Polosiklik Ovary Syndrom

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}}}
\par
\sect\sectd\sbknone\plain\pard\sl-395 \li2 \ri1075 \expndtw-6 \b \f10 \fs31 The
management of infertility associated with polycystic ovary
\plain\par
\pard\sl-359 \li2 \ri8143 \expndtw-19 \b \f10 \fs31 syndrome
\plain\par
\pard\sl-343 \li2 \ri7667 \expndtw0 \f20 \fs30 Roy Homburg*
\plain\par
\sl-144\fs14\par\sl-240\fs24\par\pard\pard\sl-189 \li2 \ri684 \expndtw0 \f20 \fs
15 Address: Division of Reproductive Medicine, Department of Obstetrics and Gyne
cology, Vrije Universiteit Medisch Centrum, Amsterdam, The
\plain\par
\pard\sl-189 \li2 \ri8721 \expndtw0 \f20 \fs15 Netherlands
\plain\par
\pard\sl-290 \li2 \ri6640 \expndtw0 \f20 \fs15 Email: Roy Homburg* - r.homburg@v
umc.nl
\plain\par
\pard\sl-229 \li2 \ri7976 \expndtw0 \f20 \fs15 * Corresponding author
\par
\plain\sl-176\fs18\par\sl-240\fs24\par\par\pard\pard\sl-189 \li2 \ri3429 \expndt
w-9 \f10 \fs15 Published: 14 November 2003
\plain\tx5079 \tab \expndtw-11 \f10 \fs15 Received: 21 March 2003
\plain\par
\pard\sl-189 \li2 \ri3133 \fi5089 \expndtw-8 \f10 \fs15 Accepted: 14 November 20
03
\plain\par
\pard\sl-97 \li2 \ri6628 \expndtw-14 \i \f10 \fs15 Reproductive Biology and Endo
crinology\i0 2003,\b 1\b0 :109
\plain\par
\pard\sl-281 \li2 \ri5608 \expndtw-6 {\field{\*\fldinst {\b HYPERLINK}{\b "http:
//www.rbej.com/content/1/1/109"}}
{\fldrslt{\f10 \fs15 This article is available from: http://www.rbej.com/content
/1/1/109
}}}
\par
\plain\pard\sl-286 \li2 \ri780 \expndtw-6 \f10 \fs15 2003 Homburg; licensee BioM
ed Central Ltd. This is an Open Access article: verbatim copying and redistribut
ion of this article are permitted in all
\plain\par
\pard\sl-189 \li2 \ri4028 \expndtw-6 \f10 \fs15 media for any purpose, provided
this notice is preserved along with the article's original URL.
\plain\par
\sl-231\fs23\par\sl-240\fs24\par\par\pard\pard\sl-214 \li1136 \ri7672 \expndtw-8
\b \f10 \fs21 Abstract
\plain\par
\pard\sl-279 \li1136 \ri1522 \expndtw-7 \f10 \fs19 Polycystic ovary syndrome [PC
OS] is the commonest cause of anovulatory infertility. Treatment
\plain\par
\pard\sl-233 \li1136 \ri1523 \expndtw-10 \f10 \fs19 modes available are numerous
mainly relying on ovarian stimulation with FSH, a reduction in insulin
\plain\expndtw-9 \f10 \fs19 concentrations and a decrease in LH levels as the ba

sis of the therapeutic principles. Clomiphene
\plain\expndtw0 \f10 \fs19 citrate is still the first line treatment and if unsu
ccessful is usually followed by direct FSH
\plain\expndtw-9 \f10 \fs19 stimulation. This should be given in a low dose prot
ocol, essential to avoid the otherwise prevalent
\plain\expndtw-7 \f10 \fs19 complications of ovarian hyperstimulation syndrome a
nd multiple pregnancies. The addition of a
\plain\expndtw-9 \f10 \fs19 GnRH agonists, while very useful during IVF/ET, adds
little to ovulation induction success whereas
\plain\expndtw-8 \f10 \fs19 the position of GnRH antagonists is not yet clear. H
yperinsulinemia is the commonest contributor
\plain\expndtw-6 \f10 \fs19 to the state of anovulation and its reduction, by we
ight loss or insulin sensitizing agents such as
\plain\expndtw-4 \f10 \fs19 metformin, will alone often restore ovulation or wil
l improve results when used in combination
\plain\expndtw-6 \f10 \fs19 with other agents. Laparoscopic ovarian drilling is
proving equally as successful as FSH for the
\plain\expndtw-1 \f10 \fs19 induction of ovulation, particularly in thin patient
s with high LH concentrations. Aromatase
\plain\expndtw-8 \f10 \fs19 inhibitors are presently being examined and may repl
ace clomiphene in the future. When all else
\plain\expndtw-7 \f10 \fs19 has failed, IVF/ET produces excellent results. In co
nclusion, there are very few women suffering
\plain\expndtw-8 \f10 \fs19 from anovulatory infertility associated with PCOS wh
o cannot be successfully treated today.
\par
\sect\sectd\sbknone\cols2\colno1\colw4822\colsr338\colno2\colw5378
w-16 \b \f10 \fs21 Review
\plain\par
\pard\sl-218 \li2 \ri0 \expndtw2 \f20 \fs19 Polycystic ovary syndrome [PCOS] is
associated with
\plain\par
\pard\sl-235 \li2 \ri0 \expndtw1 \f20 \fs19 approximately 75% of women who suffe
r from infertility
\plain\expndtw1 \f20 \fs19 due to anovulation [1,2]. It is a very heterogeneous
syn\plain\expndtw2 \f20 \fs19 drome both in its clinical presentation and laborator
y
\plain\expndtw1 \f20 \fs19 manifestations. The majority of women with anovulatio
n
\plain\expndtw1 \f20 \fs19 due to PCOS have menstrual irregularities, usually ol
i\plain\expndtw2 \f20 \fs19 gomenorrhea or amenorrhea, associated with clinical
\plain\expndtw1 \f20 \fs19 and/or biochemical evidence of hyperandrogenism. The
\plain\par
\pard\sl-235 \li2 \ri1299 \expndtw1 \f20 \fs19 main disturbances in this syndrom
e are:
\plain\par
\sl-233\fs23\par\pard\pard\sl-235 \li2 \ri0 \expndtw0 \f20 \fs19 1. Abnormal mor
phology of the ovary, detected by a char\plain\expndtw1 \f20 \fs19 acteristic hyperechogenic enlarged central stroma and
>9
\par
\column
\plain\sl-274\fs27\par\sl-240\fs24\par\par\pard\pard\sl-235 \li0 \ri502 \expndtw
0 \f20 \fs19 small follicles of 2-9 mm diameter on transvaginal ultra-
\plain\expndtw1 \f20 \fs19 sound examination of the ovaries [3].

\plain\par
\sl-235\fs23\par\pard\pard\sl-235 \li0 \ri502 \expndtw1 \f20 \fs19 2. Abnormal s
teroidogenesis, mainly increased ovarian
\plain\expndtw1 \f20 \fs19 production of androgens but also increased progestero
ne
\plain\expndtw1 \f20 \fs19 and estradiol production.
\plain\par
\sl-235\fs23\par\pard\pard\sl-235 \li0 \ri502 \expndtw3 \f20 \fs19 3. Hyperinsul
inemia, present in about 80% of obese
\plain\expndtw2 \f20 \fs19 women and 30-40% of women of normal weight with
\plain\expndtw1 \f20 \fs19 PCOS [4] and more strongly associated with anovulatio
n
\plain\expndtw1 \f20 \fs19 than any other feature of the syndrome.
\plain\par
\sl-308\fs31\par\sl-240\fs24\par\par\par\pard\pard\sl-200 \li2372 \ri504 \fi1527
\expndtw-6 \f10 \fs18 Page 1 of 9
\plain\par
\pard\sl-210 \li0 \ri501 \fi2372 \expndtw-1 \i \f10 \fs13 (page number not for c
itation purposes)
\par
\sect\sectd\sbknone\sect\sectd\sbkpage\margtsxn280\pard
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}}\margt780\margb40\margr1100\margl1080
\plain\pard\sl-239 \li2 \ri36 \expndtw-2 \i \f10 \fs18 Reproductive Biology and
Endocrinology\i0 2003,\b 1
\plain\tx7096 \tab \expndtw-3 \f10 \fs18 http://www.rbej.com/content/1/1/109
\plain\par
\sl-219\fs22\par\sl-240\fs24\par\par\pard\pard\sl-214 \li2 \ri2610 \expndtw2 \f2
0 \fs19 4. Abnormal gonadotrophin secretion, most commonly
\plain\tx5149 \tab \expndtw-4 \b \f10 \fs21 Clomiphene citrate
\par
\plain\pard\sl-217 \li2 \ri0 \expndtw0 \f20 \fs19 manifested as increased serum
LH concentrations in 40%
\plain\par
\pard\sl-235 \li2 \ri0 \expndtw1 \f20 \fs19 of women with ultrasonically detecte
d PCO [5]. A func\plain\expndtw1 \f20 \fs19 tional deficiency of the endogenous action of FSH als
o
\plain\expndtw1 \f20 \fs19 seems to be present in women with anovulatory PCOS.
\plain\par
\sl-236\fs24\par\pard\pard\sl-233 \li2 \ri0 \expndtw2 \f20 \fs19 Several modes o
f inducing ovulation for these patients
\plain\expndtw1 \f20 \fs19 will now be described. It will be seen that they basi
cally
\plain\expndtw2 \f20 \fs19 depend on either a reduction of insulin concentration
s,
\plain\expndtw1 \f20 \fs19 FSH stimulation or a reduction of LH concentrations o
r a
\plain\expndtw1 \f20 \fs19 combination of these.
\plain\par
\sl-272\fs27\par\pard\pard\sl-214 \li2 \ri3269 \expndtw-9 \b \f10 \fs21 Weight l
oss
\plain\par
\pard\sl-217 \li2 \ri0 \expndtw0 \f20 \fs19 Excess body weight is a common probl
em of modern soci\plain\par
\pard\sl-235 \li2 \ri0 \expndtw0 \f20 \fs19 ety, reaching epidemic proportions i
n some countries. For
\plain\expndtw0 \f20 \fs19 women with PCOS, an excess of body fat accentuates in
su\plain\expndtw0 \f20 \fs19 lin resistance and its associated clinical sequelae.
Central
\plain\expndtw0 \f20 \fs19 obesity and BMI are major determinants of insulin res
ist\plain\expndtw0 \f20 \fs19 ance, hyperinsulinemia and hyperandrogenemia. The rat
e
\plain\expndtw0 \f20 \fs19 of insulin resistance in women with PCOS is 50-80% an
d
\plain\expndtw0 \f20 \fs19 a large majority of these women are obese [6,7].
\plain\par
\sl-235\fs23\par\pard\pard\sl-235 \li2 \ri0 \expndtw1 \f20 \fs19 They almost ine
vitably have the stigmata of hyperandro\plain\expndtw1 \f20 \fs19 genism and irregular or absent ovulation. Insulin sti
mu\plain\expndtw0 \f20 \fs19 lates LH and ovarian androgen secretion and decreases
sex
\plain\expndtw1 \f20 \fs19 hormone binding globulin concentrations [8].
\plain\par
\sl-233\fs23\par\pard\pard\sl-235 \li2 \ri0 \expndtw0 \f20 \fs19 The successful
treatment of obesity and hyperinsulinemia
\plain\expndtw1 \f20 \fs19 is capable of reversing their deleterious effects, of
which
\plain\expndtw2 \f20 \fs19 there are several, on the outcome of treatment. More
\plain\expndtw0 \f20 \fs19 gonadotrophins are required to achieve ovulation in i
nsu\plain\expndtw1 \f20 \fs19 lin resistant women [9,10]. Obese women being treated
\plain\expndtw1 \f20 \fs19 with low dose gonadotrophin therapy have inferior pre
g\plain\expndtw2 \f20 \fs19 nancy and miscarriage rates [11]. Both obese [12] and
\plain\expndtw2 \f20 \fs19 insulin resistant [10] women with PCOS, even on low
\plain\expndtw1 \f20 \fs19 dose FSH stimulation, have a much greater tendency to
a
\plain\expndtw1 \f20 \fs19 multifollicular response and thus a relatively high c
ycle
\plain\expndtw1 \f20 \fs19 cancellation rate in order to avoid hyperstimulation.
\plain\par
\sl-233\fs23\par\pard\pard\sl-235 \li2 \ri0 \expndtw1 \f20 \fs19 Just as obesity
expresses and exaggerates the signs and
\plain\expndtw1 \f20 \fs19 symptoms of insulin resistance, then loss of weight c
an
\plain\expndtw1 \f20 \fs19 reverse this process by improving ovarian function an
d
\plain\expndtw1 \f20 \fs19 the associated hormonal abnormalities [13-15]. Loss o
f
\plain\expndtw1 \f20 \fs19 weight induces a reduction of insulin and androgen co
n\plain\expndtw1 \f20 \fs19 centrations and an increase in sex hormone binding ho
r\plain\expndtw2 \f20 \fs19 mone concentrations. Curiously, in obese women with
\plain\expndtw1 \f20 \fs19 PCOS, a loss of just 5-10% of body weight is enough t
o
\plain\expndtw3 \f20 \fs19 restore reproductive function in 55-100% within 6
\plain\expndtw0 \f20 \fs19 months of weight reduction [13-15]. Weight loss has t
he
\plain\expndtw1 \f20 \fs19 undoubted advantages of being effective and cheap wit
h
\plain\expndtw1 \f20 \fs19 no side effects and should be the first line of treat
ment in
\plain\expndtw0 \f20 \fs19 obese women with anovulatory infertility associated w
ith
\plain\expndtw-8 \f20 \fs19 PCOS.
\par
\column
\plain\pard\sl-217 \li0 \ri35 \expndtw1 \f20 \fs19 The introduction of even smal
l amounts of FSH into the
\plain\par
\pard\sl-235 \li0 \ri35 \expndtw0 \f20 \fs19 circulation either directly with FS
H injections or indirectly
\plain\expndtw1 \f20 \fs19 with with pulsatile GnRH or clomiphene citrate, is ca
pa\plain\expndtw3 \f20 \fs19 ble of inducing ovulation and pregnancy in a large
\plain\expndtw1 \f20 \fs19 number of anovulatory women with PCOS. Clomiphene
\plain\expndtw1 \f20 \fs19 citrate has long been the first line of treatment for
those
\plain\expndtw1 \f20 \fs19 with absent or irregular ovulation. It is given in a
dose of
\plain\expndtw1 \f20 \fs19 50-250 mg per day for 5 days starting from day 2-5 of
\plain\expndtw1
est
\plain\expndtw2
\plain\expndtw0
ractice,
\plain\expndtw1
day
\plain\expndtw1
a
\plain\expndtw1
\f20 \fs19 spontaneous or induced bleeding starting with the low

\f20 \fs19 dose and raising the dose in increments of 50 mg/day
\f20 \fs19 each cycle until an ovulatory cycle is achieved. In p
\f20 \fs19 I almost inevitably use a starting dose of 100 mg per
\f20 \fs19 from day 4 or 5 and have found no advantage in using
\f20 \fs19 daily dose of more than 150 mg which seems neither to
\plain\expndtw2 \f20 \fs19 significantly increase the ovulation rate nor follicu
lar
\plain\expndtw3
\plain\expndtw1
la\plain\expndtw1
ene
\plain\expndtw0
sually
\plain\expndtw1
\f20 \fs19 recruitment. This sort of regimen will cut down the
\f20 \fs19 number of 'superfluous' cycles of treatment until ovu
\f20 \fs19 tion is achieved and until those resistant to clomiph
\f20 \fs19 are identified. A course of 3-6 ovulatory cycles is u
\f20 \fs19 sufficient to know whether pregnancy will be achieved
\plain\expndtw1 \f20 \fs19 using clomiphene citrate before moving on to more com
\plain\expndtw1 \f20 \fs19 plex treatment as approximately 75% of the pregnancie
s
\plain\expndtw2 \f20 \fs19 achieved with clomiphene occur within the first three
\plain\expndtw0 \f20 \fs19 cycles of treatment [16].
\plain\par
\sl-233\fs23\par\pard\pard\sl-235 \li0 \ri35 \expndtw3 \f20 \fs19 Ovulation is r
estored in approximately 80% but will
\plain\expndtw0 \f20 \fs19 result in pregnancy in only about 35-40% of patients
who
\plain\expndtw0 \f20 \fs19 are given clomiphene [16-18]. Additionally, around 20
\plain\expndtw1 \f20 \fs19 25% of anovulatory women with PCOS will not respond
\plain\expndtw1 \f20 \fs19 at all to clomiphene citrate and are considered to be
'clo\plain\expndtw1 \f20 \fs19 miphene resistant' [19,20]. Patients who do not respo
nd
\plain\expndtw1 \f20 \fs19 to clomiphene are likely to be more obese, insulin re
sist\plain\expndtw3 \f20 \fs19 ant and hyperandrogenic than those who do respond
\plain\expndtw1 \f20 \fs19 [20]. As clomiphene citrate induces a discharge of LH
as
\plain\expndtw0 \f20 \fs19 well as FSH and elevated LH concentrations are believ
ed
\plain\expndtw0 \f20 \fs19 to impede conception, those with high basal LH levels
are
\plain\expndtw1 \f20 \fs19 also less likely to respond to clomiphene treatment [
21].
\plain\expndtw1 \f20 \fs19 The most probable factor involved in this large discr
ep\plain\expndtw1 \f20 \fs19 ancy between ovulation and pregnancy rates in patient
s
\plain\expndtw1 \f20 \fs19 treated with clomiphene is the anti-estrogenic effect
s of
\plain\expndtw1 \f20 \fs19 clomiphene at the level of the endometrium and cervic
al
\plain\expndtw0 \f20 \fs19 mucus. While the depression of the cervical mucus, oc
cur\plain\expndtw1 \f20 \fs19 ring in about 15% of patients, may be overcome by per
\plain\expndtw1 \f20 \fs19 forming intra-uterine insemination [IUI], suppression
of
\plain\expndtw1 \f20 \fs19 endometrial proliferation, unrelated to dose or durat
ion
\plain\expndtw0 \f20 \fs19 of treatment but apparently idiosyncratic, indicates
a poor
\plain\expndtw0 \f20 \fs19 prognosis for conception in my experience when endome
\plain\expndtw0 \f20 \fs19 trial thickness never reaches 8 mm. Monitoring of the
clo\plain\expndtw4 \f20 \fs19 miphene treated cycle by ultrasound evaluation of

\plain\expndtw1 \f20 \fs19 follicular growth, endometrial thickness and even est
ra\plain\expndtw0 \f20 \fs19 diol and progesterone concentrations on day 12-14 of
the
\plain\expndtw0 \f20 \fs19 cycle is justified by the identification of those who
are not
\plain\expndtw1 \f20 \fs19 responding or have depressed endometrial thickness an
d
\plain\expndtw2 \f20 \fs19 is helpful in the timing of natural intercourse or IU
I.
\plain\par
\sl-283\fs28\par\sl-240\fs24\par\pard\pard\sl-200 \li2372 \ri36 \fi1527 \expndtw
-6 \f10 \fs18 Page 2 of 9
\plain\par
\pard\sl-210 \li0 \ri33 \fi2372 \expndtw-1 \i \f10 \fs13 (page number not for ci
tation purposes)
\par
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}}}
\plain\par
\sl-182\fs18\par\sl-240\fs24\par\par\pard\pard\sl-233 \li2 \ri0 \expndtw1 \f20 \
fs19 Although this monitoring implies added expense, this is
\plain\expndtw2 \f20 \fs19 neutralized by the prevention of protracted periods o
f
\plain\expndtw1 \f20 \fs19 possibly inappropriate therapy and delay in the incep
tion
\plain\expndtw0 \f20 \fs19 of more efficient treatment.
\plain\par
\sl-235\fs23\par\pard\pard\sl-235 \li2 \ri0 \expndtw1 \f20 \fs19 The results of
clomiphene treatment may be improved by
\plain\expndtw1 \f20 \fs19 co-treatment with several proposed adjuvants. The add
i-
\plain\expndtw2 \f20 \fs19 tion of an ovulatory dose of hCG, 5,000-10,000 IU is

\plain\expndtw1 \f20 \fs19 only theoretically warranted when the reason for a no
n\plain\expndtw2 \f20 \fs19 ovulatory response is that the LH surge is delayed or
\plain\expndtw1 \f20 \fs19 absent despite the presence of a well developed folli
cle.
\plain\expndtw0 \f20 \fs19 Although the routine addition of hCG at mid-cycle see
ms
\plain\expndtw1 \f20 \fs19 to add little to the improvement of conception rates
[22].
\plain\expndtw1 \f20 \fs19 I have found it very useful, given when an ultrasonic
ally
\plain\expndtw0 \f20 \fs19 demonstrated leading follicle attains a diameter of 1
8-24
\plain\expndtw0 \f20 \fs19 mm, for the timing of intercourse or IUI.
\plain\par
\sl-235\fs23\par\pard\pard\sl-235 \li2 \ri0 \expndtw1 \f20 \fs19 Daily doses of
dexamethasone, 0.5 mg at bedtime, as an
\plain\expndtw3 \f20 \fs19 adjunct to clomiphene therapy, suppress the adrenal
\plain\expndtw0 \f20 \fs19 androgen secretion and may induce responsiveness to c
lo\plain\expndtw2 \f20 \fs19 miphene in previous non-responders, mostly hyperan\plain\expndtw0 \f20 \fs19 drogenic women with PCOS with elevated concentrations
\plain\expndtw2 \f20 \fs19 of dehydroepiandrosterone sulphate [DHEAS] [23,24].
\plain\expndtw1 \f20 \fs19 Although this method meets with some success, medium
\plain\expndtw1 \f20 \fs19 to long term glucocorticoid steroid therapy often ind
uces
\plain\expndtw1 \f20 \fs19 side effects including increased appetite and weight
gain
\plain\expndtw2 \f20 \fs19 which is not an appealing proposition for women with
\plain\expndtw-8 \f20 \fs19 PCOS.
\plain\par
\sl-235\fs23\par\pard\pard\sl-235 \li2 \ri0 \expndtw1 \f20 \fs19 The combined tr
eatment of clomiphene with metformin
\plain\expndtw1 \f20 \fs19 is dealt with in the section on metformin.
\plain\par
\sl-272\fs27\par\pard\pard\sl-214 \li2 \ri2416 \expndtw-5 \b \f10 \fs21 Aromatas
e inhibitors
\plain\par
\pard\sl-217 \li2 \ri0 \expndtw1 \f20 \fs19 Aromatase inhibitors have been sugge
sted as an alterna\plain\par
\pard\sl-235 \li2 \ri0 \expndtw1 \f20 \fs19 tive treatment to clomiphene as the
discrepancy between
\plain\expndtw2 \f20 \fs19 ovulation and pregnancy rates with clomiphene citrate
\plain\expndtw0
estro\plain\expndtw1
ot
\plain\expndtw1
hene
\plain\expndtw1
n\plain\expndtw1
mi\plain\expndtw1
i-
\f20 \fs19 has been attributed to its anti-estrogenic action and

\f20 \fs19 gen receptor depletion. The aromatase inhibitors do n
\f20 \fs19 possess the adverse anti-estrogenic effects of clomip
\f20 \fs19 but, by suppressing estrogen production, mimic the ce
\f20 \fs19 tral reduction of negative feedback through which clo
\f20 \fs19 phene works. Letrozole, the most prevalently used ant
\plain\expndtw0
ffec\plain\expndtw1
nancy
\plain\expndtw1
\plain\expndtw1
\f20 \fs19 aromatase for this indication, has been shown to be e

\f20 \fs19 tive, in early trials, in inducing ovulation and preg
\f20 \fs19 in women with anovulatory PCOS and inadequate clomi\f20 \fs19 phene response [25] and improving ovarian response to
\plain\expndtw0 \f20 \fs19 FSH in poor responders [26]. Evidence from larger tri
als is
\plain\expndtw1 \f20 \fs19 still awaited but some encouragement may be taken fro
m
\plain\expndtw1 \f20 \fs19 the solidity of the working hypothesis and the succes
s of
\plain\expndtw0 \f20 \fs19 the preliminary results.
\plain\par
\sl-272\fs27\par\pard\pard\sl-214 \li2 \ri2198 \expndtw-5 \b \f10 \fs21 Gonadotr
ophin therapy
\plain\par
\pard\sl-217 \li2 \ri0 \expndtw0 \f20 \fs19 Gonadotrophin [FSH] therapy is usual
ly the next step fol\plain\par
\pard\sl-235 \li2 \ri0 \expndtw2 \f20 \fs19 lowing failure with clomiphene, i.e.
there has been no
\par
\column
\plain\pard\sl-239 \li0 \ri36 \fi1951 \expndtw-3 \f10 \fs18 http://www.rbej.com/
content/1/1/109
\plain\par
\fs19 response to clomiphene in a daily dose of 150 mg or 4-6
\plain\expndtw0 \f20 \fs19 ovulatory cycles have not resulted in a pregnancy.
\plain\par
\sl-235\fs23\par\pard\pard\sl-235 \li0 \ri35 \expndtw1 \f20 \fs19 The main compl
ications of gonadotrophin therapy, ovar\plain\expndtw2 \f20 \fs19 ian hyperstimulation syndrome [OHSS] and multiple
\plain\expndtw0 \f20 \fs19 pregnancies, are both caused by multiple follicular d
evel\plain\expndtw1 \f20 \fs19 opment. Anovulatory women with PCOS are particularly
\plain\expndtw1 \f20 \fs19 prone to multiple follicular development when receivi
ng
\plain\expndtw1 \f20 \fs19 gonadotrophins.
\plain\par
\sl-235\fs23\par\pard\pard\sl-235 \li0 \ri35 \expndtw3 \f20 \fs19 Acceptable cum
ulative conception rates have been
\plain\expndtw0 \f20 \fs19 achieved using conventional step-up treatment with go
na\plain\expndtw1 \f20 \fs19 dotrophins for women with PCOS. However, because of
\plain\expndtw2 \f20 \fs19 the peculiarly high sensitivity of polycystic ovaries
to
\plain\expndtw3 \f20 \fs19 gonadotrophin stimulation, this form of treatment,
\plain\expndtw0 \f20 \fs19 employing incremental dose rises of 75 IU every 5-7 d
ays,
\plain\expndtw2 \f20 \fs19 characteristically induces multiple follicular develo
p\plain\expndtw1 \f20 \fs19 ment, resulting in a high frequency of multiple pregn
an\plain\expndtw1 \f20 \fs19 cies and ovarian hyperstimulation syndrome [OHSS]. A
\plain\expndtw2 \f20 \fs19 review by Hamilton-Fairley & Franks [27] reported a
\plain\expndtw0 \f20 \fs19 mean multiple pregnancy rate of 34% and severe OHSS o
f
\plain\expndtw1
roto\plain\expndtw1
r
\plain\expndtw0
mul\plain\expndtw0
al
\plain\expndtw1
e
\plain\expndtw1
ddi\plain\expndtw0
tined for
\plain\expndtw0
induce
\plain\expndtw1
uti\plain\expndtw0
o ferti\plain\expndtw4
\plain\expndtw0
\f20 \fs19 4.6%. In a further study, although this traditional p

\f20 \fs19 col produced a cumulative conception rate of 82% afte
\f20 \fs19 six cycles, it was plagued by an unacceptable rate of
\f20 \fs19 tiple pregnancies and OHSS [28]. The supraphysiologic
\f20 \fs19 doses of FSH used in the conventional protocol provok
\f20 \fs19 an initial development of a large cohort, stimulate a
\f20 \fs19 tional follicles, and even rescue those follicles des
\f20 \fs19 atresia [29]. Levels of FSH well above the threshold
\f20 \fs19 a multiple follicular development. While this can be
\f20 \fs19 lized for the induction of superovulation for in-vitr
\f20 \fs19 lization and embryo transfer, for the induction of
\f20 \fs19 ovulation in women with PCOS the problem of achieving
\plain\expndtw1 \f20 \fs19 the desired monofollicular ovulation is particularly

diffi\plain\expndtw1 \f20 \fs19 cult and acute due to the extreme sensitivity of the
poly\plain\expndtw0 \f20 \fs19 cystic ovary to gonadotrophic stimulation. This is no
t due
\plain\expndtw1 \f20 \fs19 to a difference of FSH threshold levels of the polycy
stic
\plain\expndtw0 \f20 \fs19 ovaries but probably to the fact that they contain tw
ice the
\plain\expndtw0 \f20 \fs19 number of available FSH-sensitive antral follicles in
their
\plain\expndtw0 \f20 \fs19 cohort compared with the normal ovary [30]. Any dose
of
\plain\expndtw1 \f20 \fs19 FSH overstepping the threshold of the polycystic ovar
y
\plain\expndtw1 \f20 \fs19 will, therefore, produce multifollicular development
and
\plain\expndtw1 \f20 \fs19 impending danger of multiple pregnancy and OHSS.
\plain\par
\sl-236\fs24\par\pard\pard\sl-233 \li0 \ri35 \expndtw2 \f20 \fs19 The chronic lo
w dose regimen of FSH was designed to
\plain\expndtw0 \f20 \fs19 reduce the rate of complications due to multiple foll
icular
\plain\expndtw2 \f20 \fs19 development [For review, see ref. [31], the reasoning
\plain\expndtw1
in\plain\expndtw2
\plain\expndtw1
\plain\expndtw1
f
\plain\expndtw1
ow
\plain\expndtw1
\f20 \fs19 being that the 'threshold theory', demanding the atta
\f20 \fs19 ment and maintenance of follicular development with
\f20 \fs19 exogenous FSH without exceeding the threshold require
\f20 \fs19 ment of the ovary should be employed. The principle o
\f20 \fs19 the classic chronic low dose regimen is to employ a l
\f20 \fs19 starting dose for 14 days and then use small incremen
tal
\plain\expndtw1 \f20 \fs19 dose rises when necessary, at intervals of not less t
han 7
\plain\expndtw0 \f20 \fs19 days, until follicular development is initiated [32,3
3]. The
\plain\par
-6 \f10 \fs18 Page 3 of 9
\plain\par
tation purposes)
\par
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}}}
\plain\par
fs19 dose that initiates follicular development is continued
\plain\expndtw0 \f20 \fs19 until the criteria for giving hCG are attained. This
form of
\plain\expndtw0 \f20 \fs19 therapy aims to achieve the development of a single d
om\plain\expndtw1 \f20 \fs19 inant follicle rather than the development of many la
rge
\plain\expndtw2 \f20 \fs19 follicles and thereby avoid the complications of OHSS
\plain\expndtw0 \f20 \fs19 and multiple pregnancies.
\plain\par
\sl-233\fs23\par\pard\pard\sl-235 \li2 \ri0 \expndtw0 \f20 \fs19 A comparative p
rospective study of the conventional regi\plain\expndtw2 \f20 \fs19 men with chronic low dose administration of FSH for
\plain\expndtw1 \f20 \fs19 anovulation associated with PCOS [28] involved 50 par
\plain\expndtw1 \f20 \fs19 ticipants treated with FSH, half of them using a conv
en-
\plain\expndtw1
5 IU
\plain\expndtw0
n
\plain\expndtw1
of
\plain\expndtw2
\plain\expndtw0
dose
\plain\expndtw1
%
\plain\expndtw0
\f20 \fs19 tional stepwise protocol [incremental dose rises of 7
\plain\expndtw1
\plain\expndtw2
\plain\expndtw1
\plain\expndtw1
ol
\plain\expndtw1
al
\plain\expndtw2
n
\plain\expndtw0
en\plain\expndtw1
ry
\plain\expndtw0
\plain\expndtw1
us
\plain\expndtw1
%
\plain\expndtw1
> 10
\plain\expndtw0
the
\plain\expndtw2
\plain\expndtw2
\f20
\f20
\f20
\f20
\f20 \fs19 every 5-7 days when necessary] and half with a regime
\f20 \fs19 of chronic low dose as described above. Both methods
\f20 \fs19 treatment had an initial dose of 75 IU FSH. Compared
\f20 \fs19 with the conventional dose protocol, the chronic low
\f20 \fs19 regimen yielded slightly improved pregnancy rates [40
\f20 \fs19 versus 24%] while completely avoiding OHSS and multi\fs19
\fs19
\fs19
\fs19
ple pregnancies, which were prevalent [11% OHSS and

33% multiple pregnancies] with conventional therapy.
Uniovulation was induced in 74% versus 27% of cycles
and the total number of follicles > 16 mm and estradi
\f20 \fs19 concentrations were half those observed on convention

\f20 \fs19 therapy. A large French multicentre study [34] with a
\f20 \fs19 identical objective and protocol design compared conv
\f20 \fs19 tional and chronic low dose regimens in 103 anovulato
\f20 \fs19 WHO Group II women. The comparison of low with con\f20 \fs19 ventional dose revealed pregnancy rates of 33.3% vers
\f20 \fs19 20%, and with a multiple [twins] pregnancy rate of 14
\f20 \fs19 and 22%, respectively. The total number of follicles
\f20 \fs19 mm and estradiol concentrations on the day of hCG in
\f20 \fs19 low dose group were half those seen on conventional
\f20 \fs19 therapy. Additionally, the low dose regimen tended to
\plain\expndtw1 \f20 \fs19 produce a higher rate of mono- or bifollicular develo

p\plain\expndtw0 \f20 \fs19 ment in this study.
\plain\par
\sl-235\fs23\par\pard\pard\sl-235 \li2 \ri0 \expndtw1 \f20 \fs19 Reported result
s [31] using a chronic low dose protocol
\plain\expndtw0 \f20 \fs19 identical to that described above, show a remarkably
con\plain\expndtw1 \f20 \fs19 sistent rate of uniovulatory cycles of around 70% and
an
\plain\expndtw0 \f20 \fs19 acceptable pregnancy rate of 40% of the patients and
20%
\plain\expndtw1 \f20 \fs19 per cycle. However, the justification for the adoptio
n of
\plain\expndtw1 \f20 \fs19 the chronic low dose protocol may be seen in the almo
st
\plain\expndtw1 \f20 \fs19 complete elimination of OHSS and a multiple pregnancy
\plain\expndtw0 \f20 \fs19 rate of <6%.
\plain\par
\sl-233\fs23\par\pard\pard\sl-235 \li2 \ri0 \expndtw0 \f20 \fs19 In the normal o
vulatory cycle, decreasing FSH concentra-
\plain\expndtw1 \f20 \fs19 tions are seen throughout the follicular phase. In or
der to
\plain\expndtw1 \f20 \fs19 mimic more closely the events of the normal ovulatory
\plain\expndtw1
\plain\expndtw0
the
\plain\expndtw2
\plain\expndtw1
wth
\plain\expndtw0
the
\plain\expndtw0
n\plain\expndtw1
in
\f20 \fs19 cycle, the Rotterdam group examined a step-down dose

\f20 \fs19 regimen with a starting dose of 150 IU and decreasing
\f20 \fs19 dose by 0.5 ampoules when a follicle of 10 mm ensues
\f20 \fs19 and by the same amount every 3 days if follicular gro
\f20 \fs19 continues [35,36]. A comparison of this regimen with
\f20 \fs19 classic step-up regimen from the same group [37] demo
\f20 \fs19 strated a monofollicular growth rate of 88% of cycles
\par
\column
content/1/1/109
\plain\par
\fs19 the step-down regimen compared with 56% with the step\plain\expndtw2 \f20 \fs19 up protocol. In the step-down group, duration of trea
t\plain\expndtw1 \f20 \fs19 ment and gonadotrophin requirement were significantly
\plain\expndtw2 \f20 \fs19 reduced. However, a recently concluded randomized,
\plain\expndtw1 \f20 \fs19 French multicenter study comparing the step-up versus
\plain\expndtw1 \f20 \fs19 the step-down protocol demonstrated superiority of th
e
\plain\expndtw2 \f20 \fs19 step-up regimen as regards the rates of monofollicula
r
\plain\par
\pard\sl-233 \li0 \ri556 \expndtw1 \f20 \fs19 development, overstimulation and o
vulation. [38]
\plain\par
\sl-235\fs23\par\pard\pard\sl-235 \li0 \ri35 \expndtw0 \f20 \fs19 Assuming that
the step-up protocol is superior to the step\plain\expndtw3 \f20 \fs19 down version, do the initial dose, the duration of it
s
\plain\expndtw2 \f20 \fs19 administration and the incremental dose rise influenc
e
\plain\expndtw1 \f20 \fs19 results? From the largest published series of chronic
low
\plain\expndtw2 \f20 \fs19 dose FSH therapy [12] it was possible to compare the
\plain\expndtw0 \f20 \fs19 results of a starting dose of 75 IU with that of 52.5
IU for
\plain\expndtw1 \f20 \fs19 an initial 14-day period with an incremental dose ris
e of
\plain\expndtw0 \f20 \fs19 37.5 IU or 22.5 IU respectively. There were no signif
icant
\plain\expndtw1 \f20 \fs19 differences between the two groups but pregnancy rate
/
\plain\expndtw0 \f20 \fs19 patient, uni-ovulatory cycle rate and miscarriage rat
e were
\plain\expndtw0 \f20 \fs19 all in favour of the smaller starting dose.
\plain\par
\sl-233\fs23\par\pard\pard\sl-235 \li0 \ri34 \expndtw1 \f20 \fs19 Although the m

ajority of patients with PCOS will reach
\plain\expndtw1 \f20 \fs19 criteria for hCG administration within 14 days using
75
\plain\expndtw1 \f20 \fs19 IU/day of urinary FSH [12] or 50 IU/day of recombinan
t
\plain\expndtw1 \f20 \fs19 FSH, some have attempted to cut down the initial peri
od
\plain\expndtw1 \f20 \fs19 of 14 days without change of dose to 7 days. A compar
i\plain\expndtw2 \f20 \fs19 son of 14 day versus 7 day starters [31] in 50 patien
ts
\plain\expndtw2 \f20 \fs19 showed no significant differences other than a slight
ly
\plain\expndtw0 \f20 \fs19 higher rate of multiple pregnancies in the 7-day grou
p. As
\plain\expndtw1 \f20 \fs19 we regarded a multiple pregnancy as a 'failure' of tr
eat\plain\expndtw1 \f20 \fs19 ment, we reverted back to the 14 day initial period w
ith\plain\expndtw0 \f20 \fs19 out any change of dose.
\plain\par
\sl-233\fs23\par\pard\pard\sl-235 \li0 \ri34 \expndtw0 \f20 \fs19 A recently com
pleted multicenter study employing a step\plain\expndtw1 \f20 \fs19 up protocol starting with doses of 50 IU/day of 'Pure
gon'
\plain\expndtw3 \f20 \fs19 for a minimum of 7 days, compared two randomized
\plain\expndtw2 \f20 \fs19 groups using incremental dose rises of 25 IU or 50 IU
\plain\expndtw2 \f20 \fs19 when needed [H.J. Out, personal communication]. The
\plain\expndtw0 \f20 \fs19 use of the smaller incremental dose rises was signifi
cantly
\plain\expndtw1 \f20 \fs19 more beneficial in terms of monofollicular developmen
t,
\plain\expndtw0 \f20 \fs19 ovulation rates and cancellation rates.
\plain\par
\sl-235\fs23\par\pard\pard\sl-235 \li0 \ri35 \expndtw1 \f20 \fs19 To summarise,
low dose, step-up gonadotrophin therapy
\plain\expndtw2 \f20 \fs19 should be preferred to the now outdated conventional
\plain\expndtw1 \f20 \fs19 therapy for patients with PCOS. Small starting doses
in
\plain\expndtw1 \f20 \fs19 the first cycle for a 14-day initial period without a
dose
\plain\expndtw0 \f20 \fs19 change and then a small incremental dose rise if requ
ired,
\plain\expndtw0 \f20 \fs19 seem on present evidence to give the best results.
\plain\par
\sl-272\fs27\par\pard\pard\sl-214 \li0 \ri3026 \expndtw-11 \b \f10 \fs21 GnRH ag
onists
\plain\par
\pard\sl-218 \li0 \ri35 \expndtw1 \f20 \fs19 The ability of GnRH agonists to sup
press LH concentra\plain\par
\pard\sl-233 \li0 \ri35 \expndtw2 \f20 \fs19 tions before and during ovarian sti
mulation has earned
\plain\expndtw2 \f20 \fs19 them an undisputed place in IVF treatment protocols.
\plain\expndtw1 \f20 \fs19 They confer the advantage of eliminating, almost com\plain\expndtw1 \f20 \fs19 pletely, the annoying occurrence of premature luteini
za-
\plain\par
-6 \f10 \fs18 Page 4 of 9
\plain\par
tation purposes)
\par
{\shp
ffd8ffe000104a46494600010100000100010000ffdb004300010101010101010101010101010101
01010101010101010101010101010101010101010101010101010101010101010101010101010101
010101010101010101ffdb0043010101010101010101010101010101010101010101010101010101
0101010101010101010101010101010101010101010101010101010101010101010101010101ffc0
001108067204f703012200021101031101ffc4001f00000105010101010101000000000000000001
02030405060708090a0bffc400b5100002010303020403050504040000017d010203000411051221
31410613516107227114328191a1082342b1c11552d1f02433627282090a161718191a2526272829
2a3435363738393a434445464748494a535455565758595a636465666768696a737475767778797a
0101010101010101010000000000000102030405060708090a0bffc400b511000201020404030407
05040400010277000102031104052131061241510761711322328108144291a1b1c109233352f015
6272d10a162434e125f11718191a262728292a35363738393a434445464748494a53545556575859
5a636465666768696a737475767778797a82838485868788898a92939495969798999aa2a3a4a5a6
}}}
\plain\par
fs19 tion. In addition, some investigators have reported more
\plain\expndtw0 \f20 \fs19 pregnancies, possibly better quality eggs and less mi
scar\plain\expndtw1 \f20 \fs19 riages [39]. Their possible application during ovulat
ion
\plain\expndtw1 \f20 \fs19 induction should therefore be particularly relevant i
n the
\plain\expndtw1 \f20 \fs19 presence of the chronic, tonic, high serum concentrat
ions
\plain\expndtw3 \f20 \fs19 of LH observed in a high proportion of women with
\plain\expndtw1 \f20 \fs19 PCOS. Theoretically, by suppressing LH concentrations
,
\plain\expndtw1 \f20 \fs19 GnRH agonists should eliminate premature luteinizatio
n
\plain\expndtw1 \f20 \fs19 and alleviate the relatively low pregnancy rates and
the
\plain\expndtw1 \f20 \fs19 high miscarriage rates witnessed in this group of pat
ients
\plain\expndtw0 \f20 \fs19 [9]. In a large study [40] 239 women with PCOS receiv
ed
\plain\expndtw1 \f20 \fs19 hMG with or without GnRH agonist for ovulation induc\plain\expndtw1 \f20 \fs19 tion or superovulation for IVF/embryo transfer. Of pr
eg\plain\expndtw1 \f20 \fs19 nancies achieved with GnRH agonist, 17.6% miscarried
\plain\expndtw3 \f20 \fs19 compared with 39% of those achieved with gonado\plain\expndtw2 \f20 \fs19 trophins alone. Cumulative live birth rates after fou
r
\plain\expndtw1 \f20 \fs19 cycles for GnRH agonist were 64% compared with 26%
\plain\expndtw1 \f20 \fs19 for gonadotrophins only.
\plain\par
\sl-236\fs24\par\pard\pard\sl-233 \li2 \ri0 \expndtw0 \f20 \fs19 The GnRH agonis
t has not become standard treatment for
\plain\expndtw2 \f20 \fs19 ovulation induction in PCOS despite the fact that our
\plain\expndtw2
\plain\expndtw2
\plain\expndtw1
\plain\expndtw2
\plain\expndtw1
sm.
\plain\expndtw1
\plain\expndtw2
\plain\expndtw1
er
\plain\expndtw1
\plain\expndtw0
\f20 \fs19 experience and that of others has shown an increased

\f20 \fs19 pregnancy rate and lower miscarriage rate in women
\f20 \fs19 receiving combination treatment of agonist and gonado
\f20 \fs19 trophins when tonic LH concentrations are high [42].
\f20 \fs19 There are several reasons for this apparent anachroni
\f20 \fs19 Co-treatment with GnRH agonist and low dose gonado\f20 \fs19 trophin therapy is more cumbersome, longer, requires
\f20 \fs19 more gonadotrophins to achieve ovulation, has a great
\f20 \fs19 prevalence of multiple follicle development and conse
\f20 \fs19 quently more OHSS and multiple pregnancies. This com-
\plain\expndtw0 \f20 \fs19 bination therapy should be reserved for women with hi
gh
\plain\expndtw0 \f20 \fs19 serum concentrations of LH who have repeated prematur
e
\plain\expndtw2 \f20 \fs19 luteinization, stubbornly do not conceive on gonado\plain\expndtw2 \f20 \fs19 trophin therapy alone or who have conceived and had
\plain\expndtw0 \f20 \fs19 early miscarriages on more than one occasion.
\plain\par
\sl-236\fs24\par\pard\pard\sl-233 \li2 \ri0 \expndtw2 \f20 \fs19 There is no dou
bt that GnRH agonists cannot help to
\plain\expndtw1 \f20 \fs19 reduce the incidence of OHSS and multiple pregnancies
\plain\expndtw2 \f20 \fs19 in PCOS ovulation induction. If anything, combining
\plain\expndtw1 \f20 \fs19 GnRH agonist with gonadotrophin stimulation will exac
\plain\expndtw2 \f20 \fs19 erbate the problem of multiple follicular development
\plain\expndtw1
HSS
\plain\expndtw1
v\plain\expndtw1
sm
\plain\expndtw1
r
\plain\expndtw1
nd
\plain\expndtw3
\plain\expndtw1
s of
\plain\expndtw2
\plain\expndtw1
l-
\f20 \fs19 and therefore increase rates of cycle cancellation, O

\f20 \fs19 and multiple pregnancy [41,42]. This may be due to se
\f20 \fs19 eral factors: loss of the endogenous feedback mechani
\f20 \fs19 when using GnRH agonist, reduction of intra-follicula
\f20 \fs19 androgen levels following pituitary down regulation a
\f20 \fs19 consequently postponed atresia and, most probably,
\f20 \fs19 greater stimulation of follicles by the larger amount
\f20 \fs19 gonadotrophins needed when using GnRH agonist. A
\f20 \fs19 GnRH agonist is not the solution to the problem of mu
\plain\expndtw0 \f20 \fs19 tiple follicular development.

\plain\par
\sl-235\fs23\par\pard\pard\sl-235 \li2 \ri0 \expndtw1 \f20 \fs19 The two main co
mplications of ovulation induction for
\plain\expndtw1 \f20 \fs19 PCOS are multifollicular development and the possible
\par
\column
content/1/1/109
\plain\par
\fs19 deleterious effects of high LH levels, low conception rates
\plain\expndtw0 \f20 \fs19 and high miscarriage rates. A combination of chronic
low
\plain\expndtw1 \f20 \fs19 dose FSH stimulation with GnRH agonist therapy should
\plain\expndtw0
le et al.
\plain\expndtw2
\plain\expndtw1
p
\plain\expndtw1
\f20 \fs19 theoretically therefore yield the best results. Schee

\f20 \fs19 [43] studied women with PCOS undergoing ovulation
\f20 \fs19 induction with chronic low dose FSH therapy, one grou
\f20 \fs19 with and one without adjuvant GnRH agonist therapy. A
\plain\expndtw1 \f20 \fs19 very low rate of monofollicular ovulation was achieve
d
\plain\expndtw1 \f20 \fs19 [14%] in the agonist cycles compared with 44% of thos
e
\plain\expndtw1 \f20 \fs19 treated with low dose FSH alone. Treatment with GnRH
\plain\expndtw1 \f20 \fs19 agonist abolished neither the inter- nor intra-indivi
dual
\plain\expndtw0 \f20 \fs19 variability of the FSH dose required to induce ongoin
g fol\plain\expndtw1 \f20 \fs19 licular growth but also seemed to induce an even furt
her
\plain\expndtw0 \f20 \fs19 increase in the sensitivity of the PCO follicles to g
onado\plain\expndtw2 \f20 \fs19 trophin stimulation once the threshold FSH dose had
\plain\expndtw0 \f20 \fs19 been reached.
\plain\par
\sl-272\fs27\par\pard\pard\sl-214 \li0 \ri2731 \expndtw-9 \b \f10 \fs21 GnRH ant
agonists
\plain\par
\pard\sl-218 \li0 \ri35 \expndtw1 \f20 \fs19 The antagonists have some advantage
s over the agonists
\plain\par
\pard\sl-235 \li0 \ri34 \expndtw1 \f20 \fs19 and these may well become utilized
in the treatment of
\plain\expndtw0 \f20 \fs19 anovulatory PCOS. Firstly, antagonists act by the mec
ha\plain\expndtw2 \f20 \fs19 nism of competitive binding and this allows a modula\plain\expndtw0
ent
\plain\expndtw1
hin
\plain\expndtw2
nd
\plain\expndtw1
\f20 \fs19 tion of the degree of hormonal suppression by adjustm

\f20 \fs19 of the dose. Further, antagonists suppress gonadotrop
\f20 \fs19 release within a few hours, have no flare-up effect a
\f20 \fs19 gonadal function resumes without a lag effect followi
ng
\plain\expndtw1
o an
\plain\expndtw0
ize
\plain\expndtw1
a\plain\expndtw1
ated
\plain\expndtw1
.
\plain\expndtw1
ion,
\plain\expndtw0
H con\plain\expndtw0
ndered
\plain\expndtw0
this
\plain\expndtw0
much
\plain\expndtw0
and
\plain\expndtw2
\f20 \fs19 their discontinuation. If we apply these advantages t

\f20 \fs19 ovulation induction protocol for PCOS, one can visual
\f20 \fs19 that, used in combination with low dose FSH administr
\f20 \fs19 tion, the antagonist could be given in single or repe
\f20 \fs19 doses when a leading follicle of 13-14 mm is produced
\f20 \fs19 This would theoretically prevent premature luteinizat
\f20 \fs19 protect the oocyte from deleterious effects of high L
\f20 \fs19 centrations and still allow the follicle to grow unhi
\f20 \fs19 to ovulatory size. Compared to agonist treated cycles
\f20 \fs19 would confer the, again, theoretical advantages of a
\f20 \fs19 shorter cycle of treatment, promise more conceptions
\f20 \fs19 less miscarriages, reduce the amount of gonadotrophin
\plain\expndtw2 \f20 \fs19 required and increase the incidence of monofollicular

\plain\expndtw1 \f20 \fs19 ovulation with a consequent reduction in the prevalen
ce
\plain\expndtw4 \f20 \fs19 of OHSS and multiple pregnancies. Only one trial
\plain\expndtw2 \f20 \fs19 employing a GnRH antagonist with recombinant FSH,
\plain\expndtw0 \f20 \fs19 specifically for women with PCOS, has been published
to
\plain\expndtw1 \f20 \fs19 date [44]. Following pre-treatment with oral contrace
p\plain\expndtw0 \f20 \fs19 tives, a GnRH antagonist was started on in 20 patient
s on
\plain\expndtw0 \f20 \fs19 day 2 of the cycle. When LH concentrations were found
to
\plain\expndtw2 \f20 \fs19 be suppressed, concurrent antagonist and recombinant
\plain\expndtw1 \f20 \fs19 FSH therapy was started and continued until the day o
f
\plain\expndtw0 \f20 \fs19 hCG. LH was effectively suppressed by one dose of ant
ag\plain\expndtw0 \f20 \fs19 onist and all patients ovulated. Overall clinical pre
gnancy
\plain\expndtw0 \f20 \fs19 rates were 44% and on-going pregnancy rates 28%. This
is
\plain\expndtw1 \f20 \fs19 a preliminary trial but large RCT's are needed to con
firm
\plain\expndtw0 \f20 \fs19 these results.
\plain\par
\sl-273\fs27\par\sl-240\fs24\par\par\par\pard\pard\sl-200 \li2372 \ri36 \fi1527
\expndtw-6 \f10 \fs18 Page 5 of 9
\plain\par
tation purposes)
\par
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01010101010101010101010101010101010101010101010101010101010101010101010101010101
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31410613516107227114328191a1082342b1c11552d1f02433627282090a161718191a2526272829
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05040400010277000102031104052131061241510761711322328108144291a1b1c109233352f015
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5a636465666768696a737475767778797a82838485868788898a92939495969798999aa2a3a4a5a6
}}}
\plain\par
\sl-219\fs22\par\sl-240\fs24\par\par\pard\pard\sl-214 \li2 \ri3370 \expndtw-4 \b
\f10 \fs21 Metformin
\plain\par
\pard\sl-217 \li2 \ri0 \expndtw0 \f20 \fs19 The basic etiology behind the anovul
ation associated with
\plain\par
\pard\sl-235 \li2 \ri0 \expndtw1 \f20 \fs19 PCOS is mainly insulin resistance an
d hyperinsulinemia
\plain\expndtw1 \f20 \fs19 [45,46]. This strong association between hyperinsulin
e\plain\expndtw2 \f20 \fs19 mia and anovulation would suggest that a reduction of
\plain\expndtw3
\plain\expndtw2
as
\plain\expndtw1
or
\plain\expndtw1
n
\plain\expndtw1
\plain\expndtw1
rmin
\plain\expndtw1
\f20 \fs19 insulin concentrations could be of great importance.

\f20 \fs19 Weight loss for the obese can reverse this situation
\f20 \fs19 mentioned above but for those who fail to lose weight
\f20 \fs19 are of normal weight but hyperinsulinaemic, an insuli
\f20 \fs19 sensitizing agent such as metformin is indicated. How
\f20 \fs19 ever, the indications for the administration of metfo
\f20 \fs19 to anovulatory women with PCOS in an ovulation induc-
\plain\expndtw1 \f20 \fs19 tion program have widened as it seems to be difficult

to
\plain\expndtw2 \f20 \fs19 predict which individuals will respond well with this
\plain\expndtw2 \f20 \fs19 medication [46]. Metformin is an oral biguanide, well
\plain\expndtw0 \f20 \fs19 established for the treatment of hyperglycaemia, that
does
\plain\expndtw2 \f20 \fs19 not cause hypoglycaemia in normoglycaemic patients.

\plain\expndtw1 \f20 \fs19 The sum total of its actions is a decrease in insulin
levels
\plain\expndtw0 \f20 \fs19 and, as a consequence, a lowering of circulating tota
l and
\plain\expndtw1 \f20 \fs19 free androgen levels with a resulting improvement of
the
\plain\expndtw0 \f20 \fs19 clinical sequelae of hyperandrogenism.
\plain\par
\sl-235\fs23\par\pard\pard\sl-235 \li2 \ri0 \expndtw0 \f20 \fs19 There are now a
large number of studies published on the
\plain\expndtw1 \f20 \fs19 effect of metformin in a dose of 1500-2550 mg/day in
\plain\expndtw2 \f20 \fs19 women with PCOS. The vast majority of these studies
\plain\expndtw1 \f20 \fs19 have demonstrated a significant improvement in insuli
n
\plain\expndtw1 \f20 \fs19 concentrations, insulin sensitivity, and serum androg
en
\plain\expndtw4 \f20 \fs19 concentrations accompanied by decreased LH and
\plain\expndtw1 \f20 \fs19 increased SHBG concentrations [48]. The restoration o
f
\plain\expndtw1 \f20 \fs19 regular menstrual cycles by metformin has been report
ed
\plain\expndtw0 \f20 \fs19 in the large majority of published series and the rei
nstate\plain\expndtw1 \f20 \fs19 ment of ovulation occurred in 78%-96% of patients [45
\plain\expndtw0 \f20 \fs19 50]. Fleming et al [46], in the largest randomized co
ntrol\plain\expndtw1 \f20 \fs19 led trial published to date, demonstrated a significa
ntly
\plain\expndtw0 \f20 \fs19 increased frequency of ovulation with metformin as co
m\plain\expndtw3 \f20 \fs19 pared to placebo in a group of 92 oligomenorrheic
\plain\expndtw0 \f20 \fs19 women with PCOS. This was achieved without any signif
\plain\expndtw0 \f20 \fs19 icant changes in the insulin response to glucose chal
lenge
\plain\expndtw1 \f20 \fs19 after 14 weeks of metformin treatment in a dose of 85
0
\plain\expndtw0 \f20 \fs19 mg, twice a day.
\plain\par
\sl-235\fs23\par\pard\pard\sl-235 \li2 \ri0 \expndtw0 \f20 \fs19 In a randomised
controlled trial [RCT] performed on clo\plain\expndtw0 \f20 \fs19 miphene resistant infertile patients with PCOS, compa
red
\plain\expndtw2 \f20 \fs19 with placebo, metformin markedly improved ovulation
\plain\expndtw1 \f20 \fs19 and pregnancy rates with clomiphene treatment [51]. I
n a
\plain\expndtw0 \f20 \fs19 large study, 46 anovulatory obese women with PCOS who
\plain\expndtw0 \f20 \fs19 did not ovulate on metformin or placebo for 35 days w
ere
\plain\expndtw0 \f20 \fs19 given 50 mg of clomiphene daily for 5 days while cont
in\plain\expndtw1 \f20 \fs19 uing metformin or placebo. Of those on metformin, 19
of
\plain\expndtw1 \f20 \fs19 21 ovulated compared with 2 of 25 on placebo [47].
\plain\par
\sl-233\fs23\par\pard\pard\sl-235 \li2 \ri0 \expndtw3 \f20 \fs19 When women with
clomiphene resistant PCOS were
\plain\expndtw0 \f20 \fs19 administered FSH with or without pretreatment with me

t\plain\expndtw2 \f20 \fs19 formin for one month in an RCT, those receiving met\plain\expndtw3 \f20 \fs19 formin developed significantly less large follicles,
\par
\column
content/1/1/109
\plain\par
\fs19 produced less estradiol and had fewer cycles cancelled due
\plain\expndtw0 \f20 \fs19 to excessive follicular development. The reduction of
insu\plain\expndtw3 \f20 \fs19 lin concentrations induced by metformin seemed to
\plain\expndtw2 \f20 \fs19 favour a more orderly follicular growth in response t
o
\plain\expndtw1 \f20 \fs19 exogenous gonadotrophins for ovulation induction [52]
.
\plain\expndtw0 \f20 \fs19 In the one published study on the effects of metformi
n on
\plain\expndtw1 \f20 \fs19 clomiphene resistant patients undergoing IVF/ICSI, th
e
\plain\expndtw1 \f20 \fs19 results of cycles preceded by treatment with metformi
n
\plain\expndtw2 \f20 \fs19 were compared retrospectively to those in which met\plain\expndtw1 \f20 \fs19 formin was not given. Those receiving metformin had a
\plain\expndtw0
in the
\plain\expndtw3
\plain\expndtw1
ion
\plain\expndtw2
\f20 \fs19 decreased total number of follicles but no difference

\f20 \fs19 mean number of oocytes retrieved. There were more
\f20 \fs19 mature oocytes, embryos cleaved, increased fertilisat
\f20 \fs19 and clinical pregnancy rates [70% vs 30%] in the met-
\plain\expndtw0 \f20 \fs19 formin group [53]. These latter two studies would see
m to
\plain\expndtw2 \f20 \fs19 confirm that both obese [12] and insulin resistant [1
0]
\plain\expndtw2 \f20 \fs19 women with PCOS have a much greater tendency to a
\plain\expndtw1 \f20 \fs19 multifollicular response and thus a relatively high c
ycle
\plain\expndtw0 \f20 \fs19 cancellation rate on low dose FSH stimulation.
\plain\par
\sl-233\fs23\par\pard\pard\sl-235 \li0 \ri35 \expndtw1 \f20 \fs19 The evidence s
o far is encouraging concerning the effi\plain\expndtw0 \f20 \fs19 ciency and safety of metformin as a single agent or i
n com\plain\expndtw1 \f20 \fs19 bination with clomiphene citrate or gonadotrophins fo
r
\plain\expndtw1 \f20 \fs19 induction of ovulation in women with hyperinsulinaemi
c
\plain\expndtw2 \f20 \fs19 PCOS [54]. It remains to be seen whether metformin,
\plain\expndtw3 \f20 \fs19 which probably also has a direct androgen lowering
\plain\expndtw2 \f20 \fs19 action on the ovary, will be of help to all women wit
h
\plain\expndtw2 \f20 \fs19 PCOS wishing to conceive. Not only does metformin
\plain\expndtw2 \f20 \fs19 seem to be safe when continued throughout pregnancy
\plain\expndtw0 \f20 \fs19 but preliminary data strongly suggest that this strat
egy can
\plain\expndtw0 \f20 \fs19 severely decrease the high miscarriage rate usually a
ssoci\plain\expndtw0 \f20 \fs19 ated with PCOS [55,56]. It is hoped that the apparent
lack
\plain\expndtw1 \f20 \fs19 of terratogenicity and beneficial effect of metformin
on
\plain\expndtw0 \f20 \fs19 miscarriage rates will be confirmed by future studies
.
\plain\par
\sl-235\fs23\par\pard\pard\sl-235 \li0 \ri35 \expndtw1 \f20 \fs19 Other compound
s with the property of lowering insulin
\plain\expndtw1 \f20 \fs19 concentrations, the glitazones rosiglitazone and piog
lita\plain\expndtw2 \f20 \fs19 zone, and d-chiro-inositol, are under investigation a
nd
\plain\expndtw0 \f20 \fs19 may also prove useful for women with anovulatory PCOS
.
\plain\par
\sl-272\fs27\par\pard\pard\sl-214 \li0 \ri1774 \expndtw-7 \b \f10 \fs21 Laparosc
opic ovarian drilling
\plain\par
\pard\sl-218 \li0 \ri35 \expndtw0 \f20 \fs19 Laparoscopic ovarian drilling [LOD]
by diathermy or laser
\plain\par
\pard\sl-235 \li0 \ri35 \expndtw1 \f20 \fs19 now presents a further treatment op
tion for women with
\plain\expndtw1 \f20 \fs19 anovulatory infertility associated with polycystic ov
ary
\plain\expndtw2 \f20 \fs19 syndrome. This laparoscopic version of ovarian wedge
\plain\expndtw0 \f20 \fs19 resection employs a unipolar coagulating current or p
unc\plain\expndtw0 \f20 \fs19 ture of the ovarian surface with a laser in 4-10 plac
es to a
\plain\expndtw0 \f20 \fs19 depth of 4-10 mm on each ovary. An analysis [57] of t
he
\plain\expndtw1 \f20 \fs19 first 35 reports, mostly uncontrolled series, showed
that
\plain\expndtw0 \f20 \fs19 82% of 947 patients ovulated following the operation
and
\plain\expndtw2 \f20 \fs19 63% conceived either spontaneously or after treatment
\plain\expndtw3 \f20 \fs19 with medications to which they had previously been
\plain\expndtw0 \f20 \fs19 resistant. A Cochrane data base analysis of six rando
mized
\plain\expndtw2 \f20 \fs19 controlled trials [58] mostly comparing laparoscopic
\plain\expndtw2 \f20 \fs19 ovarian drilling with gonadotrophin therapy, showed
\plain\par
-6 \f10 \fs18 Page 6 of 9
\plain\par
tation purposes)
\par
{\shp

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01010101010101010101010101010101010101010101010101010101010101010101010101010101
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0101010101010101010101010101010101010101010101010101010101010101010101010101ffc0
001108067204f703012200021101031101ffc4001f00000105010101010101000000000000000001
02030405060708090a0bffc400b5100002010303020403050504040000017d010203000411051221
31410613516107227114328191a1082342b1c11552d1f02433627282090a161718191a2526272829
2a3435363738393a434445464748494a535455565758595a636465666768696a737475767778797a
0101010101010101010000000000000102030405060708090a0bffc400b511000201020404030407
05040400010277000102031104052131061241510761711322328108144291a1b1c109233352f015
6272d10a162434e125f11718191a262728292a35363738393a434445464748494a53545556575859
5a636465666768696a737475767778797a82838485868788898a92939495969798999aa2a3a4a5a6
}}}
\plain\par
fs19 similar cumulative ongoing pregnancy rates 6-12 months
\plain\expndtw0 \f20 \fs19 after LOD and after 3-6 cycles of gonadotrophin thera
py
\plain\expndtw0 \f20 \fs19 [58]. A large, recently completed, multicenter study
in The
\plain\expndtw2 \f20 \fs19 Netherlands, showed parity in the results of LOD and
\par
\column
content/1/1/109
\plain\par
\fs19 infertility due to PCOS who will remain involuntarily
\plain\expndtw-1 \f20 \fs19 childless.
\plain\par
\sl-272\fs27\par\pard\pard\sl-214 \li0 \ri3377 \expndtw-13 \b \f10 \fs21 Referen
ces
\par
\sect\sectd\sbknone\cols3\colno1\colw4822\colsr339\colno2\colw194\colsr164\colno
3\colw4498
\plain\pard\sl-218 \li2 \ri0 \expndtw0 \f20 \fs19 low-dose FSH therapy [Bayram e
t al., submitted for publi\plain\par
\pard\sl-235 \li2 \ri0 \expndtw1 \f20 \fs19 cation]. The Cochrane analysis [58]
highlighted the main
\plain\expndtw1 \f20 \fs19 advantage of ovarian drilling - a very high prevalenc
e of
\plain\expndtw3 \f20 \fs19 monofollicular ovulation and therefore a significant
\plain\expndtw2 \f20 \fs19 reduction in multiple pregnancy rates compared with
\plain\expndtw2 \f20 \fs19 gonadotrophin therapy. Further possible advantages of
\plain\expndtw0 \f20 \fs19 LOD are a reported reduction in miscarriage rates [59
], the
\plain\expndtw2 \f20 \fs19 fact that it is an often successful "one-off" procedu
re
\plain\expndtw2
\plain\expndtw1
e.
\plain\expndtw1
\plain\expndtw1
e
\plain\expndtw2
\plain\expndtw1
\plain\expndtw2
g
\plain\expndtw1
the
\plain\expndtw1
d
\plain\expndtw0
tion,
\plain\expndtw3
\plain\expndtw1
\plain\expndtw1
\f20 \fs19 which may avoid the use of expensive medical therapy
\f20 \fs19 and the exclusion of ovarian hyperstimulation syndrom
\f20 \fs19 If ovulation is not forthcoming within 2-3 months fol
\f20 \fs19 lowing LOD, then ovulation induction can often be mor
\f20 \fs19 successfully employed than preceeding the operation.
\f20 \fs19 However, in a large number of cases spontaneous ovula
\f20 \fs19 tion has been induced even for several years followin
\f20 \fs19 LOD in a similar fashion to ovarian wedge resection,
\f20 \fs19 "predecessor" of LOD [60]. As LOD is less invasive an
\f20 \fs19 causes less pelvic adhesions then ovarian wedge resec
\f20 \fs19 there is every reason to expect similar or even more
\f20 \fs19 impressive results from LOD than present evidence sug
\f20 \fs19 gests. Those who are slim and have high LH concentra-
\plain\expndtw1 \f20 \fs19 tions seem to have the most favourable prognosis [61]
.
\plain\expndtw1 \f20 \fs19 However, the mechanism involved in the restoration of
\plain\expndtw1 \f20 \fs19 ovulation is quite unknown although the principle end
o\plain\expndtw1 \f20 \fs19 crine change is a dramatic decrease in LH concentrati
ons
\plain\expndtw1 \f20 \fs19 about two days after the operation.
\plain\par
\sl-272\fs27\par\pard\pard\sl-214 \li2 \ri3700 \expndtw-5 \b \f10 \fs21 IVF/ET
\plain\par
\pard\sl-217 \li2 \ri0 \expndtw0 \f20 \fs19 If all else fails for the infertile
PCOS patient then in-vitro
\plain\par
\pard\sl-235 \li2 \ri0 \expndtw2 \f20 \fs19 fertilization is a last resort provi
ding excellent results.
\plain\expndtw1 \f20 \fs19 Although a smaller percentage of recovered oocytes ar
e
\plain\expndtw1 \f20 \fs19 fertilized, the larger number of oocytes recovered fr
om
\plain\expndtw0 \f20 \fs19 PCOS patients balances out the pregnancy rate in comp
ar\plain\expndtw1 \f20 \fs19 ison with, for example, women with a mechanical facto
r
\plain\expndtw2 \f20 \fs19 [39]. In-vitro maturation of oocytes from women with
\plain\expndtw1 \f20 \fs19 PCOS may become a possible option [62]. However, it i
s
\plain\expndtw1 \f20 \fs19 proving technically difficult at present and concerns
over
\plain\expndtw0 \f20 \fs19 the well being of pregnancies achieved from IVM have
not
\plain\expndtw0 \f20 \fs19 yet been fully answered.
\plain\par
\sl-272\fs27\par\pard\pard\sl-214 \li2 \ri3254 \expndtw-15 \b \f10 \fs21 Conclus
ions
\plain\par
\pard\sl-217 \li2 \ri0 \expndtw1 \f20 \fs19 Following weight loss if warranted,
clomiphene citrate is
\plain\par
\pard\sl-235 \li2 \ri0 \expndtw0 \f20 \fs19 the usual first-line treatment. If c
lomiphene fails to induce
\plain\expndtw2 \f20 \fs19 ovulation and pregnancy, several therapeutic paths ar
e
\plain\expndtw2 \f20 \fs19 open depending on the individual case: low dose FSH
\plain\expndtw2 \f20 \fs19 therapy, addition of metformin to clomiphene or FSH
\plain\expndtw1 \f20 \fs19 treatment, laparoscopic ovarian drilling and finally,
IVF.
\plain\expndtw1 \f20 \fs19 Alternative possibilities for treatment in the near f
uture
\plain\expndtw1 \f20 \fs19 include aromatase inhibitors and in-vitro maturation
of
\plain\expndtw2 \f20 \fs19 oocytes. Whatever the treatment option used, there ar
e
\plain\expndtw0 \f20 \fs19 very few women today who suffer from pure anovulatory
\par
\column
\plain\pard\sl-185 \li0 \ri72 \expndtw-12 \f10 \fs15 1.
\plain\par
\sl-110\fs11\par\sl-240\fs24\par\pard\pard\sl-159 \li0 \ri72 \expndtw-12 \f10 \f
s15 2.
\plain\par
s15 3.
\plain\par
s15 4.
\plain\par
s15 5.
\plain\par
s15 6.
\plain\par
s15 7.
\plain\par
s15 8.
\plain\par
s15 9.
\plain\par
\sl-180\fs18\par\pard\pard\sl-159 \li0 \ri0 \expndtw-12 \f10 \fs15 10.
\plain\par
\sl-280\fs28\par\sl-240\fs24\par\pard\pard\sl-159 \li0 \ri0 \expndtw-12 \f10 \fs
15 11.
\plain\par
15 12.
\plain\par
\sl-211\fs21\par\sl-240\fs24\par\par\pard\pard\sl-159 \li0 \ri0 \expndtw-12 \f10
\fs15 13.
\plain\par
15 14.
\plain\par
\fs15 15.
\plain\par
15 16.
\plain\par
15 17.
\plain\par
\plain\par
15 19.
\plain\par
15 20.
\par
\column
\plain\pard\sl-185 \li0 \ri34 \expndtw-8 \f10 \fs15 Adams J, Polson DW and Frank
s S:\b Prevalence of polycystic ova\plain\par
\pard\sl-170 \li0 \ri35 \expndtw-2 \b \f10 \fs15 ries in women with anovulation
and idiopathic hirsutism.\b0\i Br
\plain\expndtw-11 \i \f10 \fs15 Med J\i0 1986,\b 293:\b0 355-359.
\plain\par
\pard\sl-169 \li0 \ri34 \expndtw0 \f10 \fs15 Hull MG:\b Epidemiology of inferti
lity and polycystic ovarian
\plain\expndtw-6 \b \f10 \fs15 disease: endocrinological and demographic studies
.\b0\i Gynaecol
\plain\expndtw-12 \i \f10 \fs15 Endocrinol\i0 1987,\b 1:\b0 235-245.
\plain\par
\pard\sl-169 \li0 \ri34 \expndtw-9 \f10 \fs15 Adams J, Franks S, Polson DW, Maso
n HD, Abdulwahid N, Tucker M,
\plain\expndtw-6 \f10 \fs15 Morris DV, Price J and Jacobs HS:{\field{\*\fldinst
{\b HYPERLINK}{\b "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db
=PubMed&dopt=Abstract&list_uids=10.1016/S0140-6736(85)92552-8"}}
{\fldrslt{\b Multifollicular ovaries: clinical
}}}
\plain\expndtw-1 {\field{\*\fldinst {\b HYPERLINK}{\b "http://www.ncbi.nlm.nih.g
ov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=10.1016/S014
0-6736(85)92552-8"}}
{\fldrslt{\b \f10 \fs15 and endocrine features and response to pulsatile gonado}}}
0-6736(85)92552-8"}}
{\fldrslt{\b \f10 \fs15 trophin releasing hormone.
}}}\b0\i Lancet\i0 1985,\b 2:\b0 1375-1379.
\plain\par
\pard\sl-170 \li0 \ri35 \expndtw0 \f10 \fs15 Dunaif A, Segal K, Futterweit W and
Dobrjansky A:{\field{\*\fldinst {\b HYPERLINK}{\b "http://www.ncbi.nlm.nih.gov/
entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=2670645"}}
{\fldrslt{\b Profound
}}}
ov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=2670645"}}
{\fldrslt{\b \f10 \fs15 peripheral resistance independent of obesity in polycyst

ic
}}}
{\fldrslt{\b \f10 \fs15 ovary syndrome.
}}}\b0\i Diabetes\i0 1989,\b 38:\b0 1165-1174.
\plain\par
\pard\sl-169 \li0 \ri36 \expndtw-9 \f10 \fs15 Balen AH, Conway GS, Kaltsas G, Te
chatrasak K, Manning PJ, West
\plain\expndtw-6 \f10 \fs15 C and Jacobs HS:\b Polycystic{\field{\*\fldinst {\b
HYPERLINK}{\b "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=Pu
bMed&dopt=Abstract&list_uids=8567849"}}
{\fldrslt{ ovary syndrome: the spectrum of
}}}
{\fldrslt{\b \f10 \fs15 the disorder in 1741 patients.
}}}\b0\i Hum Reprod\i0 1995,\b 10:\b0 2107-2111.
\plain\expndtw-6 \f10 \fs15 Legro RS, Finegood D and Dunaif A:{\field{\*\fldinst
{\b HYPERLINK}{\b "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&d
b=PubMed&dopt=Abstract&list_uids=9709933"}}
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{\fldrslt{\b Pre}}}
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{\fldrslt{\b \f10 \fs15 phene citrate induction of ovulation in normogonadotropi
c
}}}
\plain\par
-6 \f10 \fs18 Page 7 of 9
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\plain\sl-83\fs8\par\sl-240\fs24\par\par\par\par\pard\pard\sl-159 \li2 \ri0 \exp
ndtw-12 \f10 \fs15 21.
\plain\par
15 22.
\plain\par
15 23.
\plain\par
15 24.
\plain\par
15 25.
\plain\par
15 26.
\plain\par
15 27.
\plain\par
\plain\par
\fs15 29.
\plain\par
\plain\par
15 31.
\plain\par
15 32.
\plain\par
15 33.
\plain\par
15 34.
\plain\par
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\f10 \fs15 35.
\plain\par
15 36.
\plain\par
\fs15 37.
\plain\par
\fs15 38.
\plain\par
15 39.
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ulation,
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ovary syn\plain\expndtw-9 \b \f10 \fs15 drome.\b0\i Br Med J\i0 1988,\b 297:\b0 1024-2
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fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=7769057"}}
{\fldrslt{ luteum function and preg}}}
{\fldrslt{\b \f10 \fs15 nancy rates with clomiphene citrate therapy: comparison
of
}}}
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t_uids=6233176"}}
{\fldrslt{\b \f10 \fs15 with clomiphene citrate.
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trieve&db=PubMed&dopt=Abstract&list_uids=10.1016/S0015-0282(00)01705-2"}}
{\fldrslt{\b Use of aromatase inhibitor for
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{\fldrslt{\b \f10 \fs15 induction of ovulation in patients with an inadequate
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t_uids=10.1016/S0015-0282(00)01705-2"}}
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\pard\sl-170 \li0 \ri3 \expndtw-1 \f10 \fs15 Mitwally MF and Casper RF:\b Aroma
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ry.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=10.1016/S0015-0282(00)016
41-1"}}
{\fldrslt{ inhibition improves
}}}
5-0282(00)01641-1"}}
{\fldrslt{\b \f10 \fs15 ovarian response to FSH: a potential option for low resp
ond}}}
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Common problems in induc\plain\par
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{\fldrslt{ comparative prospective
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{\fldrslt{\b \f10 \fs15 study of conventional regimen with chronic low-dose admi
n}}}
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n
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{\fldrslt{\b \f10 \fs15 treatment of infertility associated with polycystic ovar
y syn}}}
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\par
\column
\plain\sl-224\fs22\par\sl-240\fs24\par\par\pard\pard\sl-159 \li0 \ri0 \expndtw-1
2 \f10 \fs15 40.
\plain\par
15 41.
\plain\par
15 42.
\plain\par
15 43.
\plain\par
15 44.
\plain\par
15 45.
\plain\par
15 46.
\plain\par
15 47.
\plain\par
15 48.
\plain\par
15 49.
\plain\par
\sl-140\fs14\par\sl-240\fs24\par\par\par\pard\pard\sl-159 \li0 \ri0 \expndtw-12
\f10 \fs15 50.
\plain\par
15 51.
\plain\par
\fs15 52.
\plain\par

15 53.
\plain\par
\fs15 54.
\plain\par
\plain\par
15 56.
\plain\par
15 57.
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15 58.
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15 59.
\par
\column
\plain\sl-213\fs21\par\sl-240\fs24\par\par\pard\pard\sl-170 \li0 \ri36 \expndtw5 \f10 \fs15 Homburg R, Levy T and Berkovitz D:{\field{\*\fldinst {\b HYPERLINK}
{\b "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=A
bstract&list_uids=8458452"}}
{\fldrslt{\b GnRH agonist reduces the
}}}
{\fldrslt{\b \f10 \fs15 miscarriage rate for pregnancies conceived in women with
}}}
\plain\par
t_uids=8458452"}}
\plain\par
\pard\sl-170 \li0 \ri35 \expndtw-7 \f10 \fs15 Van der Meer M, Hompes PGA and Sch
eele F:{\field{\*\fldinst {\b HYPERLINK}{\b "http://www.ncbi.nlm.nih.gov/entrez/
query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=8816618"}}
{\fldrslt{\b The importance of
}}}
{\fldrslt{\b \f10 \fs15 endogenous feedback for monofollicular growth in low-dos
e
}}}
{\fldrslt{\b \f10 \fs15 step-up ovulation induction with FSH in PCOS, a rand}}}
{\fldrslt{\b \f10 \fs15 omized study.
\plain\par
\pard\sl-170 \li0 \ri34 \expndtw-8 \f10 \fs15 Homburg R, Eshel A, Kilborn J, Ada
ms J and Jacobs HS:\b Combined

{\fldrslt{\b \f10 \fs15 luteinizing hormone releasing hormone analogue and exog}}}
{\fldrslt{\b \f10 \fs15 enous gonadotrophins for the treatment of infertility as
soci}}}
{\fldrslt{\b \f10 \fs15 ated with polycystic ovaries.
}}}\b0\i Hum Reprod\i0 1990,\b 5:\b0 32-37.
\plain\par
\pard\sl-169 \li0 \ri34 \expndtw-11 \f10 \fs15 Scheele F, Hompes PGA, van der Me
er M, Schoute E and Schoemaker
\plain\expndtw-4 \f10 \fs15 J:{\field{\*\fldinst {\b HYPERLINK}{\b "http://www.n
cbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids
=8314962"}}
{\fldrslt{\b The effects of a gonadotrophin-releasing hormone agonist
}}}
{\fldrslt{\b \f10 \fs15 on treatment with low dose follicle stimulating hormone
in
}}}
}}}\b0\i Hum Reprod\i0 1993,\b 8:\b0 699-704.
\plain\par
\pard\sl-170 \li0 \ri36 \expndtw-5 \f10 \fs15 Elkind-Hirsch KE, Webster BW, Brow
n CP and Vernon MW:\b Con\plain\expndtw-2 {\field{\*\fldinst {\b HYPERLINK}{\b "http://www.ncbi.nlm.nih.g
5-0282(02)04696-4"}}
{\fldrslt{\b \f10 \fs15 current ganirelix and follitropin-beta therapy is an eff
ective
}}}
-0282(02)04696-4"}}
{\fldrslt{\b \f10 \fs15 and safe regimen for ovulation induction in women with
}}}
\plain\par
t_uids=10.1016/S0015-0282(02)04696-4"}}
\plain\par
\pard\sl-170 \li0 \ri35 \expndtw-3 \f10 \fs15 Velazquez EM, Acosta A and Mendoza
SG:\b Menstrual{\field{\*\fldinst {\b HYPERLINK}{\b "http://www.ncbi.nlm.nih.g
9-7844(97)00296-2"}}
{\fldrslt{ cyclicity
}}}
9-7844(97)00296-2"}}
{\fldrslt{\b \f10 \fs15 after metformin therapy in polycystic ovary syndrome.
}}}\b0\i Obstet
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\plain\par
\pard\sl-170 \li0 \ri35 \expndtw-8 \f10 \fs15 Fleming R, Hopkinson ZE, Wallace A
M, Greer IA and Sattar N:\b Ovar\plain\expndtw-3 {\field{\*\fldinst {\b HYPERLINK}{\b "http://www.ncbi.nlm.nih.g
{\fldrslt{\b \f10 \fs15 ian function and metabolic factors in women with oligome
n}}}
{\fldrslt{\b \f10 \fs15 orrhea treated with metformin in a randomized double bli
nd
}}}
{\fldrslt{\b \f10 \fs15 placebo-controlled trial.
}}}\b0\i J Clin Endocrinol Metab\i0 2002,\b 87:\b0 569-74.
\plain\expndtw-10 \f10 \fs15 Nestler JE, Jakubowicz DJ, Evans WS and Pasquali R:
{\field{\*\fldinst {\b HYPERLINK}{\b "http://www.ncbi.nlm.nih.gov/entrez/query.f
cgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=10.1056/NEJM199806253382603"}
}
{\fldrslt{\b Effects of met}}}
ov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=10.1056/NEJM
199806253382603"}}
{\fldrslt{\b \f10 \fs15 formin on spontaneous and clomiphene-induced ovulation i
n
}}}
ov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=10.1056/NEJM
199806253382603"}}
{\fldrslt{\b \f10 \fs15 the polycystic ovary syndrome.
}}}\b0\i N Engl J Med\i0 1998,\b 338:\b0 1876-80.
\plain\expndtw-7 \f10 \fs15 Nestler JE, Stovall D, Akhter N, Iuorno MJ and Jacub
wicz DJ:{\field{\*\fldinst {\b HYPERLINK}{\b "http://www.ncbi.nlm.nih.gov/entrez
/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=10.1016/S0015-0282(01
)02963-6"}}
{\fldrslt{\b Strat}}}
5-0282(01)02963-6"}}
{\fldrslt{\b \f10 \fs15 egies for the use of insulin-sensitizing drugs to treat
infertil}}}
5-0282(01)02963-6"}}
{\fldrslt{\b \f10 \fs15 ity in women withpolycystic ovary syndrome.
\plain\par
\pard\sl-169 \li0 \ri35 \expndtw-8 \f10 \fs15 Moghetti P, Castello R, Negri C, T
osi F, Perrone F, Caputo M, Zanolin
\plain\expndtw-5 \f10 \fs15 E and Muggeo M:{\field{\*\fldinst {\b HYPERLINK}{\b

"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstr
act&list_uids=10634377"}}
{\fldrslt{\b Metformin effects on clinical features, endo}}}
{\fldrslt{\b \f10 \fs15 crine and metabolic profiles, and insulin sensitivity in
poly}}}
{\fldrslt{\b \f10 \fs15 cystic ovary syndrome: a randomized, double blind, place
bo}}}
{\fldrslt{\b \f10 \fs15 controlled 6-month trial, followed by open, long-term cl
ini}}}
{\fldrslt{\b \f10 \fs15 cal evaluation.
\plain\par
\pard\sl-169 \li0 \ri36 \expndtw-6 \f10 \fs15 Ibanez L, Valls C, Ferrer A, Marco
s MV, Rodrigues-Hierro F and de
\plain\expndtw-2 \f10 \fs15 Zegher Fl:\b Sensitization to insulin induces ovula
tion in non\plain\expndtw-6 \b \f10 \fs15 obese adolescents with anovulatory hyperandrogeni
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\plain\par
\pard\sl-170 \li0 \ri36 \expndtw-8 \f10 \fs15 Vandermolen DT, Ratts VS, Evans WS
, Stovall DW, Kauma SW and
\plain\expndtw-3 \f10 \fs15 Nestler JE:{\field{\*\fldinst {\b HYPERLINK}{\b "htt
p://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&
list_uids=10.1016/S0015-0282(00)01675-7"}}
{\fldrslt{\b Metformin increases the ovulatory rate and preg}}}
-0282(00)01675-7"}}
{\fldrslt{\b \f10 \fs15 nancy rate with clomiphene citrate in patients with poly
}}}
-0282(00)01675-7"}}
{\fldrslt{\b \f10 \fs15 cystic ovary syndrome who are resistant to clomiphene
}}}
5-0282(00)01675-7"}}
{\fldrslt{\b \f10 \fs15 citrate alone.
\plain\par
\pard\sl-169 \li0 \ri35 \expndtw-3 \f10 \fs15 De Leo V, la Marca A, Ditto A, Dit
to A, Morgante G and Cianci A:
-0282(99)00208-3"}}
{\fldrslt{\b \f10 \fs15 Effects of metformin on gonadotropin-induced ovulation
}}}
-0282(99)00208-3"}}
{\fldrslt{\b \f10 \fs15 women with polycystic ovary syndrome.
\plain\par
\pard\sl-170 \li0 \ri35 \expndtw-3 \f10 \fs15 Stadtmauer LA, Toma SK, Riehl RM a
nd Talbert LM:{\field{\*\fldinst {\b HYPERLINK}{\b "http://www.ncbi.nlm.nih.gov/
entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=10.1016/S0015-0
282(00)01766-0"}}
{\fldrslt{\b Metformin
}}}
-0282(00)01766-0"}}
{\fldrslt{\b \f10 \fs15 treatment of patients with polycystic ovary syndrome
}}}
5-0282(00)01766-0"}}
{\fldrslt{\b \f10 \fs15 undergoing in vitro fertilization improves outcomes and
is
}}}
-0282(00)01766-0"}}
{\fldrslt{\b \f10 \fs15 associated with modulation of the insulin-like growth fa
c}}}
5-0282(00)01766-0"}}
{\fldrslt{\b \f10 \fs15 tors.
\plain\par
\pard\sl-169 \li0 \ri34 \expndtw-4 \f10 \fs15 Homburg R:{\field{\*\fldinst {\b H
YPERLINK}{\b "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubM
ed&dopt=Abstract&list_uids=10.1093/humrep/17.4.853"}}
{\fldrslt{\b Should patients with polycystic ovary syndrome
}}}
ep/17.4.853"}}
{\fldrslt{\b \f10 \fs15 be treated with metformin?
}}}\b0\i Hum Reprod\i0 2002,\b 17:\b0 853-856.
\plain\par
\pard\sl-170 \li0 \ri35 \expndtw-6 \f10 \fs15 Glueck CJ, Wang P, Goldenberg N an
d Sieve-Smith L:\b Pregnancy
v/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=10.1093/humre
p/17.11.2858"}}
{\fldrslt{\b \f10 \fs15 outcomes among women with polycystic ovary syndrome
}}}
\plain\par
t_uids=10.1093/humrep/17.11.2858"}}
{\fldrslt{\b \f10 \fs15 treated with metformin.
}}}\b0\i Hum Reprod\i0 2002,\b 17:\b0 2858-2864.
\plain\par
\pard\sl-170 \li0 \ri36 \expndtw-9 \f10 \fs15 Jakubowicz DJ, Iuorno MJ, Jakubowi
cz S, Roberts KA and Nestler JE:
{\fldrslt{\b \f10 \fs15 Effects of metformin on early pregnancy loss in the poly
}}}
{\fldrslt{\b \f10 \fs15 cystic ovary syndrome.
\plain\expndtw-4 \f10 \fs15 Donesky BW and Adashi EY:{\field{\*\fldinst {\b HYPE
RLINK}{\b "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&
dopt=Abstract&list_uids=8773750"}}
{\fldrslt{\b Surgical ovulation induction: the
}}}
{\fldrslt{\b \f10 \fs15 role of ovarian diathermy in polycystic ovary syndrome.
}}}\b0\i Bail\plain\expndtw-11 \i \f10 \fs15 lieres Clin Endocrinol Metab\i0 1996,\b 10:\b0
293-310.
\plain\par
\pard\sl-170 \li0 \ri35 \expndtw-5 \f10 \fs15 Farquhar C, Vandekerkhove P and Li
lford R:\b Laparoscopic{\field{\*\fldinst {\b HYPERLINK}{\b "http://www.ncbi.nl
m.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=11687
100"}}
{\fldrslt{ "drill}}}
{\fldrslt{\b \f10 \fs15 ing" by diathermy or laser for ovulation induction in an
ovu}}}
{\fldrslt{\b \f10 \fs15 latory polycystic ovary syndrome.
}}}\b0\i Cochrane Database Syst Rev
\plain\expndtw-10 \f10 \fs15 2001,\b 4:\b0 CD001122.
\plain\par
\pard\sl-169 \li0 \ri35 \expndtw-8 \f10 \fs15 Abdel Gadir A, Mowafi RS, Alnaser
HMI, Alonezi OM and Shaw RW:
\plain\expndtw0 \b \f10 \fs15 Ovarian electrocautery versus human gondotrophins
and
\plain\expndtw0 \b \f10 \fs15 pure follicle stimulating hormone therapy in the t
reatment
\plain\par
\sl-184\fs18\par\sl-240\fs24\par\par\pard\pard\sl-200 \li2012 \ri36 \fi1527 \exp
ndtw-6 \f10 \fs18 Page 8 of 9
\plain\par
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\par
\plain\sl-83\fs8\par\sl-240\fs24\par\par\par\par\pard\pard\sl-159 \li2 \ri0 \exp
ndtw-12 \f10 \fs15 60.
\plain\par
15 61.
\plain\par
15 62.
\par
\column
w-7 \b \f10 \fs15 of patients with polycystic ovarian disease.\b0\i Clin Endocr
inol\i0 1990,
\plain\par
\pard\sl-169 \li0 \ri4678 \expndtw0 \f10 \fs15 Lunde O, Djoseland O and Grottum
P:{\field{\*\fldinst {\b HYPERLINK}{\b "http://www.ncbi.nlm.nih.gov/entrez/query
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{\fldrslt{\b Polycystic ovary syn}}}
ep/16.7.1479"}}
{\fldrslt{\b \f10 \fs15 drome: a follow-up study on fertility and menstrual patt
ern
}}}
ep/16.7.1479"}}
{\fldrslt{\b \f10 \fs15 in 149 patients 15-25 years after ovarian wedge resectio
n.
}}}
\plain\expndtw-11 \i \f10 \fs15 Hum Reprod\i0 2001,\b 16:\b0 1479-1485.
\plain\par
\pard\sl-170 \li0 \ri4679 \expndtw1 \f10 \fs15 Gjonnaess H:\b Ovarian electroca
utery in the teatment of
\plain\expndtw-1 \b \f10 \fs15 women with polycystic ovary syndrome. Factors aff
ecting
\plain\expndtw-11 \b \f10 \fs15 results.\b0\i Acta Obstet Gynecol Scand\i0 199
4,\b 73:\b0 1-5.
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il AK, Gulekli B and Tan SL:{\field{\*\fldinst {\b HYPERLINK}{\b "http://www.ncb
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{\fldrslt{\b A compar}}}
-7844(02)02193-2"}}
{\fldrslt{\b \f10 \fs15 ison of in-vitro maturation and in-vitro fertilization f
or
}}}
-7844(02)02193-2"}}
{\fldrslt{\b \f10 \fs15 women with polycystic ovaries.
}}}\b0\i Obstet Gynecol\i0 2002,
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Polosiklik Ovary Syndrom

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Polosiklik Ovary Syndrom

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\plain\expndtw-9 \f10 \fs19 concentrations and a decrease in LH levels as the ba

\plain\expndtw1 \f20 \fs19 sound examination of the ovaries [3].

\f20 \fs19 spontaneous or induced bleeding starting with the low

clo\plain\expndtw4 \f20 \fs19 miphene treated cycle by ultrasound evaluation of

\plain\expndtw2 \f20 \fs19 tion of an ovulatory dose of hCG, 5,000-10,000 IU is

\f20 \fs19 has been attributed to its anti-estrogenic action and

\f20 \fs19 aromatase for this indication, has been shown to be e

\f20 \fs19 4.6%. In a further study, although this traditional p

\plain\expndtw1 \f20 \fs19 the desired monofollicular ovulation is particularly

\f20 \fs19 tional stepwise protocol [incremental dose rises of 7

ple pregnancies, which were prevalent [11% OHSS and

\f20 \fs19 concentrations were half those observed on convention

\plain\expndtw1 \f20 \fs19 produce a higher rate of mono- or bifollicular develo

\f20 \fs19 cycle, the Rotterdam group examined a step-down dose

\sl-233\fs23\par\pard\pard\sl-235 \li0 \ri34 \expndtw1 \f20 \fs19 Although the m

\f20 \fs19 experience and that of others has shown an increased

\f20 \fs19 and therefore increase rates of cycle cancellation, O

\plain\expndtw0 \f20 \fs19 tiple follicular development.

\f20 \fs19 theoretically therefore yield the best results. Schee

\f20 \fs19 tion of the degree of hormonal suppression by adjustm

\f20 \fs19 their discontinuation. If we apply these advantages t

\plain\expndtw2 \f20 \fs19 required and increase the incidence of monofollicular

\f20 \fs19 insulin concentrations could be of great importance.

\plain\expndtw1 \f20 \fs19 tion program have widened as it seems to be difficult

\plain\expndtw2 \f20 \fs19 not cause hypoglycaemia in normoglycaemic patients.

\plain\expndtw0 \f20 \fs19 administered FSH with or without pretreatment with me

\f20 \fs19 decreased total number of follicles but no difference

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{\fldrslt{\b \f10 \fs15 peripheral resistance independent of obesity in polycyst

\plain\expndtw-1 {\field{\*\fldinst {\b HYPERLINK}{\b "http://www.ncbi.nlm.nih.g

{\fldrslt{\b \f10 \fs15 tial oestradiol response predicts outcome of exogenous

\plain\expndtw-10 \f10 \fs15 2003,\b 18:\b0 1626-1631.

\sl-280\fs28\par\sl-240\fs24\par\pard\pard\sl-159 \li0 \ri0 \expndtw-12 \f10 \fs

ms J and Jacobs HS:\b Combined

\plain\expndtw-5 \f10 \fs15 E and Muggeo M:{\field{\*\fldinst {\b HYPERLINK}{\b

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