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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2006-2716
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 4 1347-1352
Copyright © 2007 by The Endocrine Society

Pharmacokinetic Factors Contribute to the Inverse Relationship between Luteinizing Hormone and Body Mass Index in Polycystic Ovarian Syndrome

Serene S. Srouji1, Yanira L. Pagán1, Fernando D’Amato, Amsalu Dabela, Yarisie Jimenez, Jeffrey G. Supko2 and Janet E. Hall2

Reproductive Endocrine Unit (S.S.S., Y.L.P., A.D., Y.J., J.E.H.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114; Center for Reproductive Medicine, Department of Obstetrics and Gynecology (S.S.S.), Brigham and Women’s Hospital, Boston, Massachusetts 02115; and Division of Hematology/Oncology (F.D., J.G.S.), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: Janet E. Hall, Reproductive Endocrine Unit, BHX-5, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114. E-mail: hall.janet{at}mgh.harvard.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Serum LH levels decrease with increasing body mass index (BMI) in women with polycystic ovarian syndrome (PCOS).

Objective: The objective of this study was to determine whether pharmacokinetic factors contribute to the effect of obesity on LH in PCOS.

Participants/Interventions/Setting: Twenty-one women with PCOS underwent frequent blood sampling, iv administration of GnRH (75 ng/kg), and sc administration of the NAL-GLU GnRH antagonist (150 µg/kg) followed by iv recombinant human LH (rhLH; 300 IU) in the General Clinical Research Center at an academic medical center.

Main Outcome Measures: Pharmacokinetic parameters were estimated by modeling the LH serum concentration profiles after administration of GnRH and rhLH and related to BMI.

Results: Serum levels of LH and rhLH decreased in a distinctly monoexponential fashion in all patients. The apparent biological half-life of rhLH was not influenced by BMI, nor was the total body clearance or apparent volume of distribution. However, the apparent half-life of endogenous LH was inversely related to BMI (r = –0.46; P < 0.04), and the estimated total body clearance of endogenous LH was positively related to BMI (r = 0.53; P < 0.02).

Conclusion: Estimated clearance and apparent half-life of endogenous LH are influenced by BMI in women with PCOS, contributing to the inverse relationship between LH and BMI in this population. The absence of an effect of BMI on the pharmacokinetics of rhLH in these subjects suggests that the effect of obesity on clearance of endogenous LH is the result of alterations in the isoform composition of LH secreted by the pituitary.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
POLYCYSTIC OVARIAN syndrome (PCOS) is a heterogeneous disorder characterized by ovulatory dysfunction, hyperandrogenism, and polycystic ovarian morphology. Although not considered essential for the diagnosis, neuroendocrine abnormalities, including increased serum concentrations of LH, increased LH/FSH ratio, and increases in the amplitude and frequency of pulsatile LH secretion, are characteristic features of PCOS (1, 2, 3). These gonadotropin abnormalities are prevalent with 75% of women with PCOS having an elevated LH and 94% having an elevated LH/FSH ratio (4). However, there is an inverse relationship between body mass index (BMI) and serum concentrations of both LH and the LH/FSH ratio, implying that obesity modifies LH hypersecretion in patients with PCOS (4, 5, 6). We have recently demonstrated that at least part of the effect of BMI on LH levels is the result of attenuation of the pituitary response to GnRH in obese PCOS women, whereas markers of hypothalamic function are unaffected by BMI (6). However, the continuous relationship observed between serum concentrations of LH and BMI suggested that pharmacokinetic factors should also be considered in understanding the impact of obesity on LH in PCOS. Obesity generally does not alter the apparent volume of distribution of hydrophilic molecules, especially large proteins such as LH, although it does affect the volume of distribution of small, lipophilic molecules that can readily distribute in adipose tissue (7, 8). However, the elimination of LH may be influenced by changes in its isoform composition. LH is a heterodimeric glycoprotein that is composed of two subunits ({alpha} and ß) with three glycosylation sites. Posttranslational modification results in LH isoforms that differ in their degree of glycosylation (9), which ultimately impacts the elimination of the secreted hormone as well as its in vitro bioactivity (10, 11, 12). Previous studies have suggested that gonadal hormones and obesity can influence the isoform composition of secreted LH (13, 14, 15, 16, 17).

The purpose of this study was to investigate further the mechanisms accounting for the inverse relationship between LH and BMI in patients with PCOS by determining the effect of obesity on the pharmacokinetics of LH. The pharmacokinetics of endogenous LH was investigated by analyzing the time course of LH in serum after the administration of GnRH in women with PCOS across a wide range of BMIs. The pharmacokinetic behavior of recombinant human LH (rhLH) was characterized in these same subjects.


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

The study population consisted of 21 healthy women with PCOS as previously described (6). PCOS was defined as the presence of clinical and/or biochemical evidence of hyperandrogenism and oligomenorrhea (less than nine menstrual periods per year). Clinical hyperandrogenism was defined by a Ferriman-Gallwey score less than 10 (18), whereas biochemical hyperandrogenism was documented with a total testosterone greater than the 95th percentile for normal women. Late-onset congenital adrenal hyperplasia was excluded by the presence of a normal 17-hydroxyprogesterone level [less than 200 ng/dl (less than 6.1 nmol/liter)] in a baseline morning sample (19). All subjects were between the ages of 18 and 40 yr and were euthyroid, with normal serum levels of prolactin and negative ß-human chorionic gonadotropin. Renal function tests were within the normal range, and liver function tests were less than twice the upper limit of normal. Patients with a known history of drug allergy precluding treatment with the NAL-GLU GnRH antagonist were excluded from the study. The study was approved by the Institutional Review Board of the Massachusetts General Hospital, and all subjects provided written informed consent.

Protocol

Eligible subjects were required to have a negative ß-human chorionic gonadotropin and a progesterone level less than 2.0 ng/dl (64 pmol/liter) on the day of admission. Admission was delayed for any subject in whom menses had occurred in the 7 d before the scheduled admission. A transvaginal ultrasound (Toshiba Sonolayer L, SAL-778 with a transvaginal 5-MHz probe; Toshiba Medical Systems, West Sussex, UK) was obtained around the time of admission to determine the presence of a corpus luteum defined as a complex cyst with an irregular wall and/or internal echoes. Taken together, this information was used to ensure that subjects were not studied in the luteal phase or in the 7 d after a spontaneous ovulatory cycle as a result of the suppressive effect of progesterone on gonadotropin dynamics (4, 20).

At the time of admission to the General Clinical Research Center at Massachusetts General Hospital, height, weight, bioelectrical impedance, skinfold thickness in the arm and shoulder, and waist (at the iliac crest) to hip ratio were measured. A peripheral venous catheter was inserted into a forearm vein for serial blood sampling, and a second peripheral venous catheter was inserted in the contralateral arm for medication injection. Blood samples were collected, and the serum was stored at –20 C until assayed. An initial sample was obtained for baseline testosterone, estradiol, and SHBG. Blood was then sampled every 10 min for 8 h before and 1 h after iv administration of GnRH (75 ng/kg) and then every 30 min for an additional 5 h for subsequent measurement of LH. Subjects fasted overnight, and a blood sample was drawn the next morning for glucose and insulin. Endogenous LH secretion was suppressed by sc administration of the NAL-GLU GnRH antagonist (150 µg/kg) as previously described (21, 22) followed 8 h later with a 300-IU dose of rhLH administered by bolus iv injection. Serum LH was measured at 10-min intervals for 30 min before and 8 h after rhLH administration. GnRH and the NAL-GLU GnRH antagonist were obtained from the Contraceptive Development Branch of the National Institutes of Health and formulated as previously described (21); rhLH was donated by Ares-Serono International (Geneva, Switzerland) and reconstituted in sterile water before injection.

Assays

The concentrations of LH, FSH, and estradiol were measured using a two-site monoclonal nonisotopic system (AxSYM; Abbott Laboratories, Abbott Park, IL) as previously described (23, 24). The lower limit of detection of the assay for LH was 3.7 IU/liter. Interassay coefficients of variation were 7%. Gonadotropin values are expressed in units per liter as equivalents of the Second International Reference Preparation of human menopausal gonadotropins.

Pharmacokinetic model

A one-compartment open model with first-order elimination was fit to the serum LH concentration (Cs) vs. time data before and 6 and 8 h after administration of GnRH and rhLH, respectively. Basal concentrations of endogenous LH in serum (Ce) after administration of GnRH or rhLH were assumed to be constant during the sampling periods and incorporated as a parameter in the model. The general model was defined by the differential equation: dCs/dx = (CL·Ce + I – CL·Cs)/V, where x is the relative time variable, I is the LH input function, V is the apparent volume of distribution of LH, and CL is the total body clearance of LH. In the model applied to the time course of Cs after rhLH administration, I = D/Tinj, where D is the dose of rhLH, the duration of the injection (Tinj) was assumed to be 1 min, and x = t, where t is time relative to the rhLH injection. In the model applied to the time course of Cs after GnRH administration, the release of endogenous LH stimulated by GnRH was assumed to be first-order, for which I = Ar·kr exp(–kr·x), where Ar is the amount of endogenous LH released into systemic circulation and kr is the first-order rate constant for LH release. A lag time for LH release (tlag) was defined as a parameter in the model such that x = t – tlag, where t is time relative to the injection of GnRH. The variable Ar was assumed to be unity (i.e. 1 IU) for purposes of modeling the data, because Ar cannot be determined directly from the serum LH concentration data in response to GnRH administration. Thus, analogous to the paradigm for oral drug delivery (25), the estimates of CL and V provided by this application of the model are actually relative values equivalent to CLe/(Ar/1 IU) and Ve/(Ar/1 IU), where CLe and Ve are the total body clearance and apparent volume of distribution of endogenous LH. Under the assumption that V for rhLH is similar to Ve for individual patients, CLe can then be calculated from the equation: CLe = V·0.693/t1/2, for each patient, where t1/2 is the estimated value of the apparent half-life of endogenous LH. The t1/2 for LH in serum was calculated from the equation t1/2 = V·0.693/CL.

For both endogenous LH and rhLH, the differential equations were fit to the observed LH serum concentrations for each patient by nonlinear regression using WinNonlin Professional version 5.0 software (Pharsight Corp., Cary, NC). The initial condition for both applications of the model is Cs(0) = Ce.

Data analysis

Free testosterone was calculated from total testosterone and SHBG (26). The homeostatic model assessment (HOMA) (27) was used to assess insulin resistance.

Parametric statistical tests of pharmacokinetic variables were performed after logarithmic transformation of the data. Pearson sample correlation coefficients (r) were calculated to identify relationships between pharmacokinetic parameters and BMI. Mean values of pharmacokinetic parameters were calculated as the geometric mean assuming that the individual patient values are log-normally distributed (28, 29) and presented as ± SD using SDs that were estimated by the jacknife method (30). All other variables are presented as the mean ± SEM.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Results of the frequent sampling study and pituitary responsiveness to GnRH have been previously reported (6), whereas this article focuses on the pharmacokinetic analysis of endogenous LH after GnRH administration and administration of rhLH. The mean (±SEM) age of the subjects included in this analysis was 27.7 ± 1.2 yr, and BMIs ranged from 17.7 to 50.7 kg/m2 with a mean of 33.2 ± 2.1 kg/m2. Percent body fat, estimated by bioelectrical impedance, ranged from 20 to 54% with a mean of 38.8 ± 2.1%, and waist to hip ratio ranged from 0.76 to 1.02 with a mean of 0.86 ± 0.02. Polycystic ovarian morphology was present in all subjects. Baseline hormonal characteristics were consistent with PCOS with a mean estradiol level of 71.1 ± 6.4 pg/ml (261 ± 23.5 pmol/liter), mean testosterone of 81.0 ± 8.0 ng/dl (2.8 ± 0.3 nmol/liter) with a normal range of 5 to 63 ng/dl (0.2–2.2 nmol/liter), and free testosterone of 1.8 ± 0.8 ng/dl (6.2 ± 2.8 nmol/dl) with a normal range of less than 0.95 ng/dl (< 3.3 nmol/dl). Mean LH at baseline was 23.8 ± 3.3 IU/liter with a range of 3.5 to 67.9 IU/liter (normal follicular phase 6.5 ± 0.8 IU/liter) and baseline LH/FSH was 2.2 ± 0.3 (normal follicular phase 0.58 ± 0.07). The baseline concentration of endogenous LH in this patient population was inversely related to BMI (r = –0.63, P = 0.002), consistent with the results of previous studies (4, 5).

Figure 1Go demonstrates LH concentrations over time in relation to administration of GnRH, the NAL-GLU GnRH antagonist, and rhLH for two representative PCOS subjects, one lean and one obese. Also depicted are the curves generated from the best-fit pharmacokinetic models for endogenous and exogenous LH. The concentration of endogenous LH in serum increased in an apparent first-order manner from the pretreatment values after GnRH administration (Fig. 1Go). Serum levels of endogenous LH decayed in a manner that was very satisfactorily described by a one-compartment open model for all subjects. Similarly, serum LH levels decreased in a distinctly monoexponential manner after bolus iv injection of rhLH. A two-compartment open model with elimination from the central compartment did not improve the fit of the data for either LH after treatment with GnRH or iv injection of rhLH as determined by visual inspection of the best-fit curves, the estimated coefficient of variation of the parameter estimates, and the Akaike information criteria.


Figure 1
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  		FIG. 1. Observed concentrations of LH in serum (open circles) over time in relation to administration of GnRH, the NAL-GLU GnRH antagonist, and rhLH as indicated in two representative women with PCOS. The BMI in the patient shown in the top panel is 18.0 kg/m2 and that of the patient in the bottom panel is 35.4 kg/m2. The solid curves were generated from the best-fit pharmacokinetic models for endogenous LH and rhLH in these subjects. Note the different scales on the y-axis used for the two patients.

 
Mean values of the pharmacokinetic parameters and secondary variables for endogenous LH and rhLH are summarized in Table 1Go. The mean t1/2 of endogenous LH released into systemic circulation by GnRH was not significantly different from the mean t1/2 for rhLH (P = 0.31). However, intersubject variability was considerably greater for the t1/2 of endogenous LH (27.5%) than for the t1/2 of rhLH (12.4%). Mean values for the CL and V of rhLH were 1.66 ± 0.34 liters/h and 3.23 ± 0.72 liters, respectively. The CL of endogenous LH was calculated assuming that Ve is equivalent to V for each subject, yielding a mean of 1.55 ± 0.06 liters/h for this cohort of subjects.


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  		TABLE 1. Pharmacokinetic parameters for endogenous LH and rhLH

 
The CL (r = 0.19), V (r = 0.25), and t1/2 (r = 0.10) of rhLH were not associated with BMI (Fig. 2Go) or any index of body fat. In contrast, the t1/2 of endogenous LH exhibited a significant negative correlation with BMI (r = –0.46; P = 0.037; Fig. 2Go), and the estimated CL of endogenous LH was positively correlated with BMI (r = 0.53; P = 0.014). The t1/2 of endogenous LH was also negatively correlated with skinfold measurements (r = –0.56, P = 0.04) and waist to hip ratio (r = –0.50, P = 0.03).


Figure 2
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  		FIG. 2. The half-life of endogenous LH (top panel) is inversely related to BMI in patients with PCOS (r = –0.46; P = 0.037), whereas the half-life of rhLH is not influenced by BMI (r = 0.10) in these same patients.

 
Baseline estradiol was not correlated with BMI (r = –0.10, P = 0.63) or the t1/2 of endogenous LH (r = 0.35, P = 0.15) either alone or in a multiple regression analysis that included estradiol, SHBG, and testosterone. Furthermore, total testosterone, calculated free testosterone, and progesterone were not significantly correlated with BMI or the pharmacokinetic parameters of endogenous LH, and there was no correlation of the pharmacokinetic parameters of rhLH with gonadal hormones. The CL, V, and t1/2 of rhLH were independent of markers of glucose homeostasis, including fasting insulin, HOMA, or glucose/insulin ratio. Neither t1/2 nor the estimated CL of endogenous LH was associated with HOMA or fasting insulin. The t1/2 of endogenous LH was inversely associated with fasting glucose (r = –0.47, P = –0.02), and the estimated CL of LH was positively associated with fasting glucose (r = 0.55, P = 0.009). However, glucose correlated with BMI in this study population and stepwise regression indicated that fasting glucose did not add to the ability of BMI to predict the t1/2 or estimated CL of endogenous LH.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In studies designed to investigate the mechanisms underlying the inverse relationship between serum LH concentrations and BMI in patients with PCOS, we have previously demonstrated an inhibitory effect of adiposity on the pituitary response to GnRH with no evidence that BMI alters hypothalamic GnRH secretion (6). In the current study, we investigated the potential contribution of pharmacokinetic factors to the inverse relationship between LH and BMI in PCOS. Our results indicate that the apparent half-life of LH, secreted in response to GnRH, decreases with increasing BMI and suggest that this change in half-life is the result of an effect of obesity on total body clearance of LH.

Previous studies have modeled endogenous and exogenous LH using one- and/or two-compartment models (31, 32, 33, 34, 35). In the current study, the data supported the use of a monoexponential equation to describe the disappearance of both endogenous LH and rhLH from serum. Use of a two-compartment model with elimination from the central compartment did not improve the fit of the data based on the use of objective criteria. In the current study, the basal concentration of endogenous LH was incorporated into the pharmacokinetic model as a parameter. Analyzing pharmacokinetic data for the exogenous administration of an endogenous compound or induced presentation of the compound to circulation by nonlinear regression using a model with fully adjusted background, as in the current and previous studies (36), has been shown to be superior to the more simplistic method of subtracting baseline levels obtained from pretreatment samples from all posttreatment determinations before pharmacokinetic analysis (37). Definition of the terminal region of the concentration–time profile can become severely biased by the baseline subtraction method when the baseline concentration becomes similar to the posttreatment concentrations of the compound, introducing significant error into half-life estimates and even suggesting the artifactual presence of an additional slow disposition phase. Our observation that the decay of serum levels was distinctly monoexponential for endogenous LH and rhLH despite differing basal concentrations provides support for the physiological relevance of the model used.

The half-life of endogenous LH in patients with PCOS in the current study was 1.44 h. This is generally consistent with previous estimates of the half-life of LH in normal premenopausal women but shorter than that in postmenopausal women (35). The mean half-life of rhLH in our patient population was 1.35 h, not different from that of endogenous LH and also similar to previous studies using rhLH (34) or highly purified LH (31, 33). We have now shown that the half-life of rhLH is not modified by BMI in women with PCOS. In contrast, the half-life of endogenous LH, secreted in response to a physiological dose of GnRH, decreased with increasing BMI. A similar effect of obesity on the half-life of LH has been reported in men (17).

The disappearance of any protein from serum is a function of both its apparent volume of distribution and its elimination from the body. To appreciate fully the effect of BMI on the disappearance of LH, it is important to examine these two factors independently. The mean volume of distribution of rhLH in our study was similar to that in previous studies of either rhLH in normal premenopausal women (34) or highly purified LH in men with hypogonadotropic hypogonadism (33). This volume of distribution is roughly equivalent to vascular volume and the interstitial space of well-perfused organs such as the liver and kidney (7). The high molecular weight of glycosylated LH (34), its branching carbohydrate structure (38), and its water solubility undoubtedly prevent more widespread distribution. In the current studies, we have now determined the volume of distribution of rhLH across a wide range of BMIs and demonstrate that it is not influenced by obesity.

The total body clearance of rhLH in the current study was remarkably similar to that in premenopausal women (34). The current study demonstrates that total body clearance of rhLH is not influenced by BMI. We have assumed that the volume of distribution of endogenous LH would be the same as that for rhLH within an individual and used this to estimate the clearance of endogenous LH for each subject. The relationship of the estimated total body clearance of endogenous LH to BMI was even stronger than that between the half-life of endogenous LH and BMI.

Multiple isoforms of LH are secreted by the pituitary and differ in their carbohydrate structure. LH isoform heterogeneity results from posttranslational modification of the asparagine-linked oligosaccharides present on the {alpha}- and ß-subunits of LH (9). Total body clearance varies in relation to the carbohydrate structure of LH resulting from the presence of Gal/GalNAc-specific receptors on hepatic endothelial cells that recognize terminal sequence SO4-GalNacß1,4GlcNAcß-R residues on LH (38). Different LH isoforms can be separated by charge and more basic isoforms are associated with faster total body clearance along with enhanced in vitro bioactivity (10, 11, 12). We found that BMI did not influence the total body clearance of rhLH, which has a standard isoform composition, and hypothesize that the effect of BMI on the half-life and clearance of endogenous LH is the result of an effect of BMI on the isoform composition of endogenously secreted LH. We would therefore predict that obese women with PCOS would have a higher preponderance of more basic isoforms compared with lean women with PCOS. This prediction is supported by the findings in normal men in whom obesity is associated with more basic isoforms of LH with a shorter half-life (17).

It has been suggested that GnRH can influence posttranslational glycosylation of LH and its isoform composition (39, 40). However, we previously showed that neither GnRH pulse frequency nor the estimated quantity of GnRH secreted in women with PCOS varies as a function of BMI (6). LH isoform heterogeneity is also influenced by the gonadal steroid milieu such that estradiol induces the secretion of more basic LH isoforms with shorter half-lives (41, 42) through modulation of pituitary expression of GalNAc- and sulfotransferases (13). In contrast, androgens decrease the synthesis and secretion of more basic LH isoforms (14, 15, 16). In previous studies in lean women with PCOS, there was a predominance of more basic LH isoforms compared with those in control women in the early follicular phase, and the authors suggest that this may be the result of an estrogen-permissive hormonal environment (43). In the current study, there was no association of estradiol, testosterone, or calculated free testosterone with BMI and no evidence that the impact of BMI on the plasma disappearance of LH was mediated by either estradiol or testosterone. Taken together, the inverse relationship between the half-life of endogenous LH and BMI in patients with PCOS does not appear to be accounted for by either gonadal steroids or GnRH, and additional factors that mediate this relationship will need to be considered.

In summary, we found that a single one-compartment open pharmacokinetic model describes the decay of LH in serum in women with PCOS and performs equally well for endogenous LH, secreted in response to a physiological dose of GnRH, and rhLH, administered iv. The results of this study indicate that the half-life of endogenous LH is inversely related to BMI in women with PCOS and suggest that this results from an increase in its estimated clearance with increasing obesity. Because there is no effect of BMI on the pharmacokinetic parameters of rhLH, we hypothesize that the effect of BMI on the clearance of endogenous LH is the result of BMI-dependent alterations in the isoform composition of secreted LH. Further studies will be required to investigate the mechanisms underlying this effect. Taken together with results from our previous study, these data suggest that both decreased pituitary responsiveness and faster LH clearance contribute to the attenuation of LH levels as a function of obesity in PCOS.


   Footnotes
 
This work was supported by National Institutes of Health Grants K24 HD 01290 and M01 RR1066. Recombinant human LH was generously donated by Ares-Serono International, Geneva, Switzerland.

Present address for Y.L.P.: Pediatric Endocrine Unit, Research, Education and Clinical Diabetes Center for Puerto Rico, University of Puerto Rico School of Medicine, San Juan, Puerto Rico.

Disclosure Statement: S.S.S., Y.L.P., F.D., A.D., Y.J., and J.G.S. have nothing to declare. J.E.H. has served on the advisory board for Ferring Pharmaceuticals and consulted for Novartis.

First Published Online January 30, 2007

1 S.S.S. and Y.L.P. contributed equally as first authors. Back

2 J.G.S. and J.E.H. contributed equally as senior authors. Back

Abbreviations: BMI, Body mass index; CL, total body clearance; Ce, basal concentration of endogenous LH; Cs, serum LH concentration; HOMA, homeostatic model assessment; PCOS, polycystic ovarian syndrome; rhLH, recombinant human LH; V, apparent volume of distribution.

Received December 8, 2006.

Accepted January 19, 2007.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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