCOS patient then in-vitro
fertilization is a last resort providing excellent results.
33-50% OF PATIENTS REFERRED FOR
IVF HAVE PCOS
MANAGEMENT

life style and exercises

diet

insulin sensitisers

ocp’s

progesterone for bleed

statins/diabetes /antihypertensives if needed

omega 3 and micronutrients(inositol or myoinositol or n-actyl
cysteine or alternative medicines
Algorithm for ovulation induction treatment in
anovulatory infertile women with CC-resistant PCOS