Role of Metformin in Improving Fertility Outcomes

Abstract

Introduction: Polycystic ovarian syndrome is the most common endocrinopathy among reproductive age women can cause long-term reproductive and metabolic consequences, including but not limited to infertility, heart disease, diabetes and obesity.  In the majority of cases insulin resistance and hyperinsulinemia seem to have an important role in the etiology.  The aim of this research was to review the role of Metformin in improving fertility outcomes as a standalone treatment or with the use of Clomiphene.

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Methods: Databases were searched for articles that included more than 20 subjects, I English, published from 1980-present with selected keywords: polycystic ovarian syndrome or polycystic ovarian disease or polycystic ovary syndrome or PCOS or infertility AND Metformin AND Clomiphene.   The selection process was process has been presented in PRISMA flow chart.  A total of 350 articles were found were found, 12 met criteria and were analyzed.

Results: Data was summarized and presented in form of a table.  Relevant information taken from each article included: title, author(s), location, year, study design, sample size, diagnosis of polycystic ovarian syndrome criteria, intervention, ovulation measurement methods, pregnancy measurement and conclusion.  Most studies support that Metformin and Clomiphene treatment increased ovulation statistically significant.

Conclusion:  This systematic review has broadened the understanding of the use of Metformin in treating infertility in patients with PCOS alone and with the use of Clomiphene.  Suggesting the role of insulin resistance on PCOS etiology and the addition of Metformin to treatment protocols to better outcomes of fertility in terms of ovulation.  More research and studies are needed to evaluate whether Metformin addition will provide a statistically significant benefit on live birth rates and pregnancy.

Key Words: polycystic ovarian syndrome or polycystic ovarian disease or polycystic ovary syndrome or PCOS or infertility AND Metformin AND Clomiphene

Introduction:

Polycystic ovarian syndrome (PCOS) is the most common endocrinopathy among reproductive age women and leading cause of WHO Type 2 anovulatory infertility [1]. The condition, which is associated with absence of ovulation, high androgens or cysts on the ovaries, has also long term reproductive and metabolic consequences.

The criteria to diagnose PCOS is varied due to the wide-ranging features of the syndrome and the lack of accepted underlying etiologies[2].  At the US National Institutes of Health Conference in 1990, three key features were agreed upon; oligomenorrhoea, hyperandrogenism (clinical or biochemical) and absence of other endocrine disorders (congenital adrenal hyperplasia, thyroid dysfunction and androgen-secreting tumors[3]).  The following diagnostic criteria’s have been review by Nathan et al. (2014) and are summarized in Table 1.

Table 1: Diagnostic Criteria for PCOS

Clinical features can range from chronic anovulation, ovulatory infertility, heart disease, obesity and androgen-related symptoms.  PCOS may also be associated with an increased risk of developing Type II diabetes mellitus, the metabolic syndrome and endometrial cancer[5].  Endometrial cancer can be a result of endometrial hyperplasia that stems from chronic anovulation[6].

The primary etiology of PCOS remains unclear.  Although most attribute the excess androgen synthesis and symptoms of the disease due to a defect in ovarian cells[7], genetic and environmental factors both have implications in its development.  Stein and Leventhal placed emphasis on the high ratio of luteinizing hormone (LH) to follicle-stimulating hormone (FSH)[8].  Other underlying causes have been identified such as increased frequency of gonadotropin-releasing hormone (GnRH) pulses that stimulate theca cells to produce androgen, decreased levels of FSH, insulin resistance via a post-receptor defect in fat tissue and skeletal muscles, pancreatic beta-cell dysfunction and obesity[9].

Obesity plays an important role in the pathogenesis of PCOS through its contribution to insulin resistance.  Obesity also increases menstrual disorders and hyperandrogenism, while weight loss helps alleviates symptoms.  Weight gain in women with PCOS can exacerbate insulin resistance, leading to development of metabolic syndrome, acanthosis nigricans and ultimately T2DM.[10]  Achard and Thiers first described a disorder of carbohydrate metabolism and hyperandrogenism in “diabéte des femmes à barbes”, diabetes of bearded women in 1921[11].  Since the initial report by Burghen et al [12] (5) in 1980 that PCOS is associated with hyperinsulinemia it is clear that insulin has a major role on reproductive morbidities.  The relationship of insulin on gonadal function has been investigated extensively by Dunaif et al 1988[13], Barbieri et al 1983[14], Poretsky et al 1987[15] & 1991[16].

Insulin has varying effects on the gonadal / reproductive system mechanism which leads to dysfunction activity in the ovaries and menstruation.  Hyperinsulinemia secondary to insulin resistance leads to an increased ovarian response to gonadotropins that results in overexpression of LH and IGF-1 receptors[17]. Insulin also exerts its effects by increasing the sensitivity of immature granulosa cells to LH, proliferation of thecal cells and up regulation of enzymes related to androgen synthesis[18].  Insulin also reduces the synthesis of sex hormone binding globulin (SHBG).  Decreased levels of SHBG results increased bioavailability of testosterone to peripheral tissues[19].  Hyperinsulinemia also up regulates the activity of the hypothalamic-pituitary-adrenal axis, which results in excess androgen production from the adrenal glands[20].  The role of insulin resistance in PCOS is most promising considering the possibility therapeutic intervention with insulin sensitizing agents.

Lifestyle change is considered first-line treatment for infertility in women with PCOS.  A 5 to 10% loss in body weight regardless of BMI may be associated with improvement in central obesity, hyperandrogenism and ovulation rate[21]. First line pharmacological treatment for improving fertility is Clomiphene citrate (CC), an estrogen receptor modulator²⁰.  Advantages include low cost, oral administration and few side effects.  Approximately 15% of women with PCOS do not respond to the maximum dose of CC and are considered resistant to this medication[22]. Second-line pharmacological treatment of anovulation in women with PCOS includes use of gonadotropins [recombinant follicle stimulating hormone or human menopausal gonadotropin] for timed intercourse of intrauterine insemination²⁰.  The cost of this treatment is higher compared to others and it is necessary to undergo tubal patency testing prior to treatment. More invasive therapeutic modalities include laparoscopic ovarian drilling surgery, which has higher cost, requires general anesthesia and greater complications and in vitro fertilization²¹.

While first line should always be lifestyle changes, weight loss and decreasing circulating insulin levels has a promising effect on ovulation.  Metformin is a widely prescribed oral agent approved for use in the treatment of Type II diabetes mellitus.  A biguanide medication whose mechanism is to increase sensitivity to insulin, Metformin has been shown to improve hyperandrogenemia and hirsutism and reduce lipid levels in PCOS[23].  Some studies have shown that in women with PCOS, treatment with Metformin improved insulin resistance and increased the likelihood of ovulation and pregnancy, with and sometimes without Clomiphene[24].  The exact role of Metformin in the treatment of women with PCOS and its effects on fertility including ovulation and live birth rate is still unclear.

This paper aims to review the role of Metformin in improving fertility outcomes as standalone treatment or with the use of Clomiphene.

Methods:

The Preferred Reporting Items for Systematic Review and Meta-Analysis flow diagram was used to present the search strategy (Fig.1).  PubMed, NEJM were used to search for articles published from 1980 to present day.  The following key words were searched; polycystic ovarian syndrome or polycystic ovarian disease or polycystic ovary syndrome or PCOS or infertility AND Metformin AND Clomiphene.  A manual search was conducted from reference lists.  Total articles found were 270 from database and 80 from manual search.  After removal of duplicate literature, 285 remained.  Those abstracts were reviewed.  Articles were then excluded due to non-relevance, non-English language, opinion based, and case studies, gray-literature. The remaining 19 articles were reviewed in full.

Figure 1: PRISMA

Records identified through database searching
(n =270)

Additional records identified through other sources
(n =80)

Identification

Total Records Identified
(n =350)

Removal of Duplicates

(N= 65)

Screening

Records screened by title and abstract
(n =285)

Records excluded based on:

Non-English, not relevant, opinion based, gray-area, case studies, participants<20
(n =267)

Eligibility

Full-text articles assessed for eligibility
(n =19)

Full-text articles excluded, with reasons

Not RCT, another comparison, relevant data could not be retrieved
(n =  7 )

Included

Studies included in analysis
(n =12)

Full Text articles were further evaluated and narrowed based on study type, number of subjects, relevance of research and type of outcome.  Only primary research articles with greater than 20 subjects written in English in the last twenty years were chosen. 7 articles were excluded due to reasons of having another comparison or relevant data could not be extracted. Considered studies evaluated the relationship of Metformin and Clomiphene treatment on conception and pregnancy.  Included studies described criteria for PCOS diagnosis.  Valid exclusion of secondary causes like thyroid dysfunction, congenital adrenal hyperplasia, hyperprolactinemia, and androgen-secreting tumors was expected.  Exclusion of females with history of pelvic inflammatory disease or tubal disease and male factors (sperm quality) was expected. A diagnosis of PCOS must have been established using any of the following accepted methods: Rotterdam Criteria, ESHRE/ASRM Criteria or presence of irregular menstrual cycles, elevated plasma levels of testosterone, clinical symptoms of hyperandrogenism and presence of polycystic ovaries verified by transvaginal ultrasonography.  No mandatory outcomes measures of pregnancy were required.  The data was then extracted from remaining 12 articles into a table (Table 2).  Information taken from each article included: Title, Author, Location, Year, Study Design, Sample size, Diagnosis of polycystic ovarian syndrome criteria, intervention, ovulation measurement methods, pregnancy measurement and conclusion

Study Population:

The population comprised of women of childbearing age with PCOS.  In all of the studies, the number of participants and the criteria used to diagnose PCOS was recorded.

Outcome:

The effect of intervention on ovulation, and pregnancy was noted.  The criteria for measuring ovulation and pregnancy were also recorded in the chart.

Results:

Table 2: Main Characteristics and Summary of Studies Included

Discussion:

Although PCOS is the most common endocrinopathy among reproductive age women, the current treatment regimens and management depends on the symptoms.  For women who want infertility treatment, Clomiphene citrate is still the first line treatment.  Clomiphene citrate, an estrogen receptor modulator, acts directly on the hypothalamic-pituitary axis to help induce ovulation.  Multiple pregnancy rates are under 10% and hyper stimulation syndrome is rare[37].  Some patients have reported CC resistance or failure.

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Given the strong data that support the pathogenesis that hyperinsulinemia plays in PCOS, it is reasonable to opt for insulin lowering medications as treatment.  Metformin is a biguanide that is approved for treatment of Type 2 Diabetes.  Its mechanism of action is to inhibit hepatic glucose production, although it also decreases intestinal glucose absorption and promotes insulin sensitivity in peripheral tissues[38].  The metabolic benefits have been show to decrease weight loss and improve insulin resistance, which helps alleviate symptoms of PCOS.  Metformin has shown in PCOS to improve menstrual regularity, ovulation and reducing androgenemia[39].  Side effects that are most commonly experience include diarrhea and nausea.  In patients with kidney disease, congestive heart failure and sepsis, lactic acidosis is a concern.  Although there was concern of teratogenicity if used during pregnancy, recent data supports no major birth defects with no effect on motor and social development[40].

The purpose of this review was to compare Metformin in improving fertility outcomes as standalone treatment or with the use of Clomiphene.  Outcomes measured include ovulation, pregnancy rate and live birth rate.

Nestler et al¹⁸ was one of the first studies to evaluate the use of Metformin and Clomiphene on ovulation. Nineteen of the 21 women who received combined Metformin and Clomiphene ovulated; while only 2 of the 25 women in the group given placebo and Clomiphene ovulated (P<0.001).  They concluded that the ovulatory response to Clomiphene can be increased in obese women with PCOS by decreasing insulin levels with Metformin vs. placebo.  This suggests that hyperinsulinemia impedes ovulation in obese women with PCOS.

Ayaz et al²⁴ found that ovulatory response was higher in Group A (Metformin & Clomiphene group) vs. Group B (group with Clomiphene and placebo).   Group A similarly had more conception by confirmation of urine pregnancy test (66.6% vs. 28.6%, P=0.01) and presence of gestational sac on ultrasound (61.9% vs. 28.6%, P=0.03).  They concluded that a combination of Metformin and Clomiphene significantly increased ovulation and conception rate without complication and would be preferred as first line therapy.

Kar et al²⁶ found that Metformin is as efficient as Clomiphene on live birth rates.  Combined Clomiphene and Metformin had statistically significantly higher ovulation rate as compared to CC alone P=0.03; odds ratio: 95% confidence interval: 3.888 [1.08–13.997]).  No difference in ovulation was found between Metformin only group and Clomiphene only group (P=0.11)

Karimzadeh et al³⁵ found that clinical pregnancy rates between Metformin alone, Clomiphene alone, Metformin-Clomiphene, lifestyle change showed no significant difference from another (P =.56) and reported that all 3 groups had an increase in live birth rates.

Neveu et al³¹ found that Metformin is better for ovulation induction than CC alone 75.4% vs. 50%; P=.005).  Weight loss was comparable between the three groups, therefore efficacy of Metformin is not just due to weight loss alone.

Legro et al²⁷ found that the rate of live birth was lower in Metformin group than in the Clomiphene group and the combination-therapy group (P <0.001).  The rate of ovulation was higher in the combination of Metformin-Clomiphene group than any other group.  However difference of ovulation did not translate into an increase for live-birth rate.  They did find that the Metformin group had a significant decrease in BMI and total testosterone, and an increase in sex hormone-binding globulin levels.  Similarly the Clomiphene and Metformin group showed similar changes.  This study in comparison to others measured live birth rate for primary outcomes.  Although they found no significant benefit of the Metformin-Clomiphene combination, the possibility of some benefit cannot be excluded.  When ovulation was used as the primary outcome, the combination of Metformin-Clomiphene was superior to either Clomiphene alone or Metformin alone.  Also some of their subjects had a long-standing history of infertility.

Palomba et al³⁴ compared efficacy of Metformin vs. Clomiphene as first line treatment for treating anovulation in PCOS patients.  They found that both CC and Metformin are two effective-first line options even if the efficacy of theses approaches has a different proceeding over time, Metformin was higher after 6 month treatment.  No significant differences between the experimental and control groups were observed in ovulation (55.4 vs. 59.8%, respectively; P =0.396), pregnancy (10.8 vs. 11.2%, respectively; P =0.888), and abortion (19.5 vs. 26.3%, respectively; P = 0.530) rates.  This differed from their earlier study that showed that Metformin had significant advantages in comparison with CC in terms of pregnancy (Palomba et al, 2005³²).  They found that in the earlier study, the study population was composed of only nonobese patients and subjects screened for diabetes and/or glucose intolerance which is not representative of PCOS population.

Meenakumari et al²⁸ found that women treated with Metformin demonstrated a significant enhancement in luteal progesterone concentrations compared to women on a natural cycle and women treated with only Clomiphene citrate.  The deficiency of luteal phase progesterone synthesis and/or action is the leading cause of infertility or spontaneous abortion in cases of luteal phase defect, resulting in pregnancy loss.

This study measured luteal progesterone as final outcome but it is unsure if this related to successful pregnancy.

In contrast, Johnson et al²⁵ found no evidence that adding Metformin to standard care is beneficial on improving pregnancy and live birth rates in women with PCOS.  The main weakness was that the trial was insufficiently powered. In order to detect an increase in live birth rate, 590 participants would have been required (as opposed to 136).

Moll et al²⁹ similarly also found that Metformin is not an effective addition to Clomiphene citrate at inducing ovulation when compared to Clomiphene-placebo group.  The ovulation rate in the Metformin group was 64% compared with 72% in the placebo group, a non-significant difference (risk difference − 8%, 95% confidence interval − 20% to 4% ).  They found an increase in ovulation with Clomiphene and Metformin of 5% but whether a small difference is clinically relevant is doubtful.  Their study examined patients for a total of 6 ovulations or until Clomiphene resistance developed, the downside being the unexpectedly high rate of dropouts, which was not accounted for in power calculation.

Siebert et al³³ found that although identical ovulation rates were observed between patients treated with pretreatment with Metformin and Clomiphene and Clomiphene citrate only, equivalence could not be concluded.  Not using a placebo for the pretreatment in the Clomiphene citrate group only and their sample size limited this study.

Many variables exist within the study that explains the conflicting findings of the efficacy of Metformin.  While the review has shown that most of the studies agree that Metformin and Clomiphene are superior in respect to ovulation rates.  Whether Metformin and Clomiphene are superior to Clomiphene treatment alone on pregnancy and live birth rates remains to be unclear. Most studies seem to support the use of Metformin for anovulatory PCOS patients, to help with ovulation.  When the primary outcome measurement was ovulation, adding Metformin showed a significant benefit.  When the primary outcome measurement was pregnancy or live birth rate, the benefit was not statistically significant.  In the most recent studies did they start to measure outcomes such as pregnancy, live birth and pregnancy complications.

The roles of Metformin in obese and nonobese women with PCOS were similar in data.  In some studies, weight loss achieved by lifestyle changes, also provided a statistically significant effect on ovulatory rates.  Ultimately there is a correlation between improving insulin resistance and androgens levels, and ovulation rates.

Most studies reported that subjects experienced side effects limited to gastrointestinal symptoms.  While Metformin is known to cause lactic acidosis in patients with renal/hepatic impairment and cardiac disease, none of the studies reported any incidence of lactic acidosis.

Another area was the power of the study and the sample size which varied from study to study.  Most studies that followed the patients for a longer period of time experienced patient dropout rates.  One study supported that the benefit of Metformin and Clomiphene was time dependent, at least 6 months to show a statistically significant difference.

Our review is strengthened by the detailed search strategy and the types of randomized studies included.  Our review is limited by the heterogeneity among the study in the clinical intervention, and outcomes.

Conclusion: 

This systematic review provides a broader understanding of the use of Metformin and Clomiphene in the treatment of PCOS with its effects on fertility.  While Metformin and Clomiphene have been shown to have a significant effect on ovulation rates vs. Clomiphene or Metformin alone, it remains unclear if Metformin alone or the addition of Metformin improves live birth rates and pregnancy.

However, as more studies are done and live birth rates are more commonly employed as the primary outcome measure, this is an area that needs to explored.  Based on this systematic review, it shows a statistically significant benefit of adding Metformin to PCOS treatment regimens to help with ovulation and insulin resistance.  Prior to commencing Clomiphene Citrate, patients with PCOS obese and nonobese can benefit from the use of metformin to improve ovulation rates.  Metformin also seems to improve the metabolic profile of PCOS patients, thus decrasing the associated risks of having PCOS such as heart disease and diabetes mellitus. .

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