Background Insulin resistance and increased ovarian cytochromeP450c17 activity are both features of the polycystic ovary syndrome.P450c17, which is involved in androgen biosynthesis, has both17-hydroxylase and 17,20-lyase activities. Increased activityof this enzyme results in exaggerated conversion of progesteroneto 17-hydroxyprogesterone in response to stimulation by gonadotropin.We hypothesized that hyperinsulinemia stimulates ovarian P450c17activity.
Methods We measured serum steroid concentrations during fastingand the response of serum 17-hydroxyprogesterone to leuprolide,a gonadotropin-releasing hormone agonist, and performed oralglucose-tolerance tests before and after oral administrationof either metformin (500 mg three times daily) or placebo forfour to eight weeks in 24 obese women with the polycystic ovarysyndrome.
Results In the 11 women given metformin, the mean (±SE)area under the serum insulin curve after oral glucose administrationdecreased from 9303±1603 to 4982±911 µUper milliliter per minute (56±10 to 30±6 nmolper liter per minute) (P = 0.004). This decrease was associatedwith a reduction in the basal serum 17-hydroxyprogesterone concentrationfrom 135±21 to 66±7 ng per deciliter (4.1±0.6to 2.0±0.2 nmol per liter) (P = 0.01) and a reductionin the leuprolide-stimulated peak serum 17-hydroxyprogesteroneconcentration from 455±54 to 281±52 ng per deciliter(13.7±1.6 to 8.5±1.6 nmol per liter) (P = 0.01).The serum 17-hydroxyprogesterone values increased slightly inthe placebo group. In the metformin group, the basal serum luteinizinghormone concentration decreased from 8.5±2.2 to 2.8±0.5mlU per milliliter (P = 0.01), the serum free testosterone concentrationdecreased from 0.34±0.07 to 0.19±0.05 ng per deciliter(12±3 to 7±2 pmol per liter) (P = 0.009), andthe serum sex hormone–binding globulin concentration increasedfrom 0.8±0.2 to 2.3±0.6 µg per deciliter(29±7 to 80±21 nmol per liter) (P<0.001). Noneof these values changed significantly in the placebo group.
Conclusions In obese women with the polycystic ovary syndrome,decreasing serum insulin concentrations with metformin reducesovarian cytochrome P450c17 activity and ameliorates hyperandrogenism.
The polycystic ovary syndrome is characterized by anovulationand hyperandrogenism. It affects approximately 6 percent ofwomen of reproductive age.1 Insulin resistance accompanied bycompensatory hyperinsulinemia is a common feature of the syndrome,and both obese and nonobese women with the syndrome are moreinsulin-resistant and hyperinsulinemic than age- and weight-matchednormal women.2,3,4,5,6,7,8,9
Hyperinsulinemia may play a pathogenetic part in hyperandrogenismin women with the polycystic ovary syndrome by increasing ovarianandrogen production and decreasing the serum sex hormone–bindingglobulin concentration.10,11,12,13,14,15,16,17 Serum free testosteroneconcentrations decline in women with the polycystic ovary syndromewhen their insulin secretion is reduced by the administrationof diazoxide15 or metformin18 or by diet.19,20 Furthermore,the observation that adolescent girls with hyperandrogenismhave insulin resistance9 suggests that hyperinsulinemia mayplay an early and central part in the pathogenesis of the polycysticovary syndrome.
Cytochrome P450c17 is a bifunctional enzyme that has both 17-hydroxylaseand 17,20-lyase activities, and it is a key enzyme in the biosynthesisof ovarian androgens. In ovarian theca cells, P450c17 convertsprogesterone to 17-hydroxyprogesterone through its 17-hydroxylaseactivity, and then converts 17-hydroxyprogesterone to androstenedionethrough its 17,20-lyase activity. Androstenedione is then convertedto testosterone by the enzyme 17-reductase (Figure 1).
Figure 1. Possible Mechanisms of Insulin Stimulation of Ovarian Cytochrome P450c17 Activity and Androgen Production.
In theca cells, insulin may directly stimulate (plus signs) ovarian cytochrome P450c17, resulting in increased 17-hydroxylase and, to a lesser extent, 17,20-lyase activity. This would lead to increased production of androstenedione, which is then converted to testosterone by the enzyme 17-reductase. Alternatively or in conjunction with this, insulin may stimulate ovarian androgen production indirectly by enhancing the amplitude of serum luteinizing hormone (LH) pulses, and luteinizing hormone may then stimulate ovarian cytochrome P450c17 activity.
Many women with the polycystic ovary syndrome have increasedovarian cytochrome P450c17 activity,21,22 as evidenced by increased17-hydroxylase and, to a lesser extent, 17,20-lyase activity,resulting in excessive ovarian androgen production. In thesewomen, a hallmark of increased ovarian P450c17 activity is anexaggerated serum 17-hydroxyprogesterone response to stimulationby gonadotropin-releasing hormone agonists, such as nafarelin,21,22,23buserelin,24 and leuprolide.25 Whether the increased ovarianP450c17 activity in women with the polycystic ovary syndromeis an inherited or an acquired phenomenon is not known.
We hypothesized that hyperinsulinemia stimulates ovarian cytochromeP450c17 activity in women with the polycystic ovary syndrome(Figure 1) and that amelioration of insulin resistance in thesewomen would return the activity of the enzyme toward normal.To test this hypothesis, we measured the basal serum 17-hydroxyprogesteroneconcentration and the serum 17-hydroxyprogesterone responseto the administration of leuprolide in obese women with thepolycystic ovary syndrome before and after the administrationof metformin, which inhibits the production of hepatic glucoseand enhances the sensitivity of peripheral tissue to insulin,thereby decreasing insulin secretion.26,27
Methods
Subjects
We enrolled 25 women who were 18 to 35 years old, 24 of whomcompleted the study. All the women had the polycystic ovarysyndrome, as defined by oligomenorrhea (fewer than six menstrualperiods in the previous year) and hyperandrogenemia (elevatedserum free testosterone concentrations), and were obese (body-massindex [weight in kilograms divided by the square of the heightin meters], >27.5). All had hirsutism, and 15 had acanthosisnigricans. Two women had each delivered two children, five womenhad each delivered one child, and the rest were childless. Allhad normal serum prolactin concentrations and normal resultson thyroid-function tests. Late-onset congenital adrenal hyperplasiawas ruled out by a morning serum 17-hydroxyprogesterone concentrationof less than 200 ng per deciliter (6 nmol per liter). All thewomen had findings on ultrasonography of the ovaries that wereconsistent with the diagnosis of the polycystic ovary syndrome.28None had taken any medications for at least two months, andnone had diabetes mellitus. Twelve women were randomly assignedto receive metformin (Glafornil, North Medicamenta, Caracas,Venezuela) and 13 women to receive placebo. The study was approvedby the institutional review board of the Hospital de ClinicasCaracas, and each woman gave informed consent.
Study Protocol
The women were evaluated during the follicular phase of themenstrual cycle, as determined by a serum progesterone concentrationof less than 2 ng per milliliter (6.4 nmol per liter). On day1 the women came to the hospital after a 12-hour overnight fast,and their weight, height, waist-to-hip ratio, and blood pressurewhile supine were measured. Blood samples were drawn at 8:30,8:45, and 9 a.m., and equal volumes of serum were pooled forthe measurement of insulin, glucose, steroids, and sex hormone–bindingglobulin. At 9 a.m., 75 g of dextrose (Glycolab, Relab Laboratory,Caracas, Venezuela) was given orally. Blood samples were collectedfor determinations of serum glucose and insulin concentrationsat 60 and 120 minutes.
On day 2 the women ate breakfast at 9 a.m. and then fasted until2 p.m., when a leuprolide stimulation test was performed. Afterthis test the women took 500 mg of metformin or placebo orallythree times daily. They were instructed not to alter their usualeating habits, physical activity, or lifestyle during the study.
The women returned for studies four to eight weeks later, aftera low serum progesterone value had confirmed that they werein the follicular phase of the menstrual cycle. Five women hadserum progesterone values in the postovulatory range after takingmetformin for four weeks. One of them became pregnant despitelong-standing infertility; she was dropped from the study andher results were omitted from the analysis. The remaining fourwomen continued to take metformin and were studied four weekslater when their serum progesterone values were low. In theplacebo group, one woman had a serum progesterone value in thepostovulatory range after four weeks; she was studied againtwo weeks later.
Leuprolide Stimulation Test
After base-line blood samples had been obtained at 2 p.m. onday 2, leuprolide (10 µg per kilogram of body weight;Lupron, Abbott Laboratories, Takeda, Japan) was administeredsubcutaneously. Blood samples for the measurement of serum luteinizinghormone were collected immediately before and 0.5, 1, 16, 20,and 24 hours after leuprolide was administered. Blood samplesfor the measurement of serum 17-hydroxyprogesterone were collectedimmediately before and 16, 20, and 24 hours after leuprolidewas administered. The women ate an evening meal on day 2 butfasted thereafter until the completion of the test. The earlyresponse of serum luteinizing hormone was determined from pooledequal volumes of serum taken at 0.5 and 1 hour, and the lateserum luteinizing hormone response from pooled equal volumesof serum taken at 16, 20, and 24 hours. The serum concentrationof 17-hydroxyprogesterone measured immediately before the administrationof leuprolide was considered the basal value, and the highestserum concentration of 17-hydroxyprogesterone that was measuredafter the administration of leuprolide was considered the peakvalue.
Assays
The blood samples were centrifuged immediately, and the serumwas stored at -20°C until it was assayed. The serum freetestosterone concentration was determined by radioimmunoassay(Diagnostic Products, Los Angeles). All other hormones and sexhormone–binding globulin (measured as protein) were assayedas previously described.15,17,29 To avoid variation among assays,all samples were analyzed in duplicate in a single assay foreach hormone. The intraassay coefficients of variation for theinsulin and luteinizing hormone assays were 5.5 and 1.6 percent,respectively, and they were less than 10 percent for all thesteroid hormone assays.
Statistical Analysis
The results are reported as means ±SE. Within a group,we compared the results before treatment with those after treatmentby testing for normality with the Wilk–Shapiro test andusing Student's two-tailed paired t-test or the Wilcoxon signed-ranktest. Comparisons between groups were made with Student's two-tailedunpaired t-test or the Mann–Whitney rank-sum test.
We analyzed the responses of serum glucose and insulin to theoral administration of glucose and the responses of serum luteinizinghormone and 17-hydroxyprogesterone to the administration ofleuprolide by calculating the areas under the response curvesby the trapezoidal rule using absolute values.
Results
Base-Line Characteristics
The women in the metformin and placebo groups did not differsignificantly in age, body-mass index, waist-to-hip ratio, bloodpressure, or serum concentrations of sex steroids or sex hormone–bindingglobulin at base line (Table 1). They also did not differ atbase line in serum insulin or glucose values measured duringfasting, insulin or glucose responses after oral glucose administration,or basal or leuprolide-stimulated serum 17-hydroxyprogesteronevalues (Table 1 and Figure 2). The base-line serum luteinizinghormone concentration was higher in the metformin group thanin the placebo group (8.5±2.2 vs. 3.7±0.7 mIUper milliliter; P = 0.04) (Figure 3).
Table 1. Characteristics of Women with the Polycystic Ovary Syndrome at Base Line and after the Administration of Metformin or Placebo for Four to Eight Weeks.
Figure 2. Mean (±SE) Serum 17-Hydroxyprogesterone Concentrations in Women with the Polycystic Ovary Syndrome at Base Line and after the Administration of Metformin or Placebo for Four to Eight Weeks.
Metformin was administered for a mean (±SE) of 42±4 days, and placebo for 32±2 days. The women were studied before and after the administration of leuprolide (10 µg per kilogram). To convert values for 17-hydroxyprogesterone to nanomoles per liter, multiply by 0.03. AUC denotes area under the curve.
Figure 3. Mean (±SE) Serum Luteinizing Hormone Concentrations in Women with the Polycystic Ovary Syndrome at Base Line and after the Administration of Metformin or Placebo for Four to Eight Weeks.
Metformin was administered for a mean (±SE) of 42±4 days, and placebo for 32±2 days. The women were studied before and after administration of leuprolide (10 µg per kilogram). The asterisks indicate P = 0.01 for the comparison with the base-line value in same group, and the dagger indicates P = 0.04 for the comparison with the base-line value in the metformin group.
Anthropometric Variables
The body-mass index did not change significantly during thestudy in either group. The waist-to-hip ratio decreased slightlyin the metformin group (P = 0.02) but did not change substantiallyin the placebo group. There was no significant change in diastolicor systolic blood pressure in either group.
Serum Insulin and Glucose Profiles
In the metformin group, the mean serum insulin concentrationmeasured during fasting decreased from 17±3 to 9±2µU per milliliter (102±18 to 54±12 pmolper liter) (P = 0.03), and the area under the serum insulincurve decreased from 9303±1603 to 4982±911 µUper milliliter per minute (56±10 to 30±6 nmolper liter per minute) (P = 0.004) (Table 1). Neither of thesevalues changed significantly in the placebo group. The serumglucose concentration in fasting women did not change significantlyin either group. The area under the serum glucose curve increasedin the placebo group (P = 0.03) but did not change substantiallyin the metformin group.
Responses of Serum Luteinizing Hormone to Leuprolide
The basal serum luteinizing hormone concentration decreasedfrom 8.5±2.2 to 2.8±0.5 mIU per milliliter (P= 0.01) in the metformin group but did not change significantlyin the placebo group (Figure 3). The early serum luteinizinghormone responses to leuprolide were lower after the administrationof metformin than at base line (17.0±2.5 vs. 40.8±11.9mIU per milliliter, P = 0.01). The late serum luteinizing hormoneresponses were slightly but not significantly lower after theadministration of metformin (P = 0.26). In contrast, in theplacebo group the basal serum luteinizing hormone concentrationsand the early and late serum luteinizing hormone responses toleuprolide were virtually identical at base line and after theadministration of placebo (Figure 3).
Serum 17-Hydroxyprogesterone Responses
In the metformin group, the mean basal serum 17-hydroxyprogesteroneconcentration decreased by 51 percent, from 135±21 to66±7 ng per deciliter (4.1±0.6 to 2.0±0.2nmol per liter) (P = 0.01), but it did not change significantlyin the placebo group (Figure 2). Similarly, in the metformingroup the peak serum 17-hydroxyprogesterone concentration afterleuprolide administration decreased from 455±54 to 281±52ng per deciliter (13.7±1.6 to 8.5±1.6 nmol perliter) (P = 0.01), and the area under the serum 17-hydroxyprogesteronecurve decreased from 7848±945 to 4592±766 ng perdeciliter per hour (237±29 to 139±23 nmol perliter per hour) (P = 0.004), whereas these values increasedslightly in the placebo group (Figure 2). The change in thearea under the serum 17-hydroxyprogesterone curve in the metformingroup differed significantly from that in the placebo group(-3256±180 vs. 912±105 ng per deciliter per hour[-98±27 vs. 28±10 nmol per liter per hour]) (P<0.001),and the area under the serum 17-hydroxyprogesterone curve wassignificantly less after metformin administration than afterplacebo administration (4592±766 vs. 6949±685ng per deciliter per hour [139±21 vs. 210±21 nmolper liter per hour]) (P = 0.02).
Serum Sex Steroids
The administration of metformin was associated with a 44 percentdecrease in serum free testosterone concentrations, from 0.34±0.07to 0.19±0.05 ng per deciliter (12±2 to 7±2pmol per liter) (P = 0.009), and a threefold increase in serumsex hormone–binding globulin concentrations, from 0.8±0.2to 2.3±0.6 µg per deciliter (29±7 to 80±21nmol per liter) (P<0.001) (Table 1). These values did notchange significantly in the placebo group. The serum concentrationsof the other measured steroids did not change substantiallyin either group.
Discussion
In these women with the polycystic ovary syndrome, the administrationof metformin reduced the serum insulin concentration duringfasting and the insulin response to oral glucose administration.Concomitantly, ovarian cytochrome P450c17 activity decreased,as demonstrated by a substantial reduction in the response ofserum 17-hydroxyprogesterone to the administration of leuprolide(to increase luteinizing hormone secretion). The reduction inP450c17 activity was accompanied by a decline in the serum freetestosterone concentration. These findings suggest that increasedovarian cytochrome P450c17 activity in women with the polycysticovary syndrome is due to stimulation by insulin (Figure 1) andcan be reversed by reducing the secretion of insulin. We intentionallydid not screen the women for the presence of insulin resistanceor increased P450c17 activity so that our results would be applicableto unselected women with the polycystic ovary syndrome.
We cannot exclude the possibility that the decrease in ovarianP450c17 activity resulted from the reduction in serum free testosteroneor a direct action of metformin, but these possibilities seemremote. Hyperandrogenism is a consequence of increased ovarianP450c17 activity and is therefore unlikely to be the cause ofthe stimulated enzyme activity. Hyperandrogenism in women withthe polycystic ovary syndrome is ameliorated by diazoxide15— a drug structurally unrelated to metformin that suppressesinsulin release and worsens glucose tolerance — and bydiet.19,20 The common factor among these diverse therapies appearsto be the reduction in serum insulin concentrations. Becausediazoxide is not known to alter insulin sensitivity yet lowersserum testosterone concentrations in women with the polycysticovary syndrome,15 hyperandrogenism in such women appears tobe related to hyperinsulinemia itself and not to insulin resistance;moreover, insulin stimulates ovarian androgen production invitro.11,12,13,14 The recent report by Moghetti et al.30 thathyperinsulinemia may stimulate cytochrome P450c17 activity inanother steroidogenic tissue of women with the polycystic ovarysyndrome — namely, the adrenal glands — furthersupports our findings.
The early and late serum luteinizing hormone responses to leuprolideafter the administration of placebo were almost identical tothose at base line. In contrast, the administration of metforminwas associated with decreased basal and leuprolide-stimulatedserum luteinizing hormone concentrations. These observationsraise the possibility that insulin enhances both the endogenous(basal) and the exogenous (leuprolide-stimulated) release ofluteinizing hormone mediated by gonadotropin-releasing hormoneand that increased ovarian cytochrome P450c17 activity in womenwith the polycystic ovary syndrome may be related to an insulin-inducedabnormality in the dynamics of gonadotropin secretion ratherthan (wholly or partially) to direct stimulation of ovariansteroidogenesis by insulin (Figure 1). Insulin receptors havebeen identified in human pituitary tissue,31 and insulin augmentsthe release of luteinizing hormone by cultured rat pituitarycells.32
The secretion of luteinizing hormone is often increased in womenwith the polycystic ovary syndrome,33 and the diurnal changesin the serum concentrations of luteinizing hormone and insulinin these women follow a similar time course.34 Preliminary studiessuggest that insulin enhances the amplitude of serum luteinizinghormone pulses but not their frequency in obese women with thepolycystic ovary syndrome (unpublished data). An alternativepossibility is that the reduction in luteinizing hormone secretionin the women we studied was due to a decrease in the concentrationof circulating androgens. However, raising serum androgen concentrationsby parenteral administration in normal women35 or women withthe polycystic ovary syndrome36 does not stimulate the secretionof luteinizing hormone. Finally, some of the women in our studywho received metformin ovulated, and ovulation itself may influencethe dynamics of gonadotropin secretion.37 However, in our studythe results in the women who had ovulated and those who hadnot were similar.
The metformin-induced reduction in insulin secretion was associatedwith substantial decreases in serum free testosterone concentrationsand increases in serum sex hormone–binding globulin concentrations.In women with the polycystic ovary syndrome, insulin stimulatesovarian androgen production11,12,13,14,15 and lowers serum sexhormone–binding globulin concentrations.16,17 Our findings,and those of an uncontrolled trial18 of metformin in women withthe polycystic ovary syndrome, support these observations. Incontrast, Crave et al. found that neither serum testosteronenor sex hormone–binding globulin concentrations changedin women with the polycystic ovary syndrome who were treatedwith a hypocaloric diet and metformin for four months.38 Thereasons for the discrepancies among these studies are unknown.
In summary, our findings suggest that two features of the polycysticovary syndrome — hyperinsulinemic insulin resistance andincreased ovarian cytochrome P450c17 activity — are pathogeneticallylinked, and that hyperinsulinemia stimulates this enzyme eitherdirectly or indirectly by increasing gonadotropin secretion(Figure 1). The ability of insulin to stimulate ovarian cytochromeP450c17 is probably limited to women with the polycystic ovarysyndrome and may be a heritable abnormality, since many otherobese women who also are hyperinsulinemic have neither hyperandrogenismnor hyperresponsiveness to gonadotropin-releasing hormone.22The clinical implication of these results is that therapeuticmeasures directed at lowering insulin secretion in women withthe polycystic ovary syndrome should ameliorate their hyperandrogenism.
Supported in part by grants (RO1AG11227 and RO1CA64500) fromthe National Institutes of Health (to Dr. Nestler).
We are indebted to Ms. Terre Williams, Ms. Carmen Medina, andMs. Gladys Coz for technical assistance.
Source Information
From the Departments of Internal Medicine, Obstetrics and Gynecology, and Pharmacology and Toxicology, Division of Endocrinology and Metabolism, Medical College of Virginia, Virginia Commonwealth University, Richmond (J.E.N.); and the Department of Internal Medicine, Hospital de Clinicas Caracas, Caracas, Venezuela (D.J.J.).
Address reprint requests to Dr. Nestler at the Medical College of Virginia, P.O. Box 980111, Richmond, VA 23298-0111.
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