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Endocrine Care

Effects of Metformin on Endocrine and Metabolic


Parameters in Patients with Polycystic Ovary
Syndrome

Authors M. Zahra1 * , M. Shah1 * , A. Ali2, 3, R. Rahim4


1
Affiliations  Department of Physiology, Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, Pakistan
2
 Department of Histopathology, Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, Pakistan
3
 Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
4
 Department of Gynaecology and Obstetrics, Gynaecology Unit B, Lady Reading Hospital, Peshawar, Pakistan

Key words Abstract observed after metformin treatment (p  = 0.05),


● ▼

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▶ diabetes while no change was found in the size of left ovary

▶ polycystic ovary syndrome
The present study was designed to evaluate the (p > 0.12). Moreover, a significant reduction was

▶ metformin
effects of metformin on metabolic and endocrine observed in the serum levels of FSH (p > 0.01), LH

▶ insulin
parameters in patients with polycystic ovary (p > 0.001), and visfatin (p > 0.001) after metformin

▶ INSL3


▶ visfatin syndrome (PCOS). The study included 40 patients treatment. However, HOMA-IR (which is used to
with PCOS. Patients were divided into 2 groups assess insulin resistance) failed to reach the sta-
based on whether they will receive metformin tistical significance (p = 0.20). We conclude that
(500 mg 3 times a day, n = 20) or placebo (n = 20) metformin treatment in females with PCOS
for 3 consecutive months. Serum concentrations showed significant improvement in systolic and
of fasting blood glucose, insulin, HOMA-IR, INSL- diastolic blood pressures. In addition, an
3, visfatin, FSH, and LH were measured at base- improvement in the hormonal profile in the form
line and after 3 months of therapy. The key of reduction in LH, FSH, and visfatin levels was
endocrine and metabolic parameters signifi- observed. Thus, therapeutic intervention with
cantly changed after metformin treatment. The metformin could be of clinical importance in
systolic and diastolic blood pressures were sig- high-risk group of young females with PCOS.
nificantly reduced in the metformin group after Supporting Information for this article is available
treatment compared to placebo (p < 0.001). A sig- online at http://www.thieme-connect.de/products
nificant reduction in the size of the right ovary was

Introduction ance and hyperinsulinemia play a key role in the


received 26.05.2016
accepted 28.09.2016 ▼ pathogenesis of PCOS both in obese and non-
Polycystic Ovary Syndrome (PCOS) is one of the obese females. Thus, insulin resistance and
Bibliography common endocrinopathy in females of child- hyperinsulinemia were attributed as vital mark-
DOI http://dx.doi.org/ bearing age. PCOS leads to reproductive health ers of PCOS [8–10]. Insulin stimulates the intra-
10.1055/s-0042-119041 related complications especially menstrual irreg- ovary biosynthesis of steroid hormones by
Published online: 2016 ularity, infertility, and androgenemia in females interacting with luteinizing hormone (LH);
Horm Metab Res [1, 2]. The prevalence of PCOS in Pakistani females which, in turn results in immature follicle cells
© Georg Thieme Verlag KG
is similar to the prevalence in other parts of the differentiation [11, 12]. This may directly increase
Stuttgart · New York
world [3, 4]. It is described as the presence of the ovarian secretion and anomalous follicular
ISSN 0018-5043
characteristic ultrasound features of polycystic growth.
Correspondence ovaries, infrequent menstrual periods, hyper- Insulin-like peptide-3 (INSL-3) and visfatin play
M. Shah androgenism, and enhanced obesity as a result of important roles in various pathophysiological
Department of Physiology hyperinsulinemia [5]. conditions. INSL-3 and visfatin are 2 hormones
Institute of Basic Medical Recently several studies have illustrated genetic that appear to play a vital role in the etio-patho-
­Sciences and intra-ovarian origins of PCOS. Moreover, genic evolution of PCOS. INSL-3 is principally a
Khyber Medical University
environmental factors such as diet and lifestyle hormone found in adult males but it is also found
Peshawar
factors also play a significant role in PCOS [6, 7]. in a small amount in females [13, 14]. INSL-3 is
Pakistan
Tel.:  + 92/342/9620 074 In addition, it has been shown that insulin resist- expressed in the theca cells of ovarian follicles
Fax:  + 92/586/2 519 and in corpus luteum [15]. Females having PCOS
mohsin.ibms@kmu.edu.pk *
 These authors contributed equally to this work usually present with a greater number of follicu-

Zahra M et al. Metabolic and Hormonal Variations in PCOS …  Horm Metab Res
Endocrine Care

lar arrest in different stages of differentiation in a specific time, sure was measured using a standard mercury sphygmomanom-
when the expression of INSL-3 in the theca cells is at maximum eter according to standard protocol. Two blood pressure readings
[16, 17]. There is thus a good association between the concentra- were taken with the participant resting for 10 min, and the mean
tion of INSL-3 and the follicular number as revealed by ultra- of the 2 readings was taken as the final result. Venous blood
sound examination [14]. sample was obtained after overnight fast to measure the circu-
Visfatin is a novel adipo-cytokine mimicking the actions of insu- lating concentrations of luteinizing hormone (LH), follicle stim-
lin. It plays an important role in glucose metabolism and is ulating hormone (FSH), glucose, insulin, and insulin resistance.
linked to several inflammatory conditions and beta cell function
[18]. Several studies demonstrate contradictory data in humans Hormonal analysis
relating to the function of visfatin in regulation of insulin sensi- After written informed consent, 5 ml blood was taken from the
tivity [18–21]. However, a clear association is still not fully eluci- patients. Serum was separated by centrifugation at 3 000 rpm for
dated as most studies have investigated the association of 10 min. The clear transparent supernatant collected was trans-
visfatin and body mass index (BMI) or body fat percentage. ferred to Eppendorf tubes and stored at  − 20 °C until analysis.
Metformin, basically a biguanide, is an antihyperglycemic agent Serum concentrations of FSH and LH were analyzed using com-
that improves glucose intolerance. The use of metformin in mercially available immunoradiometric kits. Serum levels of
pregnant females with PCOS has shown a significant reduction insulin, Insulin-like-Peptide-3 (INSL-3) and visfatin were deter-
in the rate of preterm labor, loss of pregnancy, and poor fetal mined by Enzyme-linked Immunosorbent Assay (ELISA) method.
growth. Metformin metabolically influence the proliferation of The kits uses double-antibody sandwich ELISA to assess the level
follicular cells by enhancing insulin sensitivity, lowering plasma of human insulin, INSL3, and visfatin in serum samples. The
glucose level, and lipid profile [22]. Previous studies show con- basic principle for all the kits used in ELISA was the same. The
tradictory data on the role of metformin in the treatment of pre-coated wells with human monoclonal antibodies were used

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PCOS. Some studies show improvement in the reproductive for respective hormonal analysis. The secondary antibodies
abnormalities, while others have failed to ascertain any bio- were labeled with biotin, and combined with streptavidine-HRP
chemical and or clinical changes after metformin treatment [23]. to form the immune complex. After washing completely,
This study aims to evaluate the effects of metformin (an insulin 3,3′,5,5′-tetramethylbenzidine (TMB) liquid substrate was
sensitizing agent) on insulin resistance in PCOS and to deter- added. The TMB substrate changed to blue color when HRP
mine its relation with neo-hormones INSL-3 and visfatin. enzyme catalyzed the reaction. The reaction was terminated by
the addition of a stop solution and the color change was meas-
ured at a wavelength of 450 nm. All steps of the assay were per-
Subjects and Methods formed according to the manufacturer’s instructions. The results
▼ were analyzed by 3 independent observers apart from the
This was a randomized, placebo-controlled study, conducted in researchers of the study who were blind to the subject status.
2 tertiary care hospitals (Hayatabad Medical Complex and Leady The study was approved by the institutional ethical committee
Reading Hospital, Peshawar, Pakistan). The study included 40 of Khyber Medical University, Pakistan. After the nature of the
females with PCOS aged 18–35 years. The diagnosis of PCOS was study was explained in detail, informed consent was obtained
based on females having disturbed ovulatory function with from all the participants recruited through pre-designed ques-
chronic oligomenorrhea or amenorrhea, typical appearance of tionnaire. Hormonal assay of all the samples was performed
polycystic ovaries by ultrasound examination, hirsutism, or ele- with ELISA micro-plate reader.
vated serum androgen levels. Polycystic ovaries were diagnosed
on the basis of ESHRE/ASRM criteria 2003, on ultrasound (US) Quality assurance
examination. The criteria is as follows: US indicating 10 or more The patients were instructed to take the tablets with their meals.
follicular cysts ranging in size from 2–9 mm or showing increased No serious side effects were reported during study period. The
ovary volume of 10 cm in maximal diameter. The participants dose of the study drug was increased stepwise. Each enrolled
were then randomly divided into 2 groups. The first group (n = 20) patient was also instructed to avoid any drugs with possible hor-
received metformin, according to body weight with a maximum monal and metabolic effects throughout the study.
dose of 500 mg 3 times a day consecutively for 3 months. The
second group (n = 20) received placebo, 3 times a day consecu- Statistical analysis
tively for 3 months. Those females who dropped metformin in Means or proportions of clinical characteristics were computed
this 3 months period (due to socioeconomic reasons) or those for each group in the study. All data was expressed as
were not willing for follow-up visits were excluded from the means ± standard deviation. The differences in various parame-
study. Patients on antihypertensive drugs were also excluded ters between metformin (before and after) and placebo (before
from the study. The details of participants recruited and dropped and after) were assessed using analysis of variance (ANOVA).
from the study are shown in supplementary Fig. 1S. A p-value of < 0.05 was considered statistically significant. All
The clinical diagnosis was based on history, general physical, analyses were performed using SPSS software, version 21.
transvaginal, and transabdominal ultrasound examination. The
outcome measurement included; clinical, metabolic and endo-
crine profiles and insulin sensitivity. Evaluation of these param- Results
eters was performed at baseline and then after 3 months of ▼
metformin treatment. Clinical assessment included height, The characteristics of females in the metformin group and pla-
weight, Body Mass Index (BMI) (weight in kg/height in meter2), cebo group at baseline and after treatment for 3 consecutive
menstrual cycle frequency, and hirsutism. Resting blood pres- months are shown in ●  ▶  Table 1.

Zahra M et al. Metabolic and Hormonal Variations in PCOS …  Horm Metab Res
Endocrine Care

Table 1  Demographic, hemodynamic, metabolic, and endocrine features of patients given metformin or placebo at baseline and after treatment.

Metformin Placebo Effect of treatment


p-Value by ANOVA
Variables Baseline After Baseline After
Age (years) 25.8 ± 6.1 – 27.0 ± 6.3 –
Weight distribution (kg) 66.8 ± 14.7 63.35 ± 12.8 74.5 ± 24.6 74.2 ± 23.9 0.22
BMI (kg/m2) 26.7 ± 6.5 25.3 ± 5.7 29.6 ± 9.9 29.7 ± 9.7 0.258
Systolic B.P. (mmHg) 118 ± 9.5 104 ± 7.6 121 ± 12.1 122 ± 11.9  < 0.001
Diastolic B.P. (mmHg) 82 ± 5.2 73 ± 6.5 85 ± 8.3 89 ± 10.7  < 0.001
Ovary size left (mm) 9.8 ± 3.8 8.6 ± 2.1 10.5 ± 2.5 10.6 ± 2.6 0.12
Ovary size right (mm) 10.6 ± 2.9 9.1 ± 1.5 10.8 ± 2.9 11.1 ± 2.4 0.05
Fasting glucose (mg/dl) 100.2 ± 9.5 100.8 ± 5.3 100.6 ± 7.3 105.6 ± 6.1 0.06
Insulin (IU/l) 17.2 ± 9.2 14.1 ± 9.3 18.6 ± 7.5 18.6 ± 6.4 0.242
HOMA-IR 4.2 ± 2.3 3.5 ± 2.3 4.6 ± 1.8 4.8 ± 1.7 0.202
FSH (IU/l) 4.1 ± 1.2 3.1 ± 0.9 3.1 ± 1.1 3.09 ± 0.9  < 0.01
LH (IU/l) 5.9 ± 2.9 3.1 ± 0.9 6.5 ± 2.8 6.8 ± 2.9  < 0.001
INSL-3 (ng/ml) 7.4 ± 8.8 6.9 ± 7.5 5.8 ± 2.6 6.7 ± 1.8 0.242
Visfatin (ng/ml) 5.9 ± 2.7 5.2 ± 1.8 8.9 ± 4.9 10.1 ± 4.7  < 0.001
BMI: Body mass index; BP: Blood pressure; HOMA-IR: Homeostasis model assessment of insulin resistance; FSH: Follicle stimulating hormone; LH: Luteinizing hormone; INSL-3:
Insulin-like peptide-3. For these variables, data are presented as mean ± SD and ANOVA was applied; aSignificant differences for the comparison between treatments are in bold
type

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Demographic Profile Moreover, the mean fasting serum glucose level remained stable
No statistically significant change was observed in the met- in the metformin group before and after treatment. However,
formin and placebo group in the weight distribution (p = 0.22, the mean fasting serum glucose level increased from 100.6 (mg/
ANOVA) and BMI (p = 0.25, ANOVA). The baseline and after treat- dl) (at baseline) to 105.6 (mg/dl) (after treatment) in the placebo
ment values in both groups for weight and BMI remained almost group with a trend towards statistical significance (p = 0.06).
the same.
Hormonal profile
Hemodynamic profile At baseline, the mean FSH in the metformin and placebo group
At baseline, the mean systolic BP in the metformin and placebo was 4.1 IU/l and 3.1 IU/l respectively. After treatment the mean
group (118 mmHg and 121 mmHg) was in the normal range. FSH decreased significantly in the metformin group compared to
After treatment, the mean systolic BP decreased significantly in placebo group (3.1 IU/l vs. 3.09 IU/l) (p < 0.01, ANOVA) ( ●▶  Table 1,

the metformin group compared to placebo group (104 mmHg vs. supplementary Fig. 3Sa). Similarly, at baseline the mean LH in
122 mmHg) (p < 0.001, ANOVA) but both values are still within the metformin and placebo group was 5.9 IU/l and 6.5 IU/l,
the normal range ( ● ▶  Table 1, supplementary Fig. 2Sa). Similarly, respectively. After treatment the mean LH decreased signifi-
at baseline the mean diastolic BP in the metformin and placebo cantly in the metformin group compared to placebo group
group (82 mmHg and 85 mmHg) was in the normal range. After ▶  Table 1, supplemen-
(3.1 IU/l vs. 6.8 IU/l) (p < 0.001, ANOVA) ( ●
treatment, the mean diastolic BP decreased significantly in the tary Fig. 3Sb). Moreover, at baseline the mean visfatin in the
metformin group compared to placebo group (73 mmHg vs. metformin and placebo group was 5.9 ng/ml and 8.9 ng/ml,
89 mmHg) (p < 0.001, ANOVA) ( ● ▶  Table 1, supplementary Fig. respectively. After treatment, the mean visfatin decreased in the
2Sb). However, the mean diastolic BP in the metformin group metformin group to 5.2 ng/ml, but in the placebo group it sig-
remained in the normal range but in the placebo group the mean nificantly increased to 10.1 ng/ml (p < 0.001, ANOVA) ( ● ▶  Table 1,

diastolic BP is in the high range. supplementary Fig. 3Sc). However, the mean INSL3 remained
unchanged in both groups before and after treatment (p = 0.24).
Size of the ovaries
The ovary size was determined using ultrasound. At baseline, Other parameters
the mean right ovary size in the metformin and placebo group Subjects with menstrual irregularities (menstrual cycle fre-
was 10.6 mm and 10.8 mm, respectively. After treatment, the quency, menstrual duration, and menstrual amount of blood
mean right ovary size decreased significantly in the metformin flow) and hirsutism score were equally distributed in the 2
group compared to placebo group (9.1 mm vs. 11.1 mm) (p < 0.05, groups and no significant difference was observed after treat-
ANOVA) ( ●▶  Table 1, supplementary Fig. 2Sc). However, the ment in either group (data not shown).
mean size of left ovary remained unchanged in both groups
before and after treatment (p = 0.12).
Discussion
Metabolic profile ▼
At baseline, the mean fasting serum glucose, mean insulin and The pathophysiology of the polycystic ovary syndrome (PCOS) is
mean HOMA-IR in the metformin and placebo group were simi- due to complex interactions between the actions of different
lar. After treatment, there was no statistically significant differ- endocrine hormones. Endocrine and metabolic parameters
ence in the 2 groups for the 3 aforementioned parameters (blood glucose, insulin, INSL-3, visfatin, and HOMA-IR) signifi-
(p > 0.05). However, the mean value of insulin decreased from cantly change in PCOS, which could potentially be managed with
17.1 IU/l at baseline to 14.1 IU/l after treatment with metformin. metformin. Insulin resistance is a significant factor in PCOS,

Zahra M et al. Metabolic and Hormonal Variations in PCOS …  Horm Metab Res
Endocrine Care

which in turn deteriorates normal endocrine and metabolic Owing to the possible role of INSL-3 in the pathogenesis of PCOS,
functions [24, 25]. our data show no significant relationship between INSL-3 and
Metformin has long been the drug of choice to treat PCOS and PCOS in both PCOS females [41].
has also shown to have insulin-sensitizing role [26–28]. The pre- Our study has some limitations. We did not compare our results
sent study showed that metformin has decreased insulin resist- with females without PCOS. The inclusion of this third group
ance in females with PCOS after 3 months of therapy (4.2 vs. would have provided us evidence on metabolic and endocrine
3.5; ● ▶  Table 1), however the overall difference compared to pla- changes in all the 3 groups: metformin treated PCOS; placebo
cebo group was non-significant. This indicates that the met- treated PCOS; and normal females with no apparent diseases.
formin influences the insulin resistance but may not totally However, due to limited funding we were not able to accomplish
normalize this index. Studies also support that the metformin this part of the study but we plan to explore this aspect in a
only acts as an insulin sensitizer and improve the peripheral glu- future study. Another limitation of our study was the use of
cose uptake, which in turn regulate most of endocrine parame- serum samples as opposed to others who used plasma in their
ters associated with metabolism and PCOS [29–31]. The studies. However, serum analysis of the hormones and other
improvement in insulin sensitivity with metformin could be parameters did not appreciably change the results. Thus to
attributed to the decrease in fasting insulin levels with the use of explore the aforementioned associations more clearly, future
metformin. On the other hand, the fasting glucose levels did not studies in a large number of population are required.
show any significant change in the participants receiving met-
formin, while those on placebo showed a slight increase of fast-
ing glucose levels from baseline. Conclusion
It has been previously reported that metformin acts as insulin ▼
sensitizing agent by exerting its effects on peripheral tissues Our data show that females with PCOS exhibit higher endocrine

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thus promoting peripheral glucose utilization [32]. In the pre- and metabolic parameters at baseline and treatment with the
sent study, we observed a decrease in fasting insulin levels from insulin-sensitizing agent (metformin) could be effective to regu-
17.2 IU/l at baseline to 14.1 IU/l at the end of follow-up within late and improve the outcome in females with PCOS. This thera-
the metformin group, while no change was observed in the pla- peutic intervention with metformin could be of clinical
cebo group. However, results were not statistically significant. importance in this high-risk group of young females.
Moghetti et al., observed a similar reduction in fasting plasma
insulin level in PCOS patients treated with metformin [33]. Oner
and Muderris on the other hand observed significant reduction Author Contributions
in insulin level and also in insulin sensitivity [34]. The discrep- ▼
ancy might be due to the large sample size and duration of effect MZ collected the samples and performed the experimental
in the above studies. work. MS participated in organization of the data, preparation of
The effect metformin on endocrine parameters (LH, FSH, vis- the manuscript and supervised the study. RR helped in grouping
fatine, and INSL-3) was studied in the 2 PCOS groups (metformin of patients and co-supervised the study. AA participated in
and placebo) (  ●▶  Table 1). The levels of LH, FSH, and visfatin organization of the data, preparation of the manuscript and pro-
changed significantly while no significant change was observed vided assistance in statistical analysis and English editing. All
in the level of INSL-3. Chan et al., observed a significantly raised the authors have read and approved the manuscript.
visfatin levels in the serum of patients suffering from PCOS [35].
Tan et al., also showed an increased serum visfatin level in obese
PCOS patients and hypothesized a compensatory response to Acknowledgements
insulin resistance [36]. A similar study conducted by Karakoseet ▼
al., also demonstrated the effect of metformin on serum visfatin Authors are thankful to Mr. Safi-Ur-Rehman and Mr. Imran Khan
levels in patients with PCOS [37]. They observed a significantly for providing assistance in the laboratory work.
raised visfatin level in females with PCOS, which was reduced
after metformin treatment. However, Pagano et al., showed the Fundings:This research did not receive any specific grant from
association of visfatin with obesity and concluded that there is funding agencies in the public, commercial, or not-for-profit
no regulatory relationship between visfatin and insulin sensitiv- sectors.
ity/resistance [38].
INSL-3 is another neo-hormone, which show multifaceted link-
age with the pathogenesis of PCOS [39]. INSL-3 may reflect a Conflict of Interest
dysfunction of PCOS thecal cells, which is responsible for ▼
increased androgen production and chronic anovulation. The The authors declare no competing interest.
INSL-3 levels in our study showed a reduction in mean value
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Zahra M et al. Metabolic and Hormonal Variations in PCOS …  Horm Metab Res
Endocrine Care

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Zahra M et al. Metabolic and Hormonal Variations in PCOS …  Horm Metab Res