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Original Articles |
Departments of Obstetrics and Gynecology (J.H., G.G.), Clinical Chemistry (L.W.), Geriatrics (H.L.), and Internal Medicine (C.B.), Uppsala University, S-751 85 Uppsala, Sweden
Address all correspondence and requests for reprints to: Dr. Jan Holte, Department of Obstetrics and Gynecology, Akademiska Hospital, Uppsala University, S-751 85 Uppsala, Sweden.
Abstract
The prevalence of polycystic ovaries, according to ultrasonography, and associated clinical, endocrine, and metabolic features were investigated in women with previous gestational diabetes mellitus (GDM). Thirty-four women with GDM 3–5 yr before the investigation and 36 controls with uncomplicated pregnancies, selected for similar age, parity, and date of delivery, were investigated. The women with previous GDM showed a higher prevalence of polycystic ovaries [14 of 34 (41%) vs. 1 of 36 (3%); P < 0.0001], hirsutism (P < 0.01), irregular menstrual cycles (P < 0.01), and a higher body mass index (BMI; P < 0.001) than the controls. Five women (15%) with previous GDM had developed manifest diabetes (excluded in comparisons of metabolic variables). After dividing the women with previous GDM into subgroups according to ovarian appearance, the 2 subgroups showed similar glucose tolerance and prevalence of diabetes, whereas the women with polycystic ovaries were younger (mean ± SD, 33.3 ± 1.4 vs. 38.2 ± 1.1; P < 0.01), had higher truncal-abdominal/femoral fat ratio according to skin folds (P < 0.05), had higher concentrations of androstenedione (P < 0.01) and testosterone (P < 0.01), and had a higher LH/FSH ratio (P < 0.01), lower levels of GH (P < 0.01), higher levels of triglycerides (P < 0.05) and cholesterol (P < 0.05) in very low density lipoprotein, all independent of age and BMI, and had a higher prevalence of pregnancy-induced hypertension (50% vs. 15%; P < 0.05) during the index pregnancy compared with the women with normal ovaries.
The group of women with GDM showed a lower early insulin release after glucose (iv glucose tolerance test) for their degree of insulin resistance (euglycemic hyperinsulinemic clamp) compared with controls (P < 0.05). In the two subgroups, insulin sensitivity was lower in the polycystic ovaries group, independent of BMI (P < 0.05), than in the group with normal ovaries.
In conclusion, ultrasonographic, clinical and endocrine signs of polycystic ovary syndrome were much increased in women with a history of GDM. Compared with the women with normal ovaries and previous GDM, those with polycystic ovaries formed a distinct subgroup that may be more prone to develop various features of the insulin resistance syndrome. Both groups showed a similarly disturbed balance between ß-cell activity and insulin sensitivity, but in women with polycystic ovaries, insulin resistance may be the dominant component.
GESTATIONAL diabetes mellitus (GDM), defined as diabetes or impaired glucose tolerance with onset in pregnancy (1), complicates 0.2–8% of pregnancies, the great variation largely depending on variations in ethnic background and diagnostic criteria (2, 3, 4). GDM is a strong risk factor for noninsulin-dependent diabetes (NIDDM) (4, 5). The pathogenetic mechanisms underlying GDM involve an imbalance between the capacity of the pancreatic ß-cells and the increased demands for insulin due to decreased insulin sensitivity during pregnancy (5, 6, 7, 8, 9). Women with reduced insulin sensitivity or impaired ß-cell function in the nonpregnant state are thus highly susceptible to develop GDM.
A high prevalence of insulin resistance and abnormal ß-cell function is found in women with polycystic ovary syndrome (PCOS) (10, 11, 12, 13, 14, 15), with a substantial portion of the patients exhibiting impaired glucose tolerance and NIDDM at a young age (11, 14). Despite these aberrations of carbohydrate metabolism in PCOS, and although polycystic ovaries are found in more than 20% of premenopausal women (16, 17), a possible association with GDM has not been extensively studied. A familial association of PCOS, severe insulin resistance, and GDM has been reported (18), and two recent studies either found (19) or did not find (20) an increased prevalence of GDM in women with a diagnosis of PCOS.
The primary aim of the present study was to investigate whether the prevalence of polycystic ovaries, investigated by means of ultrasonography, and the frequency of associated clinical, anthropometric, and endocrine features were increased in women with a previous pregnancy complicated by GDM compared with those in women with a previous uncomplicated pregnancy. Second, if a substantial number of women with polycystic ovaries were found in the GDM group, the intention was to compare these women with the other women with previous GDM to evaluate whether these groups would show distinct and separate features.
Materials and Methods
General design
Women with GDM 3–5 yr earlier were offered a follow-up study, including clinical, ultrasound, endocrine, and metabolic investigations. The results were compared with those of a group of control women with previous uncomplicated pregnancies and matched for age and delivery date. Second, at the data analysis a subgrouping of the women with previous GDM was performed so that all variables were compared between those with polycystic ovaries and those with normal ovaries.
Patients and controls
All women who were diagnosed with GDM and delivered at the Department of Obstetrics and Gynecology, Akademiska Hospital (Uppsala, Sweden), during a 3-yr period 3–5 yr before the investigation were contacted. The diagnosis of GDM was based on a 2-h blood glucose level of 8.0 mmol/L or more after a 75-g oral glucose tolerance test during the third trimester. Thirty-four women of a total of 45 (76%) with previous GDM agreed to participate in the investigation. Control women were recruited in the following manner. For every patient with a previous GDM, 2 women with previous uncomplicated pregnancies and matched for age and delivery date to the GDM patient were offered the same investigations as the GDM patients. Women with pregnancy complicated by hypertension were not included as controls, as an association between hypertension and insulin resistance has been reported both in nonpregnant subjects (21, 22) and during pregnancy (23). Thirty-five women (52% of those who were offered the investigation) agreed to participate as controls. The medical history and the clinical characteristics (attained from medical charts) of the index pregnancy did not differ between the women who accepted and those who declined the offer to take part in the investigation. In addition, telephone interviews with the latter women revealed no differences in the frequency of symptoms generally associated with the polycystic ovary syndrome (excess body hair, acne, irregular menstrual cycles, and obesity) compared with that in the corresponding groups of the women who participated in the study.
Medical history
Data from the index pregnancies were attained from the medical
records of the women. Apart from data such as length of gestation,
birth weight of the offspring, etc., results from third
trimester oral or iv glucose tolerance tests, including insulin
responses by either one or both methods, were attained for the patients
with GDM (see Table 4
). The diagnosis of pregnancy-induced hypertension
(WHO criteria) was based on blood pressure recordings from the visits
to antenatal out-patient clinics. Menstrual history was obtained
through a questionnaire at the time of follow-up. Irregular menstrual
cycles were defined as menstrual intervals persistently longer than 35
days or a greater variation than 1 week from one period to the
other.
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All ultrasound examinations were performed by one operator (J.H.), either transabdominally or transvaginally (3.5- and 5-megahertz sector probe, respectively; Acuson 128/10, Acuson Corp., Mountain View, CA). Polycystic ovaries were diagnosed according to the criteria of Adams (24), i.e. 10 or more follicles/scanning plane in combination with an increase in ovarian stroma. The women were scanned on a single occasion in the follicular phase, but in a few cases an additional scan was necessary for a conclusive diagnosis of polycystic ovaries vs. normal ovaries. Hirsutism was assessed by a modified version of the protocol used by Ferriman and Gallwey (25); a woman with a score of 7 points or more was considered clinically hirsute. Anthropometric measures were performed as previously described in detail (14): height; weight with calculation of body mass index (BMI); waist and hip circumferences with calculation of waist hip ratio; skinfold measurements at subscapular, suprailiac, umbilical, and femoral sites with calculation of sums of truncal-abdominal skinfolds (umbilical, subscapular, and suprailiac); and thigh skinfolds (anterior and posterior).
Metabolic investigations
Diabetes was diagnosed according to WHO criteria (26). The iv glucose tolerance test was performed as previously described in detail (14, 22). The insulin peak was calculated as the mean value of the plasma insulin concentrations at 4, 6, and 8 min, and the insulin increment was calculated by subtracting the mean fasting plasma insulin concentrations from the peak value. The k value for the disappearance rate of glucose was calculated (22). Immunoreactive insulin and C peptide were assayed in plasma by RIA kits (Phadeseph Insulin RIA, Pharmacia, Uppsala, Sweden; RIA-gnost C-peptide, Svenska Hoechst, Stockholm, Sweden). The within-assay coefficient of variation for the insulin analysis was 4.7%, and the between-assay 6.2%. The corresponding figures for C peptide were 5% and 8%, respectively. Plasma glucose was measured by the glucose oxidase method (Beckman 2, Fullerton, CA).
The euglycemic hyperinsulinemic clamp technique was used for assessment of insulin sensitivity (27), performed as previously described in detail (14, 22). The mean plasma insulin concentration (at 120 min) was 87.0 ± 2.7 mU/L in GDM patients and 83.2 ± 3.0 mU/L in controls (P = NS). The coefficient of variation for the steady state plasma glucose concentration for a single clamp was 3.7%. The end point was the insulin sensitivity index (M/I), calculated by dividing the glucose uptake during the last 60 min of the clamp with the mean steady state insulin concentration during the same time (milligrams per kg BW/min·mU/L insulin multiplied by 100).
Lipoprotein lipid and free fatty acid assessments were performed according to previously described methods (28).
Office blood pressure recording
The woman was at rest in the supine position for 10 min before
the recording. A mercury sphygmomanometer (Kifa Ercameter, Speidel &
Keller, Jungingen, Germany; width, 12.5 cm; length, 35 cm) was used;
for obese women (arm width, 
32 cm) a larger cuff was used. Systolic
blood pressure was defined as Korotkov phase I, and diastolic pressure
was defined as phase V. The mean of three measurements 10 min apart on
one occasion was used for the analyses.
Endocrine investigation
Blood for the endocrine measurements was obtained in a standardized manner between 0730–0800 h during rest in the supine position and after 1 night of fasting. Two blood samples were drawn within 1 week, at any time in amenorrheic women and during the early follicular phase (days 1–7 of the menstrual cycle) in women with oligomenorrhea or regular menstruations. Serum levels of gonadotropins were analyzed on both of these occasions, and the mean values were used for calculations. The analyses of hormones were performed using methods previously described in detail (29). The free androgen index (FAI) was calculated from testosterone/sex hormone-binding globulin (SHBG) x 100 (30). The within- and between-assay coefficients of variation were: FSH, 2.5% and 3.6%; LH, 2.6% and 3.5%; GH, 7.3% and 8.2%; PRL, 1.6% and 3.7%; estradiol, 5.5% and 7%; testosterone, 5% and 8%; dehydroepiandrosterone sulfate (DHEA-S), 5.5% and 10%; androstenedione, 3% and 7%; and SHBG, 7% and 10%.
Statistics
The data analysis was based on the investigation of two null
hypotheses: first, that there were no differences in the prevalence of
polycystic ovaries or associated clinical, endocrine, and metabolic
features between women with previous GDM and those with a
previous uncomplicated pregnancy; and second, the same variables were
compared between the women with polycystic ovaries and the women with
normal ovaries in the GDM group. Student’s two-tailed t
test was used for comparisons of variables, which were normally
distributed either without or after log transformation, and appropriate
nonparametric tests were used for the variables that still showed a
skewed distribution after log transformation. The
2 square test was used for comparisons between
category variables. Pearson correlation coefficients were used for
linear simple correlations. Analysis of covariance (31) was used for
correcting means of variables for the impact of mainly BMI and age in
the groups. The women with manifest diabetes were excluded in all
comparisons for metabolic measures, whereas they were retained in all
other analyses, as they did not delineate as outliers in measures other
than the metabolic. All statistical analyses were performed with the
statistical program package Statistical Analysis System and JMP (SAS
Institute, Cary, NC).
Results
Women with previous GDM and controls
Index pregnancy. There were no differences in birth weight of the offspring or gestational age at delivery between the women with previous GDM and controls (data not shown). Hypertension complicated 10 (29%) of the index pregnancies in the GDM group (but none of the index pregnancies among the controls according to inclusion criteria).
Clinical characteristics. Women with previous GDM and
controls had similar age and parity and were investigated after similar
periods of time following the index pregnancy. The women with previous
GDM had higher BMI than controls (Table 1), but did not differ in body fat
distribution (data not shown). The ovarian volume was higher in the GDM
group than in the controls, and polycystic ovaries, according to
ultrasound, were found in 14 women (41%) in the GDM group
vs. 1 (3%) in the control women. Six women (18%) with
previous GDM were hirsute compared with none in the control group. In
addition, irregular menstrual cycles were more common among GDM women
(Table 1). First degree heredity for NIDDM was more prevalent among the
women with previous GDM than among the control women (24%
vs. 6%; P < 0.05)
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).
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Results of the metabolic investigation, with diabetic women
excluded (Table 3). Fasting and 90
min (IVGTT) glucose and insulin concentrations in serum were higher,
and the M/I, assessed by the euglycemic hyperinsulinemic clamp, was
lower in the women with GDM, whereas the insulin increment during the
IVGTT did not differ between the groups. After accounting for
differences in BMI, however, the difference in insulin sensitivity was
abolished, whereas this correction resulted in a lower insulin
increment in the women with previous GDM than in the control women
(Table 3). Similarly, the women with previous GDM exhibited a lower
insulin increment (P < 0.05) after adjusting the
groups to similar insulin sensitivity and BMI. Blood pressures and
lipid profiles did not differ significantly between the groups (data
not shown).
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Index pregnancy. There were no differences in gestational age
at delivery, birth weights of the offspring, or mode of delivery
between the groups (data not shown). Eight (57%) women with polycystic
ovaries and 14 (70%) women with normal ovaries received insulin
treatment during the index pregnancy (P = NS).
Pregnancy-induced hypertension was more common during the index
pregnancies of the polycystic ovary group than in the group of women
with normal ovaries [7 of 14 (50%) vs. 3 of 20 (15%);
P < 0.05]. Prepregnancy body weight and increase in
body weight during the index pregnancy did not differ significantly
between the groups (data not shown). The women with polycystic ovaries
had gained more weight after the index pregnancy at follow-up than the
women with normal ovaries [3.9 (1.1–6.6) kg vs. 0.2 (-1.6
to 2) kg; P < 0.05]. Glucose responses during the
oral or iv tolerance tests during pregnancy did not differ between the
groups, whereas the women with polycystic ovaries showed greater
insulin responses during those tests than the women with normal ovaries
(Table 4
).
Clinical, anthropometric, and endocrine investigations (Tables 5 and 6). There was no difference in the
time elapsed from delivery to the follow-up investigation between the
two groups with GDM (data not shown). The women with polycystic ovaries
were, on the average, 5 yr younger than the women with normal ovaries.
BMI was not significantly (P = 0.06) higher in the
polycystic ovary group. The women with polycystic ovaries had slightly
more sc fat at both truncal-abdominal and femoral sites and an
increased ratio between these measures (Table 5). Hirsutism, irregular
menstrual cycles, and a history of previous amenorrhea were entirely
confined to the women with polycystic ovaries. This group also had
higher serum concentrations of testosterone and androstenedione, higher
FAI and LH/FSH ratio, as well as lower serum levels of GH, all
independent of BMI and age, than the women with normal ovaries. In
addition, serum concentrations of SHBG were lower, and those of DHEA-S
were higher, but not significantly after correction for BMI. Serum
levels of LH and FSH did not differ significantly between the groups
(Table 6). Individually, only five of the patients with polycystic
ovaries showed both irregular menstruations and
hirsutism/hyperandrogenemia, i.e. a picture compatible with
classic PCOS (Table 7).
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). The k
value and glucose levels at fasting and 90 min after iv glucose were
similar in the groups, indicating similar glucose tolerance. Fasting
and 90 min insulin levels were greater, and the M/I was lower in the
polycystic ovary group than in the women with normal ovaries. This
latter difference was significant after adjusting for BMI
(P < 0.05), or the k value (P <
0.01), but nonsignificant after adjusting for the sum of
truncal-abdominal skinfolds (P = 0.11) or waist
circumference (P = 0.07). The insulin increment was not
significantly different between the groups.
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The M/I correlated strongly with the sum of truncal-abdominal
skinfolds in the two subgroups of GDM (polycystic ovaries: r =
0.87; P < 0.0001; normal ovaries: r = 0.87;
P < 0.0001) and in the controls (r = 0.66;
P < 0.0001; total r = 0.81; P <
0.00001; Fig. 1). In a stepwise
regression model for the entire population entering anthropometric and
endocrine variables, the variation in M/I was best explained by the sum
of truncal-abdominal skinfolds and BMI (P < 0.0001 and
P < 0.01, respectively; model r2 =
0.70).
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The results of this study showed an exceptionally high prevalence of polycystic ovaries in women with previous GDM. Furthermore, among the women with previous GDM, the women with polycystic ovaries were delineated as a distinct group from those with normal ovaries, with subtle but significant clinical, endocrine, and metabolic features characteristic of PCOS.
This prevalence of polycystic ovaries (41%) in the women with previous GDM is twice as large as that reported for premenopausal women overall (16, 17, 32). The figure should be regarded as approximate and in need of verification by further studies because dropouts may introduce some selection bias. Although telephone interviews regarding PCOS-associated symptoms and signs clearly indicated similar clinical profiles in the corresponding groups of women who declined to participate, the relative weakness of self-reported data must be acknowledged. However, such bias should also affect the composition of the control group, which showed a surprisingly low prevalence of polycystic ovaries. To some extent this low figure could have been influenced by the design of the study, i.e. only those women with uncomplicated, and thus normotensive, pregnancy were accepted as control women. As the results suggest an association between polycystic ovaries and gestational hypertension, it is possible that inclusion of women with pregnancies complicated by hypertension among the controls would have resulted in a higher prevalence for polycystic ovaries in this group.
Despite being significantly different from the women with normal ovaries, the typical clinical symptoms and signs of the polycystic ovary syndrome were scarce in the group of women with polycystic ovaries, and the endocrine profile was not in all aspects representative of the syndrome (33, 34). The majority of the patients had moderate oligomenorrhea, and thus presumably not chronic anovulation, which may explain the lack of significant differences in serum LH concentration between women with polycystic ovaries and those with normal ovaries (16, 35). The modest, although significant, increases in serum androgens and the LH/FSH ratio also support a fairly subtle endocrine aberration. Body fat distribution, as measured by skinfolds, showed the same truncal-abdominal predominance as in women with PCOS (14, 36, 37), albeit the women with polycystic ovaries and previous GDM also had increased sc fat on femoral sites. The reasons for these variations in the clinical picture are not clear. These women might represent the previously described less florid part of the wide, heterogeneic spectrum of women with polycystic ovaries (16, 17, 35), the relatively low androgenic profile and the low prevalence of menstrual disorders putatively being influenced by a relative diminishing of insulin secretion (38, 39, 40).
Women with GDM have been proven to have an inability to sustain the increased demands on the pancreatic ß-cells during pregnancy (4); the relative contributions of defective insulin response and insulin resistance in the course of GDM are still debated (5, 6, 7, 8, 9). The present findings suggest that the relationship between insulin secretion and sensitivity is deranged in both subgroups of women with previous GDM, but at slightly different levels. The women with polycystic ovaries, but not the women with normal ovaries, were insulin resistant, whereas the groups did not differ in glucose tolerance or prevalence of diabetes. This suggests that ß-cell dysfunction is the dominant component in the women with normal ovaries. The first phase insulin response tended to be lower in this group, but, considering its heterogeneity, the sample size was probably too small to be significant.
The degree of insulin resistance in the women with polycystic ovaries and GDM was strikingly similar to that found in Scandinavian women with polycystic ovary syndrome and normal glucose tolerance (14), whereas the early insulin release was only one third of that observed in that group of women. The decreased insulin secretion in the women with polycystic ovaries and GDM is, however, similar to that in a subgroup (14%) of the women with PCOS (14), who exhibited glucose intolerance or manifest NIDDM (14). This clearly suggests that the present group of women with polycystic ovaries is not entirely representative of Scandinavian women with polycystic ovaries, but, rather, represents a subgroup with impending ß-cell failure by being selected for decreased glucose tolerance in pregnancy. North American studies of women with PCOS have also shown a heterogeneous pattern for insulin secretion, although failing ß-cell activity is more commonly found in those study populations (13, 41, 42). Whether the great heterogeneity of insulin secretion in women with polycystic ovaries/PCOS is because the patients are evaluated in different stages of a process evolving from normal, or even exaggerated (14, 43), ß-cell activity to a gradual fatigue after superimposed stress of insulin resistance or whether the spectrum is originally composed of genetically varying subgroups cannot yet be concluded.
The women with polycystic ovaries and GDM had a higher prevalence of pregnancy-induced hypertension than the women with normal ovaries, although blood pressure did not differ significantly at follow-up. Previously, we found signs of more labile blood pressure in ambulatory recordings in women with PCOS (44). In addition, insulin resistance and hyperinsulinemia are repeatedly found in association with hypertension (21, 22, 45) and during pregnancy (23, 46). Given the high prevalence of hyperinsulinemia in PCOS, hypertensive complications in pregnancy may be common in these women.
In addition to insulin resistance, observed also during the index pregnancy, and the increased prevalence of pregnancy-induced hypertension, women with polycystic ovaries and GDM had higher serum VLDL triglycerides and cholesterol than the corresponding women with normal ovaries. These findings, together with their slightly lower age and a tendency for a higher BMI with predominance of fat localized to truncal-abdominal sites show that they form a distinct group in metabolic aspects. These metabolic features suggestive of the insulin resistance syndrome (47) are well recognized in association with the PCOS (28, 44, 48, 49, 50, 51, 52), but were only recently described in women with polycystic ovaries without overt signs of the PCOS (53).
The strong association between insulin resistance and truncal-abdominal fat mass in this study is similar to previous findings in PCOS (14, 36, 37, 43) and in other populations (54, 55, 56). Thus, in accordance with a previous study in women with PCOS (14), adjusting for truncal-abdominal fat mass, but not for BMI, abolished the difference in insulin sensitivity between women with polycystic ovaries and those with normal ovaries. Although the nature of the association between abdominal fat and insulin resistance is not fully clarified, recent results suggest a cause and effect relationship (28, 43), possibly mediated through free fatty acids (28, 43, 57).
The women with polycystic ovaries had slightly lower GH levels than the women with normal ovaries. Disturbances in the GH/insulin-like growth factor I axis have been observed in association with abdominal obesity and the insulin resistance syndrome (58) and also in women with PCOS (59, 60, 61, 62, 63). However, basal GH levels did not differ between women with PCOS and controls in a previous study from our laboratory, which again indicates a difference in the endocrine profile between the women with polycystic ovaries and GDM in the present study and Scandinavian women with PCOS (29).
In summary, polycystic ovaries and associated clinical features were much more prevalent in women with previous GDM than in those with a history of uncomplicated pregnancy. Despite the similar prevalence of diabetes mellitus and glucose intolerance, the women with polycystic ovaries and GDM formed a group with distinct clinical, endocrine, and metabolic features from the women with GDM and normal ovaries. Both groups showed a similar imbalance between ß-cell activity and insulin sensitivity, but the results suggest a relatively greater role for insulin resistance in the group with polycystic ovaries, whereas impaired ß-cell function dominated in the group with normal ovaries. These findings further support a strong association between the presumably genetic constitution of polycystic ovaries/PCOS and disturbances of carbohydrate metabolism and underline the proneness to various features of the insulin resistance syndrome in these women.
Received December 17, 1996.
Revised November 14, 1997.
Accepted December 10, 1997.
References
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R. M. Koivunen, J. Juutinen, I. Vauhkonen, L. C. Morin-Papunen, A. Ruokonen, and J. S. Tapanainen Metabolic and Steroidogenic Alterations Related to Increased Frequency of Polycystic Ovaries in Women with a History of Gestational Diabetes J. Clin. Endocrinol. Metab., June 1, 2001; 86(6): 2591 - 2599. [Abstract] [Full Text] [PDF]
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M. Mikola, V. Hiilesmaa, M. Halttunen, L. Suhonen, and A. Tiitinen Obstetric outcome in women with polycystic ovarian syndrome Hum. Reprod., February 1, 2001; 16(2): 226 - 229. [Abstract] [Full Text] [PDF]
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Polycystic Ovary Syndrome, Gestational Diabetes, and Bulimia Nervosa J. Clin. Endocrinol. Metab., December 1, 1999; 84(12): 4746 - 4746. [Full Text]
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