help button home button Endocrine Society JCEM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2005-1083
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Johnsen, S.
Right arrow Articles by Grinspoon, S. K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Johnsen, S.
Right arrow Articles by Grinspoon, S. K.
Related Collections
Right arrow Female Endocrinology
Right arrow Metabolism
The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 10 5596-5604
Copyright © 2005 by The Endocrine Society

Absence of Polycystic Ovary Syndrome Features in Human Immunodeficiency Virus-Infected Women Despite Significant Hyperinsulinemia and Truncal Adiposity

Stine Johnsen, Sara E. Dolan, Kathleen V. Fitch, Kathleen M. Killilea, Jan L. Shifren and Steven K. Grinspoon

Program in Nutritional and Metabolism (S.J., S.E.D., K.V.F., K.M.K., S.K.G.) and Vincent Memorial Obstetrics and Gynecology Service (J.L.S.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: Steven Grinspoon, M.D., Program in Nutritional Metabolism, Massachusetts General Hospital, Boston, Massachusetts 02114. E-mail: sgrinspoon{at}partners.org.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: HIV-infected women increasingly demonstrate insulin resistance and fat redistribution characterized by relative truncal adiposity. It is unknown whether insulin resistance and truncal adiposity are associated with features of the polycystic ovary syndrome in this population.

Objective: The objective of the study was to characterize ovarian morphology and reproductive indices in a large cohort of HIV-infected women in comparison with healthy age- and body mass index-matched control subjects.

Setting: The study was conducted at an academic medical center.

Subjects: Eighty-eight HIV-infected women were compared with 94 age- and body mass index-matched healthy control subjects.

Main Outcome Measures: Androgen, SHBG, and gonadotropin levels and ovarian morphology were measured.

Results: HIV-infected subjects demonstrated increased visceral adipose tissue (VAT) (101 ± 6 vs. 71 ± 5 cm2; P < 0.0001), increased VAT to sc adipose tissue ratio, and a trend toward decreased abdominal sc adipose tissue. Fasting insulin (12 ± 1 vs. 6 ± 1 µIU/ml; P < 0.001) and 2-h glucose (124 ± 4 vs. 106 ± 4 mg/dl; P = 0.001) were also significantly increased in the HIV-infected women, compared with control subjects, respectively. Despite significant hyperinsulinemia and visceral adiposity, HIV-infected women did not demonstrate irregular menses or an increased number of small ovarian follicles (8.0 ± 0.9 vs. 8.5 ± 0.7 follicles; P = 0.65, HIV-infected vs. controls). Rather, SHBG (124 ± 10 vs. 84 ± 4 nmol/liter; P < 0.001) was increased significantly in HIV-infected women, and free testosterone by equilibrium dialysis was significantly reduced (2.2 ± 0.2 vs. 2.7 ± 0.2 pg/ml; P = 0.04), as was LH to FSH ratio (0.62 ± 0.05 vs. 0.83 ± 0.07; P = 0.03). Menstrual function, androgen levels, and ovarian morphology by ultrasonography were not different between HIV-infected women and healthy controls.

Conclusions: These data demonstrate that among HIV-infected subjects with severe abdominal fat accumulation and hyperinsulinemia, common features of polycystic ovary syndrome are not seen.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
METABOLIC ABNORMALITIES INCLUDING insulin resistance, dyslipidemia, and increased visceral adiposity are frequently observed in HIV-infected women receiving highly active antiretroviral therapy (1, 2, 3). In non-HIV-infected women, truncal adiposity and insulin resistance are often associated with features of the polycystic ovary syndrome (PCOS), including amenorrhea, increased androgen levels, reduced SHBG, increased LH to FSH ratio, and multiple small ovarian follicles (4, 5, 6). Prior studies have demonstrated that the prevalence of insulin resistance and diabetes is more frequent in women with PCOS than an age- and body mass index (BMI)-matched group of women. As many as 35% of women with PCOS have impaired glucose tolerance, whereas 10% are diabetic before the age of 40 yr (7). Insulin resistance in PCOS is unique in that the ovaries are resistant to insulin-mediated glucose uptake, whereas mitogenic response to insulin is sustained (8). Hyperinsulinemia may contribute to hyperandrogenemia through enhanced LH-stimulated androgen secretion from the ovary (9, 10) and reduced circulating SHBG (11).

Among HIV-infected women, little is known regarding the prevalence of PCOS features, e.g. menstrual dysfunction, increased ovarian follicles, and hormonal dysfunction. In a prior study, we demonstrated an increased LH to FSH ratio in a small number of HIV-infected women with lipodystrophy (12). The purpose of the current study was to characterize ovarian morphology and reproductive indices in a large cohort of HIV-infected women in comparison with healthy age- and BMI-matched control subjects. To our knowledge, prior studies have not assessed PCOS features, including ovarian morphology among HIV-infected women and control subjects similar in age, weight, and race.


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

Subjects were recruited for an ongoing longitudinal cohort study. Bone density and cardiovascular risk indices have previously been reported in this cohort (13, 14). Recruitment was accomplished through community advertisement and primary care provider referral. HIV-positive patients were enrolled from March 2000 to July 2002 and the control subjects from October 2000 to October 2003. Consecutive HIV-infected subjects and control subjects were enrolled without regard to fat distribution if they met the eligibility criteria of age between 18 and 60 yr and BMI greater than 20 kg/m2. Exclusion criteria was use of megestrol acetate, ketoconazole, antidiabetic agents, steroids, GH, any form of estrogen (including oral contraceptive pills, oral estrogen replacement, or estrogen patch), medroxyprogesterone acetate, testosterone or any anabolic agent within 3 months of the study, active substance abuse, pregnant or breast-feeding in the past year, history of oophorectomy, or an acute infection within 3 months of the study. HIV-infected subjects who had changed or initiated a new antiretroviral medication less than 2 months before the study were excluded. Eighty-eight HIV-infected women and 94 HIV-negative female controls met these criteria and were included in data analysis for this study. In the control subjects, HIV-negative status was verified by ELISA. Control subjects were healthy without known acute or chronic diseases and were not receiving medication for diabetes, hypertension, or dyslipidemia.

HIV-infected patients were assessed post enrollment for the presence of lipodystrophy based on a waist to hip ratio (WHR) greater than 0.85 and the presence of significant fat redistribution, e.g. loss of fat in the face and arms and increase in abdominal fat, similar to the definition used in our prior studies to successfully identify patients with lipodystrophy (15).

Procedures were performed in accordance with the guidelines of the Helsinki Declaration on human experimentation. The study was approved by the Human Research Committee at the Massachusetts General Hospital and the Committee on the Use of Humans as Experimental Subjects at the Massachusetts Institute of Technology. All subjects gave written informed consent at the beginning of the study.

Procedures

After a screening visit to determine eligibility, subjects returned for an outpatient visit for testing. Testing was performed in the follicular phase in all eumenorrheic subjects. The following procedures and testing were included for the study.

Assessment of antiretroviral drug history and AIDS-related illnesses

Information about duration of HIV infection and antiretroviral medication, including all current antiretroviral medications and duration of all prior antiretroviral medication use, as well as history and timing of all AIDS-related illnesses were obtained from patient interview. Smoking history including duration and length of smoking (pack years) was obtained via a questionnaire.

Reproductive function

Menstrual history was obtained and all subjects were characterized as eumenorrheic (normal menstrual function), oligomenorrheic (less than three menstrual periods in the 3 months before enrollment), or amenorrheic to determine clinically significant menstrual dysfunction. History of hysterectomy and oophorectomy was obtained. Patients were studied in the follicular phase (within 10 d of initiation of menses) to avoid midcycle changes in hormone levels.

Hormonal and biochemical assessment

Blood samples were drawn after a 12-h overnight fast for serum glucose and insulin, serum gonadotrophins (LH, FSH), total testosterone, free testosterone, estradiol, SHBG, and dehydroepiandrosterone sulfate (DHEAS), cholesterol, triglyceride, high-density lipoprotein (HDL), and direct low-density lipoprotein (LDL). The free testosterone concentration was determined as the product of the percent free testosterone concentration, measured by equilibrium dialysis, and the total testosterone concentration (Endocrine Sciences, Inc., Calabasas Hills, CA). A standard 75-g oral glucose challenge was performed. Patients were scored for hirsutism using the Ferriman-Gallwey scale. CD4 count and viral load were measured.

Ovarian ultrasonography

Assessment of the pelvis was performed by transvaginal ultrasound using a 7.5-MHz vaginal probe transducer (LOGIQ 400 MD; General Electric, Fairfield, CT). Uterine size was measured in the sagittal, transverse, and coronal plane, and the double-layer endometrial thickness was assessed in the sagittal plane. Both ovaries were measured in the sagittal, transverse, and coronal plane, and the number of small follicles (2–8 mm diameter) were counted. Any ovarian cysts over 10 mm in size were measured. Ovaries were classified as polycystic based on the presence of 12 or more follicles in each ovary measuring 2–8 mm in diameter and/or increased ovarian volume (>10 ml) (16).

Body composition

Weight and anthropometric measurements were obtained by the bionutrition staff of the General Clinical Research Center before breakfast. The WHR was calculated dividing the waist circumference measured at the iliac crest by the hip circumference measured at the horizontal level of maximum extension of the buttocks. All measurements were obtained in triplicate, with the patient undressed. To assess visceral abdominal tissue (VAT) and sc adipose tissue (SAT), a cross-sectional abdominal computed tomography (CT) scan at the level of the L4 pedicle was performed. Scan parameters for each image were standardized (144 table height, 80 kV, 70 mA, 2 sec, 0.25 cm x 4 slice thickness, 48 FOV). Fat attenuation coefficients were set at –50 to –250 (Hounsfield units). Total fat was measured by dual-energy x-ray absorptiometry (Hologic) with a precision error of 3.0%. Regional fat in the extremities was determined as previously described.

Assay methods

Insulin levels were measured in serum using a RIA (Diagnostic Products Corp., Los Angeles, CA). Intraassay and interassay coefficients of variation (CVs) range from 3.1–9.3 to 4.9–10.0%. LDL cholesterol was measured directly (Genzyme Diagnostics, Cambridge, MA). Total cholesterol, HDL cholesterol, triglyceride, and glucose were measured using standard techniques. Serum estradiol was measured by RIA kit (Diagnostic Systems Laboratories, Inc., Webster, TX) with an intraassay CV of 6.5–8.9%. Serum LH was measured using a solid-phase immunoradiometric assay (Diagnostic Products Corp.) with an intraassay CV of 1.0–1.6%. Serum FSH was measured using a solid-phase immunoradiometric assay (Diagnostics Products Corp.) with an intraassay CV of 2.2–3.8%. CD4+ count was determined by flow cytometry (Becton Dickinson Biosciences, San Jose, CA), and HIV viral load was determined by ultrasensitive assay (Amplicor HIV-1 monitor assay, Roche Molecular Systems, Branchburg, NJ) with limits of detection of 50 to 75,000 RNA copies/ml.

Statistical analysis

Comparisons were made by HIV status using Student’s t test for continuous variables and the {chi}2 test for noncontinuous variables. Pairwise comparisons were made in a subanalysis between HIV subjects with and without lipodystrophy and healthy control subjects using the Tukey-Kramer test for multiple comparisons. For nominal variables, Bonferroni adjusted P values were used to demonstrate statistical significance. Univariate regression analyses were performed relating endocrine and metabolic parameters among HIV and control subjects. Nonparametric test (Spearman rho) were used for variables not normally distributed. Multivariate regression analyses were performed among all subjects to determine the relationship of free testosterone, insulin, WHR, HIV status, and age to follicle number and hirsutism score. All values are expressed as mean values ± SEM unless otherwise indicated. Significant differences were defined as P < 0.05. Statistical analyses were performed using JMP for SAS (version 5.1; SAS Institute, Cary, NC).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Demographics

Between March 2000 and October 2003, 124 HIV-infected women and 140 HIV-negative controls were screened. Of these 88 HIV-infected women and 94 HIV-negative controls were found eligible for the study. HIV-infected and control subjects were similar in age (41 ± 1 vs. 41 ± 1 yr, P = 0.98), BMI (25.7 ± 0.4 vs. 26.6 ± 0.04 kg/m2, P = 0.13), and race (61 vs. 63% non-Caucasian, P = 0.85) (HIV infected vs. controls, respectively) (Table 1Go).


View this table:
[in this window]
[in a new window]
  		TABLE 1. Demographics for HIV patients vs. controls

 
A significant proportion of HIV-infected women were currently smoking, compared with the control group (45 vs. 29%, P = 0.02), and smoking pack-years were also significantly different between the two groups (9.1 ± 1.2 vs. 2.4 ± 0.5, P < 0.001, HIV infected vs. controls) (Table 1Go). The mean CD4 cell count was 387 ± 20 cells/mm3, and 41% of patients had undetectable HIV viral load (Table 1Go).

Metabolic and body composition parameters

Several metabolic and body composition parameters were significantly different between HIV-infected patients and controls (Table 2Go). Two-hour blood glucose level on standard oral glucose tolerance test testing was increased, compared with the control group (124 ± 4.0 vs. 106 ± 4 mg/dl, P = 0.001, HIV infected vs. controls), whereas the mean fasting glucose was not different between the two groups (84 ± 1 vs. 83 ± 1 mg/dl, P = 0.78, HIV infected vs. controls) (Table 2Go). Fasting insulin (12 ± 1 vs. 6 ± 1 µIU/ml, P < 0.001; Fig. 1Go) and 2-h insulin levels after glucose tolerance testing were significantly increased in the HIV-infected patients (73 ± 8 vs. 42 ± 4 µIU/ml, P < 0.001), HIV infected vs. controls, respectively (Table 2Go). Based on World Health Organization criteria, impaired glucose tolerance (19 vs. 7%, P = 0.02) but not diabetes (2.7 vs. 2.2%, P = 0.83) was more common in HIV-infected subjects (Table 2Go).


View this table:
[in this window]
[in a new window]
  		TABLE 2. Metabolic, endocrine, and gynecological parameters for HIV-positive patients vs. controls

 


View larger version (16K):
[in this window]
[in a new window]
  		FIG. 1. HIV-infected subjects (black bars) and healthy controls (white bars). Bars depict mean of DHEAS, free testosterone, total number of follicles, fasting insulin, SHBG, and iliac WHR within each group. Error bar, SEM. *, P ≤ 0.05; **, P ≤ 0.001.

 
Hip circumference was significantly lower in the HIV-infected subjects, compared with the control subjects. Abdominal visceral fat area was significantly higher among the HIV-infected subjects, compared with control individuals as was WHR and the ratio of visceral to sc fat determined by CT. Subcutaneous fat area was not significantly different between the two groups, although a trend toward lower sc fat in the HIV-infected subjects was seen (P = 0.09) (Table 2Go).

Reproductive parameters

Cycle day of testing and estradiol levels were similar between the groups. Five percent of control subjects were oligomenorrheic, and 10% were amenorrheic. Twelve percent of HIV-infected subjects were oligomenorrheic and 16% were amenorrheic, overall P = 0.10 by {chi}2 analysis). Hirsutism scores were not different between the groups (1.1 ± 0.3 vs. 0.9 ± 0.2, P = 0.56, HIV infected vs. controls) (Table 2Go).

Patients (n = 9) who had an oophorectomy were excluded from the analysis. Eight HIV and one control subject had an oophorectomy. The reasons for oophorectomy could not be definitively established in all cases, but no subject indicated PCOS as a reason for oophorectomy.

Endocrine parameters

FSH, estradiol, and LH levels were not significantly different between the two groups (Table 2Go). The LH to FSH ratio was decreased in the HIV patients, compared with the controls (0.62 ± 0.05 vs. 0.83 ± 0.07, P = 0.03, HIV-infected vs. controls). Seven percent in each group (HIV infected and control subjects) demonstrated an FSH level greater than 15 IU/liter and were classified as perimenopausal. Excluding perimenopausal subjects from the analysis did not change the LH to FSH ratio in either group. SHBG levels were significantly increased in HIV-infected patients (124 ± 10 vs. 84 ± 4 nmol/liter, P = 0.0002, HIV infected vs. controls). Free testosterone was significantly lower in the HIV-infected patients (2.2 ± 0.2 vs. 2.7 ± 0.2 pg/ml, P = 0.04, HIV infected vs. controls), but there was no difference in total testosterone level between the two groups. DHEAS levels tended to be reduced in HIV-infected women (101 ± 9 vs.125 ± 10 µg/dl, P = 0.10, HIV infected vs. controls) (Table 2Go).

Ovarian morphology

By transvaginal ultrasonography, uterine size, endometrial thickness, ovarian size, and the number and size of all follicles were determined. The size of the uterus was significantly larger in the control group. No difference in the prevalence of fibroids was noted. No difference was detected between groups with regard to ovarian volume or number of follicles. The percentage of subjects characterized with polycystic ovarian morphology according to the Rotterdam criteria were almost identical with 23 and 24% for HIV-infected women and healthy controls, respectively (Table 2Go).

Subanalysis by lipodystrophy status

Fifty-nine HIV patients were subclassified as lipodystrophic and 29 were classified as nonlipodystrophic (Table 3Go). HIV-infected patients with lipodystrophy demonstrated significantly increased insulin, VAT, and triglycerides and lower HDL, compared with healthy controls. In contrast, there were no differences between nonlipodystrophic and control subjects in metabolic and anthropometric variables other than reduced HDL in the nonlipodystrophic subjects (Table 4Go). Androgen and gonadotropin levels were not different between lipodystrophic and control subjects, whereas DHEAS was reduced in the nonlipodystrophic group, compared with control subjects. SHBG levels were increased in both HIV groups vs. control (lipodystrophic vs. control and nonlipodystrophic vs. control), although levels were most prominently increased in the nonlipodystrophic group (Table 4Go). Despite severely increased insulin and VAT in the lipodystrophic group, there were no significant differences in total ovarian follicle number or volume between the lipodystrophic and control groups (Table 4Go).


View this table:
[in this window]
[in a new window]
  		TABLE 3. Demographics for HIV patients with and without lipodystrophy vs. controls

 

View this table:
[in this window]
[in a new window]
  		TABLE 4. Metabolic, endocrine, and gynecological parameters for HIV patients with and without lipodystrophy vs. controls

 
Regression analyses

Univariate regression analyses were performed comparing total follicle number, fasting insulin, WHR, free testosterone, SHBG, DHEAS, and CD4 count among the HIV-infected and controls separately (Table 5Go). Interestingly, there was no correlation between SHBG and insulin in the HIV-infected patients (r = –0.15, P = 0.21), whereas in the healthy controls SHBG was inversely correlated with insulin (r = –0.34, P = 0.001). Among the HIV-infected subjects, free testosterone but not DHEAS correlated with total number of ovarian follicles, whereas both free testosterone and DHEAS correlated with total number of ovarian follicles in the healthy control subjects (Table 5Go). In the HIV patients, CD4 counts were significantly inversely correlated to SHBG (r = –0.22, P = 0.05), whereas this association was not significant for the healthy control subjects. Ovarian follicle number and SHBG did not correlate with use of antiretroviral therapy (data not shown).


View this table:
[in this window]
[in a new window]
  		TABLE 5. Correlation matrix for HIV patients and health controls

 
Multivariate regression analysis

In a combined analysis among all subjects, fasting insulin, age, WHR, free testosterone, and HIV status were assessed in least squares regression modeling for total follicle number and hirsutism score. In the model for follicle number, free testosterone (beta = 0.90, P = 0.009) and age (beta = –0.56, P < 0.0001) but not fasting insulin (P = 0.68), HIV status (P = 0.72), or WHR (P = 0.99) were significant. In the model for hirsutism score, free testosterone (beta = 0.39, P = 0.005) but not age (P = 0.95), fasting insulin (P = 0.85), HIV status (P = 0.19), or WHR (P = 0.83) were significant. For every 1 pg/ml increase in free testosterone, follicle number increased by approximately 1 and hirsutism score increased by 0.39.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In this study we sought to characterize and compare ovarian morphology and reproductive indices in consecutively recruited HIV-infected women and age-, BMI-, and race-matched control subjects. Metabolic abnormalities including hyperinsulinemia and changes in body composition are frequently observed in female patients with HIV (17). Indeed, in this study HIV-infected patients were not chosen on the basis of fat distribution, but these changes were common and seen in approximately two thirds of patients. Among HIV-negative women, accumulation of truncal fat and high levels of fasting insulin are associated with features of PCOS (4, 7). In this study, we demonstrate that despite significant hyperinsulinemia and visceral adiposity, HIV-infected women did not demonstrate irregular menses, increased numbers of ovarian follicles, increased LH to FSH ratio or phenotypic features of PCOS, including hirsutism. SHBG was significantly increased in HIV-infected women, and free testosterone was decreased as measured by equilibrium dialysis. There was no difference between the two groups with regard to number of follicles or ovarian morphology as assessed by vaginal ultrasonography. Twenty-three vs. 24% of HIV-infected and healthy controls had ovarian morphology consistent with a PCOS pattern based on the revised 2003 consensus criteria (15).

Although HIV patients were not recruited based on hyperinsulinemia, insulin levels and rates of impaired glucose tolerance were significantly increased, compared with the normal control subjects. The insulin levels reported among the HIV-infected subjects are in the range of previously reported data for PCOS (18, 19, 20, 21). Furthermore, visceral fat area and WHR were significantly increased among HIV infected women, compared with control subjects. The relationship between hyperinsulinemia and androgen excess in non-HIV-infected patients is not well understood, but insulin may increase androgen production through effects on gonadotropin secretion, direct effects on ovarian thecal androgen production, or reduction in SHBG through hepatic exposure to increased portal insulin levels (9, 10, 22). Indeed, treatment of hyperinsulinemic women with PCOS with metformin, an insulin-sensitizing agent that reduces insulin levels, increases SHBG and reduces free testosterone (23, 24, 25). Despite elevated levels of fasting insulin and accumulation of truncal fat, features often associated with PCOS (26), HIV-infected women did not demonstrate increased androgen levels, changes in ovarian morphology, or increased number of follicles, compared with the healthy control group. Moreover, neither the prevalence of menstrual dysfunction nor hirsutism was increased. This was true even among the group classified as lipodystrophic.

In women with PCOS, levels of SHBG are decreased. The mechanism for low SHBG levels in PCOS is unclear, but hyperinsulinemia may suppress hepatic SHBG production directly or indirectly through increased ovarian thecal cell androgen production (11, 24). Despite elevated levels of fasting insulin, SHBG levels were not suppressed in the HIV group. On the contrary, levels of SHBG were elevated significantly, compared with the healthy controls, and there was no relationship between SHBG and insulin in the HIV-infected patients, which may indicate relative resistance to the suppressive action of insulin on SHBG at the level of the liver. In contrast, hyperinsulinemia was associated with increased WHR and reduced SHBG in the control subjects. A large number of studies have demonstrated increased SHBG in men with severe illness or HIV (27, 28, 29), but our study is among the first to document increased SHBG in a large cohort of HIV-infected women and matched controls. Our data suggest a link between the degree of illness, immunosuppression, and SHBG production. We found a significant inverse relationship between SHBG and CD4 in our population. Patients with HIV and no lipodystrophy had the lowest CD4 count and the highest SHBG, in comparison with both HIV patients with lipodystrophy and controls subjects. These data are in accord with the theory that illness per se is associated with increases in SHBG that may in turn influence androgen levels.

Free testosterone levels measured by equilibrium dialysis were reduced among the HIV-infected patients, consistent with prior data demonstrating reduced androgen levels in this population (17, 30, 31). In a prior study enrolling significantly fewer subjects, hyperandrogenemia and increased LH to FSH ratio were seen among HIV-infected women, but reduced levels of SHBG in that study may account for differences with the current study (12).

In prior studies we have shown reduced DHEAS levels and shunting away from adrenal androgen production in this population (30). In the current study, we show a nearly significant reduction in DHEAS among all the HIV-infected patients and significantly reduced DHEAS level in the nonlipodystrophic group, compared with control subjects.

We demonstrate an inverse relationship between DHEAS and SHBG in control subjects, consistent with data from prospective studies in which DHEA was given to young women, resulting in SHBG reduction (32, 33). However, among HIV-infected subjects, there was no relationship between SHBG and DHEAS, likely reflecting the unique regulation of SHBG in this population. Among HIV-infected women, increased SHBG may further contribute to reduced free testosterone levels.

The HIV patients did not demonstrate any differences, compared with the healthy controls, in regard to estrogen levels. In PCOS, estrogen levels are often normal or even increased, whereas an increased LH to FSH ratio is often observed due to increased LH and decreased FSH (34, 35). LH increases the secretion of androstenedione, and FSH facilitates the conversion of androgen precursors to estrone and estradiol; hence, the increased LH to FSH ratio predates hyperandrogenism and is associated with moderate increases in estradiol. In this study, the LH to FSH ratio was not elevated but rather decreased in the HIV-infected women, compared with healthy controls.

In a subgroup analysis, HIV patients were classified as either lipodystrophic (n = 59) or nonlipodystrophic (n = 29) based on history, physical examination, and lipodystrophy score. Classification was made at the baseline visit before knowledge of any laboratory or ultrasound results. HIV-infected women classified as lipodystrophic presented with significantly higher levels of fasting insulin, elevated 2-h insulin, and 2 h-glucose on glucose tolerance testing. Additionally the lipodystrophic group demonstrated increased WHR and increased VAT. Despite severe hyperinsulinemia, menstrual function, androgen levels, ovarian follicle number, and volume were not different between lipodystrophic subjects and healthy controls, whereas DHEAS levels were reduced in nonlipodystrophic subjects, compared with healthy controls.

In regression analysis, we examined the relationship between SHBG, insulin, androgen levels, and ovarian follicle number. In the healthy controls, SHBG was significantly inversely related to levels of insulin, whereas this association could not be found in the HIV-infected women. Taken together, these data demonstrate that the normal inverse relationship between insulin and SHBG is not seen among HIV-infected patients, perhaps because SHBG levels are very increased. Reduced free testosterone levels may be one factor contributing to the absence of polycystic ovaries in hyperinsulinemic, viscerally obese, HIV-infected women. However, other unknown factors may also contribute, and further research is needed to determine the relationship of sex steroids to menstrual function and ovarian morphology in HIV-infected women. In multivariate regression analyses among all the subjects, increased free testosterone was associated with increased follicle number and hirsutism index, controlling for insulin, age, and WHR. In contrast, insulin was not associated with either follicle number or hirsutism index.

In conclusion, this study suggests that despite severe abdominal fat accumulation and hyperinsulinemia, increased ovarian follicle number, irregular menses, hirsutism, and increased LH to FSH ratio are not seen among HIV-infected women.


   Acknowledgments
 
We are grateful to the nursing and bionutrition staff for their dedicated patient care and Jeff Breu for help with the RIAs for the protocol.


   Footnotes
 
This work was supported in part by National Institutes of Health Grants R01 DK59535 and M01-RR-01066.

First Published Online August 2, 2005

Abbreviations: BMI, Body mass index; CT, computed tomography; CV, coefficient of variation; DHEAS, dehydroepiandrosterone sulfate; HDL, high-density lipoprotein; LDL, low-density lipoprotein; PCOS, polycystic ovary syndrome; SAT, sc adipose tissue; VAT, visceral abdominal tissue; WHR, waist to hip ratio.

Received May 16, 2005.

Accepted July 27, 2005.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Hadigan C, Miller K, Corcoran C, Anderson E, Basgoz N, Grinspoon S 1999 Fasting hyperinsulinemia and changes in regional body composition in human immunodeficiency virus-infected women. J Clin Endocrinol Metab 84:1932–1937[Abstract/Free Full Text]
  2. Gervasoni C, Ridolfo AL, Trifiro G, Santambrogio S, Norbiato G, Musicco M, Clerici M, Galli M, Moroni M 1999 Redistribution of body fat in HIV-infected women undergoing combined antiretroviral therapy. AIDS 13:465–471[CrossRef][Medline]
  3. Dong KL, Bausserman LL, Flynn MM, Dickinson BP, Flanigan TP, Mileno MD, Tashima KT, Carpenter CC 1999 Changes in body habitus and serum lipid abnormalities in HIV-positive women on highly active antiretroviral therapy (HAART). J Acquir Immune Defic Syndr 21:107–113
  4. Azziz R, Woods KS, Reyna R, Key TJ, Knochenhauer ES, Yildiz BO 2004 The prevalence and features of the polycystic ovary syndrome in an unselected population. J Clin Endocrinol Metab 89:2745–2749[Abstract/Free Full Text]
  5. Chang RJ 2004 A practical approach to the diagnosis of polycystic ovary syndrome. Am J Obstet Gynecol 191:713–717[CrossRef][Medline]
  6. Ehrmann DA 2005 Polycystic ovary syndrome. N Engl J Med 352:1223–1236[Free Full Text]
  7. Ehrmann DA, Barnes RB, Rosenfield RL, Cavaghan MK, Imperial J 1999 Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care 22:141–146[Abstract/Free Full Text]
  8. Book CB, Dunaif A 1999 Selective insulin resistance in the polycystic ovary syndrome. J Clin Endocrinol Metab 84:3110–3116[Abstract/Free Full Text]
  9. Nestler JE, Jakubowicz DJ, de Vargas AF, Brik C, Quintero N, Medina F 1998 Insulin stimulates testosterone biosynthesis by human thecal cells from women with polycystic ovary syndrome by activating its own receptor and using inositolglycan mediators as the signal transduction system. J Clin Endocrinol Metab 83:2001–2005[Abstract/Free Full Text]
  10. Barbieri RL, Makris A, Ryan KJ 1984 Insulin stimulates androgen accumulation in incubations of human ovarian stroma and theca. Obstet Gynecol 64:73S–80S
  11. Nestler JE, Powers LP, Matt DW, Steingold KA, Plymate SR, Rittmaster RS, Clore JN, Blackard WG 1991 A direct effect of hyperinsulinemia on serum sex hormone-binding globulin levels in obese women with the polycystic ovary syndrome. J Clin Endocrinol Metab 72:83–89[Abstract/Free Full Text]
  12. Hadigan C, Corcoran C, Piecuch S, Rodriguez W, Grinspoon S 2000 Hyperandrogenemia in human immunodeficiency virus-infected women with the lipodystrophy syndrome. J Clin Endocrinol Metab 85:3544–3550[Abstract/Free Full Text]
  13. Dolan SE, Huang JS, Killilea KM, Sullivan MP, Aliabadi N, Grinspoon S 2004 Reduced bone density in HIV-infected women. AIDS 18:475–483[CrossRef][Medline]
  14. Dolan SE, Hadigan C, Killilea KM, Sullivan MP, Hemphill L, Lees RS, Schoenfeld D, Grinspoon S 2005 Increased cardiovascular disease risk indices in HIV-infected women. J Acquir Immune Defic Syndr 39:44–54
  15. Driscoll SD, Meininger GE, Lareau MT, Dolan SE, Killilea KM, Hadigan CM, Lloyd-Jones DM, Klibanski A, Frontera WR, Grinspoon SK 2004 Effects of exercise training and metformin on body composition and cardiovascular indices in HIV infected patients. AIDS 18:465–473[CrossRef][Medline]
  16. 2004 Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 81:19–25
  17. Grinspoon S, Corcoran C, Miller K, Biller BM, Askari H, Wang E, Hubbard J, Anderson EJ, Basgoz N, Heller HM, Klibanski A 1997 Body composition and endocrine function in women with acquired immunodeficiency syndrome wasting. J Clin Endocrinol Metab. [Erratum (1997) 82:3360] 82:1332–1337
  18. Tarkun I, Arslan BC, Canturk Z, Turemen E, Sahin T, Duman C 2004 Endothelial dysfunction in young women with polycystic ovary syndrome: relationship with insulin resistance and low-grade chronic inflammation. J Clin Endocrinol Metab 89:5592–5596[Abstract/Free Full Text]
  19. Erturk E, Kuru N, Savci V, Tuncel E, Ersoy C, Imamoglu S 2004 Serum leptin levels correlate with obesity parameters but not with hyperinsulinism in women with polycystic ovary syndrome. Fertil Steril 82:1364–1368[CrossRef][Medline]
  20. Talbott EO, Zborowski JV, Boudreaux MY, McHugh-Pemu KP, Sutton-Tyrrell K, Guzick DS 2004 The relationship between C-reactive protein and carotid intima-media wall thickness in middle-aged women with polycystic ovary syndrome. J Clin Endocrinol Metab 89:6061–6067[Abstract/Free Full Text]
  21. Escobar-Morreale HF, Botella-Carretero JI, Villuendas G, Sancho J, San Millan JL 2004 Serum interleukin-18 concentrations are increased in the polycystic ovary syndrome: relationship to insulin resistance and to obesity. J Clin Endocrinol Metab 89:806–811[Abstract/Free Full Text]
  22. Nelson VL, Qin Kn KN, Rosenfield RL, Wood JR, Penning TM, Legro RS, Strauss 3rd JF, McAllister JM 2001 The biochemical basis for increased testosterone production in theca cells propagated from patients with polycystic ovary syndrome. J Clin Endocrinol Metab 86:5925–5933[Abstract/Free Full Text]
  23. Ortega-Gonzalez C, Luna S, Hernandez L, Crespo G, Aguayo P, Arteaga-Troncoso G, Parra A 2005 Responses of serum androgen and insulin resistance to metformin and pioglitazone in obese, insulin-resistant women with polycystic ovary syndrome. J Clin Endocrinol Metab 90:1360–1365[Abstract/Free Full Text]
  24. Toscano V, Balducci R, Bianchi P, Guglielmi R, Mangiantini A, Sciarra F 1992 Steroidal and non-steroidal factors in plasma sex hormone binding globulin regulation. J Steroid Biochem Mol Biol 43:431–437[CrossRef][Medline]
  25. Sepilian V, Nagamani M 2005 Effects of rosiglitazone in obese women with polycystic ovary syndrome and severe insulin resistance. J Clin Endocrinol Metab 90:60–65[Abstract/Free Full Text]
  26. Adams JM, Taylor AE, Crowley Jr WF, Hall JE 2004 Polycystic ovarian morphology with regular ovulatory cycles: insights into the pathophysiology of polycystic ovarian syndrome. J Clin Endocrinol Metab 89:4343–4350[Abstract/Free Full Text]
  27. Grinspoon S, Corcoran C, Lee K, Burrows B, Hubbard J, Katznelson L, Walsh M, Guccione A, Cannan J, Heller H, Basgoz N, Klibanski A 1996 Loss of lean body and muscle mass correlates with androgen levels in hypogonadal men with acquired immunodeficiency syndrome and wasting. J Clin Endocrinol Metab 81:4051–4058[Abstract/Free Full Text]
  28. Martin ME, Benassayag C, Amiel C, Canton P, Nunez EA 1992 Alterations in the concentrations and binding properties of sex steroid binding protein and corticosteroid-binding globulin in HIV+ patients. J Endocrinol Invest 15:597–603[Medline]
  29. van den Berghe G, Weekers F, Baxter RC, Wouters P, Iranmanesh A, Bouillon R, Veldhuis JD 2001 Five-day pulsatile gonadotropin-releasing hormone administration unveils combined hypothalamic-pituitary-gonadal defects underlying profound hypoandrogenism in men with prolonged critical illness. J Clin Endocrinol Metab 86:3217–3226[Abstract/Free Full Text]
  30. Grinspoon S, Corcoran C, Stanley T, Rabe J, Wilkie S 2001 Mechanisms of androgen deficiency in human immunodeficiency virus-infected women with the wasting syndrome. J Clin Endocrinol Metab 86:4120–4126[Abstract/Free Full Text]
  31. Sinha-Hikim I, Arver S, Beall G, Shen R, Guerrero M, Sattler F, Shikuma C, Nelson JC, Landgren BM, Mazer NA, Bhasin S 1998 The use of a sensitive equilibrium dialysis method in the measurement of free testosterone levels in healthy cycling women and human immunodeficiency virus-infected women. J Clin Endocrinol Metab 83:1312–1318[Abstract/Free Full Text]
  32. Dhatariya K, Bigelow ML, Nair KS 2005 Effect of dehydroepiandrosterone replacement on insulin sensitivity and lipids in hypoadrenal women. Diabetes 54:765–769[Abstract/Free Full Text]
  33. Morales AJ, Haubrich RH, Hwang JY, Asakura H, Yen SS 1998 The effect of six months treatment with a 100 mg daily dose of dehydroepiandrosterone (DHEA) on circulating sex steroids, body composition and muscle strength in age-advanced men and women. Clin Endocrinol (Oxf) 49:421–432[CrossRef][Medline]
  34. Anttila L, Ding YQ, Ruutiainen K, Erkkola R, Irjala K, Huhtaniemi I 1991 Clinical features and circulating gonadotropin, insulin, and androgen interactions in women with polycystic ovarian disease. Fertil Steril 55:1057–1061[Medline]
  35. Arroyo A, Laughlin GA, Morales AJ, Yen SS 1997 Inappropriate gonadotropin secretion in polycystic ovary syndrome: influence of adiposity. J Clin Endocrinol Metab 82:3728–3733[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 J. Lipid Res.Home page
R. A. Hegele, T. R. Joy, S. A. Al-Attar, and B. K. Rutt
Thematic review series: Adipocyte Biology. Lipodystrophies: windows on adipose biology and metabolism
J. Lipid Res., July 1, 2007; 48(7): 1433 - 1444.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
S. Johnsen, S. E. Dolan, K. V. Fitch, J. R. Kanter, L. C. Hemphill, J. M. Connelly, R. S. Lees, H. Lee, and S. Grinspoon
Carotid Intimal Medial Thickness in Human Immunodeficiency Virus-Infected Women: Effects of Protease Inhibitor Use, Cardiac Risk Factors, and the Metabolic Syndrome
J. Clin. Endocrinol. Metab., December 1, 2006; 91(12): 4916 - 4924.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Johnsen, S.
Right arrow Articles by Grinspoon, S. K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Johnsen, S.
Right arrow Articles by Grinspoon, S. K.
Related Collections
Right arrow Female Endocrinology
Right arrow Metabolism

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals