Restoration of Reproductive Potential by Lifestyle Modification in Obese Polycystic Ovary Syndrome: Role of Insulin Sensitivity and Luteinizing Hormone1
M.-M. Huber-Buchholz,
D. G. P. Carey and
R. J. Norman
Reproductive Medicine Unit, University of Adelaide, Queen Elizabeth
Hospital, Woodville, South Australia 5011; and the Department of
Diabetes and Endocrinology, Princess Alexandra Hospital, Brisbane,
Queensland 4102, Australia
Address all correspondence and requests for reprints to: Prof. R. J. Norman, Reproductive Medicine Unit, University of Adelaide, Queen Elizabeth Hospital, 23 Woodville Road, Woodville, South Australia 5011, Australia. E-mail: rnorman{at}medicine.adelaide.edu.au
Weight reduction and exercise have been shown to help with menstrual
disturbanceand infertility in obese women with polycystic ovary
syndrome.We studied the relationship between insulin sensitivity and
ovulationpatterns in 18 infertile anovulatory obese polycystic ovary
syndrome(PCOS) women (NO) with normal glucose tolerance, aged between
22–39yr with a body mass index of 27–45 kg/m2, before
and aftera 6-month diet and exercise program. This program promotes
healthylifestyle factors, but does not lead to rapid weight loss. The
anthropometric,metabolic, and endocrine factors of these subjects were
comparedto those of 10 age- and weight-matched PCOS women with regular
monthlyovulation (RO).
Before lifestyle modification, the anovulatory subjects hadgreater
central obesity than regular ovulators, as assessedby percent central
fat (NO, 45.7 ± 0.8%; RO, 42.2 ±1.6%;
P < 0.05), higher glucose increment after glucose
challenge(NO, 10.1 ± 1.0 mmol/L; RO, 6.4 ± 1.1 mmol/L;
P< 0.02), lower insulin sensitivity index (NO,
1.2 ±0.2; RO, 2.8 ± 0.6 µmol/kg·min/pmol/L;
P< 0.005), higher plasma LH (NO, 8.9 ± 0.9;
RO, 4.6± 0.9 IU/L; P < 0.005), and lower
plasma sex hormone-bindingglobulin (NO, 18.0 ± 2.5; RO,
27.8 ± 5.7 nmol/L;P < 0.05].
Anovulatory subjects were classified as responders (R) to the
interventionif they regained ovulation during the study. As a result
ofintervention, R showed an 11% reduction in central fat, a 71%
improvementin insulin sensitivity index, a 33% fall in fasting
insulinlevels, and a 39% reduction in LH levels. None of these
parameterschanged significantly in nonresponders (NR). At the end of
thestudy, R had lower fasting insulin (R, 13.6 ± 1.7; NR,
23.0± 3.5 mU/L) and LH levels (R,5.0 ± 1.7; NR, 7.4
±1.4 IU/L), but similar androgen levels compared to NR.
We conclude that lifestyle modification without rapid weightloss leads
to a reduction of central fat and improved insulinsensitivity, which
restores ovulation in overweight infertilewomen with PCOS. Lifestyle
modification is the best initialmanagement for obese women seeking to
improve their reproductivefunction.
IN WESTERN countries, up to 40% of
all women are overweight(1). These women often have a decreased
reproductive potential,as evidenced by menstrual disturbances,
anovulation, time toconception, poor response to ovulation induction,
and reducedpregnancy outcome (2, 3, 4, 5, 6). Where obesity and polycystic
ovarysyndrome (PCOS) are present, there is a higher prevalence of
insulinresistance and hyperinsulinemia together with raised LH levels
(7,8). Insulin and LH appear to be key hormones in the stimulationof
androgen production by the ovary. The hormone leptin is alsoincreased
in obesity (9) and, although not increased specificallyin PCOS (10, 11), is thought to have an action on the ovary(12).
Several studies show that acute weight reduction induced bylow calorie
diets improves hyperandrogenemia, insulin resistance,and menstrual
function (4, 13, 14). Weight loss is, however,rarely sustained. We
have recently shown that alteration indiet combined with exercise
leads to ovulation within weeks,with long term restoration of
reproductive potential and ultimatelysustained weight loss (15, 16).
Surprisingly, this occurredwith minimal weight loss, an observation
seen by others (17,18).
The aim of this prospective study was to investigate the relationship
betweenchanges in insulin sensitivity, LH, and ovulation patterns
afterlifestyle modification in overweight women who were trying to
becomepregnant or restore menstrual regularity. We examined the
hypothesisthat changes in exercise pattern and sensible eating in
obeseand anovulatory women lead to an improvement in insulin
sensitivity,resulting in a decrease in LH and consequently a rise in
ovulationrates and pregnancy.
Eighteen healthy overweight-obese women [body mass index (BMI),
27–45kg/m2], with a history of irregular menstrual
cycles of morethan 35 days for more than 12 months were enrolled from
hospitalinfertility clinics. Subjects were between 22–39 yr ofage,
were nonsmokers, were taking no medications, had a normalglucose
response to a 75-g oral glucose tolerance test, andhad no endocrine
disease or medical conditions that would havecompromised participation
in a diet and/or exercise program.Ten obese women without menstrual
irregularities or hirsutismbut with polycystic ovaries on ultrasound
were enrolled as acontrol group. Fifteen anovulatory and six control
subjectsfully completed the study (Fig. 1). Some women participatedin the study
to become pregnant and others only to improve theirmenstrual
cycles.
Figure 1. Numbers of patients in each component of the
study.
All participants underwent a 2-month observation period to confirm
theirovulatory status. During this time, hormone analysis,
anthropometry,and ultrasound were performed. The occurrence of
ovulation wasdetermined by assessment of urinary pregnanediol
glucuronideand total urinary estrogens twice weekly. All had
polycysticovaries (PCO) defined on ultrasound scanning. PCOS was
definedas the presence of PCO with clinical or biochemical
hyperandrogenism,menstrual irregularity, or hirsutism in the absence
of othercauses of anovulation. The study was approved by the
institutionalethics committee.
After an initial evaluation, subjects received either a groupor an
individual diet and exercise counselling and support for6 months as
described previously (15, 19). During the study,body composition was
measured by dual energy x-ray absorptiometry(DEXA) at 0, 12, and 24
weeks; waist and hip circumference wasmeasured monthly; weighing
occurred weekly. BMI was calculated(kilograms per m2), and
waist circumference was measured atthe smallest part of the waist.
Central abdominal fat (L2–L4)was assessed by using DEXA (Lunar Corp., Madison, WI) afterexclusion of pregnancy (20).
Glucose tolerance [75-g 2-h oral glucose tolerance test with30-min
sampling and calculation of the area under the curve(AUC)] was
assessed at 0 and 24 weeks, and insulin sensitivitywas determined at
0, 8, 16, and 24 weeks by the euglycemic hyperinsulinemicclamp
technique (100 m/U/kg·h Actapid Human, Novo Nordik,Copenhagen,
Denmark). Euglycemia (4.5 mmol/L) was maintainedwith a 25% variable
glucose infusion rate. The insulin sensitivityindex (ISI) was
calculated by dividing the glucose infusionrate by the mean clamp
insulin during the last 40 min of theclamp. Women were studied in the
follicular phase of the cycleor when there was no obvious ovarian
activity.
Blood samples were taken every 4 weeks for LH, fasting insulin
(FI),androstenedione, testosterone, dehydroepiandrosterone sulfate,17
hydroxyprogesterone, progesterone, estradiol, sex hormone-binding
globulin(SHBG), FSH, and leptin. Hormones were measured as described
previously(10, 21, 22). LH was measured using the mean of three
samplestaken within 20 min.
Women were classified as having ovulated on the basis of their
menstrualhistory in relation to urine concentrations of total urinary
estrogensand urinary pregnanediol glucuronide (St. Patrick’s Natural
FamilyPlanning, Melbourne, Australia). The clinical responsivenessto
the program was evaluated by comparing the frequency of ovulationafter
the treatment period with that before treatment. All comparisonsbefore
and after intervention between group means were performedwith ANOVA
factorial for variables normally distributed beforeand after log
transformation. Bonferroni-Dunn corrections andFisher’s protected
least significant differences post-hoctest for multiple
comparisons were performed. Data was expressedas the mean ±
SEM.
Changes in individual parameters over time were studied in eachsubject
using repeated measures ANOVA. An autogressive errorstructure was
assumed, and a significance value of P < 0.01adopted
to overcome the number of tests of significance.
Comparison of ovulatory and anovulatory subjects (Table 1a)
There were no statistically significant baseline differencesin
most parameters. The nonovulatory (NO) group, however, hadhigher
central abdominal fat, higher glucose AUC, lower ISI,higher LH
and free testosterone index, and lower SHBG levels(Figure 2).
Figure 2. Insulin sensitivity (a; micromoles per
kg/min·pmol/L) and central fat (b; percentage) at the start and end
of the program.
Ovulation and pregnancy rates vs. metabolic changes (Table 1b
and Fig. 2)
Nine of the NO women responded to the program with regular
ovulation,and two of these women became pregnant. All of the regularly
ovulating(RO) subjects continued to ovulate regularly during the
study;however, none became pregnant. There was no significant
metabolicor endocrine baseline difference between responders (R) and
nonresponders(NR) at the commencement. Mean weight loss was between
2–5%of starting weight over the program. At the end of the study,
therewas a significant difference in waist circumference betweenthe
groups, with R having a statistically significant reducedwaist girth
and central abdominal fat and improved ISI, lowerFI, and lower LH
levels. Leptin, testosterone, free testosterone,and SHBG levels did
not differ between groups. R had a 71% improvementin ISI
(P < 0.05), a 33% decrease in FI (P
< 0.05), anda 39% decrease in LH (P < 0.05). NR had
no significant improvementsin ISI (10%), FI, or LH. There was a 34%
improvement in ISIin the control group, but this was not statistically
significant.Using repeated measures of variance over the 6 months with
variablesof central fat, FI, SHBG, leptin, and androgens, ovulation
statusat the time of measurement was not a significant predictor for
changesin the variables, whereas central fat, FI, and leptin were
positivelyassociated with body mass index, and ISI was negatively
associated.Figure 3 shows the change
over time for waist circumference,central fat, ISI, and FI, with
differences among RO, R, andNR values over the 6 months. ISI increased
in R and NR, butwas statistically more marked in R than NR. This was
even morepronounced for FI. Both groups showed marked, but parallel,
reductionsin LH over time, with no significant difference in the slope
ofdecrease.
Figure 3. Changes in waist (centimeters), central fat
(percentage), ISI (micromoles per kg/min·pmol/L), and fasting insulin
(U/l x 10-3) over the course of the study. , RO; ,
R; , NR.
Eight controls and eight anovulatory subjects at commencementwere
matched for BMI (RO, 36.4 ± 1.7; NO, 36.7 ±1.6
kg/m2). LH values (RO, 4.1 ± 0.9; NO, 9.1 ±0.9
IU/L) and testosterone values (RO, 1.5 ± 0.3; NO,2.8 ± 0.4
nmol/L) were significantly higher in the NOwomen, whereas ISI values
(RO, 2.5 ± 0.6; NO, 1.5 ±2 µmol/kg·min/pmol/L) were
lower. Four RO, fourR, and three NR were matched for identical BMI
values at theend of the study. The following values were significantly
differentby ANOVA: waist circumference, central fat, AUC glucose, ISI,
andFI. In all cases the differences were in the NR group.
The results of this study support the hypothesis that it is
possibleto improve insulin sensitivity and, in turn, restore normal
menstrualfunction and fertility in obese women with PCOS. By using a
lifestyleprogram that sets realistic weight loss and exercise goals,
subjectswere able to sustain an improvement in carbohydrate metabolism
overa 6-month period and hence improve their likelihood of pregnancy.
Althoughweight loss as a percentage of body weight was small, a 70%
improvementin ISI was obtained, and this was associated with the
returnof reproductive function.
In this study, ISI at commencement correlated well with central
fat,waist circumference, and FI. The ISI was significantly different
betweenRO and NO at the start of the study. Correction for BMI didnot
eliminate differences in ISI. LH levels were also higherin NO than RO,
again with BMI standardization. These observationsconfirm the presence
of insulin resistance in PCOS (8, 23, 24)and the observation of higher
concentrations of immunologically(and probably bioactive) LH in
anovulatory PCOS. Nine womenestablished regular ovulation, and two
became pregnant duringthe 6 months. In all cases of regular ovulation
occurring inprevious NO women, ISI and FI showed significant
improvementspreceding ovulation.
Previous studies have recommended weight loss as an effective
methodof inducing ovulation in obese women with menstrual disturbances
(15,17, 25, 26, 27), but there have been few studies that have attempted
toexplain the mechanism of the return of ovulation or have used
sustainablediet and exercise programs. Low calorie, short dietary
restrictionleads to a decrease in free testosterone and FI and an
increasein insulin growth factor-binding protein-1 and SHBG (6, 26),
butthese diets are associated with a poor compliance rate overthe
long term, with little maintenance of weight loss. In ourprevious
study (15), the average weight loss was only 6.3 kg,which was a small
percentage (<10%) of the starting weight.Despite this, 12 of 13
subjects resumed ovulation, and 11 becamepregnant. Hollmann et
al. (17) reported a weight loss of lessthan 10% with menstrual
period improvement in 80% and pregnancyin 29%. These are relatively
small weight losses and are notcomparable to the results of the
studies where short term caloricrestriction over several weeks has
been practiced with subsequentinduction of ketosis. Our results
emphasize that large changesin fasting insulin and ISI can be induced
in a group of womenin whom unimpressive changes in weight resulted,
but increaseduse of exercise and sensible eating patterns achieved
metabolicchanges sufficient to alter reproductive function.
Redistributionof body fat may be important, as shown by the DEXA
results,indicating that central fat is correlated with the likelihood
ofincreased insulin sensitivity and restored ovarian function.The
loss of a small volume of critical intraabdominal fat, whichmay be
only a small percentage of the total body fat may explainthese
results. In addition, calorie restriction may lower lipidavailability
and improve sensitivity independent of changesin body composition.
Arroyo et al. (28) have recently shown that
interpretation ofLH levels in subjects with PCOS should take BMI into
account.They found that BMI negatively influences LH pulse amplitude
inPCOS women principally by an effect at the pituitary. In ourstudy,
however, a high LH value was predictive of anovulationand was
independent of BMI either at the start or the end ofthe study.
Accelerated LH pulse frequency in PCOS women is notinfluenced by BMI,
but is a basic component of hypothalamicdysfunction in PCOS. In the
current study, there were no significantchanges in leptin values
between RO and NO women either beforeor after intervention. This
confirms many studies showing thatleptin values are related to body
mass and fat rather than toovulatory status or PCOS per se
(10, 11). Although the exactrole of leptin in ovarian physiology
remains unclear, the changesin ovulation seen in this study cannot be
explained by an alterationin circulating leptin.
In summary, our results indicate that lifestyle modificationthrough
exercise and sensible eating patterns can lead to improvedreproductive
function. These changes occurred with minimal weightloss, which is
encouraging for women who have constantly failedto achieve
reproductive success on a variety of short term lowcalorie diets.
Changes in insulin sensitivity and falling seruminsulin values may be
the metabolic mediator of these results.
Acknowledgments
We thank Drs. X. J. Wang and P. Leppard for statistical
advice,and Dr. Anne Clark for advice in running the program.
Footnotes
1 This work was supported by the Swiss National Foundation, the
Ciba-GeigyJubilee Foundation (Switzerland), the
University of AdelaideReproductive Medicine Unit, and the Queen
Elizabeth ResearchFoundation.
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T. Bridger, S. MacDonald, F. Baltzer, and C. Rodd Randomized Placebo-Controlled Trial of Metformin for Adolescents With Polycystic Ovary Syndrome
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T. Tang, J. Glanville, C. J. Hayden, D. White, J. H. Barth, and A. H. Balen Combined lifestyle modification and metformin in obese patients with polycystic ovary syndrome. A randomized, placebo-controlled, double-blind multicentre study
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D.H. Abbott, D.K. Barnett, C.M. Bruns, and D.A. Dumesic Androgen excess fetal programming of female reproduction: a developmental aetiology for polycystic ovary syndrome?
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R. V. Mehta, K. S. Patel, M. S. Coffler, M. H. Dahan, R. Y. Yoo, J. S. Archer, P. J. Malcom, and R. J. Chang Luteinizing Hormone Secretion Is Not Influenced by Insulin Infusion in Women with Polycystic Ovary Syndrome Despite Improved Insulin Sensitivity during Pioglitazone Treatment
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V. Jayagopal, E. S. Kilpatrick, S. Holding, P. E. Jennings, and S. L. Atkin Orlistat Is as Beneficial as Metformin in the Treatment of Polycystic Ovarian Syndrome
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L. J. Moran, M. Noakes, P. M. Clifton, G. A. Wittert, L. Tomlinson, C. Galletly, N. D. Luscombe, and R. J. Norman Ghrelin and Measures of Satiety Are Altered in Polycystic Ovary Syndrome But Not Differentially Affected by Diet Composition
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R. J. Norman, M. Noakes, R. Wu, M. J. Davies, L. Moran, and J. X. Wang Improving reproductive performance in overweight/obese women with effective weight management
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S. E. Kasim-Karakas, R. U. Almario, L. Gregory, R. Wong, H. Todd, and B. L. Lasley Metabolic and Endocrine Effects of a Polyunsaturated Fatty Acid-Rich Diet in Polycystic Ovary Syndrome
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The Rotterdam ESHRE/ASRM-sponsored PCOS consensus Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS)
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M. S. Coffler, K. Patel, M. H. Dahan, R. Y. Yoo, P. J. Malcom, and R. J. Chang Enhanced Granulosa Cell Responsiveness to Follicle-Stimulating Hormone during Insulin Infusion in Women with Polycystic Ovary Syndrome Treated with Pioglitazone
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K. Patel, M. S. Coffler, M. H. Dahan, R. Y. Yoo, M. A. Lawson, P. J. Malcom, and R. J. Chang Increased Luteinizing Hormone Secretion in Women with Polycystic Ovary Syndrome Is Unaltered by Prolonged Insulin Infusion
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V. De Leo, A. la Marca, and F. Petraglia Insulin-Lowering Agents in the Management of Polycystic Ovary Syndrome
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J. L. Sharpless Polycystic Ovary Syndrome and the Metabolic Syndrome
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L. Harborne, R. Fleming, H. Lyall, N. Sattar, and J. Norman Metformin or Antiandrogen in the Treatment of Hirsutism in Polycystic Ovary Syndrome
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P. G. Crosignani, M. Colombo, W. Vegetti, E. Somigliana, A. Gessati, and G. Ragni Overweight and obese anovulatory patients with polycystic ovaries: parallel improvements in anthropometric indices, ovarian physiology and fertility rate induced by diet
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L. J. Moran, M. Noakes, P. M. Clifton, L. Tomlinson, and R. J. Norman Dietary Composition in Restoring Reproductive and Metabolic Physiology in Overweight Women with Polycystic Ovary Syndrome
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T. Hickey, A. Chandy, and R. J. Norman The Androgen Receptor CAG Repeat Polymorphism and X-Chromosome Inactivation in Australian Caucasian Women with Infertility Related to Polycystic Ovary Syndrome
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T. Sir-Petermann, S.E. Recabarren, A. Lobos, M. Maliqueo, and L. Wildt Secretory pattern of leptin and LH during lactational amenorrhoea in breastfeeding normal and polycystic ovarian syndrome women
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T. L. Butzow, M. Lehtovirta, R. Siegberg, O. Hovatta, R. Koistinen, M. Seppala, and D. Apter The Decrease in Luteinizing Hormone Secretion in Response to Weight Reduction Is Inversely Related to the Severity of Insulin Resistance in Overweight Women
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[Abstract][Full Text]
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Abstract
Introduction
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