1 Department of Obstetrics and Gynecology, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168 Roma and 2 OASI Institute for Research, Troina, Italy
3 To whom correspondence should be addressed. e-mail: alanzone{at}rm.unicatt.it
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Abstract |
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Key words: androgens/insulin/obesity/PCOS/pioglitazone
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Introduction |
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Obesity is present in 50% of women
with PCOS and a similar percentage of these patients shows exaggerated
circulating insulin levels and reduced insulin-mediated glucose
metabolism. Furthermore, although
70% of obese women with PCOS
exhibit an increased insulin secretion, the same feature is also
represented in 2040% of non-obese subjects (Ciampelli and Lanzone,
1998
).
The association between metabolic disturbances and
PCOS seems to be genetic in origin (Norman et al., 1996), but despite
the large number of studies published on the matter in recent years, the
underlying mechanism remains unclear. An alteration in glucose disposal
into peripheral tissues has been demonstrated and some reports concluded
that insulin resistance in subjects with PCOS could be ascribed to
post-binding defects in signal transduction, rather than to an altered
affinity of the binding domain of the insulin receptor (Dunaif et al., 1992
;
Ciaraldi et al.,
1997
).
Several pieces of data support the hypothesis that
insulin resistance and hyperinsulinaemia may play a pathogenic role in this
syndrome. At the central level this hormone seems to be involved in the
dysregulation of LH secretion (Adashi et al., 1981; Unger et al., 1991
). At a
peripheral level, insulin promotes ovarian androgen secretion by enhancing
cytocrome P450c17
activity, having a synergic action with
gonadotrophins both directly and by stimulating insulin-like growth
factor 1 (IGF-1) secretion (Cara and Rosenfield, 1988
). Insulin also
decreases serum sex hormone binding globulin synthesis in the liver
(Nestler et al.,
1991
), thus increasing free androgen levels. Furthermore, our
previous reports suggest that hyperinsulinaemia is able to potentiate
in vivo adrenocorticotropin hormone (ACTH)-stimulated adrenal
androgen production in women with PCOS (Lanzone et al., 1994
).
Based
on this evidence, insulin-sensitizing agents have been recently
proposed as a useful primary or adjunctive treatment in women affected by
PCOS. In several studies, the biguanide metformin has been used to improve
insulin sensitivity in PCOS patients (Velazquez et al., 1994; Moghetti et al., 2000
;
Nestler et al.,
2002
). However, its major action on glucose homeostasis derives
from the inhibition of hepatic gluconeogenesis, resulting in decreased
glucose output from the liver (Stumvoll et al., 1995
). On the other
hand, there are many controversies about the relation between the direct
insulin-sensitizing effect and the body weight reduction induced by
this agent (Crave et al.,
1995
).
The thiazolidinediones are a novel class of
insulin-sensitizing agents, able to enhance insulin action with a
post-insulin receptor mechanism of action: they behave as a selective
ligand for the peroxisome proliferator-activated receptor , a
nuclear hormone receptor expressed predominantly in adipose tissue
(Lehmann et al.,
1995
), where it plays a central role in the control of
adipocyte gene expression and differentiation (Keller and Wahl, 1993
; Kliewer et al., 1995
). In addition,
it has been documented that these drugs are responsible for a marked
improvement in muscle insulin-sensitivity (Hofmann and Colca, 1992
; Nolan et al., 1994
;
Hauner et al.,
2002
).
In recent years, several authors have studied the
effects of one of these agents, troglitazone, in PCOS women to determine
whether it could improve insulin sensitivity and result in amelioration of
their clinical endocrine characteristics (Dunaif et al., 1996; Ehrmann et al., 1997
;
Azziz et al.,
2001
). Notwithstanding some discrepancies, the whole of these
studies have demonstrated the therapeutic effect of troglitazone on the
ovulatory dysfunction, hirsutism, hyperandrogenism and
insulin-resistance of PCOS. However, the manufacturer has recently
withdrawn the marketing of troglitazone because of rare, but serious, acute
hepatic failure associated with the use of this drug in patients with type
2 diabetes (Scheen,
2001
).
Pioglitazone is a new compound belonging to the
thiazolidinediones class. In placebo-controlled clinical trials,
monotherapy with pioglitazone 1545 mg/day has been shown to
ameliorate insulin sensitivity, decrease blood glycosylated haemoglobin
levels and improve serum lipid profile in patients with type 2 diabetes
mellitus. A decrease in blood pressure has also been reported in these
subjects. The drug has been well-tolerated by adult patients of all
ages and no cases of hepatotoxicity have been reported in clinical studies
(Gillies and Dunn,
2000).
In the present open single-centre study, pioglitazone was tested for the first time in PCOS patients with a normal glucose tolerance. The aim was to evaluate descriptively whether treatment with pioglitazone (45 mg/day) for 6 months could improve glucose and lipid metabolism, abnormalities of insulin secretion, ovarian steroidogenesis, hirsutism, menstrual pattern by the attenuation of insulin-resistance and subsequent reduction of hyperinsulinaemia. The safety of the drug in long-term treatment of patients with PCOS was also evaluated.
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Materials and methods |
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PCOS was diagnosed on the basis of clinical findings (the
presence of amenorrhoea or oligomenorrhoea, hirsutism and/or acne), plasma
androgen levels at the upper limit of, or above, the normal range
(androstenedione 2.06.98 nmol/l; testosterone 0.62.0 nmol/l),
and the presence of bilaterally normal or enlarged ovaries containing at
least 710 microcysts (<5 mm in diameter) on ultrasonography,
with an augmented stromal area/total area ratio (Adams et al., 1985; Fulghesu et al., 2001
). A
normal LH/FSH ratio was not considered an exclusion criterion. The presence
of a late-onset adrenal enzyme defect was excluded by an
adrenocorticotrophic hormone test (250 µg i.v., Synachten;
Ciba-Geigy, Basel, Switzerland) according to published criteria
(New et al.,
1983
). Obesity was defined as a body mass index (BMI) of
>25 kg/m2 (normal range 1925).
The
menstrual patterns were defined according to van Hooff et al. (1999): regular
cycles, length of cycle between 22 and 41 days; irregular cycles:
oligomenorrhoea, length of cycle between 42 and 180 days; polymenorrhoea,
length of cycle 21 days or less; amenorrhoea, absence of menstruation for
180 days or more (two or more such irregularities during the past
year).
Pregnancy or possibility of pregnancy and nursing, significant liver [aspartate transaminase (AST), alanine transaminase (ALT), total bilirubin or alkaline phosphatase more than twice the upper limit of normal] or renal impairment (serum creatinine >1.8 ng/dl), neoplasm, cardiovascular disease and unstable mental illness were considered exclusion criteria.
Because of the impact of body fat
distribution on androgen levels and glucose metabolism (Ciampelli et al., 1999;
De Simone et al.,
2001
), waist to hip ratios (WHR) were measured. Waist
circumference was taken to be the minimum value between the iliac crest and
the lateral costal margin, and hip circumference was the maximum value over
the buttocks.
The ratio of testosterone x 100/sex hormone binding globulin (SHBG) was used to calculate the free androgen index (FAI).
Informed consent was obtained from each patient, and the study protocol was approved by our Institutional Review Board.
Studies were conducted during the early follicular phase of spontaneous or induced [medroxyprogesterone acetate (MPA) 10 mg/day for 7 days] menstrual cycles (day 37). On the first visit, the patients were hospitalized and underwent a gynaecological and medical examination. After following a standard carbohydrate diet (300 g/day) for 3 days and fasting overnight for 1012 h, blood samples were collected in order to perform the following laboratory investigations: basal hormone assessment, ALT, AST, alkaline phosphatase, cholesterol, lipoproteins, total proteins, albumin, creatinine, nitrogen urea, Ca2+, Na2+, K+, partial thromboplastin time (PTT) and fibrinogen.
Patients then underwent an oral glucose tolerance test (OGTT). The following day, after another overnight fasting, a euglycaemic hyperinsulinaemic clamp was performed.
All
patients also underwent a transvaginal ultrasonography and the grade of
hirsutism was detected using the FerrimanGallwey (F-G) score
(score <8, no hirsutism; score 816, low hirsutism; score
1724, moderate hirsutism; score >24, severe hirsutism)
(Ferriman and Gallwey,
1961).
The first day of the following menstruation, therapy with pioglitazone was started: one pill of 45 mg was taken daily in the morning for 6 months. During the study, chronically stabilized therapies not interfering with the parameters under evaluation were permitted. The use of antidiabetic and/or estroprogestinic drugs was not allowed. Patients were recommended not to modify their usual diet.
After 2 months of therapy, patients returned to hospital (visit 2) for a transvaginal ultrasonographic examination and for the evaluation of the F-G score.
Visits 3 and 4 were performed after 4 and 6 months of treatment respectively: each time patients underwent a transvaginal ultrasonography, an OGTT, a euglycaemichyperinsulinaemic clamp and a blood drawing for the determination of laboratory and endocrinological assessment [plasma levels of testosterone, dehydroepiandrosterone sulphate (DHEA-S), androstenedione, 17-hydroxyprogesterone (17-OHP), progesterone, FSH, LH, SHBG, prolactin]. The grade of hirsutism was determined by the above-mentioned score.
Triglycerides, total cholesterol, high-density lipoprotein (HDL), very low-density lipoprotein (VLDL), low-density lipoprotein (LDL) and non-esterified fatty acids (NEFA) were determined in basal conditions (visit 1) and after 4 and 6 months of treatment (visits 3 and 4).
The main liver function parameters were monitored each month during the treatment.
On each visit, compliance with the treatment was checked with a questionnaire about the side-effects and a subjective evaluation of the tolerability of the administered drug. The patients were also asked about accidentally missed administrations, but all reported to have correctly followed the scheduled treatment. A count of returned capsules was performed on each control visit.
The OGTT was performed as follows: at 09:00 after overnight fasting, an indwelling catheter was inserted into the antecubital vein of one arm. Blood samples were collected basally and, after ingestion of 75 g glucose in 150 ml water within 5 min, at 30, 60, 90, 120, 180 and 240 min. Insulin, glucose and C-peptide were assayed in all samples.
Plasma samples for glucose concentration were collected in tubes containing an inhibitor of glycolysis (sodium fluoride) to be analysed within 5 h. Plasma samples for insulin and C-peptide concentrations were placed in tubes standing in ice, centrifuged for 10 min at 1000 g using a 4226 ALC Centrifuge (ALC, Milan, Italy) and kept frozen at 30°C until assayed.
OGTT data were analysed as area under the curve (AUC) after glucose ingestion, calculated by the trapezoidal rule and expressed as pmol/l/240 min for insulin and C-peptide and nmol/l/240 min for the glucose plasma levels.
Hepatic insulin extraction was estimated according to the following: difference between molar secretory areas of C-peptide and insulin divided by molar secretory area of C-peptide.
The glycaemic responses were
defined in accordance with the criteria of the National Diabetes Data Group
(National Diabetes Data Group,
1979). To define a normal insulinaemic response to OGTT was
considered a threshold AUC value of 107.625 pmol/l/240 min, as
described previously (Ciampelliet al., 1997
).
The
hyperinsulinaemiceuglycemic clamp was performed after a 10 h
overnight fast to estimate peripheral insulin sensitivity. At 08:00 h,
an i.v. catheter was placed in the antecubital vein for the infusion of
glucose and insulin. Another catheter was placed in the dorsal vein of the
controlateral hand for blood withdrawal and warmed to 65°C with a
warming box. A primed constant infusion of insulin (Actrapid HM; Novo
Nordisk, Copenhagen, Denmark) 40 mIU/m2 x min
(De Fronzo et al.,
1979). After reaching the steady-state velocity for the
insulin infusion within 10 min in order to achieve steady-state
insulin levels of
717 pmol/l (range 574897) during the clamp, a
variable infusion of 20% glucose was begun via a separate infusion
pump and the rate was adjusted, on the basis of plasma glucose samples
drawn every 5 min, to maintain plasma glucose between 4.4 and 4.99
mmol/l. The plasma glucose level was determined by the glucose oxidase
technique with a glucose analyser (Beckam Instruments, Palo Alto, CA, USA).
The glucose infusion rate during the last 60 min of a 2 h
infusion was then taken as the estimate of peripheral insulin sensitivity
and measured as M (mg/kg/min). We preferred the use of this index as the
measure of insulin sensitivity because the M/I ratio fails to narrow the
range of individual sensitivity values (Bergman et al., 1985
).
All hormone assays were performed with commercial radioimmunoassay kits (Radim, Rome, Italy). The intra-assay and interassay coefficients of variation for all hormones were <8 and <15% respectively. For each determination, all samples from the same patient were assayed simultaneously.
Glucose plasma concentrations were determined by the glucose oxidase technique with a glucose analyser (Beckam, Fullerton, CA, USA).
Total cholesterol and triglyceride concentrations were
determined by an enzymatic assay (Bristol, Paris, France). HDL
concentrations were determined after precipitation of chylomicrons, VLDL
and LDL (Boehringer, Mannheim, Germany), VLDL was separated (as the
supernatant) from LDL and HDL by lipoprotein ultracentrifugations. A
magnesium chloride/phosphotungstic acid technique was used to precipitate
LDL from the bottom fraction after ultracentrifugation. NEFA were
determined by an acyl-coenzyme A oxidase-based colorimetric
method. All lipids assay were performed according to our standard
laboratory procedures, as previously reported (Ciampelli et al.,
1999).
Data analysis
All data are presented
as mean ± SD. On main efficacy variables, an analysis of variance
(ANOVA) model for repeated measures was applied in order to describe the
within-subjects time profile during the study. Descriptive statistics
per visit and ANOVA were employed in the evaluation of the clinical
features.
The significance of differences among the visits measures was determined with the use of one-way ANOVA, and any significant difference was identified by using the Bonferroni correction for multiple comparisons. For all analyses a P < 0.05 was considered to indicate statistical significance.
The incidence rate
of adverse events were evaluated and calculated using the medical
dictionary for regulatory activity (MedDRA) code (Brown et al.,
1999).
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Results |
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One patient entered the study and had the visit at baseline, but did not take any of the drug and was excluded from the study after 2 months for lack of compliance. One woman, showing hyperinsulinaemia and severe hirsutism, was given pioglitazone in the intention-to-treat analysis only; however, data from this patient were not considered in the statistical analysis because of the diagnosis of a late-onset adrenal enzyme defect and the assumption of drugs interfering with the investigated clinical and metabolic parameters. One patient took the medication for 6 months, but refused to undergo the last evaluation visit.
Only one patient discontinued the study after 4 months of treatment because of a non-serious adverse event (oedema). This symptom resolved spontaneously within 2 weeks after the interruption of drug therapy.
Mild upper abdominal pain was reported by three of the treated patients. Three women experienced an augmented frequency of headache and two complained of asthenia. Only one case of diarrhoea was reported. Finally, paraesthesia appeared in one patient. The intensity of such events ranged from mild to moderate. Side-effects were represented in the great majority of cases by isolated episodes or occurred intermittently, and promptly resolved after the discontinuation of the treatment.
No abnormalities were detected in hepatic or renal chemistries (Table I), in complete blood counts or in electrocardiograms throughout the treatment.
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All patients presented clinical signs of hyperandrogenism (acne and/or hirsutism) at baseline. With the exception of two patients with a F-G score <8 (5 and 7 respectively), all study subjects were hirsute and most of them were markedly so (mean F-G score 16.30 ± 6.63, range 529). Hirsutism score improved consistently from baseline values to those at the end of therapy (P = 0.005 for visit 2 versus baseline and P < 0.0001 for visits 3 and 4 versus baseline). Acne improved from baseline to visit 4; the overall F-ratio for visit effect is 10.56 (P < 0.0001). The P-values for single contrasts were 0.009 for visit 3 versus baseline and <0.0001 for visit 4 versus baseline (data not shown).
None of the studied patients suffered from hypertension. Systolic and diastolic blood pressures remained stable during the therapy.
According to the insulinaemic response to OGTT, 12 PCOS patients (67%) were classified as hyperinsulinaemic (H-PCOS), while the remaining 6 (33%) constituted the normoinsulinaemic group (N-PCOS). Overall, there was no significant difference between hyperinsulinaemic and normoinsulinaemic patients in relation to age, BMI, WHR, grade of hirsutism both at baseline and after treatment; therefore, the data presented refer to the entire study group.
After 6 months of pioglitazone therapy, we achieved restoration of menstrual cyclicity in 10 hyperinsulinaemic patients (83%, P < 0.001) and in two normoinsulinaemic patients (33%). In the remainder of the subjects the treatment failed to change the menstrual pattern.
Hormone levels
Table
III shows the
endocrine features of normo- and hyperinsulinaemic patients at
baseline and at each evaluation visit. At baseline there were no
significant differences between the two groups.
|
A similar absolute and relative
trend of decrease was seen for androstenedione plasma levels: visit 4
versus baseline [N-PCOS absolute decrease () =
2.16 nmol/l, percentage decrease 29.3%; H-PCOS
= 2.41 nmol/l and 31.5%]; however
statistical significance was reached only in the H-PCOS group
(P < 0.05). Also 17-OHP plasma values were significantly
decreased at visit 4 versus baseline only in the H-PCOS group
(P < 0.01), whereas they remained unchanged in N-PCOS
patients.
Other hormonal parameters did not change during treatment, with no significant difference between H- and N-PCOS subjects.
Metabolic parameters
Concerning the
changes in insulin action induced by pioglitazone treatment, several
differences seem to emerge from the comparison between hyperinsulinaemic
(H-PCOS) and normoinsulinaemic (N-PCOS) patients (Figures
13).
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In these subjects there was a significant decrease in insulin levels in response to the glucose load at visit 3 (AUC I: P < 0.05 for visit 3 versus baseline), which was maintained after 6 months of drug treatment (AUC I: P < 0.05 for visit 4 versus baseline). In the same group of patients, pioglitazone induced a progressive improvement in insulin sensitivity, documented by the increase of M value during the euglycaemichyperinsulinaemic clamp, reaching statistical significance after 6 months of therapy (P < 0.01 for visit 4 versus visit 1). A contemporaneous raise in the hepatic clearance of insulin is suggested by the significant increase of hepatic insulin extraction observed in these patients at visit 3 and 4, when it is no longer possible to observe a significant difference in the comparison with the normoinsulinaemic group (P < 0.01 for H-PCOS visit 3 versus H-PCOS visit 1, and P < 0.05 for H-PCOS visit 4 versus H-PCOS visit 1).
In N-PCOS, there was an improvement in insulinaemic response to OGTT in terms of AUC I after 4 months of treatment (P < 0.05 for visit 3 versus baseline), followed, in the last 2 months of therapy, by a return to AUC I values similar to those observed before the treatment. In these patients, pioglitazone administration failed to significantly modify insulin sensitivity and hepatic insulin extraction during the study (Figures 13).
Fasting and 2-h post-glucose load glucose levels did not change significantly in either of the study groups.
Lipid profile
As regards the lipid profile, there is a slight trend of improvement of all the parameters taken into consideration (total cholesterol, HDL, LDL, VLDL cholesterol, NEFA and tryglicerides); nevertheless, statistical significance is not evident from ANOVA results (Table IV).
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Discussion |
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In recent years, few studies have demonstrated that troglitazone is able to induce an attenuation of insulin resistance and hyperinsulimaenia associated with PCOS, resulting in an improvement of several clinical and biochemical parameters typical of the syndrome (Dunaif et al., 1996; Ehrmann et al., 1997
; Azziz et al., 2001
). However, rare but serious acute hepatic failure following the administration of this drug to diabetic subjects has been described, thus suggesting the need to test other compounds of this class (Goldstein, 2002
). Since pioglitazone, a new compound belonging to the thiazolidinediones class, seems to exhibit similar therapeutic properties with low-risk side-effects in diabetic patients, it was reasonable to explore this opportunity in PCOS.
This is the first study on the effect of pioglitazone in PCOS patients; it is a pilot, and all data are descriptive and exploratory. The primary objective of the present trial was to evaluate the potential role of this new drug in a chronic administration as an insulin-sensitizing agent in obese women affected by PCOS.
In the study population, a small subset of patients showed a normal insulin secretion; hence, the effect of pioglitazone treatment was examined in relation to the different insulin secretion. To our knowledge, this specific aspect was not considered in previous studies in which troglitazone and metformin were administered to PCOS patients, probably because of the assumption that all obese PCOS subjects are hyperinsulinaemic and insulin resistant. However, several reports have clearly demonstrated the heterogeneity of insulin secretion also in this specific subset of patients (Dunaif et al., 1989; Lanzone et al., 1990
; Ciampelli et al., 1997
).
The present data clearly demonstrate the therapeutic effect of pioglitazone in PCOS subjects with exaggerated insulin secretion: in fact these patients showed an improvement of both sensitivity and hepatic clearance of insulin, which in turns led to a significant decrease of AUC I in response to OGTT. In contrast, in the small group of normoinsulinaemic obese PCOS patients, pioglitazone failed to induce any significant variation in the investigated metabolic parameters.
Interestingly, a marked decrease of LH plasma levels and LH/FSH ratio was obtained in both the treated groups, reaching statistical significance in H-PCOS patients. Several lines of evidence suggested that insulin-lowering drugs are associated with a decrease of LH levels: metformin and troglitazone long-term administration was able to obtain this effect in obese PCOS subjects (Velazquez et al., 1994; Hasegawa et al., 1999
; Kowalska et al., 2001
). Moreover, naltrexone and somatostatin have been shown to exert a blunting of LH response to GnRH only in hyperinsulinaemic subjects in a closely related manner (Lanzone et al., 1983
; 1995
; Ciotta et al., 1999
). Since these drugs act via different mechanisms, it has been hypothesized that the insulin decrease may reduce directly or through an unknown mechanism, the pituitary LH synthesis and discharge, as suggested also by the blunted hypophyseal response to GnRH acute injection observed in so-treated subjects. This contention is indirectly supported by in-vitro studies in which the IGFs exert a positive effect on LH discharge from cultures of rat pituitary cells (Soldani et al., 1994
; 1995
). However, more recently it has been observed that the administration of N-acetylcysteine induced a reduction of insulin secretion and improvement of insulin sensitivity without any change in LH secretion (Fulghesu et al., 2002
). Results from the present work indicate that pioglitazone was able to reduce LH secretion by a similar magnitude in both groups independently of its effect on insulin secretion and sensitivity, thus suggesting a mechanism of action for this drug unrelated to pre-treatment circulating insulin levels.
The bulk of these results indicates that pioglitazone may have a dual differentiated effect on PCOS population; in normoinsulinaemic patients the long-term administration of pioglitazone produced a decrease of LH, while in hyperinsulinaemic subjects this effect is associated with a significant improvement of insulin metabolism. In this concern, it is interesting to note that a similar 2535% decrease in androstenedione plasma levels was obtained in both groups, indicating a relationship with the above-mentioned effects on insulin and/or LH secretion. Recently, troglitazone was found to repress combined stimulation by LH and insulin of de-novo androgen biosynthesis by porcine thecal cells in vitro (Veldhuis et al., 2002), providing a plausible mechanicistic basis for at least part of the observed clinical efficacy of thiazolidinediones in mitigating the androgen excess in PCOS. Moreover, similar results have been obtained from rat, in which the administration of troglitazone decreased both basal and insulin-, LH- and hCG-stimulated androstenedione production by theca interstitial cells (Mitwally et al., 2002
). Therefore, the effect of pioglitazone on androgens observed in this study may also be due, at least in part, to a direct mechanism on ovarian function.
Few papers have reported that insulin may exert a stimulatory action on adrenal gland; this contention is supported by in-vivo studies in humans as well as by in-vitro observations (Holte, 1990; Lanzone et al., 1994
; Dunaif, 1997
). In the present work, the decrease in insulin secretion obtained with pioglitazone treatment seems not to affect the adrenal production of DHEA-S, while a reduction of 17-OHP levels was observed only in hyperinsulinaemic patients, reaching statistical significance after 6 months of therapy.
Pioglitazone treatment did not show any significant effect on total and free testosterone, and SHBG plasma levels, although in this last case an increase of 38% was seen in hyperinsulinaemic patients as compared with a 9% increase in normoinsulinaemic patients; however, it is possible that the relatively small number of patients recruited did not permit statistical significance to be reached. Moreover, no significant effect was seen for the other hormonal parameters, in contrast with the results observed in other studies after troglitazone treatment. Beyond the differences in chemical properties, the dose, the longer clinical protocol with respect to the present work (Dunaif et al., 1996) and the different metabolic conditions at baseline may account for these discrepancies.
Consistent with the improvement in endocrine and biochemical parameters, this study shows that pioglitazone administration is able to ameliorate some clinical features typical of PCOS. The majority of our hyperinsulinaemic patients, who had been suffering from oligomenorrhoea since the immediate post-menarchal age, recorded an improvement or a restoration of menstrual cyclicity. This clinical effect of pioglitazone is similar to that found with other insulin-lowering drugs (Moghetti et al., 2000; Azziz et al., 2001
). Moreover, clinical signs of hyperandrogenism (acne or hirsutism) significantly improved during the treatment. In this respect, both normo- and hyperinsulinaemic obese patients receive a beneficial effect, indicating that high insulin levels did not constitute a determinant of the clinical response to the drug.
Overall, these findings are in line with those of Nestler and Jakubowicz (1997), who described a reduction in hyperandrogenism with the use of metformin in lean normoinsulinaemic women with PCOS. More recently, Azziz and colleagues reported the effectiveness of troglitazone at inducing ovulation in PCOS patients, even in the absence of marked hyperinsulinaemia (Azziz et al., 2001
).
Since LH as well as the androstenedione plasma levels declined in normoinsulinaemic patients, it is possible that reduction of LHovary axis function, along with a possible direct action of pioglitazone on the ovary, may account for the significant modification of clinical features in this group of patients (who theoretically could not be recruited for treatments based on the hypothetical target of insulin lowering). It is likely that in hyperinsulinaemic subjects the net amelioration of insulin metabolism may justify, from a physiopathological point of view, the clinical use of this treatment.
The second objective of the current study was to assess the side-effect incidence after 6 months of pioglitazone treatment. Overall, notwithstanding the limited number of cases under observation, in our experience we did not have any documented case of biochemical and/or clinical abnormalities ascribable to liver dysfunction. This finding supports previous studies demonstrating that hepatotoxicity related to thiazolidinediones administration is not a class effect (Tolman, 2000).
In conclusion, the data reported here indicate that pioglitazone may be considered as a possible new treatment for patients with PCOS, since it was able to restore normal menstrual cyclicity and to improve clinical signs of hyperandrogenism. Moreover, due to the virtual absence of side-effects, this drug may be an alternative to other thiazolidinediones. Interestingly, both normo- and hyperinsulinaemic patients showed clinical and endocrine effects partially independent from the specific action on insulin metabolism, which was differentiated in the two groups: hyperinsulinaemic subjects had an improvement of insulin secretion, metabolism and sensitivity, whereas no effect was seen in normoinsulinaemic subjects. These results suggest that beyond the effect of insulin metabolism, other possible sites of action may be triggered by pioglitazone.
Further studies are needed to elucidate the full mechanism of action of the drug and the possible applications to the various subsets of PCOS population.
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Acknowledgements |
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Submitted on January 6, 2003; accepted on March 7, 2003.