Ir aq i J.Pharm.Sc i., Vol.15 (1 )  ,2006 33

Effect of  Metformin and Antioxidant Agents on Hirsutism in 
Women with Polycystic Ovary Syndrome  

Mohamme d A.Taher  
Received  26-2-2003          Accepted  13-6-2004  

ABSTRACT 
 F orty s ix Ira qi wo men with PCOS we re  inv olved  in this  s tudy . They we re  tre ated  with 
metformin a lo ne  a nd with antioxida nt age nts (vita min E o r C).It was found that all pa tie nts who  treated  
with me tformin or with co mbina tion o f metformin with antioxid ant agents  s ho wed s ignifica nt d ec re ase  
in hirs utis m s co re . The trea tme nt of me tformin with antioxidant agents  is of great benefit in trea tme nt 
of hirs utis m in PCOS due  to tha t there was  no worse ning e ffec t after trea tme nt. This  may indica te that 
antioxid ant agents  ma y pa rticipate in alleviation of hirs utism so  it c an b e sa id  tha t o xidative s tres s may 
play a n importa nt ro le  in de ve lo ping of hirs utism in PCOS.     

 
   -:الخالصة 

ــالث              ن إلــى ث ن قســم عــد إ ة ب ســ را هــده الد كن فــي  شــار ــاس  كي عــدد األ مبــيض مت ة ال مــ متالز راقيــة مصــابات ب ون امــرأة ع عــ رب ســتة وأ
وعات  ار      .مجم عـق ن  ـم ف  مؤـل مركـب  ن ب ن فقد عـولج موعتان الباقيتا مج ر المبتفورين منفردا إما ال موعات أعطيت عقا إحدى هده المج

سد مع مضادات التأك مين  ور رتيب )  Eاو  Cفيتامين (  الميتف ار     . على الت عـق جن ب ول واتي عـ مريضـات الـل كل ال ن  ة إ وجد في هده الدراس
ودلك النه لم يكـن   الكياس  عدد ا مت ة المبيض  زم متال ة في  عراني الج الش كبير لع ر  سد له اث مع مضادات التأك ركبا  ورين منفردا أو م الميتف

عالج  رانية بعد ال هور في مقدار الشع مكـن      هدا .هناك تد دلك ي شـعرانية ـل دار ال ف مـق خفـي كسد قد تشارك في ت ت التأ ن ان مضادا ر يبي التأثي
كياس عدد اال ة المبيض مت زم ساء المصابات بمتال شعرانية عند الن ور ال سيا في تط ي قد يلعب دورا رئي كسد هد التا ول ان الج   . الق

  
INTRODUCTION   
     Hirsutism is  the  pres ence of e xce ss  ha ir 
growth in wo men a nd affects  5% - 8% of the 
to tal fema le  po pulation of fertile age  (1).The  
hirs utism in polyc ys tic o vary synd ro me 
(P COS) is  ma inly c ause d by ov aria n andro ge n 
ove rp ro duc tio n a nd in id io pathic hirs utis m 
there is  p erip he ral hyp erse nsitiv ity to normal 
androge n circ ulating le vels  (2).5α – re ductas e 
type  2  has be en s tudied for the  d iffe re ntiatio n 
of e xterna l ge nitalia  a nd pros ta te in ma le s and 
is  ess ential fo r ha ir growth in both s exe s (3). A 
prerequis ite  for the ce llular action of andro ge n 
on the  p ilos eba ce ous  unit is the  c onv ersion of 
te stos terone  to dihydrotes to sterone thro ugh the 
enzymatic  a ction of 5α- re duc ta se  (4). Howe ver 
the wo men with PCOS ma y a mplify the 
manifes tatio n of hirsutism by the  a vailable  of 
insulin growth fac to r -1 due  to ind uction of 5α- 
re ductase  activity w hich is med ia te d by ins ulin 
growth factor -1 (5).  
  
 

Antia nd rogens a re  substa nce s tha t preve nt 
and ro gens from exp re ss ing the ir a ctiv ity at 
ta rget s ite s. The inhibiting effe cts of 
antiandro ge n a re  d iffere nt from those    
comp ounds  tha t dec re as e relea se  or inhibit 
biosynthe sis o f hypo thalamic  and  ante rior 
pituitary hormones (6 ).Oral co ntra cep tive  
trea tme nt o f hirsutis m is mo st effec tive  in 
women with  o varian hype ra nd rogenis m 
esp ec ia lly with P COS.The atte mpt to  a llev ia te  
hirs utis m cause d by a ndrogen e xce ss  with oral 
contrac ep tive  repres ents  temp orary meas ure. 
The  preferre d tre atment is to targe t the  
patho ge nic site of hype ra nd ro genis m or the  site  
of a ctio n. Me tformin trea tment of wo men with 
PCOS res ults  in a  d ecline of insulin as  well as  
to ta l and bioav aila ble te stos te ro ne  lea ding to 
signific ant improve ment of clinic al 
manifes ta tions o f hype ra nd rogenis m 
(7).The refore the use  o f metfo rmin in PCOS 
may afford an alternative  wa y in ma nageme nt 

of hirsutis m. 

 
 
 
 
 
 
 
 
 
Dep artmen t of Clin ic al Labo rator y Sc ie nce s ,Colle ge  o f Ph arma cy,Un iver sity of Baghdad , Baghdad 
–I raq  .  
 

  



Ir aq i J.Pharm.Sc i., Vol.15 (1 )  ,2006 34

MATERIALS and METHODS   
      Fo rty –s ix Ira qi P COS women with mea n 
age (2 8 ±4.5 ye ars) and  e le ve n control wome n 
with co mparab le  a ge were e nrolle d in this 
stud y. The p atie nts were a ttending the out 
pa tients  clinic at Al-Elwe a Hos pita l for 
Obs te tric & Gynec ology (Ba ghd ad) and  the y 
ha d a me an hirsutism s co re  (20 .8 ±3.6) 
ac cording to the  mo dified  F erriman –  Ga llwe y 
sc oring system (8).  
 The P COS wo men ha d menstrual 
irregula ritie s (oligome norrhea ), chro nic 
anovula tion, o bes ity; elev ated s erum andro ge n 
le ve ls , a s erum LH/F SH ≥ 2 a nd typical 
arre sted  follicles  we re  s hown b y ultras ound 
stud y. All p atie nts ha d norma l fa sting gluc os e 
le ve ls  and normal ma rkers o f thyroid, and 
kidney func tion. No ne of them had  taking any 
drug for a t le as t 6 months before enrollment. 
The  p atie nts were clas sifie d a cc ording to the 
type  o f tre atment: 
Gro up Ι: 1 6 p atie nts we re  trea ted with 
metformin (50 0 mg t.i.d). 
Gro upⅡ: 14 p atie nts trea te d with 
co mbination of me tfo rmin (5 00 mg t.i.d) and 
vita min C (25 0 mg t.i.d). 
Gro upⅢ: 16 p atie nts we re  trea ted with 
co mbination of me tfo rmin (5 00 mg t.i.d) and 
(v itamin E 2 00 mg t.i.d). 
`The pa tie nts in all the se groups  were 
maintaine d on the  trea tme nt for a pe riod  o f 
thre e mon ths. 
 
 
 
 
 
 
 
 

 
Clinical Study:-  
   A modifie d Ferrima n – Gallwe y System was  
use d to c linic ally gra de bo dy ha ir growth (8 ). 
In p articula r, the de gree o f hirs utism was  rated  
on a sc ale fro m 0  to 4 on 8  b ody regio ns . The  
hirs utis m s co re  wa s o btaine d b y to ta ling the  
sco re  fo r ea ch b ody regio n and was  determined 
before the s tudy a nd again after e ac h month for 
a period of 3  mo nths of trea tme nt. The sc ore  
eva luation was  performed b y a single  
physician who was  una ware of the trea tment . 
Bioc hemic al Analysis:-  
    Bloo d sa mples for s erum testos terone  we re  
collecte d be fore the  trea tment a nd a fter 
inte rv als o f 1  month of trea tme nt for 3  
suc ce ss iv e months. The s erum leve ls  of 
te stos te ro ne were mea sure d b y TESTO-CTZ 
which is  ra dioimmunoas sa y Kit (CIS bio  
inte rnatio na l – ORIS Group  –  F ra nce ). 
Statiscal Analysis:- 
   Value s a re  exp re ss ed as means ±  SD. 
Stude nt’s  paired test was  use d fo r co mparison 
of the  p arame te rs  b efore and afte r tre atment. A 
p v alue  < 0.05 was  co ns id ered statistic ally 
signific ant. 
RESULTS 
The  a ge of the p atients  in group  1  wa s (29 .2  
±2.9 ye ars ) , in gro up 2 the mean a ge  was  
( 27± 3.9 yea rs  ) and  in the group 3 the mean 
age  w as ( 3 0.1±3 .6  yea rs  ) . 
The  b as al v alues  of total se rum tes tosterone of 
eac h group are shown in table 1. 

 
Ta ble  – 1 

Effec t o f me tfo rmin an d ant io xida nt age nts  o n se rum tes tostero ne  (nmo l/l). 

 
 
 
 
 
 
 
 
 
                   

** P<0 .0 5   
                    n=nu mbe r of the  s ubjec ts 
 

Contro l 
le ve ls 

Ba se line  
levels of 
pa tients 

A fter  1      
mon th  o f 
tre atmen t 

After 2 m onths 
o f tre atment 

After 3 months 
o f tre atment 

1.1±  0.37 
(n=1 1) 

4 .1±  1.3* * 
(n=1 6) 

2.4±  1.3* *  2 .4±  1.02 ** 1 .5±  0.7**  

1.1±  0.37 
(n=1 1) 

4 .5± 1.7* * 
(n=1 4) 

3.1± 1.1**    2 .5±   0.92 **  2 .3 ±  1 .2 ** 

1.1±  0.37 
(n=1 1) 

5 .2±  2.2* * 
(n=1 6) 

3.31± 1 .2 **  3  ±   1 .5**  2  ±  0.7** 



Ir aq i J.Pharm.Sc i., Vol.15 (1 )  ,2006 35

Clinical and Hormonal Effects: 
  Clinical re sults are s umma rize d in ta ble 2 and 
figure s 1,2 and 3 . 

Table  - 2 - 
Effec t of me tformin and a nt io xidant age nts 

on hirsutis m sc ore  in PCOS patie nts. 

*P<0.05 
**P<0.00 5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fig  .1 : Hirsutism s core  afte r tre atme nt with 

me tfo rmin  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fig .2  :Hirs utis m s co re  after tre atme nt with 
Combinatio n of me tformin a nd vita min C 

 

 
 
 
 
 
 
 
 
 

 
 
 
 
 
 

Fig.3:Hirs utis m s co re  a fter tre atme nt with 
combinatio n of me tformin a nd vita min E 

      
     In a ll gro ups  metformin a nd a ntioxida nt 
age nts de creas ed  the histurism sc ore  
signific antly a fter 1,2 a nd 3  months  of 
trea tme nt .The le ve ls  o f se rum tes toste rone in 
all groups we re higher than normal lev els and  
the se rum tes tosterone de cre as ed s ignifica ntly 
in all group s a fter 1,2 and  3 mo nths  of 
trea tme nt (tab le  -1).   
Evaluation of Clinic al Outcome 
The  e valua tion o f the clinical outco me at the  
end  o f the  treatme nt is s umma rize d in ta ble -3 . 

Ta ble  - 3 
Ra ting  o f clinical outc ome  at the  e nd o f 

tre atme nt 
 

Rating N o. 
(grou p1 ) 

 No. 
(grou p 2) 

No. 
( g ro up 3) 

Exc ellent 1 (6 .25%) 2 (1 4.2%) 6(37 .5 %) 
Goo d 
effe ct 

4 ( 2 5%) 4 (2 8.5%) 4(25 %) 

No effec t 9 (5 6.2%) 8 (5 7.1%) 6(37 .5 %) 
Bad  e ffe ct 2 (1 2.5%) 0  0 
 
The  pa tients trea te d with metfo rmin showed  
12.5% bad   (worsening) e ffec ts  while the  
patients  treate d w ith co mbina tion o f metformin 
and  antioxidant age nts show no wo rs ening 
effe cts .The patients  tre ated  with metformin 
and  v itamin E repo rted  3 7.5% of an e xc elle nt 
effe ct. 
DISCUSSION   
 The c ommo n unde rlying c aus es  of 
hirs utis m a re  P COS and  idiopa thic hirs utis m 
(9). The goal o f trea tment is  to interrupt the  
steps  lead ing to the  increas ed  and ro gen 
exp re ss io n of the  p ilos eba ce ous  unit. Sev eral 
stra te gies  are av aila ble. Mec hanic al ha ir 
re mova l ca n improv e his turis m, but it is a  
te mporary mea sure . In mos t ca se s hirs utis m 
re sults from a  c omb inatio n of mildly increa se d 
and ro gen productio n and increa se d skin 
sensitiv ity to a nd rogen (10).The po lycystic

Gr oups Be fore  
treatmen

t 

After  
1 

mont
h 

After  2  
mon th

s 

After 3 
mon th

s 

Ⅰ 2 0.5±  
5 .3 

1 9.3
±  
5.4* 

19 .7±  
5 .5* 

16 .6±  
7.7* 

Ⅱ 2 0.8±   
20 

1 9±     
1.75*

* 

17 .5±   
3 .8* 

16±   
4 .8* 

Ⅲ 2 1.2±  
2.2 

1 9.1
±  

1.5** 

16 .1±  
5.4** 

14 .2±  
6.3** 

0

5

1 0

1 5

2 0

2 5

B e fo re
t re a t m e n t  

Du r a t io n  o f t r e a t m e n t  (m o n t h s )

H
ir

s
u

ti
s
m

 s
c
o

re
 (

m
e
a
n

)

A f t er  1 A f te r  2 A f te r  3

0

5

1 0

1 5

2 0

2 5

B e fo re
tre a t m e n t  

D u r a t io n  o f  t r e at m e n t  ( m o n t h s )

H
ir

s
u

ti
s

m
 s

c
o

re
 (

m
e

a
n

)

A f te r  1 A f t er  2 A f te r  3

0

5

10

15

20

25

Before
t reatm ent 

Dur at ion of tr e atm e nt (m onths )

H
ir

s
u

ti
s
m

 s
c
o

re
 (

m
e
a

n
)

A f ter 1 A f ter 2 A f ter 3



 

ova ry syndrome  is c harac terized c linica lly by a 
history of c hronic  a nov ulatio n in c omb inatio n 
with s ome  e vidence of andro ge n exc es s, s uc h 
as  his turism and a cne (11). Ma ny drugs  with 
antiandroge nic prop erties , s uch as c yproterone 
(12) , s pirono la ctone  (13)  and  flutamide  (14) hav e 
be en us ed  to trea t his turism in PCOS, but the 
effic acy o f thes e drugs has  b ee n sho wn to  b e 
only pa rtial.The hyp erinsuline mia  in PCOS 
was  rec ognized  a s the cardina l manifes tatio n 
of ins ulin res istance. It was hypo thesized that 
in PCOS , ins ulin may dire ctly stimulate 
ova rian cytoc hrome  P 450 c17 α, res ulting in a n 
increa se p rod uc tion o f andros te ned io ne  whic h 
is  then may c onv erte d to  tes to sterone b y the 
enzyme 17β- re ductas e(15). Ho weve r the use of 
metformin in this study may re so lv e the main 
challe nge  of PCOS which is ins ulin res is ta nc e 
and this  may reduce  the  action of insulin on the 
ova ry and c onseq ue ntly re duce the 
ove rp ro duc tio n o f testos terone  (ta ble 1).This 
re sult is  in agre ement with that of 
ko lo dziejczyk e t al. who fo und  that me tformin 
trea tment with PCOS  res ults  in imp ro vement 
of c linic al ma nife station of hyp erand ro genism 
(7)..Re ce ntly it wa s found tha t P COS is 
as soc ia ted with o xidative stres s (16).In pres ent 
stud y the use  o f me tformin alone and   
co mbination of metformin with antioxid ant 
agents  (v itamins C or E ) ,dec re as es the 
histurism sco re  s ignifica ntly a fter 1 ,2  a nd 3 
months of trea tme nt (tab le  -2,figure 1,2,and  3 ). 
The  de creme nt of total s erum tes to sterone   
as soc ia ted with dec line  of his turis m s co re  in all 
groups and this may s upp ort the hyp othe sis 
that hirsutism in PCOS  is  ma inly due to 
androge n ove rp ro duc tion. 
   In this  s tudy, it wa s fo und that the perce ntage 
of p atie nts who  get e xce lle nt e ffec t (ta ble -3) 
was  mo re  in group of metfo rmin with v itamins 
C (1 4.2%) and E (3 7.5%) tha n that in gro up of 
metformin alone  (6.25 %). Moreov er the 
worse ning effec t in p atie nts who  treated  with 
metformin a lo ne  is (1 2.6%) while the pa tie nts 
who  tre ated with me tformin a nd antioxid ant 
agents  show no suc h bad  effect. This  ma y 
indica te  tha t antioxid ant agents  pa rticipate  in 
alle viation of  hirsutism s o it c an be  s aid that 
oxid ativ e stre ss  may play a n important role 
in de velop ing of  hirs utism in 
PCOS .Therefore, the pa thoge ne sis of histurism 
in PCOS ma y d iffer from othe r c onditions 
whe re  it may cause d by the androge n 
ove rp ro duc tio n in a dditio n to o xida tive  s tres s. 
In co nc lusion, it ca n b e s aid tha t us e of 
antioxid ant a ge nts a re  of grea t b enefit in 
PCOS ; in add ition to their excellent effe ct o n 
histurism s co re  at leas t they may prev ent 
worse ning e ffec t. 
 
 

REFERENCES 
1.Barbieri RL. Hyp erand ro genic  diso rd ers, 
Clin Ob stet Gyne co l 19 90.,33:64 0-54;. 
 2 . Kuttenn F, Mo wszowics I, S chaison G, 
Ma uv ais, J aris  P. Androgen production and 
skin metabo lis m in histurism.J Endo crinol 
197 7;75:83 -9 1. 
3.Dia ni AR, Mulhollamd MJ , S hull KI., 
Kubice k MF, J ohnso n GA, Sc hos tarez HJ  ,et 
al. Hair gro th e ffec ts  o f oral adminis tration of 
fina sterid e , a  s te ro id  5 α- reductas e inhibitor , 
alone  o r in combination with to pical minoxid il 
in the b alding stump tial ma caq ue . J  Clin 
Endo crinol Me tab 19 92;74 :3 45-50 . 
4. Wils on JD. Wa lker J . The  c onv ersion of 
te stos te ro ne to 5 α-a nd ro stan-17 -β-o l-3-one  
(dihydrotes to sterone) b y skin s lice s of ma n. J  
Clin Inve st 196 9,48;3 71. 
5.Horto n R. P asupule nti V. Antonipillia I. 
Androgen inductio n o f steroid 5 α-re ductase  
may be med ia te d v ia  insulin –like gro wth 
fa ctor-1 . Endoc rino lo gy1 993 , 13 3:447 . 
6. Do rfman RI. Biolo gica l ac tivity of 
and ro gen , Br J  Dermatol 1 97 0;82:3-8. 
7. Ko lo dziejczyk B. et a l. Me tformin therapy 
dec re as es hyperandroge nism and  
hyp erinsuline mia  in wo men with po lycystic  
ova ry syndrome . Fe rtl and  Steril 200 0, 
37(6):1 149 -1 154 . 
8. F erriman D, Gallwey J D. Clinic al 
ass es sme nt o f bod y hair growthin women .J  
Clin Endoc rino l Metab  196 1;21:14 40-7. 
9.Rittmas te r RS . Histurism,Clin 
Endo crinol ,1 997 ,4 7:29. 
10. Delahunt JW. Histurism. Drugs 19 93; 45: 
223 -31 . 
11. M Ra fe t Ga za vani, Mark Hamilto n,Cha ries  
R Kingsland, A Tee mpeton. P olycystic ova rian 
disea se  : a mislead ing labe l. La nce t 2 000  ; 355  
(92 01): 4 11-2. 
12.Neumann F . Pha rmaco lo gy and p otential 
use  o f cyproterone  a ceta te . Horm Me tab Res  
197 7; 9 ,1 -1 3. 
13.Tremb la y RR. Trea tment of his turism with 
spirono la ctone . Clin Endoc rino l Metab  
198 6;15,36 3-9. 
14.Iptis am I., F ahri B., a nd Muhamme d G. A 
pro sp ective , randomized tria l c ompa ring 
flutamide  (25 0 mg/d) and fina steride (5 mg/d) 
in the  tre atment of his turis m. Fe rtl and Steril 
200 0, 7 3(5),9 84-987 . 
15. Hunte r, S J., Ga rv ey, W, T . Insulin ac tion 
and  insulin re sistance : d is ea se  involving 
defec ts  in ins ulin re cep tors , s igna l tra ns duc tion 
and  the  gluco se tra ns port effec te r system. Am 
J Med, 198 8;105 (4 ),33 1-45. 
16.Ta her ,M.A.,P hD. The sis, "Effect of 
Me tfo rmin and Antio xidant Agents on Lipid 
Pro file and  , Hormone s and Oxidative Stress  
Status in Wo men with P olycystic Ova ry 
Syndrome", 2 002    P.XVIII.