Archives of Perinatal Medicine 18(1), 27-36, 2012 REVIEW PAPER
PCOS and metformin: from pharmacology
to clinical use for women’s health
Metformin is an old compound optimal for treatment of type 2 diabetes. Since when PCOS patients have been
reported to have insulin resistance, metformin has been demonstrated to modulate several aspects of PCOS and to improve the most common cause of menstrual irregularity, inesthetisms and infertility. Metformin induces a better control of glucose uptake inducing a lower synthesis/secretion of insulin. Such effect permits to reduce insulin resistance which is the cause of the compensatory hyperinsulinemia typical in most but not all of PCOS patients. The positive control of metabolism has many positive effects on the hormonal patterns such as the restoration of menstrual cyclicity, ovulatory cycles and fertility since abnormal insulin levels affect the hypo- pthalamus-pituitary-ovarian functionas well as peripheral tissues use of glucose. The combination of an improved life-style with metformin treatment improves the impairments typically observed in hyperinsulinemic PCOS patients, reducing the possible evolution towards to the metabolic syndrome and type 2 diabetes; and when pregnancy occurs, it consistently reduces the risk of gestational diabetes, eclampsia and hypertension. Though it might seem that metformin is the “optimal treatment” for PCOS patients, only hyperinsulinemic PCOS patients are those with higher chances to get the best results from metformin administration, mainly if diet and life-style are attentively combined.
Key words: PCOS, metformin, hyperinsulinemia, chronic anovulation, obesity, BMI, insulin resistance
mia, thyroid diseases, androgen-secreting tumors and Metformin is quite an old compound introduced into adrenal dysfunction/hyperplasia) [4]. These criteria did clinical use in 1957. From the chemical point of view is not include the presence of polycystic ovaries at ultra- 1,1-dimethylbiguanide hydrochloride, a biguanide cur- sound examination because it was observed that poly- rently used as an oral antihyperglycemic agent for dia- cystic ovaries could also be present in healthy eumenor- betes mellitus. In these last 20 years, growing evidences rheic women [5]. A few years later, during the Euro- occurred to demonstrate that a large percentage of pean Society of Human reproduction and Embryology PCOS patients with or without obesity, show insulin re- (ESHRE)/American Society for reproductive Medicine sistance and a reactive compensatory hyperinsulinemia (ASRM) conference, the diagnostic criteria were expand- and that the use of metformin is optimal not only in the ed and PCOS was considered as present when at least presence of diabetes mellitus Type 2, but also in patients two of three features were diagnosed: oligo or anovula- with PCOS and hyperinsulinemia, resolving several tion, clinical/ biochemical hyperandrogenism and poly- issues such as menstrual cyclicity, fertility, hormonal cystic ovaries as assessed by ultrasound examination [5].
levels and metabolic syndrome (MS) [1].
This evolution was relevant because it permitted theinclusion of women with PCOS who were excluded by PCOS characteristics
previous NIH criteria [4]: those with polycystic ovaries Polycystic ovary syndrome occurs in as many as affected by hyperandrogenism and ovulatory cycles, or 8-10% of women of reproductive age [2], with onset ma- chronic anovulation and normal androgen levels. nifesting as early as puberty [3]. From the very begin- More recently, the Androgen Excess and PCOS So- ning, diagnostic criteria proposed by the NIH for PCOS ciety indicated that PCOS should always be considered were the presence of hyperandrogenism and chronic an androgen excess disorder and concluded that PCOS anovulation with clear exclusion of related ovulatory or was, above all, a disorder of androgen biosynthesis, utili- other androgen excess disorders (i.e., hyperprolactine- 1 Department of Obstetrics and Gynecology, Gynecological Endocrinology Center, University of Modena and Reggio Emilia2 Department of General Surgery, University of Modena and Reggio Emilia, Modena, Italy A.D. Genazzani, F. Ricchieri, A. Prati et al.
Despite the diagnostic criteria, PCOS is still an un- quent anovulatory cycles. All this results in a chronic clear disease in terms of pathogenesis, and although the hyperestrogenic state with the reversal of the estrone: main clinical features related to the syndrome are men- estradiol ratio that might predispose to endometrial pro- strual irregularities, anovulation and clinical/biochemical liferation and to a possible increased risk for endome- signs of hyperandrogenism, PCOS patients frequently show other physiopathological characteristics. Recently Normally, less than 3% of testosterone circulates as it has been made clear that both genetic and environ- unbound in the serum. In fact, most circulating andro- mental factors may contribute to the onset of PCOS fea- gens are bound to SHBG, thus being biologically in- tures [7, 8]. On such genetic predisposition, environmen- active. Any condition that decreases the levels of SHBG tal factors may play a key role, such as peculiar lifestyle, or other binding proteins can lead to a relative excess of types of food, living conditions and also the impact free circulating androgens. In PCOS, hirsutism usually during the intrauterine growth [8]. In fact, if intrauterine occurs with decreased SHBG levels and obesity [13, 15].
growth is characterized by an exposure to exaggerated A great percentage of PCOS patients show over- androgen levels, this peculiar situation may lead to the weight up to severe obesity, and typically any excess of development of hyperandrogenism and ovarian dysfunc- weight can induce a reduction of peripheral tissues sen- sitivity to insulin, thus inducing the compensatory hyper-insulinism. Endocrine profile of PCOS patients
It is relevant to say that hyperinsulinemia may be Polycystic ovary syndrome is characterized by in- central to the pathogenesis of the syndrome in many creased ovarian and adrenal androgens, increased lutei- cases, because it can induce higher ovarian androgen nizing hormone (LH) levels, high estrogen levels (espe- production and anovulation [16, 17], sustained also by cially estrone) due to extraglandular conversion from the abnormal LH secretion, with a higher frequency of androgens, lower levels of sex hormone-binding globulin menstrual abnormalities than in normoinsulinemic wo- (SHBG) and higher levels of insulin, the latter often in men with PCOS [18, 19]. Insulin resistance and compen- satory hyperinsulinemia are metabolic disturbances easi- Hyperandrogenism is a key feature of the syndrome, ly observable in at least 45-65% of PCOS patients, and fre- although it is not constant [9]. It is mainly of ovarian quently appear to be related to excessive serine phos- origin with an adrenal contribution, since a certain per- phorylation of the insulin receptor [11, 20]. centage of PCOS patients might show a mild steroido-genetic defect in adrenal glands (such as for 21-hydro- Metabolism & PCOS
xylase) or just a higher adrenal hyperactivation due to In PCOS patients, there is an increased risk of stress [10]. Androstenedione and testosterone are the developing Type 2 diabetes and coronary heart disease best markers of ovarian androgen secretion, while de- (CHD) [21-23]. Such risk has also been demonstrated to hydroepiandrosterone sulfate (DHEAS) is the best mar- be higher in postmenopausal women, previously demon- ker of adrenal secretion. Most testosterone is derived strated to be PCOS during fertile life [24, 25]. PCOS has from peripheral conversion of androstenedione and from been reported to have an increased risk of MS, which direct ovarian production. Dysregulation of cytochrome refers to a clustering within the same individual of hy- p450c17, the androgen-forming enzyme in both the perinsulinemia, mild-to-severe glucose intolerance, dis- adrenal glands and the ovaries, is the central pathogenic lipidemia and hypertension, and an increased risk for mechanism underlying hyperandrogenism in PCOS [11, cardiovascular disease (CVD) and diabetes [26-28]. 12]. In the presence of 5a-reductase, testosterone is In 2006, the International Diabetes Federation de- converted within the cell to the more potent androgen fined the features of the MS, and defined central obesity dihydrotestosterone. Excess or normal 5a-reductase ac- as present when the waist circumference is above 80 tivity in the skin determines the presence or absence of cm; in European women, this was considered as a ne- hirsutism [13]. Additionally, estrone plasma levels, cessary prerequisite risk factor for the diagnosis of MS a weak estrogen with biological activity 100-times less [29]. However, it is of great relevance to point out that than estradiol, are increased as a result of peripheral although the MS has been identified for more than 80 conversion of androstenedione by aromatase activity – years, only in these last years has controversy about its more active in PCOS than in healthy controls – while estradiol levels are normal or low because of the fre- PCOS and metformin: from pharmacology to clinical use for women’s health recruitment and maturation [7, 43, 44]. 45-65% of PCOS patients show insulin resistance and the compensatory • Elevated triglycerides ($ 1.7 mmol/l), hyperinsulinemia [7, 45], and this percentage is signifi- • Reduced HDL (< 1.29 mmol/l in women), cantly higher than age- and BMI-matched healthy con- • Specific treatment for lipid abnormalities, trols [46]. Obviously, when insulin resistance is present • Elevated blood pressure (systolic $ 130 mm Hg or independently from obesity, whatever the weight gain that might occur, it certainly exaggerates insulin resis- • Specific treatment or precedent diagnosis of hyper- tance and more severely alters the glucose metabolism • Fasting plasma glucose at least 5.6 mmol/l, It is important to remember that several studies • Previous diagnosis of Type 2 diabetes mellitus. reported that insulin modulates LH secretion from The prevalence of MS in polycystic women is appro- pituitary cells in vitro [40] and in vivo, and that the re- ximately 40-45% [30], and the main predictor factors are duction of hyperinsulinemia induces the significant the elevated free serum testosterone and reduced serum decrease of LH plasma levels [38, 47, 48], although it is SHBG level [31]. The association of MS with PCOS not clear whether decreased LH levels are due to the appears to be particularly strong in those PCOS women reduced insulin levels or secondary to the recovery of who are young (< 30 years) and overweight or obese ovarian function (i.e., estrogen production) induced by Women with PCOS have lower HDL levels, higher Excess insulin increases androgen concentrations LDL:HDL ratios and higher triglyceride levels than blocking follicular maturation and increasing cytochrome healthy eumenorrheic women [22]. All these are induc- P450c17a activity, a key enzyme in the synthesis of both tors of subclinical atherosclerosis as demonstrated by ovarian and adrenal androgens [7, 40]. This situation the increased thickness of the carotid intima media and typically increases 17-hydroxyprogesterone (17OHP), by the higher endothelial dysfunction observed in PCOS androstenedione and testosterone plasma levels. The patients [33, 34], probably related to the insulin resis- excess of intraovarian androgens negatively modulates tance and/or to the higher free testosterone plasma level follicular function and ovarian activity, thus inducing the typical stromal hypertrophy and maintaining ovarian Indeed, several studies reported an increased risk factor profile for cardiovascular disease in women with When abnormal insulin sensitivity is diagnosed, the PCOS [37]. It is of great relevance the fact that women use of metformin might be suggested [7, 50]. Metformin with PCOS have an increased risk for impaired glucose reduces hepatic glucose production from 9 to 30% and tolerance and Type 2 diabetes mellitus [38, 39], with on peripheral tissues, such as muscle cells and adipo- a tendency to an early development of glucose intolerance cytes, metformin acts by increasing glucose uptake state [40, 41]. In fact, the decrease of insulin sensitivity in PCOS women appears to be quite similar to that ob- Patients with PCOS are insulin resistant and this served in patients with Type 2 diabetes mellitus and to condition typical y decreases insulin’s ability to stimulate be relatively independent from obesity, fat distribution glucose disposal into peripheral cells and decreases the and lean body mass [42]. On the other hand, there is glucose response (i.e., glucose uptake by the cells) to strong evidence that obesity, particularly the abdominal insulin [7]. In addition, metformin positively acts on phenotype, represents an important independent risk hormonal PCOS abnormalities through a direct and/or factor for glucose intolerance in PCOS women [39]. indirect action on steroidogenesis [7]. In fact, the reco-very of normal ovulatory function is probably due to thedirect modulation of metformin on the ovarian tissues Rationale of metformin use in PCOS women
and to the metformin-induced normalization of the ova- The logic for the use of insulin sensitizer drugs, rian steroidogenesis (lowering androgen production), such as metformin, to treat patients with PCOS is the thus determining the normal feedback on pituitary, fact that a large percentage of PCOS patients have been lowering LH secretion and LH pulse characteristics demonstrated to have insulin resistance and a compen- [47, 48]. Metformin improves steroidogenesis not only satory hyperinsulinemia that negatively affect ovarian at the ovarian, but also at the adrenal level, since insulin function in terms of steroid biosynthesis and follicular plays specific modulatory roles on these two distinct A.D. Genazzani, F. Ricchieri, A. Prati et al.
endocrine glands that have the same enzymatic path- increased, slowly, up to the most effective dosage for the ways [51, 52]. In fact, it has been demonstrated that patient, as reported by Nestler [58, 59]. metformin administration ameliorates adrenal enzyme The known side-effects, although very limited in incidence, are abdominal discomfort, constipation, diar- A recent meta-analysis of the published studies de- rhea, flatulence, heartburn, indigestion, nausea and monstrated that the use of insulin sensitizers do not re- vomiting [7, 60]. It is relevant the fact that the patient duce hyperandrogenism better than oral contraceptives needs to help metformin modulation(s) on the metabolic [54], but as recently reported, the typology of PCOS to side following all the advices concerning feeding and be treated is of great relevance, since only when insulin weight control. The experience suggests that metformin sensitivity is abnormal metformin shows a greater effi- positively affects the metabolic problems of hyperinsu- cacy on all the PCOS features, including hyperandro- linemic, overweight/obese women together with a low genism [48]. Obviously, it cannot be excluded that other caloric diet and a minimum of physical activity. Since metabolically active hormones (e.g., leptin, resistin, metformin modulates insulin sensitivity, it works per- adiponectin and gherelin) are positively activated by met- fectly to restore insulin sensitivity within the normal formin administration and thus participate in the im- ranges, and this usually happens when physical activity provement of the reproductive function at the hypo- and loss of weight also induce the reduction of peri- thalamus-pituitary-ovarian level [55]. However we have pheral tissue insulin resistance together with metformin to remember that metformin effectiveness on repro- action [82]. However, it should be noted that previous ductive and on metabolic parameters is mainly exerted data demonstrated that withdrawal of metformin treat- in association with a reduction of circulating insulin ment can be followed within 3 months by a reversal to- levels, thus supporting the hypothesis that a high insulin ward a pretreatment hyperinsulinemic state [57, 61, 62].
level is one of the main effectors/modulators of the cli- Recent data suggest that metformin is more effective nical and endocrine dysfunctions of PCOS [7, 56]. in insulin-resistant PCOS patients, with normal BMI,probably because some constitutional abnormality might Metformin therapeutic regimens
be at the basis of the insulin resistance. Nevertheless, The therapeutic dose of metformin cannot be stan- overweight (but not necessarily obesity) remains a fea- dardized. Since its main indication is to treat diabetes, ture that represents a strong indicator of good results most of the dosages have been set according to the when coupled with insulin resistance [53, 47], since a levels of glycemia achieved with the treatment, and the recent report showed equal response to metformin in amount of metformin administered may vary from 500 to those who were lean and obese [63]. However, it is inte- 1500 mg or more per day [7]. On the contrary, an ex- resting to point out that lifestyle changes have been tremely variable dosage has been used to treat PCOS, demonstrated to be more effective in preventing diabe- but up to now, no dose-finding study is available for tes risk and MS than treatment with metformin [64] and PCOS, probably because there are various end points that metformin suspension induced a certain percentage and goals for PCOS patients to reach, such as the re- of reversion of the beneficial effects on insulin sensitivity covery of menstrual cyclicity and of ovulation, loss of and on hyperandrogenism, and is probably related to the weight, reduction of hirsutism and skin defects. It is, simultaneous worsening of both the ovarian function and however, important to point out that clinical studies clearly demonstrated that after long-term metformin In our opinion, the positive effects induced by met- treatment, drug suspension induces a quick reversion of formin administration can be maintained when treatment the beneficial effects on peripheral insulin sensitivity [7, is prolonged over the time (up to 12 months or more) and 57]. In addition, because recent data showed that better it is combined with a controlled diet and with moderate clinical results were obtained in insulin-resistant rather physical activity to aid metabolism and weight loss, than in non-insulin-resistant PCOS patients [48], a clear especially when overweight or obesity is present [1, 65].
adjustment of the dose of metformin must be performedaccording to the BMI and insulin resistance. The When is metformin usefull?
treatment must be started with a low dose, administered Metformin shows beneficial effects according to the few minutes before lunch and dinner (10-15 min before), clinical characteristics of the patient, and the more of because an empty stomach minimizes the possible drug- these features present at the same time, the higher the related side affects [7], and only after 3-7 days can it be chance of metformin treatment being effective [86]. PCOS and metformin: from pharmacology to clinical use for women’s health weight or obesity as well as of compensatory hyperinsuli- Body weight, evaluated as BMI, is a fundamental nemia. However, this cannot be extended to all PCOS characteristic. The higher the BMI is the higher the patients. Recent data clearly reported that there are amount of fat is present triggering a compensatory hy- several kinds of genetic situations that are the genetic perinsulinism. Unfortunately, this is not a general rule; causal triggers or might just be the starting triggers if it is valid for overweight or obese patients only. In fact, combined with predisponent environmental factors several studies reported that a certain percentage of [7, 8]. It is important to observe that ethnic background PCOS patients as well as a certain percentage of the is probably relevant as these genetic factors, since PCOS normal population have constitutional insulin resistance and/or mild-to-severe hyperandrogenism are more fre- concomitantly with a lean body mass [7, 66, 67], and quent in some populations than in others, as well as the when patients were treated independently from the incidence of metabolic diseases (i.e., diabetes Type 2), BMI, all of them demonstrated a beneficial effect in in- quite often mirroring a greater use of carbohydrates in sulin plasma levels, insulin sensitivity and in AUC for insulin under the OGTT [66]. Our data demonstrateda great efficacy of metformin administration in non-obese What metformin can ameliorate
PCOS patients, mainly in those with abnormal insulin From the clinical point of view it cannot be stated response to OGTT and/or fasting hyperinsulinism [48].
that metformin is the treatment for PCOS patients, but These data let us infer that the ability to be sensitive to it is rather important to underline that metformin can be insulin is probably a real constitutional aspect; every of great relevance when two or more of the aforemen- patient has their own and it is worsened when BMI in- tioned possible predictors are present [7]. Let’s see Insulin sensitivity/resistance
Effects on menstruation
This is the most important feature. Metformin has 80% of PCOS have oligomenorrhea or amenorrhea more indications for PCOS patients with high basal and oligoovulation or anovulation [69, 70]. Metformin insulin levels and/or with abnormal response to the administration was reported to restore normal menstrual OGTT [48], independently from BMI. Only insulin-re- cyclicity in a high percentage of the patients affected by sistant individuals may benefit from metformin admini- oligomenorrhea or amenorrhea [53, 71, 72], but was less stration in terms of both insulin sensitivity and of insulin- effective than oral contraceptives [73, 74] since ita acts induced metabolic and hormonal functions [7, 48]. through a specific effect on metabolism and on the re-duction of hyperinsulinemia.
Androgen excess
Effects on fertility
In general, hyperandrogenism is a common feature The fact that metformin improves metabolism, re- of PCOS patients and cannot be considered a predictor solves hyperinsulinemia and all hormonal impairments of metformin efficacy. However, since hyperinsulinism induced by this latter, explains how it might be possible might be a relevent trigger of anovulation and oligome- a specific effect of metformin on fertility. Recent reviews norrhea, it can be argued that the combination of men- and data clearly reported that metformin is not better strual irregularities, hyperandrogenism and anovulation than clomiphene citrate (CC) to induce ovulation [61, can be positively affected by metformin administration.
75-77], but it is fundamental to remember that these two compounds are affecting the hormonal profiles in com- Waist-to-hip ratio
pletely different ways! It is important to remember that The presence of overweight or obesity is certainly metformin and CC have completely different mecha- a risk factor for CVD in PCOS patients, and it is of great nisms of action, and metformin may act on the repro- importance to state that a high waist-to-hip ratio (> 0.8) ductive axis as a secondary hormonal effect, mainly rela- specifically indicates a greater amount of fat at the abdo- ted to the improved (i.e., lowered) insulin plasma levels minal level, which is the typical android distribution [68].
and insulin resistance [7, 58, 59]. In fact, while met-formin acts on insulin pathways, CC acts directly on the Genetic factors
reproductive axis. Clinical data suggested that hyper- For sure, environmental factors (such as lifestyle insulinemia and insulin resistance could be responsible and feeding) deeply condition the occurrence of over- for the ovarian abnormal response occurring in OHSS A.D. Genazzani, F. Ricchieri, A. Prati et al.
[78]. Although no clear evidence has been provided, stration that both hyperandrogenism and impaired peri- hyperinsulinemic PCOS patients undergoing metformin pheral insulin sensitivity may increase the risk of CVD administration before and/or during ovarian stimulation [84, 85], although prospective controlled data on CVD for the search of spontaneous pregnancy or IVF might morbidity and mortality in PCOS patients has never Effects on hyperandrogenism
Effects on pregnancy & on risk of miscarriage
Improvement of ovarian function under metformin Patients with PCOS are likely to develop gestational treatment determines a relative improvement of hyper- diabetes in 30-40% of cases [86, 87], with a higher chan- androgenism and its clinical signs, such as acne and ce than normal pregnant women [88]. Various data also hirsutism. In general, hyperandrogenism and its signs demonstrated that metformin use during pregnancy are reduced by metformin administration because it reduced the risk of gestational diabetes through the reduces ovarian androgen production, ovarian P450c17a reduction of preconceptional BMI, fasting insulin levels activity and free testosterone concentration [7], and and insulin resistance [87, 89]. Various reports con- within few months it also reduces the Ferriman–Gallway firmed the efficacy of metformin treatment in PCOS pregnant women reducing significantly the risks ofgestational diabetes [89-92] and of preeclampsia [93], Effects on body weight
although others did not show beneficial effects on mis- Metformin treatment and lifestyle intervention have carriage risk [76]. Although such data are of extremely been reported to be more effective in reducing body great clinical relevance, not all of the reports studied weight, BMI and visceral fat in obese subjects than large populations or were a placebo-controlled study. In lifestyle intervention alone [50, 65]. This means that any case, a recent meta-analysis confirmed that there is metformin cannot be considered a specific antiobesity no difference in abortion risk in PCOS patients under- drug because lifestyle changes and a balanced diet to- going metformin treatment before pregnancy when gether with physical activity are fundamental to metfor- compared with normal population [94, 95]. However, the min co-treatment and might improve the chances of safety of metformin administration during pregnancy success [79, 80]. However, it is of relevance to point out was attently evaluated, and no congenital abnormalities that metformin has been demonstrated to improve body or adverse fetal outcomes were related to metformin weight control in obese PCOS patients by acting both [96, 97]. Moreover, no negative effects on growth, motor directly on the CNS and indirectly via adiponectin modi- and social development in infants were reported when fication [81], but in general it has a marginal effect on metformin was administered to PCOS women during the weight loss as monotherapy, as recently reviewed by Palomba et al., who stated that lifestyle modifications re-main the cornerstone for weight loss in obese PCOS Effects on mood & quality of life
patients, although metformin cotreatment might impro- Last but not least, one important aspect is the quality of life. PCOS patients have been demonstrated toperceive life significantly worse than healthy controls or Effects on the risk of Type 2 diabetes & CVD
other patients affected by other diseases [100]. In ge- PCOS patients with insulin resistance have a higher neral, women are nearly twice as likely to experience risk for developing Type 2 diabetes [50, 80]. The preva- major depressive disorders as men [101], but it is of lences of insulin resistance and diabetes in PCOS pa- great interest to report that several studies suggest qua- tients, especially if they are obese, is approximately 30- lity of life, body age concerns and sexual dissatisfaction 40% and 5-10%, respectively, and this is three- to seven- in PCOS [100-103], as well as a high degree of occur- fold greater than the normal population [82, 79]. Since rence of depressive state [104]. Obesity, clinical signs of the incidence of cardiovascular diseases is quite high in hyperandrogenism (acne, hirsutism and alopecia) and diabetics, it has to be seriously considered that PCOS infertility seem to be the main elements on which such patients might also be exposed to a higher risk of CVD great psychosocial discomfort find basis [105, 106], and and/or its precursors such as hypertension [83, 37], when an adequate treatment improved all such features, since they are at a higher risk for diabetes than the quality of life and well-being improved again [107].
normal population. This fact is enforced by the demon- Interestingly, such a positive effect was also observed PCOS and metformin: from pharmacology to clinical use for women’s health under metformin administration. Indeed, a significant [In:] Polycystic Ovary Syndrome. Dunaif A., Givens J.R., improvement of quality of life in PCOS patients, espe- Haseltine F.P., Merriam G.R. (Eds). Blackwell, MA, USA, cially for the psychological aspects, occurred and inte- [5] Polson D.W., Adams J., Wadsworth J., Franks S. (1988) resting correlations were observed between the clinical Polycystic ovaries-a common finding in normal women.
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