Effects of metformin plus simvastatin on polycysticovary syndrome: a prospective, randomized,double-blind, placebo-controlled study
Talieh Kazerooni, M.D.,a Azam Shojaei-Baghini, M.D.,a Sedigheh Dehbashi, M.D.,a Nasrin Asadi, M.D.,aFariborz Ghaffarpasand, M.D.,b and Yasaman Kazeroonic
a Department of Obstetrics & Gynecology, Shiraz University of Medical Sciences, Shiraz, and b Student Research Committee,Fasa University of Medical Sciences, Fasa, Iran; and c New Mexico Tech University, Socorro, New Mexico
Objective: To evaluate the effect of a combination of simvastatin and metformin on biochemical parameters inwomen with polycystic ovary syndrome (PCOS).
Design: A prospective, randomized, double-blind, placebo-controlled study.
Setting: University hospital.
Patient(s): Eighty-four women with PCOS randomly divided to two study groups.
Intervention(s): Patients were randomly assigned to receive metformin (500 mg three times a day) plus simvastatin(20 mg/day, n ¼ 42; group 1) or metformin (500 mg three times a day) plus placebo (once a day, n ¼ 42; group 2) for12 weeks. Blood samples were obtained before and after treatment.
Main Outcome Measure(s): Testosterone.
Result(s): After 12 weeks of treatment, serum T levels decreased by 25.5% in group 1 and by 16.8% in group 2.
There was a greater decrease of LH (45.5% vs. 6.7%) and a greater decline of the LH/FSH ratio (38.3% decreasedvs. 4.4% increased) in the ﬁrst group. In group 1 there was a greater decrease of total cholesterol (29.5% vs. 4.2%),low-density lipoprotein (LDL; 18.5% vs. 1.5%), and triglycerides (32% vs. 5.3%). High-density lipoprotein (HDL)increased in the ﬁrst group by 14%, whereas it decreased by 1% in the second group.
Conclusion(s): This report has demonstrated that the combination of metformin and simvastatin could lead to a bet-ter reduction of T and LH levels and thus reversing the LH:FSH ratio, lipid proﬁle, and insulin resistance in patientswith PCOS and may be an appropriate management option for patients with PCOS. (Fertil Steril� 2010;-:-–-.
�2010 by American Society for Reproductive Medicine.)
Key Words: Polycystic ovary syndrome, metformin, simvastatin, testosterone, lipid proﬁle
Polycystic ovary syndrome (PCOS) is a common endocrinopathy
Treatment for subjects with PCOS typically includes implemen-
affecting 6.5%–6.7% of women in reproductive age, and is
tation of lifestyle changes, especially weight loss and adjuvant
commonly associated with obesity, menstrual irregularity, insulin
pharmaceutical intervention including oral contraceptives (OC),
resistance, infertility, and clinical hyperandrogenism or hyperandro-
antiandrogen therapy, and insulin-lowering drugs (e.g., metformin)
genemia (1, 2). The PCOS is also associated with increased risk of
(6). Metformin is a biguanide, used extensively in type 2 diabetes.
abnormal lipoproteins and hypertension, as well as cardiovascular or
It inhibits hepatic glucose production and increases peripheral insu-
cerebrovascular morbidity (3). The lipid and lipoprotein proﬁle in
lin sensitivity, but does not cause hypoglycemia. Several studies
androgenized women with polycystic ovaries (PCO) is similar to
have shown an increase in insulin sensitivity and pregnancy rate
the pattern with higher levels of cholesterol, low-density lipoprotein
(PR), accompanied by decreased insulin and androgen levels, in
(LDL), and lower levels of high-density lipoprotein (HDL), and this
patients with PCOS taking metformin (7).
abnormal pattern is independent of body weight (4). Insulin resis-
The 3-hydroxy-3-methylglutaryl coenzyme A (hMG-CoA)
tance is associated with reproductive abnormalities in women with
reductase inhibitors (statins) are the rate-limiting step in cholesterol
PCOS. Improving insulin sensitivity through both lifestyle and phar-
biosynthesis, and inhibition of this enzyme decreases cholesterol
macologic intervention can ameliorate these abnormalities. Insulin
synthesis and a compensatory increase in the expression of LDL
resistance in women with PCOS is common (up to 50%), both in
receptors in the liver. Statins reduce plasma triglycerides in dose-de-
obese and nonobese women (5), and disordered insulin action
pendent fashion and also have a modest HDL raising effect, which is
not dose-dependent (8, 9). Furthermore, statins pose other cardio-protective properties, including antioxidant and anti-inﬂammatoryactions (10, 11).
Received July 20, 2009; revised November 21, 2009; accepted November
Some studies have reported that simvastatin decreases serum
androgen levels in women with PCOS (12, 13) by inhibiting prolif-
T.K. has nothing to disclose. A.S.-B. has nothing to disclose. S.D. has
eration and steroidogenesis of ovarian theca interstitial cells (14).
nothing to disclose. N.A. has nothing to disclose. F.G. has nothing to
According to these previous ﬁndings, we hypothesized that a combi-
disclose. Y.K. has nothing to disclose.
nation therapy with simvastatin and metformin will result in lower
Reprint requests: Fariborz Ghaffarpasand, M.D., PO Box: 7173646199,
androgen levels and cardiovascular risk factors in women with
987116483561; E-mail: firstname.lastname@example.org).
Fertility and Sterility� Vol. -, No. -, - 2010
Copyright ª2010 American Society for Reproductive Medicine, Published by Elsevier Inc.
All hormonal assays were performed in Endocrinology and Metabolism
Research Center of Nemazee Hospital. Serum FSH (FSH-IRMA,KIP0264; BIOSOURCE, Nivelles, Belgium), LH (LH-IRMA CT, REF
The study was performed at the infertility clinic of Zeinabieh hospital, a ter-
KP7CT; RADIM, Rome, Italy), DHEAS (DHEA-S-IRMA, KIP0481;
tiary care center afﬁliated with Shiraz University of Medical Sciences. We
BIOSOURCE), and PRL (PRL-IRMA, KIP1406; BIOSOURCE) were mea-
screened 92 patients with PCOS ranging in age from 17–29 years between
sured by RIA. Serum T levels were measured by RIA (ESTO-RIA-CT,
January and March 2008. The review board of Shiraz University of Medical
KIP1709; BIOSOURCE). The intra-assay and interassay coefﬁcients of
Sciences approved the study and all recruited patients ﬁlled the informed
variation (CV) were <6% for all assays performed.
Polycystic ovary syndrome was deﬁned according to Rotterdam European
Society for Human Reproduction and Embryology (ESHRE)/American
Society for Reproductive Medicine (ASRM) PCOS consensus workshop
Thirty-seven patients were required in each group for a study to have 90%
(5). All patients had at least two of three following criteria:  chronic anov-
power to detect signiﬁcant differences between corresponding variables
ulation,  clinical or biochemical evidence of androgen excess, and 
(P¼.05, two-sided). To compensate for possible nonevaluable data, we en-
polycystic-appearing ovaries on transvaginal ultrasound (TVUS). Patients
rolled 42 participants in each group. The Statistical Package for Social
with Cushing’s syndrome, hyperprolactinemia, diabetes mellitus, thyroid
Science, SPSS for Windows, version 15.0 (SPSS, Chicago, IL) was used
disease, adrenal hyperplasia, and androgen-secreting tumors or other
for data analysis. Paired t-tests were used to compare results within groups;
endocrinopathies, have been excluded from the study. Patients with adrenal
independent t-tests were used to compare results between the groups; c2 tests
hyperplasia were excluded by ACTH-stimulated 17a-hydroxyprogesterone
were used to compare proportions. Data are reported as means � SD for 95%
(17-OHP) levels less than 10 ng/mL (15), and ACTH-stimulated 11-deoxy-
conﬁdence interval (CI) with 5% degree of freedom. A two-sided P value
cortisol levels less than 21 ng/mL (threefold the 95th percentile (16) of a his-
< .05 was considered statistically signiﬁcant.
toric control group of 60 healthy women controls). Those subjects who hadkidney or liver diseases and those who were smoker or had breast cancer were
also excluded from the study. None of the participants received OCs, steroidhormones, or any medications that would interfere with lipid metabolism,
All participants ﬁnished the study. The baseline characteristics of
ovarian, pituitary, and hypothalamic function, or insulin sensitivity in the 3
the two study groups are shown in Table 1. All baseline measure-
months before study entry. All patients used barrier methods of contraception
ments were comparable. Patients in both treatment groups tolerated
during the study regarding the potential teratogenic actions of statins. The
the treatments well, and none of them experienced signiﬁcant side
possible teratogenicity of statins was explained to all the participants and
effects. In particular, none of the subjects developed symptoms of
they were asked to use barrier contraception. This was obeyed by all the par-
muscle damage, and liver function tests remained normal through-
ticipants. All the patients followed almost the same exercise and diet proto-
out the study. Also, none of the patients conceived during the
cols during the study period. All subjects were nonsmokers and had normal
physical activity, and none drank alcoholic beverages.
Table 2 shows the mean � SD of the variables before and after
12 weeks of treatment and Table 3 represents the changes in the
parameters in each study group. The BMI was signiﬁcantly
Patients were given a sealed envelope containing their admission number by
decreased by 7.7% in group 1 (P¼.039) and by 7.5% in group 2
a nurse who was blinded to the study and in the order of presentation. This
(P¼.041); there was no signiﬁcant difference between groups
admission number became the participant’s medical chart number. Another
(P¼.341). Total cholesterol declined after 12 weeks of treatment
researcher (a physician) who was blinded to the study opened the envelope
by 29.5% in group 1 and by 4.2% in group 2 (P<.001). The
and gave the patients a red box if they had odd numbers and a green one if
HDL levels increased in group 1 by 14%, whereas it decreased
they had even numbers. He did not know the content of the boxes. The par-
by 1% in group 2 (P<.001). The LDL levels decreased in group
ticipants with odd numbers (n ¼ 42) were assigned to the simvastatin (20 mg/
1 by 18.5% and by 1.5% in group 2 (P<.001). The TG levels
day) plus metformin (500 mg three times a day, n ¼ 42; group 1) group andthose with even numbers (n
were also decreased in both groups: 32% in group 1 and 5.3%
¼ 42) were assigned to the placebo (once a day)
plus metformin (500 mg three times a day, n ¼ 42; group 2) group.
Serum T level declined by an average of 25.5% (P¼.001) in
group 1 and by 16.8% (P¼.002) in group 2; the difference in the
treatment effect between groups was signiﬁcant at P<.001. The
On the ﬁrst day of a spontaneous or P-induced menstrual cycle, after an
change in the DHEAS value was also signiﬁcant between groups
overnight fast, blood samples were drawn to determine serum FSH, LH, total
(P¼.007); it declined by 3% (P¼.043) and 0.2% (P¼.973) in group
T, PRL, DHEAS, fasting blood sugar, fasting insulin, total cholesterol, HDL,
1 and 2, respectively. Serum LH level and LH:FSH ratio were both
LDL, and triglycerides (TG). In addition, in a 75-g oral glucose tolerance test
signiﬁcantly decreased in group 1, whereas they remained un-
(OGTT), blood samples were drawn at 60 and 120 minutes to determine in-sulin and glucose responses. Insulin sensitivity was assessed by quantitative
changed in group 2. The FSH level did not change signiﬁcantly
insulin sensitivity check index deﬁned as 1/[log(fasting insulin) þ log(fasting
in either groups. The decline in the LH level (P¼.001) and LH:FSH
glucose)] (17). Participants were diagnosed as having insulin resistance when
ratio (P¼.009) were signiﬁcant between groups (Table 3). The
the fasting glucose-to-fasting insulin ratio was less than 4.5 (18). Body mass
hirsutism score (on the Ferriman–Gallwey scale) declined signiﬁ-
index (BMI, as weight in kilograms divided by height in meters squared) was
cantly in both groups by 13% and 7 % in group 1 and 2, respec-
calculated by a single physician who was blinded to the study groups. Hirsut-
tively; the difference between groups was signiﬁcant at P¼.019.
ism was also scored according to the Ferriman–Gallwey scale by the same
Table 4 summarizes the 75-g OGTT results. Fasting insulin level
physician (19). All measurements were taken again from all participants after
and fasting blood sugar, as well as 60- and 120-minute insulin and
12 weeks of treatment. The participants were instructed to report in a daily
glucose levels were signiﬁcantly decreased after 12 weeks of treat-
diary the onset of any adverse experiences (especially muscle pain), specify-
ment. However, these changes were not signiﬁcant between groups.
ing the severity, duration, and a possible cause–effect relationship with drugadministration. To evaluate compliance with the treatment and with the pro-
Also, the insulin sensitivity increased in groups 1 and 2 by 3.2%
tocol, number of tablets forgotten, changes in diet, physical activity, and
(P¼.014) and 2.7% (P¼.029), respectively, but it was not signiﬁcant
weight, as well as the timing of intercourse were also recorded in the diary.
between groups (P¼.084). In the ﬁrst group, 27 participants (64.2%)
Liver function tests were performed at baseline and at 12 weeks.
were insulin resistant at baseline, whereas 11 (26.2%) were on week
We tested the hypothesis that combination therapy with metformin
Baseline characteristics of two study groups.
and simvastatin in patients with PCOS will have better results inreducing the hyperandrogenism and normalizing other biochemical
parameters than using metformin alone, with a possible synergic
mechanism. A few studies have assessed the beneﬁcial effect of sim-
vastatin in PCOS (12, 13). This study shows that in the presence of
simvastatin, metformin is much more effective in reducing the T,
DHEAS, clinical hyperandrogenemia (hirsutism), LH, and reversing
the LH:FSH ratio in patients with PCOS. Elevated T level and a high
LH:FSH ratio are the hallmarks of the hypothalamic-pituitary-ovar-
ian dysfunction that is characteristic of PCOS. Metformin alone
could not reduce these parameters, except for T level and hirsutism.
Several studies have indicated the beneﬁcial effect of metformin
on biochemical and clinical aspects (7, 20–22). Metformin therapy
leads to a rapid improvement of hyperandrogenemia and hyperan-
drogenism and is effective in reducing insulin resistance in women
with high baseline androgen levels similar to PCOS (7, 23).
Three previous randomized controlled trials have shown that sim-
vastatin could successfully reduce T and LH levels and the LH:FSH
ratio (12, 13, 24). However, none of them could reduce the insulin
resistance assessed by insulin indices. Evidence of an association
between PCOS and glycometabolic dysfunction has accumulatedduring the past few years, and that a large percentage of women
Note: Values are expressed as the mean � SD. Signiﬁcant difference
with this condition have hyperinsulinism and insulin resistance.
BMI ¼ body mass index; FBS ¼ fasting blood glucose; HDL ¼ high-density
lipoprotein; LDL ¼ low-density lipoprotein; QUICKI ¼ quantitative
increased androgen production by stimulating ovarian steroidogen-
insulin sensitivity check index; TG ¼ triglycerides; WHR ¼ waist-to-
esis. At higher concentrations, insulin binds to the insulin-like
growth factor (IGF) receptors, transmits its signals to the ovary
Kazerooni. Metformin plus simvastatin in PCOS. Fertil Steril 2010.
already in a hyperandrogenic state because of an enzymatic dysregu-lation of cytochrome P450c17-a, and inhibits the synthesis of thehepatic sex hormone-binding globulin (SHBG) (25). We showed
12 of the study (P¼.001). In the second group, 26 participants
that combination therapy with simvastatin and metformin not only
(61.9%) were insulin resistant at baseline, whereas 12 (28.7%)
decreased hyperandrogenemia more effectively but also reduced
were at the end of the study (P¼.003).
the number of PCOS patients with insulin resistance and increased
Hormonal and metabolic parameters in both groups before and after 12 weeks of treatment.
Note: Values are expressed as the mean � SD. Signiﬁcant change from baseline in each group (P< .05).
BMI ¼ body mass index; FBS ¼ fasting blood glucose; HDL ¼ high-density lipoprotein; LDL ¼ low-density lipoprotein; QUICKI ¼ quantitative insulin sensitivity
Kazerooni. Metformin plus simvastatin in PCOS. Fertil Steril 2010.
for the lowering of plasma cholesterol (10). Steroid hormone synthe-
sis depends on a supply of cholesterol, which may be derived from
Changes in the baseline values of 84 patients with
the uptake of plasma lipoproteins or from endogenous synthesis
polycystic ovary syndrome after 12 weeks of treatment
with metformin plus simvastatin (group 1) and metformin
Because of the design of our study we cannot dissociate the
effects of statins on the ovary from the effects on the hypothalamus
and pituitary. However, it is likely that the primary actions are taking
place in the level of the ovary. Several lines of evidence support this
concept. First, statins had no effect on serum T level in postmeno-pausal women in whom the main source of androgens is extraovar-
ian (26). Second, paravastatin signiﬁcantly decreased cholesterol
level in patients with heterozygous familial hypercholesterolemia
in whom delivery of LDL to the adrenal cortex is impaired and
thus have demonstrable deﬁciencies of adrenal steroid production
(27). Third, it was shown that statins decrease ovarian theca
interstitial proliferation and T production in vitro (14). And the
last evidence is that surgical resection or ablation of a portion of the
ovary (wedge resection or laparoscopic diathermy, which decreases
ovarian androgen production) leads to marked decline of T, LH, and
The precise metformin mechanism of action is yet to be eluci-
dated. Attia et al. (30) found that metformin directly inhibited andro-
gen production in human ovarian thecal cells. It still remains unclear
whether metformin improves ovulation by direct inhibition of
androgen production or by improving insulin sensitivity, and thus
Note: Values are expressed as the mean � SD. Signiﬁcant change from
indirectly lowering serum androgens. The mechanisms of action
of simvastatin on inhibition of T levels are likely related to inhibition
BMI ¼ body mass index; FBS ¼ fasting blood glucose; HDL ¼ high-den-
of the mevalonate pathway. Such an inhibition has a broad range of
sity lipoprotein; LDL ¼ low-density lipoprotein; QUICKI ¼ quantita-
consequences, including decreased availability of cholesterol
tive insulin sensitivity check index; TG ¼ triglycerides.
(a substrate for androgen production), as well as inhibited growth
Kazerooni. Metformin plus simvastatin in PCOS. Fertil Steril 2010.
demonstrated previously by in vitro studies (14). Statins mightalso decrease the expression of several key enzymes involved in T
the insulin sensitivity, and the 75-g OGTT supported these results.
production: cholesterol side chain cleavage (P450SCC), 17a-hydrox-
These effects are attributable to metformin, as they were observed
ylase/17,20-lyase (P450c17), and 3b-hydroxysteroid dehydrogenase
(3bHSD). Such effects of statins were noted in adrenocortical cells
The hMG-CoA reductase inhibitors (statins), the rate-limiting
(31, 32). The mechanisms of these actions might be due to the inhib-
enzyme in cholesterol synthesis is the most effective agent available
itory effects of statins on isoprenylation (33), leading to decreased
Fasting insulin and glucose levels and response to 75-g oral glucose tolerance test in 84 women with polycystic ovary syndrome.
Note: Values are given as mean � SD. P< .05 is considered signiﬁcant.
a No signiﬁcant differences were observed between the mean of variables in the studied groups before therapy (P>.05).
b No signiﬁcant difference compared with metformin plus placebo group (P>.05).
Kazerooni. Metformin plus simvastatin in PCOS. Fertil Steril 2010.
function of small guanosine triphosphatases, such as Ras, Rho, and
We noted some limitations to our study. First, this study evaluated
Rac. Ras might increase expression of P450SCC, P450c17, and
only the effects of metformin in the presence of a single dose of a sin-
3bHSD, and statin might abrogate Ras-induced steroidogenesis
gle statin. Therefore we cannot attribute the primary and secondary
(32). In addition, statin-induced inhibition of proliferation of theca
end pints of this study to any of these drugs alone. However, we
interstitial cells (14) might reduce T output of the ovary by reducing
decided to use this combination to ﬁnd their synergic effects.
the size of the theca interstitial compartment.
Metformin can reduce insulin resistance, whereas simvastatin can
An abnormal lipid proﬁle is a common ﬁnding in PCOS and
improve the lipid proﬁle, and both reduce the androgen levels in
includes elevated total cholesterol, triglycerides, and LDL and
patients with PCOS. Therefore combination therapy may result
decreased levels of HDL (3, 6). The most characteristic lipid alter-
in a better reduction of androgen levels, as well as lipid proﬁle
ation in patients with PCOS is decreased levels of HDL (3). It was
and insulin resistance. Adding a simvastatin plus placebo group to
also shown that patients with PCOS have higher levels of serum
a similar study will sheds light on the single effects of these two
TG, very LDL, LDL:HDL ratio, and signiﬁcantly lower levels of
drugs. Second, although simvastatin plus metformin can success-
HDL compared with the normal population (26). There are several
fully reduce hyperandrogenism, insulin resistance, and lipid proﬁle,
lines of evidence suggesting that women with PCOS are also at
but its clinical signiﬁcance is yet to be characterized. More long-
increased risk of cardiovascular disease due to dyslipidemia, insu-
term studies are needed to make this obvious. Third, the course of
lin-resistant increased (3–7 times), and markers of abnormal vascu-
the study was 3 months, which does not reﬂect the clinical usage
lar function (3, 6). Another ﬁnding of our study was improvement of
of these drugs that tends to be chronic once initiated. A limitation
the lipid proﬁle. Simvastatin signiﬁcantly reduced TG, total choles-
is that we do not know the risk-to-beneﬁt ratio beyond 3 months
terol, LDL and increased HDL. These ﬁndings are consistent with
for women with PCOS. And fourth, we used barrier contraception
previous studies regarding the LDL, HDL and cholesterol levels
during the study. Regarding the potential teratogenicity of statins,
(12, 13). However, the TG levels were unchanged (12) or increased
this method of contraception is not ideal and needs strict patient
(13) in these two studies that may be due to OC usage in these stud-
compliance with constant and perfect use and should be replaced
ies. Therefore, reduction of TG in our study may suggest a synergic
by other methods when used in practice.
effect of metformin added to simvastatin. Taking all together,
In summary, this report demonstrates that the combination of
simvastatin and metformin can reduce cardiovascular risk factors
metformin and simvastatin could lead to a better reduction of T
in patients with PCOS by making beneﬁcial changes in lipid proﬁles,
and LH levels and thus reversing the LH:FSH ratio, lipid proﬁle,
direct effect on vascular tissue due to positive impact on vascular
and insulin resistance in patients with PCOS and may be an appro-
and glomerular nitric oxide production, attenuation of vascular
priate management option for patients with PCOS.
inﬂammation, improvement in insulin sensitivity, and androgen
Acknowledgment: The authors acknowledge all the patients and their
families who patiently participated in this study.
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OTDR AND OLTS TWO DIFFERENT TOOLS FOR SPECIFIC NEEDS When referring to outside plant test instruments, managers are often hear to say, "Why should I measure loss with an optical loss test set(OLTS) when an optical time domain reflectometer (OTDR) gives me a value for optical loss?" While these instruments seem to take similarmeasurements, they serve different purposes; the choice b
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