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Endocrine Care |
Division of Pediatric Endocrinology, Metabolism, and Diabetes Mellitus, Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15213
Address all correspondence and requests for reprints to: Silva A. Arslanian, M.D., Division of Endocrinology, Children’s Hospital of Pittsburgh, 3705 Fifth Avenue at DeSoto Street, Pittsburgh, Pennsylvania 15213. E-mail: . arslans{at}chplink.chp.edu
Abstract
Functional adrenal hyperandrogenism occurs in women with polycystic ovary syndrome (PCOS). Insulin, similar to its ovarian effect, may impact the regulation of adrenal steroidogenesis by modulating the activity of P450c17
, the rate-limiting enzyme in androgen biosynthesis. We previously demonstrated that obese adolescents with PCOS are severely insulin resistant and are at heightened risk for impaired glucose tolerance and type 2 diabetes. In the present study we tested the hypothesis that metformin therapy in obese adolescents with PCOS will attenuate the adrenal steroidogenic response to ACTH, with reduction of insulin resistance/insulinemia. Fifteen adolescents with PCOS and impaired glucose tolerance received 3 months of metformin (850 mg, twice daily) therapy. Pre- and posttherapy they had oral glucose tolerance testing, ACTH stimulation test, a 3-h hyperinsulinemic (80 mU/m2·min)-euglycemic clamp to assess insulin sensitivity and a hyperglycemic clamp to assess insulin secretion.
After 3 months of metformin treatment, glucose intolerance improved, with eight subjects having normal glucose tolerance. Total and free T decreased [1.5 ± 0.2 vs. 1.0 ± 0.1 nmol/liter (P = 0.022) and 41.3 ± 8.3 vs. 22.2 ± 2.1 pmol/liter (P = 0.028), respectively]. Insulin-stimulated glucose disposal increased (21.5 ± 2.2 vs. 25.0 ± 2.2 µmol/kg·min; P = 0.041). Fasting insulin and oral glucose tolerance test insulin and glucose area under the curve decreased significantly. ACTH-stimulated increases in androstenedione, 17-hydroxyprogesterone, and 17-hydroxypregnenelone were lower after metformin treatment [2.8 ± 0.4 vs. 1.7 ± 0.3 nmol/liter (P = 0.014), 7.0 ± 0.6 vs. 5.3 ± 0.5 nmol/liter (P = 0.011), and 30.4 ± 3.7 vs. 25.7 ± 4.2 nmol/liter (P = 0.054)]. Fasting insulin correlated with the 17-hydroxypregnenelone response to ACTH stimulation (r = 0.52; P = 0.008).
In summary, metformin treatment of obese adolescents with PCOS and impaired glucose tolerance is beneficial in improving glucose tolerance and insulin sensitivity, in lowering insulinemia, and in reducing elevated androgen levels. Moreover, metformin therapy is associated with attenuation of the adrenal steroidogenic response to ACTH. Metformin therapy was well tolerated. In conclusion, double blind, placebo-controlled studies will determine whether insulin-sensitizing therapy corrects not only ovarian hyperandrogenism but also functional adrenal hyperandrogenism in adolescents with PCOS.
FUNCTIONAL ADRENAL hyperandrogenism (FAH) is observed in 40–70% of women with polycystic ovary syndrome (PCOS) (1, 2, 3, 4, 5, 6). The most common adrenal abnormality in FAH is hyperresponsiveness to ACTH of dehydroepiandrosterone and 17-hydroxypregnenelone, followed by androstenedione and 17-hydroxyprogesterone (1). The mechanism(s) underlying the exaggerated adrenal androgen response to ACTH in FAH remains unknown. One mechanism that has gained popularity is dysregulation of P450c17, the rate-limiting enzyme in androgen biosynthesis (1, 3, 5, 7). Insulin is proposed as the candidate responsible for both ovarian and adrenal dysregulation, resulting in both ovarian and adrenal hyperandrogenism (1, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18). Several studies have demonstrated that insulin-sensitizing agents such as metformin or troglitazone decrease hyperinsulinemia and ovarian hyperandrogenism in women with PCOS (10, 11, 12, 14, 15, 17, 19, 20). Data are limited in adolescents. A recent study of metformin therapy in nonobese adolescents with anovulatory hyperandrogenism after precocious pubarche found results similar to adults (21, 22). The data regarding insulin sensitization and adrenal hyperandrogenism in adults are limited and conflicting (23, 24).
We previously demonstrated that obese adolescents with PCOS are severely insulin resistant, with hyperinsulinemia (25). Moreover, they are at increased risk for developing type 2 diabetes mellitus (26). The aim of the present investigation was to test the hypothesis that metformin treatment in obese adolescents with PCOS will ameliorate FAH and attenuate the adrenal steroidogenic response to ACTH consequent to reducing insulinemia. There are no studies in the pediatric age group that have investigated the impact of insulin-sensitizing therapy on FAH. In an open label trial we assessed the effects of 3 months of metformin treatment (850 mg, twice daily) on glucose tolerance, insulin sensitivity and secretion, and ACTH-stimulated adrenal androgen response.
Subjects and Methods
Study subjects
Fifteen adolescents (six Black and nine Caucasian) with PCOS and impaired glucose tolerance (IGT) participated in this study. They were referred to the endocrine service at Children’s Hospital of Pittsburgh for evaluation of irregular menses (n = 11), and hirsutism and acne (n = 4). The age at menarche ranged from 9–13 yr, with a mean of 11.0 ± 1.3 yr. The diagnosis of PCOS was made as in our previous studies (25, 26). All had IGT based on a 2-h plasma glucose measurement during an oral glucose tolerance test (OGTT). None was receiving any medication at the time of enrollment. The studies were approved by the human rights committee of Children’s Hospital of Pittsburgh. Research participants and parents gave written informed consent after thorough explanation and before initiation of research studies. The clinical characteristics of the study subjects are summarized in Table 1
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Each subject was evaluated before and after 3 months of metformin treatment. Metformin hydrochloride (Glucophage) was administered as an investigational new drug from the FDA (IND 57, 282). The starting dose of metformin was 850 mg/d for 1–2 wk, and this was escalated to 850 mg, twice daily. Each participant had identical evaluations before and after 3 months of metformin therapy. For each evaluation they were admitted twice to the General Clinical Research Center, 1–2 wk apart, for a 3-h OGTT, a hyperinsulinemic-euglycemic and a hyperglycemic clamp, and a 30-min ACTH stimulation test. The sequence of evaluations for the different tests was random. All General Clinical Research Center admissions were on the previous afternoon for testing the following morning.
Metabolic studies
The methodologies for evaluation of insulin sensitivity, insulin secretion, and hepatic glucose production have been described by us previously (25, 26). Briefly, fasting hepatic glucose production was measured with a primed (2.8 µmol/kg) constant infusion (0.28 µmol/kg·min) of [6,6-2H2]glucose for 2 h. In vivo insulin sensitivity was measured during a 3-h hyperinsulinemic (80 mU/m2/m2·min)-euglycemic clamp in conjunction with indirect calorimetry. In vivo insulin secretion was assessed during a 2-h hyperglycemic clamp (12.5 mmol/liter). ACTH stimulation test consisted of administering Cortrosyn (Organon,, West Orange, NJ; 0.25 mg, iv) over 1 min. Blood samples were obtained for 17-hydroxypregnenelone, 17-hydroxyprogesterone, androstenedione, and dehydroepiandrosterone (DHEA) before administration of Cortrosyn and 30 min postinfusion (27). An ACTH stimulation test performed in 26 healthy women with regular menstrual cycles (age range, 16–35 yr) reported from our center was used as reference normative data (27). Body composition, by dual energy x-ray absorptiometry, and abdominal adiposity, by computed tomography scan, were assessed pre- and postmetformin therapy as we previously described (26).
Biochemical measurements
The biochemical methods are identical to what we have described in the past (25, 26). Briefly, total and free T and 17-hydroxypregnenelone were measured by RIA at the Esoterix Endocrinology previously known as Endocrine Sciences, Inc. (Calabasas Hills, CA). Plasma androstenedione and DHEA were measured using solid phase competitive immunoassay kits with 125I-labeled steroids (Coat-A-Count, Diagnostic Products, Los Angeles, CA). Respective interassay coefficients of variation were 8.4% and 8.4%, and intraassay coefficients of variation were 5.7% and 7.5%. Plasma 17-hydroxyprogesterone was measured using a double antibody RIA kit (Diagnostic Systems Laboratories, Inc., Webster, TX) with inter- and intraassay coefficients of variation of 5.7% and 4.6% (27). Plasma lipids were measured using the standards of the Centers for Disease Control and Prevention. Deuterium enrichment of glucose in plasma was determined as we previously described (26).
Calculations
Glucose turnover at baseline was calculated during the last 30 min of the fasting 2-h isotopic infusion period according to steady state tracer dilution equations reported by us previously (26). Insulin-stimulated glucose disposal was calculated during the last 30 min of the 80 mU/m2·min hyperinsulinemic clamp. The insulin-stimulated carbohydrate oxidation rate was calculated from indirect calorimetric data (26). Nonoxidative glucose disposal was estimated by subtracting glucose oxidation from total glucose disposal.
During the hyperglycemic clamp, the first phase and the second phase insulin concentrations were calculated as previously reported (25, 26). Glucose and insulin areas under the curve during the OGTT were calculated according to the trapezoidal rule.
Statistical analysis
Data are presented as the mean ± SE. Paired t test was used to compare pre- and posttreatment data. To evaluate univariate relationships, least squares regression analysis was applied. Statistical significance is implied by P < 0.05. Data are reported for 14 subjects, because one subject admitted to poor compliance. She did not take her metformin more than 50% of the time. One subject did not have an ACTH stimulation test pre- and posttherapy, and another subject did not have an ACTH stimulation test before initiating metformin treatment.
Results
Body composition (Table 1
)
After 3 months of metformin treatment, BMI was significantly lower. This was due to a statistically significant increase in height and a decrease in weight that did not reach statistical significance. There was no significant change in various parameters of total body composition (Table 1). However, sc abdominal adipose tissue decreased slightly and significantly. No subject discontinued therapy because of adverse events. Two patients experienced mild gastrointestinal discomfort, which was transient.
Glucose tolerance, insulin sensitivity, and secretion (Table 2 and Figs. 1 and 2)
After 3 months of metformin therapy, oral glucose tolerance improved significantly, with eight patients having normal glucose tolerance. Two-hour glucose values were lower posttreatment (9.1 ± 0.3 vs. 7.4 ± 0.3 mmol/liter; P = 0.005). Also, the glucose area under the curve was lower (1,471.3 ± 33.5 vs. 1,319.6 ± 57.0 mmol/liter·min; P = 0.004). The insulin area under the curve decreased from 325,620 ± 51,372 to 258,804 ± 34,620 pmol/liter·min (P = 0.033).
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). However, in the face of significantly lower insulin concentrations (Table 1) this is suggestive of improved hepatic insulin sensitivity. During the hyperinsulinemic-euglycemic clamp there were no differences in steady state plasma glucose concentrations (5.6 ± 0.03 vs. 5.5 ± 0.07 mmol/liter) and insulin levels (2028.6 ± 145.8 vs. 2128.8 ± 197.4 pmol/liter) before and after metformin treatment. Insulin-stimulated total glucose disposal and nonoxidative disposal were significantly higher after 3 months of metformin treatment (Fig. 1). First and second phase insulin levels during the hyperglycemic clamp were not different before and after metformin treatment (first phase, 1567.8 ± 229.2 vs. 1464.0 ± 213.0 pmol/liter; second phase, 2156.4 ± 283.8 vs. 1922.4 ± 299.4 pmol/liter). Pre- and postmetformin treatment there was no significant difference in fasting cholesterol (4.4 ± 0.3 vs. 4.2 ± 0.3 mmol/liter), triglycerides (1.4 ± 0.2 vs. 1.3 ± 0.1 mmol/liter), low density lipoprotein (2.7 ± 0.2 vs. 2.5 ± 0.2 mmol/liter), and high density lipoprotein (1.1 ± 0.1 vs. 1.1 ± 0.1 mmol/liter).
Plasma androgen profile and adrenal response to ACTH stimulation (Table 1 and Fig. 2)
After 3 months of metformin treatment, total and free T decreased significantly, with no change in SHBG and DHEA sulfate (DHEAS) levels (Table 1). Menstrual cyclicity improved in six subjects.
Figure 2 depicts the change in hormone levels (30 min value minus baseline 0 min value) during ACTH stimulation before and after metformin treatment. After 3 months of metformin, the change in levels of androstenedione, 17-hydroxyprogesterone, and 17-hydroxypregnenelone in response to ACTH stimulation were significantly lower. Fasting insulin concentrations correlated with the 17-hydroxypregnenelone response to ACTH stimulation (r = 0.52; P = 0.008; Fig. 3) and androstenedione (r = 0.41; P = 0.055).
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The present investigation of obese adolescent girls with PCOS and IGT demonstrates that 3 months of metformin therapy at 850 mg, twice daily, was associated with 1) improvement of glucose intolerance, 2) improvement in hepatic and peripheral insulin resistance, 3) lowering of fasting insulinemia, 4) lowering of total and free T, and 5) attenuation of adrenal hyperresponsiveness to ACTH.
Adult women with PCOS, obese or lean, have profound insulin resistance with ß-cell dysfunction and are at increased risk for IGT and type 2 diabetes (9, 28, 29). The prevalence of IGT is 31–35%, and that of type 2 diabetes is 7.5–10% (28, 29). We previously demonstrated that, similar to adults, adolescents with short duration of PCOS are severely insulin resistant (25). Moreover, these adolescents are at heightened risk to develop type 2 diabetes (26). The metabolic features conducive to IGT and type 2 diabetes, i.e. insulin resistance, impaired insulin secretion, and increased hepatic glucose production, are present early in the course of PCOS in obese adolescents (26). In adult women with PCOS, insulin-sensitizing therapy is effective in lowering androgen levels, inducing ovulation, and facilitating normal menses and pregnancy (10, 11, 12, 14, 15, 20, 30, 31). Similar results were reported recently in nonobese adolescents with anovulatory hyperandrogenism (21, 22). We elected to use metformin for its long-standing history of relative safety as an antidiabetic agent (32). In agreement with previous reports, metformin treatment in the present study was associated with 1) approximately 35–45% lowering of total and free T levels (11, 12, 14, 15, 20, 21, 22, 30, 31, 33), 2) a reduction in insulin area under the curve during OGTT (12, 14, 20, 21, 24, 30, 33), 3) a 15% improvement in insulin sensitivity (15, 30), and 4) a 4% reduction of sc adipose tissue (11, 30, 31). However, unlike most adult studies, we did not detect a significant increase in SHBG, although there was a tendency. This could be ascribed to the severe hyperinsulinemia in our patients and the need for longer periods of treatment. Our study is the first comprehensive approach in obese adolescents with PCOS. In these obese glucose-intolerant adolescents, 57% had normalization of glucose intolerance after 3 months of metformin treatment. However, this cannot be solely attributed to metformin, because of reported spontaneous reverting to normal glucose tolerance without any intervention in non-PCOS populations. Despite a significant, albeit small, reduction in peripheral insulin sensitivity, we did not detect any change in insulin secretion during the hyperglycemic clamp. This is in agreement with a previous study of metformin treatment in obese nondiabetic women with PCOS (34). Based on the described hyperbolic relationship of insulin sensitivity and insulin secretion (35), it is possible that the magnitude of the reduction in insulin sensitivity in our patients was not sufficient to elicit a change in insulin secretion. On the other hand, we had shown in the past that insulin secretion is severely impaired (50% lower) in obese PCOS adolescents with IGT vs. those with normal glucose tolerance. Therefore, the lack of change in insulin secretion might be a reflection of a failing pancreas. It is possible that with longer duration of treatment, changes in insulin secretion might become evident. Also, the reduction in insulinemia in response to oral vs. iv glucose is more relevant to normal daily alimentary events.
Our main objective in conducting the present study was to investigate whether insulin-sensitizing therapy will lessen functional adrenal hyperandrogenism similar to its effect on ovarian hyperandrogenism. Our results demonstrate that after 3 months of metformin treatment there is a significant reduction in the androstenedione, 17-hydroxypregnenelone, and 17-hydroxyprogesterone responses to ACTH stimulation. Although the ovary is the principal source of androgen excess in patients with PCOS, 40–70% also demonstrate FAH with elevated levels of adrenal androgens, particularly DHEAS (1, 2, 3, 4, 6, 36). There is a significant inverse relationship between DHEAS and body weight (36). The normal DHEAS levels in our patients could be explained on the basis of obesity. This is in keeping with increased MCR of DHEAS in obesity (37). The lack of change in DHEAS after metformin treatment could be attributed to the short duration of therapy or the lack of significant changes in body weight. The mechanism(s) for the exaggerated adrenal androgen response to ACTH in FAH remains unclear. It has been proposed that insulin may affect the regulation of adrenal steroidogenesis, similar to its role in ovarian steroidogenesis through dysregulation of cytochrome P450c17 activity (5, 7, 13). In vivo investigations in favor of insulin playing a role in adrenal hyperandrogenism are the following. Insulin infusion in hyperandrogenic women potentiates ACTH-stimulated 17-hydroxypregnenelone and 17-hydroxyprogesterone responses (38). In normal men, acute elevation of serum insulin levels into the high physiological range impairs adrenal 17,20-lyase activity assessed in response to ACTH stimulation (39). Metformin treatment of adult women with PCOS led to a reduction in 17-hydroxyprogesterone and androstenedione responses to ACTH stimulation (23). This is in agreement with our findings in obese adolescents with PCOS. Our study in addition demonstrates that there is a significant positive relationship between insulin levels and 17-hydroxypregnenelone and androstenedione responses to ACTH stimulation. Even though correlations do not imply causation, such a relationship may be suggestive of a role for insulin in adrenal hyperandrogenism. On the other hand, contrary to our findings and the latter study, metformin therapy in women with PCOS did not alter 17-hydroxyprogesterone and androstenedione responses to ACTH (24). This conflicting result could be due to the lower dose of metformin used (500 mg, twice daily).
In summary, our present investigation demonstrates that in obese adolescents with PCOS and IGT, metformin is beneficial in improving glucose tolerance and insulin sensitivity, in lowering insulinemia, and in reducing elevated androgen levels. Moreover, metformin therapy may prove helpful in correcting functional adrenal hyperandrogenism by lowering the exaggerated adrenal response to ACTH stimulation. Metformin therapy was well tolerated, with no serious adverse events and with no patient dropout due to side-effects. Of course, with every open label drug trial the question of compliance remains an issue. Therefore, the next step would be a double blind, placebo-controlled study. Obese as well as lean adolescents with PCOS should be candidates for such trials. Until the results of such trials are available, one cannot with certainty attribute to metformin the observed effects mentioned above.
Acknowledgments
We thank Lynnette Orlansky and Kathy Brown for coordinating the various aspects of the research, the General Clinical Research Center for expert nursing assistance, and Pat Antonio for secretarial assistance. We also thank Drs. Selma Witchel and Peter Lee for the ACTH stimulation test normative data. Last, but not least, the greatest gratitude goes to the children who volunteered for the research studies and their families.
Footnotes
This work was supported by USPHS Grant RO1-HD-27503 (to S.A.), K24-HD-01357 (to S.A.), MO1-RR-00084 General Clinical Research Center, Renziehausen Trust Fund (to V.L.), Bristol Myers-Squibb (to S.A.), and Eli Lilly \|[amp ]\| Co. (to V.L. and R.S.). This work was presented at the Sixth Joint Meeting of the Lawson Wilkins Pediatric Endocrine Society and the European Society for Pediatric Endocrinology, Montréal, Canada, July 2001.
Abbreviations: DHEA, Dehydroepiandrosterone; DHEAS, dehydroepiandrosterone sulfate; FAH, functional adrenal hyperandrogenism; IGT, impaired glucose tolerance; OGTT, oral glucose tolerance test; PCOS, polycystic ovary syndrome.
Received November 2, 2001.
Accepted January 4, 2002.
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) hormone levels (30 min value minus 0 min value) in response to ACTH stimulation pre- and postmetformin treatment. RN, Reference normative data reported from our center based on 26 healthy women with regular menstrual cycles (age range, 16–35 yr) (