Choice of stimulation in polycystic ovarian syndrome:
the influence of obesity
F.Galtier-Dereure1'3, P.Pujol1, D.Dewailly2 and J.Bringer1
Service d'Endocrinologie, Hopital Lapeyronie, 34295 Montpellier Cedex 5, and 2Service
d'Endocrinologie, CHR Lille, 59037 Lille Cedex, France
3
To whom correspondence should be addressed
Obesity modifies insulin sensitivity and gonadotrophins dynamics, and is associated with
disorders of spontaneous ovulation. High concentrations of leptin are possibly a link between
weight and spontaneous ovulation. Weight
excess in polycystic ovary syndrome (PCOS)
patients increases hyperinsulinaemia, which
may result in altered follicular maturation.
Obese PCOS women are characterized by a
decreased efficiency of the different stimulation
treatments. Although clomiphene resistance is
not associated with obesity, the dose of clomiphene required to achieve ovulation is positively
correlated with body weight. Obese PCOS
women also require higher doses of gonadotrophins than their lean counterparts, with ultimately poorer results in pulsatile gonadotrophin
releasing hormone-stimulated cycles. The first
stage in the optimal management of obese PCOS
anovulatory women is a weight loss programme,
which helps to correct the clinical and endocrine
abnormalities.
Key words: clomiphene citrate/leptin/obesity/
ovulation induction/polycystic ovaries
Introduction
Polycystic ovary syndrome (PCOS) is one of the
most common causes of endocrine infertility in
women (Hull, 1987). Clomiphene citrate (CC)
is widely used for ovulation induction for this
condition. However, the ovulation rate following
CC treatment is quoted as ~80% (Gysler et al,
1982; Franks et al, 1988). As the reasons for
failure to ovulate in the remaining 20% of patients
are unclear, it is difficult to identify non-responders
to CC prior to induction attempts. Clomiphene
resistance is poorly understood, and could be
mediated in part by intra-ovarian regulators. It has
been suggested that weight excess in PCOS patients
might be related to CC resistance, as well as
resistance to other stimulation treatments.
Obesity and spontaneous ovulation
It is tempting to speculate that obesity could
influence the results of stimulated ovulation, since
increased body fat has been associated with disorders of spontaneous ovulation.
Excessive visceral body fat is associated with
insulin resistance, hyperinsulinaemia, and high
insulin-like growth factor-I (IGF-I) bioactivity as
a result of decreased concentration of insulinlike growth factor binding protein-1 (IGFBP-1)
concentration. Insulin and IGF-I receptors
(Poretsky etal, 1985) and IGFBPs (Giudice, 1992)
have been characterized in human ovary. IGF-I is
a sensitizing factor that enhances the ability of
granulosa cells in small antral follicles to respond
to follicle stimulating hormone (FSH) (Mondschein
et al, 1989), facilitating the induction of LH
receptors (May et al, 1980). In thecal cells, both
insulin and IGF-I stimulate ovarian androgen
synthesis (Cara and Rosenfield, 1988). Therefore,
insulin and IGFs are important intra-ovarian
regulators, and systemic or local disturbances may
directly result in alterations of spontaneous
ovulation.
In addition to this direct role on ovarian function,
body fat appears to be strongly related to the
activity of the hypothalamo-pituitary axis. Weight
European Society for Human Reproduction & Embryology
Human Reproduction Volume 12 Supplement 1 1997
Obesity and stimulation in polycystic ovaries
excess particularly influences luteinizing hormone
(LH) concentration, which is probably the key
hormone in the relationship between reproduction
and metabolism. Obesity is associated with excessive LH concentrations (Reid and Van Vugt, 1987),
and it has been shown that a high concentration
of LH results in a lower chance of conception
(Regan et al, 1990). Conversely, undernourished
women exhibit low LH concentrations. In both
cases the concentration of FSH remains generally
unaffected. However, the mechanisms by which
nutritional status influences hypothalamic activity
are poorly understood. The aromatizing function
of adipose tissue is possibly a means by which
obesity impairs gonadotrophin secretion. As hyperinsulinaemia decreases sex hormone-binding
globulin (SHBG) concentration, obesity is associated with high concentrations of unbound androgens. Excessive bioavailability and aromatization
of androgens generates increased oestrone concentrations (Deslypere et al, 1982), which in turn
trigger a rise in LH secretion. LH subsequently
stimulates the production of ovarian androgens,
thus enhancing substrate availability for the
aromatizing system. However, the use of the
aromatase inhibitor Al-testolactone in PCOS did
not modify the LH/FSH ratio (Dunaif et al, 1985).
Leptin and reproduction
Among the humoral signals which possibly inform
the reproductive axis about nutritional status, leptin
is currently emerging as a convincing candidate.
Leptin is a recently identified 16 kDa proteic
hormone synthesized and secreted by mature adipocytes (Zhang et al, 1994), and serves as an
indicator of fat stores to the brain. Leptin receptor
was first cloned in 1995 (Tartaglia et al, 1995), and
several splice variants have since been identified
(Wang et al, 1996). In response to leptin stimulation, the hypothalamic areas involved in energy
homeostasis increase basal metabolism and
decrease appetite (Halaas et al, 1995; Weigle
etal, 1995).
Interestingly, rodents harbouring mutations in
the leptin gene (ob/ob mice) or in the leptinreceptor gene (db/db mice and fa/fa rat) exhibit
both obesity and infertility (Swerdloff et al, 1978;
Garris et al, 1986). In the leptin-deficient female
ob/ob mice, treatment with leptin produces a significant weight loss, increases serum concentrations
of LH and ovarian and uterine weight in comparison with pair-fed controls (Barash et al, 1996),
and restores fertility (Chehab et al, 1996). Similarly, the correction of the starvation-induced fall
in serum leptin concentration with exogenous leptin
corrects the starvation-induced changes in the
reproductive function in mice (Ahima et al, 1996).
Since rodent hypothalamus expresses the leptin
receptor gene (Mercer et al, 1996; Schwartz et al,
1996), the leptin-induced rise in gonadotrophins
probably proceeds from an effect on the reproductive neuroendocrine system. Direct action by leptin
on the ovary has also been demonstrated in rat
ovarian granulosa cells, where leptin counteracts
the synergistic effect of IGF-I on FSH-stimulated
oestradiol production (Zachow and Magoffin,
1997).
In the human, the leptin receptor gene is
expressed in the hypothalamus (Considine et al,
1996) and ovary (Cioffi et al, 1996), raising the
possibility of a direct effect of leptin on follicular
development. In non-PCOS subjects, leptin concentrations seem mainly to be explained by total fat
mass, gender and age (Ostlund et al, 1996), while
other parameters such as insulinaemia, insulin
sensitivity, and visceral fat appear to be dependent
factors (Dua et al, 1996; Kohrt et al, 1996;
Ostlund et al, 1996). However, 29% of PCOS
women have leptin concentrations higher than
expected according to their body mass index (BMI)
(Brzechffa et al, 1996). The hypotheses raised by
this observation include resistance to leptin action,
excessive insulin-stimulated leptin production, or
decreased metabolic clearance of leptin. Additional
experiments will have to be carried out in order to
establish fully the role of leptin in reproductive
endocrinology.
Endocrine profile of obese PCOS patients
Hyperandrogenism and a high LH/FSH ratio are
common biological features of PCOS (Koskinen
et al, 1996), and gonadotrophin and androgen
concentrations are similar in both lean and obese
PCOS patients (Pekonen et al, 1989; Rajkhowa
et al, 1994; Titinen et al, 1995). Hyperinsulinaemia and insulin resistance, usually associated
89
F.Galtier-Dereure et al.
with obesity, have been described even in lean
PCOS women (Burghen et al, 1980; Chang et al,
1983; Pasquali et al, 1983), but are amplified by
weight excess. Insulin concentrations increase in
obese women, in comparison with lean PCOS
women (Burghen et al, 1980; Dunaif et al, 1988;
Rajkhowa et al, 1994). Insulin administration to
obese PCOS women alters their steroid metabolism
(Dunaif and Graf, 1989) and diazoxide-induced
suppression of serum insulin reduces their serum
testosterone concentrations (Nestler et al, 1989).
IGF-I bioactivity is also increased as a result of
decreased IGFBP-1 concentrations (Pekonen et al,
1989; Suikkari et al, 1989; Titinen et al, 1995).
Given the deleterious impact of insulin resistance
on ovarian steroidogenesis (Barbieri et al, 1988),
obese PCOS women are prone to major alterations
in spontaneous ovulation. However, the relationship between insulin resistance and the effectiveness of stimulation treatment remains
hypothetical.
Weight loss and spontaneous ovulation in
obese PCOS women
Weight loss improves spontaneous ovulation and
should be considered as the first line of therapy
proposed to obese PCOS women, prior to any
chemical treatment. Most data on the consequences
of weight loss among obese anovulatory women
are uncontrolled open studies with no control group
(Bates and Whitworth, 1982; Pasquali et al, 1989;
Hollmann et al, 1996), or with a control group
consisting in patients who failed to complete the
study programme (Kiddy et al, 1992; Clark et al,
1995). They all report an improvement in menstrual
function, as measured by the resumption of
ovulatory cycles or the incidence of pregnancy
(Table I). When hormonal characteristics are
analysed, testosterone (Bates and Whitworth, 1982;
Pasquali et al, 1989; Kiddy et al, 1992; Clark
et al, 1995) and fasting insulin concentrations
(Pasquali et al, 1989; Kiddy et al, 1992; Clark
et al, 1995) drop, while SHBG concentration
increases (Kiddy et al, 1992; Clark et al, 1995)
in relation to weight loss (Table II). In the only
report where basal insulin is unchanged, an
improvement in blood glucose and insulin response
to oral glucose load is noted (Hollmann et al,
90
1996). Those results are corroborated by a prospective controlled study (Guzick et al, 1994), in which
12 hyperandrogenic anovulatory obese women
were randomly assigned to a weight loss programme including exercise and diet, or to a waiting
list. Women in the treatment group (n = 6)
lost an average of 16.2 kg, with four resuming
spontaneous ovulation (Table I); they showed a
decline in androgens and fasting insulin concentrations, and a rise in SHBG concentration, while
gonadotrophin concentrations were not modified.
The hormonal profile remained unchanged in the
untreated group (Table II).
Response to clomiphene in obese PCOS
infertile women
When anovulation remains after weight loss, CC
is usually proposed to induce ovulation. There is
no clinical evidence that obese PCOS patients are
resistant to CC therapy, but their response to CC
is blunted. In a prospective study carried out among
158 anovulatory women, the dose of CC required
to achieve an ovulation was positively correlated
with body weight (Lobo et al, 1982). Lean PCOS
patients more often respond to a standard dose of
CC. However, the doses necessary to achieve
ovulation in obese patients, although higher, remain
within the usual dosages (=^250 mg/day for 5
days); hence, those patients cannot be considered
as non-responders (Shepard et al, 1979; Lobo
et al, 1982). In a case-control study, actual nonresponders to CC showed the same clinical characteristics (age, BMI and degree of hirsutism) as
responders, but only six patients were studied in
each group (Sir-Petermann et al, 1990).
Hormonal characteristics of CC resistant
women
The difficulty in establishing a link between obesity
and CC resistance in PCOS patients might be
explained by an heterogeneity within the different
groups studied. An increase in body weight encompasses different metabolic situations (increased fatfree mass, excessive subcutaneous fat, excessive
visceral fat). CC resistance in women with PCOS
might be related to insulin resistance rather than
to obesity itself. This hypothesis was evaluated by
Obesity and stimulation in polycystic ovaries
Table I. Clinical consequences of weight loss among anovulatory obese women
Reference
Included patients
n
Weight loss
Spontaneous
ovulation (n)
Spontaneous
pregnancy (n)
Bates et al., 1982
Pasquali et al., 1989
obese PCOS
obese
hyperandrogenic
amenorrhoeic
obese PCOS
18
> 15% in 13 subjects
NA
10/18
20
9.0 ± 3.1 kg
18/20
4/20
24
(13 complete)
> 5% in 13 subjects
11/13*
NA
6
6
18
(13 complete)
16.2 kg
unchanged
6.3 ± 4.2 kg
in 13 subjects
4/6
1/6
0
0
12/13
5/13
35
10.2 ± 7.9 kg
NA
10/35
Kiddy et al, 1992
Guzick et al, 1994
patients
controls
Clarke? al, 1995
Hollmannef a/., 1996
obese
hyperandrogenic
anovulating
obese
anovulating
CC resistant
obese with menstrual
dysfunction
*Two patients were ovulating before diet programme; NA = not available.
Table II. Biological modifications related to weight loss among anovulatory obese women
Reference
LH
total T
freeT
SHBG
fasting insulin
Bates etal, 1982
Pasquali et al, 1989
Kiddy et al, 1992
Guzick et al, 1994
patients
controls
Clark etal, 1995
Hollmann et al, 1996
NA
decreased
unchanged
decreased
decreased
NA
NA
unchanged
decreased
NA
NA
increased
NA
decreased
decreased
unchanged
unchanged
unchanged
unchanged
decreased
unchanged
decreased
unchanged
decreased
unchanged
NA
NA
increased
unchanged
increased
NA
decreased
unchanged
decreased
unchanged
T = testosterone: NA == not available.
Venturini et al. (1993), who conducted an oral
glucose tolerance test (OGTT) in 10 women showing constant resistance to a daily CC dose of 250
mg over 5 days. No association was found between
resistance to CC and altered glucose metabolism.
However, in a recent prospective study, insulin,
IGF-I and IGFBP-1 were measured fasting and
after OGTT in 23 PCOS women, 10 of whom
unresponsive to a daily CC dose of 200 mg for 5
days. The IGFBP-1 concentrations were lower in
lean CC non-responders than in lean CC responders
(Titinen et al, 1995), but were constantly low in
obese patients regardless of CC response. In the
same study, no significant difference was reported
in IGF-I and insulin concentrations between
responders and non-responders to CC treatment.
Therefore there is no consistent data definitely
establishing a link between resistance to CC and
glucose metabolism disorders.
Endogenous gonadotrophins, basal LH and FSH
concentrations, as well as the LH to FSH ratio, are
all similar both in responders and non-responders to
CC treatment (Lobo et al, 1982; Prough et al,
1990; Sir-Petermann et al, 1990; Titinen et al,
1995). However, modifications in the pulsatile
pattern of LH have been described in non-responders. LH pulse amplitude and transverse LH mean
concentration are higher in CC-resistant women
(Sir-Petermann et al, 1990) and response rates are
poor in women exhibiting a high frequency of LH
pulses (Morishita et al, 1987).
Testosterone, oestradiol and SHBG concentrations are unable to predict accurately CC responsiveness (Lobo et al, 1982; Titinen et al, 1995).
91
F.Galtier-Dereure et al.
Table III. Biological predictors of clomiphene responsiveness in polycystic ovary syndrome (PCOS)
Possible predicting factors
Non-predicting factors
IGF-BP-P (Titinen et al, 1995)
Pulsatile LH pattern (Morishita et al, 1987;
Sir-Petermann et al., 1990)
DHEASb (Hoffman et al, 1985)
Oral glucose tolerance test (Venturini et al,
Insulin (Titinen et al, 1995)
IGF-I (Titinen et al, 1995)
Basal LH (Lobo et al, 1982; Prough et al,
LH/FSH ratio (Lobo et al, 1982; Prough et
Basal Testosterone, E2, SHBG (Lobo et al,
1993)
1990; Titinen et al, 1995)
al, 1990; Titinen et al, 1995)
1982; Titinen et al, 1995)
''Only in lean PCOS; bOnly if serum dehydroepiandrostendione sulphate (DHEAS) >5 (Xg/ml.
A decreased response rate to CC treatment was
described in patients exhibiting very high serum
dehydroepiandrostendione sulphate (DHEAS) concentrations (>5 |Lig/ml), compared with patients
with moderately high or normal DHEAS concentrations (response rate, 55 versus 83 and 78% respectively) (Hoffman and Lobo, 1985). However, there
was no linear correlation between the ovulating
CC dose and DHEAS concentration.
Finally, there is no clinical nor routine biological
data reliably predicting response to CC, either in
lean or in obese PCOS women (Table III). Ovulation induction attempts with increasing dosages of
CC are therefore fully justified in this group
of patients.
rapidly until the response threshold is reached.
Even moderately overweight women (BMI 25-28)
need a gonadotrophin dose 50% higher than normal
weight women (Franks and Hamilton-Fairley,
1994). In this latter study, the FSH concentration
during HMG treatment was higher in overweight
women, suggesting that the relative HMG resistance is not the result of a decreased biodisponibility.
In a retrospective analysis of PCOS women undergoing a step-up gonadotrophin treatment, BMI was
the only factor that significantly influenced cycle
outcome. Overall, the cumulative pregnancy rate
was 57 versus 46.8% in overweight women, with
cancellation rates of 15 and 31% respectively
(White et al, 1996).
Response to gonadotrophins in obese PCOS
infertile women
Patients who fail to ovulate with CC are candidates
for gonadotrophin therapy. In non-PCOS patients,
the response to gonadotrophin-induced ovulation
induction is inversely related to BMI (Chong et al,
1986; Crosignani et al, 1994). Obese women with
PCOS also require higher doses of gonadotrophin
than their lean counterparts. McClure et al (1992)
reported on 224 human menopausal gonadotrophin
(HMG)-stimulated cycles among 71 infertile
women with PCOS. The dose of HMG required
to achieve ovulation was significantly correlated
with both weight and BMI. However, although a
majority of obese women finally required a higher
HMG regimen, the cycle had to be cancelled in
four of them because of over-response. Modifying
the usual starting dose of HMG for obese PCOS
women appears therefore unjustified, but in case
of slow response, the daily dose may be increased
Response to GnRH in obese infertile PCOS
patients
Since the initial report of successful induction of
ovulation and pregnancies with pulsatile GnRH
administration in hypothalamic amenorrhoeic
women (Leyendecker et al, 1980), this treatment
has been increasingly proposed for different ovulation disorders. The sensitivity to pulsatile GnRH
appears to be altered in obesity (Molloy et al,
1985; Filicori et al, 1994) and could be related to
endocrine abnormalities, such as hyperinsulinaemia, high LH and testosterone concentrations
(Filicori et al, 1994). In PCOS women resistant
to CC, obesity also reduces the effectivenes of
pulsatile GnRH to achieve follicular growth
(Bringer et al, 1985). In association with overweight, hypertestosteronaemia and high LH concentrations are also related to a poorer efficiency
of pulsatile GnRH treatment (Eshel et al, 1988).
Therefore, contrary to lean PCOS women in whom
92
Obesity and stimulation in polycystic ovaries
obese
PCOS
lean
PCOS
1
i
Weight loss
programme
J
CC treatment
(usual dosage, increase if necessary)
Gonadotropin:
- step-up
- rapid increase
if no response
Gonadotropin:
- step-up
- low increments
pulsatile GnRH
after pituitary
suppression
Figure 1. Management of ovulation induction in patients with polycystic ovary syndrome (PCOS) according to their weight.
a satisfactory ovulation rate could be expected,
obese PCOS women are unsuitable for treatment
with pulsatile GnRH.
Weight and ovarian electrocautery
The surgical approach to women with PCOS is
sometimes useful in cases of resistance to chemical
treatments. The influence of weight on the results of
ovarian electrocautery is controversial. Gjonnaess
(1994) reported a response rate of 96-97% in the
lean and moderately obese women, decreasing to
70% in obese women, while for Farhi et al. (1995),
the BMI is similar between responders and nonresponders to electrocautery.
Conclusions
In view of the foregoing, a therapeutic management
of ovulation induction in PCOS patients is proposed
in Figure 1. PCOS constitutes an heterogenous
disease in terms of phenotype, endocrine abnormalities and response to stimulation. Since PCOS
patients are globally hyper-responsive to the different stimulation treatments, a hyperstimulation syn-
drome is one of the major risks in stimulated
cycles. On the other hand, a subgroup of PCOS
women are resistant to clomiphene citrate, less
responsive to gonadotrophins and pulsatile GnRH,
and will ensuingly require high drugs dosages to
ovulate. If this resistance could be accurately
predicted, increasing the starting therapeutic doses
would be justified. However, neither clinical nor
biological parameters allow the practitioner to tell
apart hyper-responders and hypo-responders in this
disease, although a decreased efficiency of the
different treatments may be expected in obese
women. It must be emphasized that weight loss
will improve the prognosis either of spontaneous
or stimulated ovulation, as well as that of the
possibly resulting pregnancy. There is little doubt
that a correct subclassification of PCOS patients
might help in understanding their various sensitivities to the different therapeutic approaches.
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