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The Management of Polycystic Ovary

Syndrome
VINCENZA BRUNI, METELLA DEI, VALENTINA PONTELLO,
AND PAOLO VANGELISTI
Department of Gynecology-Perinatology and Human Reproduction,
University of Florence, Forence, Italy

ABSTRACT: It is well known that subjects with polycystic ovary syndrome


(PCOS) show very variable clinical and biochemical aspects. Considering
long-term repercussions, two main disturbances, not always strictly related,
need to be countered: hyperandrogenism and insulin resistance, with com-
pensatory hyperinsulinemia. The aim of this review is to summarize thera-
peutic perspectives for PCOS, starting from basic approach, such as weight
reduction and changes in lifestyle. The benefits of long-term use of oral con-
trceptives and the criteria of choice of the estro–progestin combinations are
discussed. With severe hyperandogenism, a pure antiandrogen should be
added. The experiences with insulin-sensitizing drugs, especially metformin,
are reviewed; while their beneficial role as an adjuvant to treatment of ovu-
latory infertility has been well established, the effects of a long-term treat-
ment, especially in very young patients, are still under debate. Current
studies are testing the results of combinations of different treatments at low
dosage; randomized comparative trials on the long-term efficacy of these ap-
proaches have yet to be scheduled.

KEYWORDS: polycystic ovary syndrome (PCOS); insulin; obesity; infertility;


menstruation; hyperandrogenism

POLYCYSTIC OVARY SYNDROME: DEFINITION


AND CLINICAL ASPECTS

The clinical definition of the polycystic ovary syndrome (PCOS) has been the
subject of dispute since the 1990s. The criteria adopted by the American authors1 de-
fine the presence of anovulation and hyperandrogenism, both clinical and biochem-
ical, as mandatory for the diagnosis of PCOS, but not the ultrasound appearance of
the ovaries as classically described.2 In the European evaluation, on the other hand,
the polycystic appearance of the ovaries as revealed by ultrasound is a fundamental
element of diagnosis; other requirements are the presence of one or more clinical
symptoms, such as menstrual disturbances, hyperandrogenism, and obesity, and of

Address for correspondence: Vincenza Bruni, Department of Gynecology-Perinatology and


Human Reproduction, University of Florence, Forence, Italy. Voice: +39-055-4277551; fax: +39-
055-4277552.
vbruni@unifi.it

Ann. N.Y. Acad. Sci. 997: 307–321 (2003). © 2003 New York Academy of Sciences.
doi: 10.1196/annals.1290.034

307
308 ANNALS NEW YORK ACADEMY OF SCIENCES

one or more endocrine indicators, such as elevated levels of LH, testosterone, ∆4


androstenedione, or insulin.
Only very recently has Homburg3 put forward a diagnostic criterion capable of
unifying the two approaches: the presence of one or more clinical symptoms such as
a disturbed menstrual pattern, manifestations of hyperandrogenism (hirsutism,
acne), and anovulatory infertility, when combined with a micropolycystic appear-
ance of the ovaries observed through ultrasound, make it possible to confirm the di-
agnosis of PCOS even without the performance of biochemical tests. On the other
hand, in the event of a negative ultrasound examination, the diagnosis can only be
confirmed if one or more of the following biochemical markers is present: elevated
LH and testosterone, elevated free androgen index (FAI), glucose/insulin ratio < 4.54
evaluated on a single sample taken on the morning on fasting.
The combination and the degree of clinical expression of the alterations in the en-
docrine and reproductive functions and the metabolism, and of the repercussions on
the general state of health, are extremely variable from one individual to another;
such divergence relates to genetic factors (such as the polymorphism of the insulin
gene,5 of the insulin receptor substrate,6 of several key steroidogenesis enzymes,7
and of the androgen receptor8) or acquired factors, such as obesity.9,10 For this rea-
son, the clinical symptoms of hyperandrogenism (acne, seborrhoea, hirsutism, an-
drogenetic alopecia) are not always present,10 even though hyperandrogenism can
almost always be demonstrated biochemically. As a result, menstrual alterations
(anovulation, oligomenorrhoea, secondary amenorrhoea) are represented in a vari-
able way. The prevalence of insulin resistance, with compensatory hyperinsuline-
mia, in individuals with polycystic ovary syndrome is around 40% in nonobese
patients and 60% in obese patients,11 and proves to be closely related to a reduction
in the levels of SHBG.12 It has been shown that the insulin response to OGTT is sig-
nificantly higher in normoinsulinemic patients with PCOS, whether they are of nor-
mal weight or overweight, in comparison to control subjects; moreover, in
hyperinsulinemic patients the response is significantly higher, not only in respect of
the control subjects, but also in comparison to the normoinsulinemic patients. The
hepatic insulin clearance proves to be significantly higher in the obese normoin-
sulinemic PCOS, but distinctly lower in hyperinsulinemic patients who are both thin
and overweight.13

LONG-TERM REPERCUSSIONS OF POLYCYSTIC


OVARY SYNDROME

At the level of the reproductive function, women with PCOS tend to represent a
subgroup with a greater risk of infertility connected with anovulation; they also have
a greater probability of overstimulation of the ovaries in response to treatments with
gonadotropin and a greater incidence of first-trimester abortion.14 Finally, unbal-
anced estrogen production, which is associated with obesity, elevated levels of insu-
lin, and low levels of SHBG, leads over time to a greater incidence of endometrial
carcinoma.15
At a metabolic level, the evolution of the syndrome involves a tendency to obesity
in over 50% of individuals, with a characteristic increase of abdominal fat, which is
BRUNI et al.: POLYCYSTIC OVARY SYNDROME 309

present even in 70% of normal weight patients.16 This characteristic, which can be
measured using the waist–hip ratio, is closely linked to insulin resistance. Moreover,
a greater incidence of disturbances in nutritional behavior, especially bulimia ner-
vosa,17 has also been observed in patients suffering from this syndrome.
Retrospective studies on women with PCOS recorded an increased risk (from 2
to 5 times greater) of developing type 2 diabetes when compared with the control
samples. A recent longitudinal study18 highlighted the fact that 11.9% of patients
with PCOS who are >30 suffer from a type 2 diabetes, as compared with the 1.4%
of the control samples. Diabetes represents the major cause of death among these
women in a long-term follow-up.19 An impaired glucose tolerance, assessed accord-
ing to the WHO criteria (glucose levels 2 h after the administration of 75 mg of glu-
cose > / = 140 mg/dL), is present in 40% of women with PCOS.20 Consequently,
patients who show distinct symptoms of hyperinsulinemia (severe hyperandro-
genism or acanthosis nigricans), young women for whom a course of therapy is to
be formulated, and those who are planning an induction of ovulation, must be tested
through assessments of the levels of both glucose and insulin after OGTT.
Insulin resistance and hyperinsulinemia play a fundamental role in the increased
risk of cardiovascular pathology, which develops more precociously than in other
women.21 Obesity, hyperinsulinemia, and insulin resistance are associated with high
levels of PAI (plasminogen activator inhibitor), which determine a condition of hy-
pofibrinolysis; numerous studies have observed an increase in the PAI of women af-
fected by PCOS, to the extent that several authors consider it as a marker of the
syndrome.22 Insulin increases the synthesis of the PAI by the hepatic cell in vitro,
and the degree of hyperinsulinemia correlates positively with the activity of the PAI
in vivo. Moreover, the increase in the PAI may also be genetically determined: con-
ditions of heterozygosis or homozygosis caused by the 4G polymorphism of the PAI
gene, more frequent in the female population affected by PCOS, are associated with
an increase in the activity of the PAI.23 The levels of plasma homocystein, an impor-
tant cardiovascular risk factor, also prove to be higher in women affected by
PCOS.24 Hyperlipoproteinemia are also more frequent in such patients, who, inde-
pendently of the overweight factor, reveal concentrations of LDL greater than those
attributable to hyperinsulinemia, lower levels of HDL and an increase in triglycer-
ides.25 Furthermore, an endothelial dysfunction has also been recorded in such pa-
tients, with reduced endothelium-dependent vasodilatory capacity26 and a reduction
of the antioxidant substances.27
In the literature the data regarding an increase in hypertension in women affected
by PCOS are fairly discordant, although greater plasma renin levels have been re-
corded in normotensive patients,28 along with a greater risk of blood pressure in-
crease in secondary pregnancies featuring induced ovulation,29 as well as a distinct
prevalence of cerebrovascular pathologies in a broad retrospective study.30

BASIC THERAPEUTIC APPROACH

The first level of treatment for overweight women of all ages affected by PCOS,
whether they reveal insulin resistance or not, is a balanced diet, which enables a re-
duction of the weight levels. The diet has to be accompanied by changes in lifestyle
that include adequate physical activity, a reduced alcohol intake, and no or limited
310 ANNALS NEW YORK ACADEMY OF SCIENCES

smoking. Weight loss effectively improves sensitivity to insulin,31,32 reduces the in-
sulin response to OGTT and to IVGTT,33,34 improves the ovarian function in terms
of percentage of ovulations, and also improves the clinical hyperandrogenism, re-
ducing in a statistically significant manner the Ferriman and Gallwey score.35

THE USE OF ORAL CONTRACEPTIVES


IN THE TREATMENT OF PCOS

Undoubtedly, estro–progestins have been and are, to date, the therapy most wide-
ly used in the long-term treatment of PCOS. Their use effectively results in:
• Suppression of pituitary secretion of LH, and consequent reduction of the
ovarian production of LH-dependent androgens;
• Decrease in the adrenal production of androgens;
• Increase of the SHBG;
• Reduction of the risk of developing endometrial carcinoma.
We have at our disposal very few comparative clinical studies on the use of the
various estro–progestin combinations available in the treatment of PCOS, and of the
hyperandrogenism associated with the syndrome. At least at a strictly theoretical
level, the choice of the progestin contained in the estro–progestin combinations
ought to feature a favorable profile in terms of progestative potency (inhibition of
ovulation and secretive transformation of the endometrium), of the ratio between
progestative and androgenic activities, and of the eventual antiandrogenic and anti-
mineralocorticoid activities. Beyond this, the progestin utilized should not antago-
nize the SHBG synthesis induced by the estrogens.
In effect, on a strictly clinical level, the suppression of the ovarian and adrenal
steroid production and the increase of the SHBG are in any case present,36,37 albeit
differently represented in the various specific combinations, and have a positive in-
fluence on the control of the clinical manifestations of hyperandrogenism. Regard-
ing the symptoms of hyperandrogenism, comparison between the various
preparations does not appear to highlight particular differences in the long-term
therapy.
Using these combinations in patients with insulin resistance and occasionally hy-
perinsulinemia, we have to tackle the problem of possible modifications of the car-
bohydrate metabolism induced by estro–progestins: the data at our disposal are
partially discordant. Several studies have recorded a modest increase in insulin and
glucose in response to OGT38 during the course of treatment with OCs containing
gestodene (75 mcg) and EE (30 mcg) observed in women over the age of 26 and not
in younger patients.39 A modest increase in the response to the glucose tolerance test
and of glycemia in fasting, but not of insulinemia in fasting or under stimulus, was
also encountered with preparations featuring a low estrogen dosage with gestodene
and desogestrel.40 Other reports have not recorded modifications in insulinemia and
glycemia after 6 months assumption of the triphasic combination containing
gestodene and of other combinations containing levonorgestrel, desogestrel, and
BRUNI et al.: POLYCYSTIC OVARY SYNDROME 311

noretisterone;41 nor were variations in insulin sensitivity recorded after 6 months of


treatment with low dosage estro–progestins.42 Even considering patients with previ-
ous gestational diabetes, no modifications in the glucose, insulin, and glucagon re-
sponse to the OGTT were observed during treatment with levonorgestrel;43 on the
other hand, using the euglycemic clamp technique, a greater reduction in the periph-
eral sensitivity to insulin was observed in comparison to the control samples treated
with the same combination.
There are a number of estro–progestin combinations that merit special comment:
• Ethinylestradiol 35 mcg + cyproterone acetate
• Ethinylestradiol 30 mcg + dienogest
• Ethinylestradiol 30 mcg + drospirenone
In Europe, the contraceptive combination containing cyproterone acetate and
ethinylestradiol has been widely used. Falsetti’s statistics44 on 140 women of pre-
menopause age and 40 control samples monitored for 60 consecutive months, with
a subsequent 6-month follow-up, revealed a reduction in LH levels, in the LH/FSH
ratio, in total and free testosterone, in androstenedione, and in DHEAS, and an in-
crease in SHBG. At a morphological level, a decrease in the ovarian volume was re-
corded, with a reduction both of the stromal component and of the number and size
of follicles. From a clinical point of view, a distinct improvement in acne and sebor-
rhoea was observed in almost all patients between the 12th and 24th cycle, while hir-
sutism was still present in 69.4% of the patients after 60 cycles of treatment. In the
cases of severe hirsutism, the condition improved, but did not resolve. A high body-
mass index appeared to limit the benefits of the treatment as measured by clinical
and biochemical markers of hyperandrogenism.45 Regarding the metabolic impact
of this combination, an increase in total cholesterol, in HDL, and in triglycerides was
observed, combined with a decrease in LDL.46,47 Other authors have observed in-
stead a slight deterioration both of the lipid profile (increase in triglycerides and in
LDL-cholesterol) and of the late glucose response after the oral load.48 The effects
on the carbohydrate metabolism nevertheless appear to be modest; the OGTT re-
mains within normal limits, although the secretion of insulin and peptide C after load
increase.49 Studies carried out using the euglycemic clamp have shown that the prep-
aration does not alter the peripheral sensitivity to insulin in a significant manner, but
it does slightly increase the hepatic clearance of the hormone itself.50
A recent synthesis is dienogest, a progestin derived from norethisterone through
the substitution of a cyanometilic group in place of the ethinylic group in position
17 and by the introduction of a double bond in position C4–C5. It is considered a “hy-
brid progestin” despite being a derivative of 19nor-testosterone. It is characterized
by an antiandrogen effect,51 especially in relation to the skin 5α reductase.52 There
are as yet no specific clinical case studies on the use of the combination of ethi-
nylestradiol 0.03 mg and dienogest in patients with polycystic ovary syndrome; in
the literature, however, there is a study that has demonstrated how this combination
induces favorable modifications in the lipid profile, with an increase in the HDL cho-
lesterol, of the apolipoprotein A1 and with a significant decrease in the Lp(a).53
Another interesting combination is that with drospirenone, a 17α derived from
spironolactone with a progestational efficacy similar to that of natural progesterone,
with antimineralcorticoid and antiandrogen activities, in the absence of estrogenic,
312 ANNALS NEW YORK ACADEMY OF SCIENCES

androgenic, and glycocorticoid activities.54 This preparation brings about a distinct


increase in the SHBG55 in combination with a significant antiandrogen activity,
which proves to have an efficacy comparable with that of the combination containing
cyproterone acetate in individuals with acne, seborrhoea, and modest hair excess.56
In conclusion, the treatment with estro–progestins of a combined nature may be
a valid therapy in the presence of moderate clinical symptoms of hyperandrogenism,
if contraception is called for and if the patient does not present contraindications to
their use. There do not appear to be major differences in the long-term clinical re-
sponse to the use of the various different combinations currently available.57 Limi-
tations to this type of treatment include: the reappearance of the symptoms and the
clinical indicators of hyperandrogenism when treatment is suspended, and the ab-
sence of improvement in the metabolic aspects of the syndrome, especially in rela-
tion to glucose tolerance. A long-term follow-up study58 reevaluated 37 women with
PCOS 10 years after their first assessment, concluding that hyperinsulinemia and in-
sulin resistance tended to worsen in these subjects, without any contemporary wors-
ening of hyperandrogenism. Long-term estro–progestin treatment countered this
tendency, probably improving the pattern of body fat distribution.

THERAPEUTIC COMBINATIONS WITH ESTRO–PROGESTINS

In situations of severe hyperandrogenism (marked hirsutism, androgenetic alope-


cia) the therapeutic effect of the estro–progestins requires strengthening. For this pur-
pose, various combinations with antiandrogens and GnRH analogs have been utilized.
Boosting of treatment is achieved by using pure antiandrogens. This results in
both the blocking of the androgen receptor and an improvement of the lipid profile.59
Cyproterone acetate binds in a competitive manner with the androgen receptor,
inhibits the activity of the skin 5α reductase, and increases the metabolic clearance
of the androgens. It is also characterized by a marked progestagen activity and by a
long half-life with accumulation in the adipose tissue.
Flutamide, an androgen receptor agonist, is capable of inhibiting the bonding of
DHT to its receptor, and the activity of the 17β hydroxylase and 17–20 desmolase,
obtaining significant effects as an antiandrogen at both clinical and humoral level.60
Its employment, in association with estro–progestins, or with the GnRH analog,
brings about a distinct reduction in the circulating androgens, a decrease in ovarian
volume, and a recovery of the ovulatory cycles.61 It has, moreover, been observed
that the use of flutamide is capable of eliminating the hypothalamic block exerted by
the androgens, restoring the sensitivity of the Gn-RH pulse-generator to endogenous
estradiol and progesterone.62 At a metabolic level, a reduction of insulin levels at
baseline and after stimulation by glucose have been observed.63 Finally, a significant
decrease in the LDL/HDL ratio through the decrease in LDL cholesterol, total cho-
lesterol, and triglycerides emerges.59 At a clinical level it is one of the most effective
antiandrogens that we have at our disposal,64 even though it demands careful moni-
toring in view of the possible hepatotoxicity.
Spironolactone is also an agonist of the androgen receptor, as well as of the al-
dosterone receptor; it also inhibits the activity of the 17β hydroxylase and 17–20
desmolase and of the skin 5α reductase; it slows down the metabolic clearance rate
BRUNI et al.: POLYCYSTIC OVARY SYNDROME 313

of testosterone. It has a weak progestative effect. At a dosage of 100 mg per day, it


has been proven effective in reducing the signs of hirsutism.65 It can cause menstrual
irregularity if used on its own, nausea, and muscular cramps.
Finasteride is characterized by a marked inhibition of the type-2 5α reductase,
which is mainly represented in the genital tissues, and by a minimal inhibition of the
type-1 5α reductase, which is more prevalent at skin level. At a dosage of 2.5 mg per
day over prolonged periods, it has been proven effective in the treatment of hirsut-
ism,66 without evident collateral effects.
The rationale behind combining estro–progestins with a GnRH analog agonist is
to achieve complete suppression of the ovarian function. The results of clinical stud-
ies of this combination are divergent: some have recorded an improvement of the en-
docrine profile, but without a concomitant improvement of the hirsutism score in
comparison with the use of the pill on its own,67 while for other authors the clinical
markers of hyperandrogenism regressmore rapidly and last longer.68,69 Castelo
Branco70 studied women with severe hirsutism that was treated with tryptorelin
combined with a preparation containing desogestrel, as compared with the cyproter-
one acetate preparation: the modifications in the hormonal profile in the two groups
are comparable in terms of the reduction of the androgen index and of the SHBG in-
crease; significant variations of the bone mineral density were not observed; at a
clinical level, better results were obtained after 6 months of the combined treatment,
but at 12 months the results were comparable between the two groups.

THE USE OF INSULIN SENSITIZERS

In patients with insulin resistance an inverse correlation between menstrual dis-


orders and peripheral insulin sensitivity was observed.71 The improvement of the pe-
ripheral insulin sensitivity ameliorates the menstrual pattern, as observed in
numerous case studies in which insulin-sensitizing drugs were used for the induction
of ovulation. At present clinical data exist that are related predominantly to the epi-
sodic correction of the anovulation rather than to the long-term treatment of insulin
resistance, a key pathogenetic mechanism in the maintenance of the syndrome itself.
Among the insulin-sensitizing drugs, there are numerous and positive experienc-
es with metformin, a biguanide capable of producing a reduction in the hepatic se-
cretion of glucose and of increasing its peripheral uptake; the drug moreover appears
to increase the oxidation of the glucose by the adipose tissue and to facilitate the
bonding of insulin to its receptor. In women with PCOS who are under treatment
with metformin, a significant reduction in fasting insulinemia, as well as after glu-
cose load, was observed, along with an increase of insulin sensitivity assessed using
the euglycemic clamp technique.72–74 Several authors75,76 record a reduction of the
BMI, which is not confirmed by others;72,73 it does nevertheless appear to improve
the waist/hip ratio and the percentage of visceral adipose tissue,77,75,72 even if this
parameter has not been observed in all the studies. Better results, in terms of body
composition, have been obtained through the association of a hypocaloric diet and
the administration of metformin in a dosage of 850 mg × 2/die.75
It has emerged from numerous case studies that metformin at a dosage of 500 mg
3 times a day (better if begun in graduated doses, so as to reduce the collateral effects
314 ANNALS NEW YORK ACADEMY OF SCIENCES

to a minimum) can improve menstrual cyclicity,72,73,75,79 obtaining a greater per-


centage of spontaneous ovulations and pregnancies. More specifically, Glueck78 by
using 1500–2250 mg/die in 43 patients suffering from amenorrhoea obtained men-
strual regularity in 91% of cases, and the presence of ovulatory cycles in 39%. A
study by Moghetti73 recorded 75% of positive responses in terms of regularization
of the cycle in 75% of the obese patients and in 18% of women of normal weight,
with an overall percentage of ovulatory cycles of 44%.
The responsiveness of metformin appears to be greater in situations of higher ba-
sic plasma levels of insulin, of lower plasma levels of androstenedione, and of less
severe menstrual disorder.73 Considering the data related to adolescent patients, a
study79 on 18 girls with previous precocious pubarche, not obese and not selected
for insulin resistance, treated with 1275 mg/die, recorded a recovery of the menstrual
cycle in 100% of the cases, with 78% ovulatory cycles. Similar results were also ob-
tained in another study on 11 young girls with anovulatory cycles, subjected to a hy-
pocaloric diet plus treatment with metformin, in which a recovery of ovulation was
recorded in 29% of the cases, along with an improvement of the lipid profile, even
after correction of the effect correlated to the reduction of body weight.80 Beyond
this, certain preliminary data would also appear to indicate that treatment with met-
formin could also reduce the risk of early pregnancy loss in polycystic ovary
syndrome.81
As far as the endocrine parameters are concerned, under treatment with metform-
in a decrease of the levels of LH and of the LH/FSH ratio have been recorded, as has
a reduction in the concentrations of testosterone,74–77 ∆4 androstenedione,73,76,82,83
DHEAS,76 and basal 17OHP, under GnRH analog,76 and after stimulus with
ACTH.74 Under treatment with metformin, an increase in the concentrations of
SHBG84 and a reduction in the levels of IGF1 and in the IGF1/IGF binding protein
1 ratio have also been observed.85 These laboratory data also have a clinical corrob-
oration;86 effectively, in patients treated with metformin for 6 months at a dosage of
1500 mg/die, a reduction of 10.7% in the Ferriman and Gallwey score has been re-
corded, and of 11.8% in the speed of hair growth.
The use of metformin may also give rise to certain collateral effects of a gas-
trointestinal nature (diarrhoea, nausea, anorexia) and an increase in the basic and
postprandial concentrations of lactic acid, through induction of the conversion of
glucose to lactate by the intestinal wall. The risk of a veritable lactic acidosis is es-
timated at around 0.08 per 1000 patients per year.87 This incidence is, however, in-
creased in the case where alcohol is involved. It remains to be proven whether a long-
term treatment can affect the long-term fertility and the distant repercussions of the
syndrome.
Other insulin-sensitizing drugs, such as troglitazone, D-chiro-inositol, and rosigl-
itazone, have been proposed as treatment for patients with PCOS and insulin resis-
tance. Regarding the former, a multicentric clinical trial of over 400 women studied
for a year has been published,88 showing a distinct dose-dependent increase in the
ovulatory capacity. The drug was however withdrawn from circulation by the FDA
in view of suspected hepatotoxicity. For D-chiro-inositol, too, a double-blind, place-
bo-controlled study demonstrated an increased frequency of ovulation in overweight
women with PCOS.89
It is proposed, however, that these drugs be used predominantly in brief cycles,
in combination with ovulation inducers to boost their effects.
BRUNI et al.: POLYCYSTIC OVARY SYNDROME 315

THERAPEUTIC COMBINATIONS WITH METFORMIN

Metformin has also been proposed for the treatment of ovulatory infertility, in the
absence of a response to clomifene or as an adjuvant to therapy with gonadotropins.
It also has been observed that the use of metformin increases the number of mature
ovocytes retrieved from women with PCOS subjected to in vitro fertilization and em-
bryo transfer after gonadotropin stimulation.90
The association with antiandrogen drugs appears to have beneficial results not
only in the improvement of the clinical symptoms of hyperandrogenism, but also in
the effects on other metabolic parameters. The use of flutamide in a dosage of 250
mg/die in association with metformin in a dosage of 1250 mg/die can significantly
improve the peripheral sensitivity to insulin, as compared with metformin used on
its own, further reducing the levels of ∆4 androstenedione and the LDL/HDL ratio,
and increasing the percentage of ovulatory cycles.91 Even minor dosages of fluta-
mide, such as 125 and 62.5 mg/die appear to be capable of producing a synergistic
effect with metformin on corporeal composition, hyperandrogenism, and the lipid
profile.
The proposal of the metformin–oral contraceptive association is based on two
fundamental requirements:
(1) To obtain a further decrease of hyperandrogenism, given the known direct
effect of insulin in association with LH on ovarian androgen production;
(2) To improve the peripheral sensitivity to insulin in the course of treatment
with estro–progestins.
Finally, the combination of flutamide 125 mg, metformin 1275 mg, and an oral
contraceptive with 20 µg of ethinylestradiol has recently been presented as a treat-
ment for nonobese young women with PCOS.92

OTHER THERAPEUTIC OPTIONS


Other proposals for the treatment of women with PCOS have been put forward,
for which only a few reports exist in the literature.
One such proposal concerns the use of naltrexone,93 which is based on the theory
that the endogenous opiates are involved in the control of insulin secretion in pa-
tients with PCOS. Ten obese women with PCOS were treated with 50 mg a day for
6 months, resulting in the reduction of BMI, free testosterone, androstenedione,
DHAS, cortisol, and insulinemia as a result of the hepatic clearance of the hormone;
no significant effect on menstrual cyclicity was observed.
Octreotide, also a somatostatin analog, was tested on patients with PCOS, result-
ing to a reduction in the adrenal response to stimulus with CRF94 and a reduction in
the sensitivity threshold of the ovary to treatment with FSH.95 However, the possi-
bility of altering the carbohydrate homeostasis makes this treatment inadvisable for
long-term use.
Finally, the effect of N-acetyl-cysteine treatment (1.8–3 g pro die) on insulin se-
cretion and on the peripheral resistance to insulin was studied in 6 thin and 31 obese
women with PCOS, revealing a significant reduction of the AUC of the insulin after
OGTT, and an improvement in the peripheral sensitivity to insulin, without modifi-
cations of the hepatic clearance.96
316 ANNALS NEW YORK ACADEMY OF SCIENCES

CONCLUSIONS
Starting with the consideration that PCOS represents a complex clinical profile,
it is impossible to define an univocal line of treatment. The selection of the therapeu-
tic approach has to be guided by:
• The predominant symptomatology;
• The desire for pregnancy, or otherwise;
• The metabolic profile;
• The age of the patient.
The various therapeutic tools at our disposal can be used in sequence or even in
combination, depending on the requirements, clinical priorities, and the evolution of
the symptomatology. Randomized comparative studies on the long-term efficacy of
the various therapeutic approaches have yet to be planned and carried out.

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