Polycystic Ovary Syndrome and Pregnancy: Is Metformin the Magic Bullet?
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In Brief
From Research to Practice / Diabetes and Pregnancy
This article reviews the literature regarding the effects of metformin therapy in
pregnant women with polycystic ovary syndrome on weight loss, fertility, early
pregnancy loss, malformations, gestational diabetes mellitus, perinatal mortali-
ty, placental clearance, lactation, and early childhood development. The phar-
macology of metformin is also presented. Preliminary data suggest that met-
formin for this population may be both safe and effective. Large blinded,
randomized clinical trials are underway to confirm the preliminary safety data.
Polycystic Ovary Syndrome and Pregnancy:
Is Metformin the Magic Bullet?
History of Polycystic Ovary mon now, although some centers still
Syndrome employ laser drilling of the ovary as a
Although the first description of poly- means of inducing ovulation.4
Howard Craig Zisser, MD cystic ovary syndrome (PCOS) is gen-
erally credited to Stein and Leventhal Definition of PCOS
in 1935, it may have been observed as Much has changed over the past 80
early as 1721, when the Italian scien- years in the way we understand, diag-
tist Antonio Vallisneri observed nose, and treat PCOS. PCOS is the
“young married peasant women, most common endocrine disorder
moderately obese and infertile, with among women of reproductive age,
two larger than normal ovaries, affecting 5–10% of premenopausal
bumpy and shiny, whitish, just like females in the United States.5 PCOS
pigeon eggs.”1 This depiction sounds encompasses a broad spectrum of
strikingly similar to the subfertility signs and symptoms of ovary dysfunc-
and obesity commonly found in tion. The 2003 Rotterdam consensus
PCOS. It was not until 1921 that workshop6 concluded that PCOS is a
Achard and Theirs2 noticed a relation- syndrome of ovarian dysfunction,
ship between hyperandrogenism and with the cardinal features of hyperan-
insulin resistance in their study of the drogenism and polycystic ovary
“bearded diabetic woman.” And in morphology.
1935, Stein and Leventhal3 made the PCOS remains a clinical syndrome.
connection between amenorrhea and Fortunately or unfortunately, no single
polycystic ovaries. In addition, they diagnostic criterion (such as hyperan-
also noticed the occurrence of mas- drogenism or polycystic ovaries) is suf-
culinizing changes, such as hirsutism ficient for clinical diagnosis. The diag-
and acne, in many patients with poly- nostic code of 620.2 merely requires a
cystic ovaries. clinical judgment and is not dependent
Several, but not all, of Stein and on laboratory confirmation. Assigning
Leventhal’s original case studies a code allows for reimbursement for
involved women who were over- tests and treatment. The clinical mani-
weight. In all seven of their case festations of PCOS include menstrual
reports, attempts to treat ovulatory irregularities, signs of androgen excess
dysfunction with estrogenic hormone (alopecia, acne, hirsutism), and obesity.
failed, and wedge resection was Insulin resistance and elevated serum
employed. All of their patients gained luteinizing hormone levels are also
normal menstruation, and two became common features in PCOS. A fasting
pregnant. Surgery for PCOS is uncom- insulin level > 20 mU/l correlated in
85
Diabetes Spectrum Volume 20, Number 2, 2007one study with an abnormal glucose- testinal in nature: abdominal pain, rats and rabbits at doses up to 600
to-insulin ratio, an indication of insulin constipation, distended abdomen, mg/kg/day.12 This represents an expo-
resistance.7 PCOS is associated with an diarrhea, dyspepsia/heartburn, taste sure of about two and six times the
increased risk of the metabolic syn- disturbance, and flatulence. Serum lev- maximum recommended human daily
drome (11 times greater), gestational els of metformin during pregnancy dose based on body surface area com-
diabetes mellitus (GDM) (2.4 times may be altered because pregnant parisons for rats and rabbits, respec-
greater), type 2 diabetes, hypertension, women often have gastrointestinal tively. Determination of fetal concen-
dyslipidemia, subfertility, spontaneous motility disturbances and increased trations demonstrated a partial pla-
abortions, cardiovascular events, renal blood flow. cental barrier to metformin, although
and the premature development of In controlled clinical trials of met- the rat placenta has different charac-
hormone-sensitive carcinomas.8–10 formin of 29 weeks’ duration, a teristics than the human placenta.
decrease to subnormal levels of previ-
Metformin Therapy ously normal serum vitamin B12 levels Weight Loss and Insulin Sensitivity
A magic bullet therapy for PCOS without clinical manifestations was In a recent 4-year study,13 metformin
would result in weight loss, improve observed in ~ 7% of patients. Such a in combination with diet was shown
insulin resistance, restore normal ovu- decrease, possibly resulting from inter- to safely reduce weight by 8% in
latory cycles, increase fertility, decrease ference with vitamin B12 absorption women with PCOS while also improv-
hyperandrogenism, decrease the rate of from the B12-intrinsic factor complex, ing their lipid profiles (11% decrease
spontaneous abortions, and decrease is, however, very rarely associated in LDL cholesterol and 11% increase
the risk of GDM. The current front- with anemia and appears to be rapidly in HDL cholesterol). A modest weight
runner for this magic bullet is the reversible with discontinuation of met- loss often translates to improved
biguanide metformin. It appears to formin hydrochloride tablets or vita- insulin sensitivity. Insulin resistance is
do all of the above—but is it safe to min B12 supplementation. Therefore, a major trigger of metabolic and
continue throughout pregnancy? B12 levels and red blood cell indexes reproductive abnormalities in women
should be monitored frequently in all with PCOS. Elevated insulin levels,
Metformin Pharmacology pregnant patients taking metformin. associated with insulin resistance,
While studying effects of parathy- Replacement therapy should be initiat- leads to thecal thickening in the
roidectomy, it was discovered that ed if patients are found to be B 12 ovary, which in turn leads to anovula-
guanide derivatives had hypoglycemic deficient. tion and infertility. 14 PCOS may
actions. 11 The initial guanides were account for > 75% of the anovulatory
toxic. Metformin, a biguanide, is Animal Toxicity and Teragenicity infertility.15 Metformin has shown to
an antihyperglycemic agent that Long-term carcinogenicity studies be an effective means of achieving
improves glucose intolerance. In have been performed in rats (dosing ovulation in women with PCOS (odds
patients with type 2 diabetes, it lowers duration of 104 weeks) and mice ratio = 3.88).16
both basal and postprandial plasma (dosing duration of 91 weeks) at
glucose concentrations. Its pharmaco- doses < _ 900 mg/kg/day and 1,500 Early Pregnancy Loss
logical mechanisms of action are dif- mg/kg/day, respectively.12 These doses PCOS is also associated with an ele-
ferent from other classes of oral anti- are both approximately four times the vated rate of early pregnancy loss.
hyperglycemic agents. Metformin maximum recommended human daily The etiology of this association is not
decreases hepatic glucose production, dose of 2,000 mg based on body sur- known. It may be related to plasmino-
decreases intestinal absorption of glu- face area comparisons. No evidence of gen activator inhibitor activity, 17
cose, and improves insulin sensitivity carcinogenicity with metformin was unrecognized hyperglycemia, or a yet-
by increasing peripheral glucose found in either male or female mice. to-be-determined factor associated
uptake and utilization. Similarly, there was no tumorigenic with PCOS itself. Metformin has ben-
The liver does not metabolize met- potential observed with metformin in eficial metabolic, endocrine, vascular,
formin. Renal excretion is the primary male rats. There was, however, an and anti-inflammatory effects on the
mode of clearance from the body. It is increased incidence of benign stromal risk factors contributing to first-
contraindicated in patients with signifi- uterine polyps in female rats treated trimester abortion in PCOS patients.
cant renal dysfunction. The most sig- with 900 mg/kg/day. A prospective cohort study18 was
nificant risk associated with metformin There was no evidence of a muta- set up to determine the beneficial
is that of lactic acidosis. Although lac- genic potential of metformin in the effects of metformin on PCOS
tic acidosis is associated with 50% following in vitro tests: Ames test patients during pregnancy. Two hun-
mortality, it is exceedingly rare in sub- (S. typhimurium), gene mutation test dred nondiabetic PCOS patients were
jects with normal renal function. In > (mouse lymphoma cells), or chromoso- evaluated while undergoing assisted
20,000 patient-years of exposure to mal aberrations test (human lympho- reproduction. One hundred and
metformin in clinical trials, there were cytes). Results in the in vivo mouse twenty patients became pregnant
no reports of lactic acidosis. Renal micronucleus test were also negative. while taking metformin and continued
function should be monitored frequent- Fertility of male or female rats was taking metformin at a dose of
ly, however. In addition, metformin unaffected by metformin when admin- 1,000–2,000 mg daily throughout
therapy should be suspended after istered at doses as high as 600 pregnancy. Eighty women who dis-
radiological procedures requiring con- mg/kg/day, which is approximately continued metformin use at the time
trast or surgical procedures until renal three times the maximum recom- of conception or during pregnancy
function has been reevaluated. mended human daily dose based on comprised the control group. Both
The most common side effects asso- body surface area comparisons. groups were similar with respect to all
ciated with metformin are gastroin- Metformin was not teratogenic in background characteristics (age, BMI,
86
Diabetes Spectrum Volume 20, Number 2, 2007waist/hip ratio, and levels of follicle- maternal lactic acidosis, no maternal formin passes the placenta, and fetal
From Research to Practice / Diabetes and Pregnancy
stimulating hormone, luteinizing or neonatal hypoglycemia, and no serum levels are comparable to mater-
hormone, estradiol, and dehy- congenital malformation in live births. nal values.27
droepiandrosterone sulfate). The rate The question of whether to use met- Despite the traditional response that
of early pregnancy loss in the met- formin in the treatment of GDM all oral hypoglycemic agents are
formin group was 11.6% compared remains a hotly debated subject.23 absolutely contraindicated during preg-
with 36.3% in the control group nancy, evidence that metformin is prob-
(P < 0.0001; odds ratio = 0.23, 95% Perinatal Mortality ably safe during the first trimester of
confidence interval 0.11–0.42). One of the first reports of using pregnancy and beyond is accumulating.
Administration of metformin through- biguanides in pregnancy was present- Results of another recent meta-analy-
out pregnancy to women with PCOS ed at a symposium in Rimini, Italy, in sis28 by the Motherisk Program showed
was associated with a marked and sig- 1968.24 Forty subjects were studied, no increase in incidence of major mal-
nificant reduction in the rate of early including 32 taking metformin and 8 formations and a potential protective
pregnancy loss. A smaller prospective taking phenformin. Most subjects effect in this patient population.
pilot study19 in 19 women with PCOS were treated with insulin as well. The
demonstrated a 63% decrease in perinatal mortality rate was 150 per Lactation
spontaneous abortions in women 1,000 births, which was comparable Metformin is excreted into breast
treated with metformin. to insulin-treated patients at the time. milk, but the amounts seem to be clin-
One of the first reported organized ically insignificant. No adverse effects
GDM studies using metformin in GDM was on blood glucose were measured in a
A prospective observational study of the Cape Town Experience.25 In Cape small study of three nursing infants.29
42 pregnancies in 39 women with Town in the mid-1970s, the perinatal Metformin during lactation appears
PCOS that was published in 2004 mortality rate of the offspring of to be safe in the first 6 months post-
demonstrated the effectiveness of met- patients with untreated GDM was partum. There was not any difference
formin in reducing the incidence of 264 per 1,000 births. The study was in the weight, height, or motor-social
GDM in this high-risk population. designed to achieve the best possible development between breast- and for-
Metformin was used in conjunction control of the blood glucose levels by mula-fed infants.30
with preconception calorie restriction means of diet with or without oral
(1,500–2,000 calories/day, including hypoglycemic medications. If diet Type 2 Diabetes, Pregnancy, and
26% protein and 44% carbohydrate). alone was unable to achieve eug- Metformin
Calorie restriction was stopped after lycemia, metformin or glibenclamide The prevalence of type 2 diabetes in
conception. GDM developed in 7.1% was administered. Metformin was women of childbearing age continues
of these pregnancies. The median chosen if the patient was obese. If to grow as the incidence of type 2 dia-
insulin levels fell 40% from baseline at euglycemia was not achieved on betes increases. Recent evidence
their last preconception visit. Testos- monotherapy and diet, both oral med- shows that treatment of GDM and
terone levels fell 30% from baseline at ications were combined. If the combi- normalization of postprandial glucose
their last preconception visit.20 nation of both oral agents failed, concentrations ensure the best possi-
The main limitation in this study is insulin was added. Fifty-nine of the ble outcome for pregnancy complicat-
that there was an average weight loss 476 patients in the study were given ed by GDM. Metformin is a logical
of 11.8 kg before conception. The only metformin. None of the women treatment in these circumstances, but
decrease in GDM may not have been was given metformin before the first there has always been concern about
the result of continuation of met- trimester. The perinatal mortality its safety for fetuses, particularly
formin, but rather may have resulted rates of the metformin-treated group because it crosses the placenta and
from one of the cornerstones of thera- and the diet-alone group were 15 and may increase the risk of teratogenesis.
py for women with PCOS who are 16 per 1,000 births, respectively, but Although evidence is accumulating
planning to become pregnant: precon- the macrosomia rate was ~ 20% com- that metformin is useful and has a
ception weight loss. Another prospec- pared to 10% in a control population role in PCOS, a condition of insulin
tive study in 33 women with PCOS without GDM. resistance, it is not yet accepted as
demonstrated a tenfold decrease (from treatment for type 2 diabetes in
31 to 3%) in the incidence of GDM Malformations pregnancy and GDM. Observational
when metformin was continued dur- Based on the limited data available data support the use of metformin in
ing gestation compared with a retro- today, a recent meta-analysis26 did not type 2 diabetes in pregnancy, and its
spective control group.21 demonstrate evidence of an increased role in GDM is currently under inves-
Metformin therapy (2.55 g/day) risk for major malformations when tigation. 31 Because metformin does
during conception and continued dur- metformin is taken during the first not effectively target the postprandial
ing pregnancy in 72 oligo/amenorrhe- trimester of pregnancy. Large studies glucose concentration, the macroso-
ic women with PCOS was safely asso- are needed to corroborate these pre- mia rate may not be normalized with
ciated with reduction in spontaneous liminary results. Eight studies (con- metformin treatment alone.
abortion (17% with metformin vs. ducted between 1966 and 2004) were Metformin may become an impor-
62% without) and in GDM (4% with included in the meta-analysis. After tant treatment for women with either
metformin vs. 26% without), was not pooling the studies, the malformation GDM or type 2 diabetes in pregnancy
teratogenic, and did not adversely rate in the disease-matched control and indeed may have additional impor-
affect birth weight or height, weight, group was ~ 7.2%, statistically signifi- tant benefits for women, including
and motor and social development at cantly higher than the rate found in reducing insulin resistance, body
3 and 6 months of life.22 There was no the metformin group (1.7%). Met- weight, and the long-term risk of dia-
87
Diabetes Spectrum Volume 20, Number 2, 2007betes. There is a need for a random- When metformin treatment is being 55:1582–1589, 2006
ized, controlled trial in women with considered, the individual risks and 14
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