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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 6 1692-1696
Copyright © 1997 by The Endocrine Society

Reproductive Endocrinology

Serum Leptin Levels in Women with Polycystic Ovary Syndrome: The Role of Insulin Resistance/ Hyperinsulinemia1

G. A. Laughlin, A. J. Morales and S. S. C. Yen2

Department of Reproductive Medicine, School of Medicine 0633, University of California, San Diego, La Jolla, California 92093-0633

Address all correspondence to: Samuel S. C. Yen, Department of Reproductive Medicine, School of Medicine 0633, University of California, 9500 Gilman Drive, La Jolla, California 92093-0633. Reprints not available.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Polycystic ovary syndrome (PCOS) is associated with chronic anovulation, hyperandrogenemia, insulin resistance (IR)/hyperinsulinemia, and a high incidence of obesity. Thus, PCOS serves as a useful model to assess the role of IR and chronic endogenous insulin excess on leptin levels. Thirty-three PCOS and 32 normally cycling (NC) women of similar body mass index (BMI) were studied. Insulin sensitivity (SI) was assessed by rapid ivGTT in a subset of 28 PCOS and 29 NC subjects; percent body fat was determined by dual-energy x-ray absorptiometry (DEXA) in 14 PCOS and 17 NC. Fasting (0800 h) and 24-h mean hourly insulin levels were 2-fold higher (P < 0.0001), and SI was 50% lower (P = 0.005) in PCOS than in NC, while serum androstenedione (A), testosterone (T), 17-{alpha} hydroxyprogesterone (17OHP), and estrone (E1) levels were elevated (P < 0.0001), and sex hormone-binding globulin (SHBG) levels were decreased (P < 0.01). Twenty-four hour LH pulse frequency, mean pulse amplitude, and mean LH levels were elevated in PCOS (P < 0.001) as compared with NC.

Serum leptin levels for PCOS (24.1 ± 2.6 ng/mL) did not differ from NC (21.5 ± 3.5 ng/mL) and were positively correlated with BMI (r = 0.81) and percent body fat (r = 0.91) for the two groups (both P < 0.0001). Leptin levels for PCOS and NC correlated positively with fasting and 24-h mean insulin levels (r = 0.81, P < 0.0001 for both PCOS and NC) and negatively with SI and SHBG levels. Leptin concentrations for PCOS, but not NC, correlated positively with 24-h mean glucose levels and inversely with 24-h mean LH levels and 24-h mean LH pulse amplitude. Leptin levels were not correlated with estrogen or androgen levels for either PCOS or NC, although leptin levels were positively related to the ratios of E1/SHBG and E2/SHBG for both PCOS and NC and to the ratio of T/SHBG for PCOS only. In stepwise multivariate regression with forward selection, only 24-h mean insulin levels contributed significantly (P < 0.01) to leptin levels independent of BMI and percent body fat for both PCOS and NC. Given this relationship and the presence of 2-fold higher 24-h mean insulin levels in PCOS, the expected elevation of leptin levels in PCOS was not found. This paradox may be explained by the presence of adipocyte IR specific to PCOS, which may negate the stimulatory impact of hyperinsulinemia on leptin secretion, a proposition requiring further study.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
LEPTIN, the hormone product of the obesity (ob) gene (1), is synthesized exclusively in adipose tissue (2), and its expression and release in rodents is stimulated by insulin (3, 4, 5, 6, 7). In humans, serum leptin levels are highly correlated with percentage body fat and fall in response to weight loss (8, 9, 10, 11, 12). Increasing adiposity is accompanied by insulin resistance (IR) and compensatory hyperinsulinemia (13), suggesting the possibility of an interaction between insulin and leptin. Studies of insulin regulation of leptin in humans have yielded conflicting results. Prolonged exposure of cultured human adipocytes to insulin increased levels of leptin messenger RNA and protein (14, 15). Expression of adipose tissue leptin messenger RNA and circulating leptin levels were increased during hyperinsulinemic clamp studies of long (6–72 h) (14, 16, 17), but not short (18, 19, 20, 21, 22, 23, 24), duration. These observations, together with our recent report of hypoleptinemia in association with hypoinsulinemia in women athletes (25), suggest that chronic alterations in endogenous insulin levels modulate leptin synthesis. Attempts to discern the effect of insulin sensitivity on leptin levels (21, 22, 23, 26, 27) are confounded by the coupling of obesity and IR/hyperinsulinemia and by the dominating influence of the adipose tissue mass on leptin levels. Women with polycystic ovary syndrome (PCOS) serve as a model to assess the role of IR and chronic insulin excess on leptin levels by virtue of the presence of a unique component of IR/hyperinsulinemia in PCOS beyond that associated with obesity per se (28, 29, 30, 31, 32, 33). In this study we have examined leptin levels in PCOS and normal women of similar body mass index (BMI) and adiposity and their relationship to insulin sensitivity, fasting, and 24-h mean insulin levels, as well as to 24-h LH pulsatility and sex steroid levels.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Thirty-three women with the diagnosis of PCOS and 32 women of similar age and BMI with regular menstrual cyclicity (NC) were studied. The age range of the subjects was 17–36 yr; BMI ranged from 19–42 kg/m2. The diagnosis of PCOS was based on perimenarcheal onset of oligomenorrhea, elevated serum levels of androstenedione (A) and/or testosterone (T), and ultrasound evidence of bilateral enlarged polycystic ovaries. Neuroendocrine-metabolic hormonal data on 16 PCOS and 16 NC subjects were reported in a previous publication (31). All subjects were euglycemic, euthyroid, and had normal prolactin levels. They were nonsmokers and had not been on any medications for at least three months before the study. In PCOS subjects, late-onset congenital adrenal hyperplasia was excluded by a normal 17-hydroxyprogesterone (17OHP) level 60 min after an ACTH stimulation test. The protocol for this study was approved by the Committee on Investigations Involving Human Subjects of the University of California, San Diego, and written informed consent was obtained from each participant.

Procedures

Studies were conducted in regularly cycling controls during the early follicular phase (day 2–5) of their menstrual cycle and in PCOS women on a random day. In no case had recent ovulation occurred in PCOS as evidenced by retrospective measurement of serum progesterone levels. Subjects were admitted to the General Clinical Research Center (GCRC) of the UCSD Medical Center at 0700 h after an overnight fast. Blood samples were drawn through an indwelling iv catheter every 10 min for 24 h beginning at 0800 h. Subjects refrained from napping and drinking caffeinated beverages during the study and received standard meals at 0800 h, 1200 h, and 1700 h and a 200 kcal snack at 2200 h. The total caloric content of meals was adjusted to 30 kcal/kg body weight with a nutrient composition of 15% protein, 55% carbohydrate, and 30% fat, and a caloric division of 1/5, 2/5, 2/5 for breakfast, lunch, and dinner, respectively. Subjects were allowed to sleep from 2300–0700 h. Serum concentrations of leptin, FSH, sex hormone binding globulin (SHBG), and steroid hormones were determined on 0800 h fasting samples. LH concentrations were determined at 10 min intervals. Serum insulin and plasma glucose levels were measured hourly and 30 min after each meal. Each individual’s samples were analyzed in the same assay in duplicate.

Insulin sensitivity (SI) was assessed in a subset of 28 PCOS and 29 control subjects by a modified rapid ivGTT (34). After an overnight fast of 10 h, an iv line was established in each forearm, and baseline samples were drawn at -10 and 0 min before administration of an iv bolus of glucose (0.3 g/kg 50% dextrose) over 1 min in the opposite arm. At 20 min after the glucose injection, an iv bolus of regular insulin (0.03 u/kg for lean women and 0.05 u/kg for obese women) was injected over 20 sec and the line immediately flushed with saline. Blood samples were then drawn at 2, 4, 8, 19, 22, 30, 40, 50, 70, 90, and 180 min. Plasma glucose and serum insulin concentrations were determined for each sample. Body composition was determined in a subset of these subjects (14 PCOS and 17 controls) by dual-energy x-ray absorptiometry (DEXA) (Hologic QDR-2000, Waltham, MA).

Data analysis

SI was analyzed by the MINMOD computer program (copyright RN Bergman) (34). LH pulsatile activity was analyzed using the Cluster pulse detection algorithm (35). A cluster configuration of 2 x 1 and t statistics of 2.1 x 2.1 were chosen to minimize false positive and false negative errors. Dose dependent intrasample variance was assessed by employing a second degree polynomial regression of SD as a function of hormone concentration. Pulse number/24-h, mean pulse amplitude (the difference in concentration between the preceding nadir and the pulse peak), and 24-h mean concentration were determined for each subject.

Assays

Serum leptin levels were determined by RIA using recombinant human leptin as standard (Linco Research, Inc., St. Charles, MO.) (10) with intra- and interassay CVs <=5%. Serum LH and FSH concentrations were measured by RIA. The respective intra- and interassay CVs were 5.4% and 8.0% for LH and 3.0% and 4.6% for FSH. Serum insulin levels were measured by a double-antibody RIA with an assay sensitivity of 15 pmol/L, and intra- and interassay CVs of 7% and 9%, respectively. Plasma glucose concentrations were determined by the glucose oxidase method (Yellow Springs Instrument Co., Yellow Springs, OH) with an intraassay CV less than 2% and an interassay CV of 3%. SHBG was measured by a time resolved immunofluorometric assay (Delfia® SHBG kit; Wallac Inc., Gaithersburg, MD) with intra- and interassay CVs of 7% and 9%, respectively. Serum concentrations of estrone (E1), estradiol (E2), androstenedione (A), testosterone (T), and 17-hydroxyprogesterone (17OHP) were measured by established RIAs with intraassay CVs less than 7%.

Statistical analyses

Non-Gaussian distributed variables were log10 transformed to achieve normality. This applied to insulin sensitivity, fasting levels of leptin and insulin, 24-h mean insulin and LH levels, and 24-h mean LH pulse amplitude. Results for PCOS and NC were compared by group t-tests. Relationships between variables were sought by Pearson product moment correlations and stepwise multivariate linear regression analysis with forward selection. When more than five correlations were performed, a protected P value of 0.01 was used to reduce false positive assignment of significance to no more than 1/100. Results are expressed as the mean ± SE. P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Clinical and endocrine-metabolic characteristics (Table 1Go)

When compared with NC of similar age and BMI, PCOS displayed 2-fold elevations (P < 0.01) of fasting (0800 h) and 24-h mean insulin levels and increased 24-h mean glucose levels (P < 0.02). Insulin sensitivity was 50% lower (P < 0.01) in PCOS than NC. Serum 17OHP, A, T, and E1 levels were elevated (P < 0.0001) in PCOS as compared with NC. Serum concentrations of SHBG were decreased (P < 0.01), and the ratios of E1/SHBG, E2/SHBG and T/SHBG, reflecting nonprotein bound steroid levels, were increased (P < 0.01) in PCOS. 24-h LH pulse frequency was accelerated (P < 0.0001) and 24-h mean LH pulse amplitude was augmented (P < 0.001) in PCOS, resulting in 2-fold higher (P < 0.0001) 24-h mean LH levels. FSH concentrations were normal in PCOS, thus the LH/FSH ratio was elevated 2-fold (P < 0.001) in PCOS as compared with NC.


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  		Table 1. Clinical and endocrine-metabolic characteristics for normal control (NC) and PCOS women

 
Relationship of leptin levels to BMI and percentage body fat

Fasting (0800 h) leptin levels for PCOS (24.1 ± 2.6 ng/mL) did not differ from those of NC (21.5 ± 3.5 ng/mL) and were positively correlated with BMI with no difference in the relationship between BMI and leptin levels for the two groups (r = 0.81, P < 0.0001 for PCOS and NC together) (Fig. 1aGo). A subset of 14 PCOS and 17 NC matched for percentage body fat (PCOS, 40.0 ± 2.8%; NC, 35.8 ± 2.7%) also had indistinguishable fasting leptin levels (PCOS, 29.3 ± 4.4; NC, 27.4 ± 5.3 ng/mL) with a similar relationship between percentage body fat and leptin concentrations (r = 0.91, P < 0.0001 for PCOS and NC together) (Fig 1bGo).



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  		Figure 1. Regression of serum leptin levels (log-transformed) vs. body mass index (BMI) (a) and percent body fat (b) for PCOS (•) and NC ({circ}) women (both P < 0.0001). Values on the y-axis are antilogs. Dashed lines indicate 95% confidence intervals.

 
Relationship of leptin levels to endocrine-metabolic parameters

Correlation results for fasting leptin levels vs. endocrine-metabolic parameters for PCOS and NC are given in Table 2Go. Leptin levels for PCOS and NC correlated positively with fasting and 24-h mean insulin levels (r = 0.81, P < 0.0001 for both PCOS and NC) and negatively with SI and SHBG levels. Leptin concentrations for PCOS, but not NC, correlated positively with 24-h mean glucose levels and inversely with 24-h mean LH levels and 24-h mean LH pulse amplitude. Leptin levels were not correlated with estrogen or androgen levels for either PCOS or NC, although leptin levels were positively related to the ratios of E1/SHBG and E2/SHBG for both PCOS and NC and to the ratio of T/SHBG for PCOS only.


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  		Table 2. Correlation of leptin concentrations with endocrine-metabolic parameters for PCOS and control (NC) women

 
Stepwise multivariate regression analyses were performed separately for PCOS and NC including each of the variables significantly correlated with leptin levels (Table 2Go), as well as BMI. Relationships of leptin levels with insulin sensitivity, glucose levels, 24-h mean LH levels and pulse amplitude, and nonprotein bound steroid levels were found to be BMI dependent for both PCOS and NC. Only 24-h mean insulin levels contributed significantly (Table 3Go) to fasting leptin levels, independently of BMI, for both PCOS and NC (Fig. 2Go). The independent influence of insulin levels was also evident for the subset of PCOS and NC subjects for whom percentage body fat was available.


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  		Table 3. Model fitting results for stepwise regression of leptin levels vs. significantly correlated variables (Table 2Go) for PCOS and NC

 


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  		Figure 2. Relationship of serum leptin levels (log-transformed) vs. 24-h mean serum insulin levels (log-transformed) for PCOS (•) and NC ({circ}) women. Values on both axes are antilogs. r = 0.81, P < 0.0001 for both PCOS and control women.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
We found that leptin levels in PCOS did not differ from those of normal cycling women with similar BMI or adiposity. Of note, none of the 33 PCOS women studied here displayed hyperleptinemia such as that recently reported in about 30% of both obese and nonobese women with PCOS (36). However, it is unclear whether the finding of hyperleptinemia in PCOS subjects reported by Brzechffa et al. (36) would be sustained after transformation of the data to achieve normality and covariance analysis to account for the distribution of BMI between the controls and PCOS women. Importantly, we observed a positive influence, independent of BMI or percentage body fat, of 24-h mean insulin levels on fasting leptin levels in both PCOS and control women.

Given this relationship and the presence of 2-fold higher 24-h insulin levels in PCOS, the expected elevation of serum leptin levels in PCOS was not found. The mechanism underlying the apparent diminished impact of insulin on leptin levels in PCOS women is unclear. Consideration should be given to the 2-fold greater degree of IR (i.e. reduced SI) in women with PCOS as compared with control women (see Table 1Go). IR at the level of the adipocyte in women with PCOS differs from that associated with obesity per se: both insulin-stimulated glucose transport (28, 29, 30) and the cellular expression of GLUT-4 glucose transporter (32) are diminished in adipocytes of PCOS women independent of obesity. Moreover, a reduced insulin-induced receptor serine phosphorylation has been observed in PCOS (33), a defect not seen in obesity. Either one or all of these cellular abnormalities of insulin action in the adipocyte may account for the apparently reduced impact of insulin on leptin levels in PCOS. Thus, we suggest that adipocyte IR specific to PCOS may negate the stimulatory impact of hyperinsulinemia in PCOS and may explain the unaltered leptin levels (Fig. 3Go).



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  		Figure 3. Mean (± SE) values for insulin sensitivity, 24-h mean serum insulin levels, and fasting serum leptin levels in NC and PCOS women. * - P < 0.01 PCOS vs. NC.

 
The independent influence of insulin on fasting leptin levels reported here for both PCOS and control women was only evident with 24-h mean levels. Although we and others (11, 16, 19, 22, 24) found a significant correlation of leptin with fasting insulin levels, an effect independent of adiposity has seldom been demonstrated (11, 22). Thus, insulin’s influence on adipocyte leptin production appears to be related to the cumulative impact of insulin excursions during the feeding/fasting phases of the day.

Leptin has been proposed to serve as a signal relating nutritional status to hypothalamic regulators of reproductive function (37). Leptin administration increases serum LH levels and ovarian and uterine weights in ob/ob mice (37) and circumvents the fasting-induced inhibition of gonadotropin and androgen levels in both ob/ob (37) and normal (38) mice. In this study, although 24-h mean LH levels and pulse amplitude and nonprotein bound steroid levels were weakly correlated with fasting leptin levels for PCOS, these relationships were not significant when BMI was taken into consideration, and fasting leptin levels did not relate to any feature of LH pulsatility in normal women. Thus, leptin does not appear to play a role in either hyperandrogenemia or hypersecretion of LH in PCOS women nor in the regulation of LH pulsatility in normal women.

In conclusion, fasting leptin levels are not altered in PCOS women. However, we have identified a positive influence of insulin on fasting leptin levels, independent of adiposity, the expression of which is not in accord with the hyperinsulinemic state of PCOS. We speculate that the opposing effects of hyperinsulinemia (stimulatory) and adipocyte IR (negative) specific to PCOS may negate the impact of insulin excess and account for the maintenance of normal levels of serum leptin in PCOS. Further investigations are needed to confirm the proposed mechanism.


   Acknowledgments
 
The authors are grateful to Ms. Pam Malcom, Mr. Jeff Wong, Ms. Shannon Petze, Ms. Erlinda Imson, and the nurses and staff of the Clinical Research Center for their important contributions to this manuscript.


   Footnotes
 
1 This work was supported by NICHD Center Grant HD-12303–19 and the General Clinical Research Center, NIH Grant MO1-RR00827. Back

2 Clayton Foundation investigator. Back

Received February 26, 1997.

Accepted March 14, 1997.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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