Ayisha Raja, Shoaib Naiyar Hashmi*, Nadra Sultana**, Haroon Rashid*.
Department
of Gynaecology and Obstetrics Combined
Background: This study was carried out to determine the pattern
of presentation of Polycysitc ovary syndrome (PCOS) in patients presenting at
our unit and to compare effects of clomiphene alone and in combination with
metformin in management of PCOS. Methods:
This study was conducted was conducted from Jan 2001-2003 at
KEY
WORDS: PCOS, metformin, ovulation induction.
INTRODUCTION
Anovulatory infertility comprises about one quarter of
patients attending an infertility clinic1. The polycystic ovary syndrome (PCOS) is the commonest
endocrine disturbance leading to anovulatory infertility and oligomenorrhoea2. PCOS is characterized by the
presence of enlarged ovaries with multiple small cysts (2-8 mm dia) and
a hypervascularized androgen secreting stroma3. The disease is manifested clinically by signs of androgen
excess including hirsuitism, alopecia, obesity and menstrual cycle disturbance
either oligomenorrhoea or amenorrhoea4. Normal ovulatory mechanism which includes selection of an
ovarian follicle which grows in response to appropriate secretion of FSH,
becomes dominant and ovulates, gets disturbed in women with PCOS due to
androgen excess and hyperestrogenism5. Ovarian overproduction of androgens is due to
hyperinsulinism, and raised insulin levels are recognized as an important
feature of PCOS6.
Insulin lowering therapies such as metformin can bring improvement in insulin
resistance and ovarian hypergonadism7. It has also been shown that the ovulatory response to
clomiphene the elective drug for induction of ovulation can be increased in
PCOS by decreasing insulin secretion with metformin8.
The objective of this study was to determine
pattern of presentation PCOS in patients presenting at our unit and to compare
effects of clomiphene alone and in combination with metformin.
MATERIAL AND METHODS
One hundred cases of
PCOS were selected out of all patients who presented with infertility at the Department
of Gynaecology and Obstetrics,
·
Oligomenorrhoea (<6 cycles in preceding year)
·
hirsuitism
·
hyperandrogensim
·
Elevated LH or LH : FSH >2.
All other endocrinal causes of female infertility
including congenital adrenal hyperplasia, Cushing syndrome, hyperprolactinemia
and thyroid disease were excluded by relevant investigations. Tubal patency was
confirmed by hysterosalpingography performed jointly by gynaecologist and
ultrasonologist at the Department of Radiology Military Hospital,
The following hormonal investigations were performed on
all patients,
·
Serum FSH and LH level alongwith LH/FSH ratio
·
Serum prolactin and testosterone
·
Fasting serum insulin levels.
Semen analysis of the male partner to rule out male
factor infertility was also carried out.
The patients were divided into two groups. First group
of fifty patients were given Metformin (Glucophage-Efroze) 500 mg three times
daily alongwith clomiphene citrate(cerophene-Hilton) 50 mg daily for five days
starting from 2nd day of menstrual cycle. The second group comprising of fifty patients
was started on clomiphene citrate 50 mg daily for five days starting on 2nd day
of menstrual cycle. The first group was labelled as metformin plus CC group and
the second only CC group. All patients
were followed for six cycles for evidence of ovulation and conception.
Ovulation was detected by follicle tracking on ultrasonography by experts who
were blind to the therapy being given to the patients. Dominant follicles on
9th day with absent follicles on day 16th indicated occurrence of ovulation. Day-21
serum progesterone levels were noted and a value of >26 n mol/L (>8
mg/ml) was indicative of ovulation. Conception was confirmed by positive urine
pregnancy test, serum B- HCG levels >25 miu/ml and presence of gestational
sac on ultrasonography. All the hormonal investigations were done at the
department of endocrinology Armed Forces Institute of Pathology, Rawalpindi by
chemiluminescent essay method using DPC immulite kits Los Angeles USA.
The findings of both the groups were compared. These
were analysed statistically by application of Chi-square test and student
t-test. Descriptive data was analysed by SPSS version 10
RESULTS
Patient in the metformin plus CC group and CC group
didn't differ significantly in age, age at menarche, duration and type of
infertility (Table–1).
Table–1: Clinical data of women with pcos In both groups
|
Demographic Data |
Metformin
–CC n = 50 |
Only CC n = 50 |
|
Age (yrs) |
26.52±2.3 |
26.88±2.4 |
|
Menarche
(age) |
13.12±1.33 |
13.84±1.59 |
|
Duration of
infertility |
4.16±1.4 |
4.88±1.42 |
|
Primary
infertility |
56% |
68% |
|
Secondary
infertility |
44% |
32% |
Hirsuitism and oligomenorrhoea were the commonest
clinical features seen in both study groups, other features are detailed in
(Table - 2).
Table-2:
Clinical features of women with pcos
in both groups
|
Clinical Feature |
Metformin – CC n = 50 |
Only CC n = 50 |
|
Normal Menstrual Cycle |
32% |
28% |
|
Amenorrhea |
8% |
4% |
|
Oligomenorrhea |
52% |
64% |
|
Polymenorrhea |
4% |
4% |
|
Dysmenorrhea |
52% |
56% |
|
Hirsuitism |
64% |
66% |
|
Galactorrhoea |
28% |
32% |
Baseline
hormone profile and fasting insoulin level were found raised alongwith
testosterone levels (Table - 3).
Table–3: Hormonal investigation for patients With pcos in both groups
Hormonal Investigation
|
Metformin
+ CC
Group
n = 50 |
Only
CC
Group
n = 50 |
Serum LH levels
(mIu / ml)
|
12.67 + 4.14
up to 15 |
11.78 + 3.70
|
Serum FSH levels
(mIu / ml)
|
6.16 + 4.14
up to 11 |
5.52 + 1.60
|
LH : FSH
|
2 : 1 > 2 : 1
|
2 : 1
|
Serum Prolaction
(mIu / ml)
|
324.8 + 170.3
up to 470 |
251.44 + 149.75
|
Serum Testosterone
(n mol / L)
|
0.8 – 3.2 n mol / L
|
0, -3.5n mol / L
|
In
the study group receiving metformin 68% ovulated whereas 36% in only CC group.
Ovulatory response varied in both groups. Rising trend was seen in metformin
group and falling in CC group (Table-4). Different rates of conception were observed.
52.9% in first group and 44% in only CC group (Table – 5).
Table-4: Ovulatory response in patients with pcos
|
Outcome |
Metformin –
CC n = 50 |
Only CC n = 50 |
|
No of women who ovulated |
34 |
18 |
|
% of women who ovulated |
68%* |
36% |
*: P<0.05
|
Outcome |
Metformin – CC n = 34 |
Only CC n = 18 |
|
No of women who conceived |
18 |
8 |
|
% of women who conceived |
52.9%* |
44% |
*: P<0.05
Out of the patients who received metformin
only six had mild nausea and diarrhoea in the initial three weeks of treatment.
None of the patients had severe side effects of lactic acidosis. No teratogenic
effects were observed in patients who conceived after treatment with metformin
for ovulation induction and ever its continuation upto 12 wks of pregnancy.
DISCUSSION
The most common clinical features of PCOS
include menstrual irregularities, hirsuitism and obesity.9,10. In a study carried out by
Balen et al11
oligomenorrhoea was found in 47% of the cases whereas hirsuitism was present in
66.2% of the cases. These figures correlate well with our findings as far as hirsutism
is concerned which was present in 65% of our cases. Oligomenorrhoea was present
in 60% of our cases as compared
to 47% in patients of Balen et al11.
The reason for this lower frequency of oligomenorrhoea in patients of Balen et
al was the presence of other menstrual irregularities like amenorrhoea in
greater proportion in their patients. Amenorrhoea was present in 19.2% the
patients of Balen et al as compared to 6% in our patients.
In a study carried out by
Fauzia et al12 on
Pakistani patients oligomenorrhoea was found in 75% of their cases which is
comparable to 64% in our cases. In the same study12, hirsuitism was found in 84.6% of cases which is quite
high as compared to 65% in our cases. The higher incidence of hirsuitism in the
cases of Fauzia et al may be due to smaller number of patients (52) in this as
compared to larger number of patients (100) included in our study.
Although
amenorrhoea and oligomenorrhoea are the most common findings, normal menses may
be present in PCOS,11,13 Balen et al11 found normal menses in 29.7% of their cases which is in
agreement with our figure of 30% patients who had normal menses. The figures
for normal menses in other two studies carried out by Goldzieher et al10 and Lobo et al13 are half of what was noted by
Balen et al,11 and
our study. The reason may be a very strict criteria for selection of patients
in the studies carried out by Goldzieher10 and Lobo et al13.
PCOS
demonstrates the levels of sex steroids in relatively steady state in contrast
to the fluctuating levels in normal menstrual cycle. An exaggerated response of
serum LH to gonadotrophin releasing hormone as compared with that occurring in
various phases of normal menstrual cycle has been well documented in PCOS since
long.14,15 As serum
FSH may be low and LH may not always be elevated, it has been suggested that
the use of the LH : FSH ratio would be most discriminatory for a hormonal
diagnosis and a ratio of greater than two in the presence of suggestive clinical features and
ultrasound finding is taken as diagnostic.3,13 The increased LH in PCOS results from a heightened
pituitary sensitivity to GnRH stimulation secondary to hyper-estrogenism.16 This has been supported by
statistical correlations observed by Lobo & Carmina13 between estrogens and with LH
and the LH : FSH ratio in PCOS. In our study a raised LH was found in 35% of
cases which is comparable to 39.8% patients in study of Balen et al11. All our cases of PCOS had LH
: FSH > 2. Another feature of hyperestrogenism in PCOS is mild increase in
serum prolactin in some patients17.
In our study raised level of serum prolactin were found in 18% of the cases
which is comparable to the figure of 12% in Lobo & Carmina.13 Ovarian hyperandro-genism is
a cardinal feature of PCOS and elevation of serum testosterone is a frequently
encountered finding in these patients.13
The
basic problem in the ovary is the conversion of normal estrogen
microenvironment to abnormal androgen environment. This is due to failure of
granulosa cells to convert testosterone produced by ovary to estrogen18. The androgen excess in PCOS
is milder than that observed in ovarian tumours & hyperethicosis and
circulating testosterone level doesn't generally exceed 150 ng/dl.19 In our study all cases had
raised serum testosterone levels which is in conformity with all other studies.
Insulin
resistance giving rise to hyperandrogenism with resultant anovulation is a
recently realized important pathogenetic mechanism in PCOS.5,6,20 Insulin resistance occurs
not only in obese women with PCOS, where it might be expected because obesity
is often associated with insulin resistance, but also in 50% of normal weight
women with PCOS.21
Clomiphene citrate and gonadotrophins were most commonly used drugs for
ovulation induction in PCOS, but realization of this pathogenetic mechanism has
given a new direction to the treatment of PCOS with insulin sensitizing drugs,
giving promising results and significantly higher success rates of ovulation
and pregnancy22,23 as
compared with clomiphene citrate.23,24
Among these drugs metformin is most widely used being safe without any
teratogenic effects.7,8
After this new development many
studies have been carried out world wide to establish the role of metformin in
patients of PCOS8,24,25,
but only one such study on Pakistani population is available before our study.26 In a study carried out by
Vandermolen et al24
75% of the patients taking metformin and clomiphene citrate ovulated whereas
only 27% of the patients taking CC only ovulated, conception rate in those who
ovulated in metformin group was 75% whereas in only CC group it was 33%. In
another study carried out by Malikawi and Qublan25 ovulation rate (68.8%) in patients who took CC plus
metformin were significantly higher than the patients who received only CC 25%.
Pregnancy rates in metformin +CC and only CC group were 56.3% and 16.6%
respectively. Imtiaz et al26
studied the role of metformin in ovulation induction and subsequent conception
in Pakistani patient of PCOS having hyperinsulinaemia, 72% of his patients
ovulated within 3-9 months of treatment of metformin, and 32.5% of those who
ovulated conceived. In our study, addition of metformin alongwith CC
significantly increased the ovulation and the conception rate during six months
treatment 68% of our patients who took a combination of metformin and CC
ovulated whereas only 36% of the patients who received only CC ovulated.
Conception rate in those who ovulated with metformin + CC was 52.9% as compared
with 44% in cases who ovulated with clomiphene only. Our findings on the role
of metformin in increasing the ovulation rate and subsequent conception are in
agreement with the results of above quoted studies. 24-26 In our study
comparatively increased ovulatory rates in the CC group was probably due to the
fact that clomiphene resistance was not the criteria for enrollment in our
study. Another limitation of our study is that we didn't screen the woman for
insulin resistance and obesity was not a criteria for inclusion so our results
are applicable to unselected PCOS patients.
CONCLUSION
Menstrual irregularities and
hirsuitism are the two most common clinical presentation of PCOS.
A combination of metformin
and clomiphene citrate significantly increases the ovulation and conception
rates in these patients. Further studies in a larger population are needed to
determine the minimum dose and length of treatment to achieve the desired
effects.
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_____________________________________________________________________________________________
Address
for Correspondence:
Dr Ayisha Raja, Gynaecologist, CMH Badin Cantt, Sindh
Email: h_ chaudry @ hotmail.com