The therapeutic dilemma in PCOS patients not desiring pregnancy: A systematic review and meta-analysis

Combined oral contraceptive (COC) and anti-androgens (AA) are more effective than metformin for treating the symptoms of excess androgens and offer endometrial protection in adult women with polycystic ovary syndrome (PCOS) as compared to metformin alone. Addition of metformin to the treatment regimen improves glucose sensitivity and bring about weight loss report the results of a systematic review and metanalysis published in current issue of Journal of Human Reproduction Update.

PCOS is common endocrine disorder in women of the reproductive age and beyond. Most treatments are directed towards achieving conception in younger women who desire fertility but the treatment of women with PCOS who do not desire pregnancy is not standardized.

COC and anti-androgens with or without insulin sensitizers are commonly used.  But, the efficacy and safety of these treatments in treating hyperandrogenemia and its effect on cardiometabolic risk factor are not well documented.

This review of RCTs was conducted to seek better therapeutic approach in this subset of women who do not desire fertility in terms of efficacy and safety.

The authors found 1522 articles abstract after going through PubMed and EMBASE until September 2017. After exclusion, 33 studies and 1521 women were included in the quantitative synthesis and in the meta-analyses. After statistical analysis, the outcomes were:

• COC and/or AA significantly improved the hirsutism score as compared to metformin alone.

• COC and/or AA also was more effective in preventing endometrial hyperplasia as compared to metformin alone.

• COC was also found more effective in regularizing the menstrual cycle.

• Metformin helped in improving the cardiometabolic profile in these women because of its favorable effect on BMI.

• The use of COC and/or AA along with metformin did not affect the mean glucose levels but it did help bring down the fasting glucose levels.

• Both the therapies were comparable in terms of the effect on lipid profile, blood pressure or prevalence of hypertension, but the quality of evidence was low when these effects were explored.

The results of this systematic review and metanalysis provide scientific evidence to choose between treatment for adult women with PCOS based on symptoms and desired goal of therapy.

Abstract 

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Clomiphene compared with other drugs in terms of ovulation, EMT, pregnancy and live births: systematic review and meta-analysis

Ovulation induction with Clomiphene Citrate (CC) in women with WHO group II ovulatory disorders results in lower endometrial thickness (EMT) as compared to other regimens. The regimen also resulted in lower number of pregnancies and live births reports the results of systematic review and meta-analysis published in Journal Ultrasound in Obstetrics and Gynecology.

WHO group II ovulation disorders are defined as dysfunctions of the hypothalamic-pituitary-ovarian axis. This category includes conditions such as polycystic ovary syndrome (PCOS) and hyperprolactinaemic amenorrhoea. Around 85% of women with ovulation disorders have a group II ovulation disorder.

This systematic review and meta-analysis only focused on randomized control trials(RCTs) and included all those studies comparing CC with any other regimens and looked at EMT and rates of ovulation, pregnancy and live births.

The other regimens included in the study were Letrozole, CC plus metformin, CC plus N-acetyl cysteine (NAC), CC + nitric oxide (NO) donor and Tamoxifen.

The researchers selected 33 RCTs from 1718 articles that fitted the inclusion criteria amounting a total of 4349 women and 7210 ovulation induction cycle.

Maximum number (15) of RCTs compared CC with Letrozole. Overall the mean EMT was 1.39mm lower in CC group as compared to Letrozole. (WMD, −1.39; 95% CI, −2.27 to −0.51; I² = 100%), and women on CC had a 22% lower chance of pregnancy and 30% lower chance of live births. The ovulation rates were comparable between the two groups.

Only 2 RCTS were found comparing CC with CC plus metformin and no significant difference were noted in any of the outcome parameters between the groups.

When comparing CC with CC plus N-acetyl cysteine (NAC) and CC plus nitric oxide (NO) donor, EMT was lower in CC only group, along with ovulation and pregnancy rates.

When the CC regimen was compared with Tamoxifen, lower EMT and comparable ovulation and pregnancy rates were noted.

The authors concluded that in women with WHO group II ovulatory disorders, Letrozole seems to benefit these women more in terms of increased EMT, ovulation, pregnancy rates and live births. 

Whether the increase pregnancy rates and live births rates are due to increase in EMT has not been looked at in this study.

Abstract

In case you missed it: Here are the top 5 posts this month

September was a very busy month with lots of good research papers and systematic reviews published on various topics. We also saw many guidelines and recommendations updates from ACOG, ASRM and USPSTF. Here are the top 5 most read posts for the month of September.

USPSTF simplifies cervical cancer screening recommendations: Dual testing no longer advised

The US Preventive Services Task Force (USPSTF) has issued new draft recommendations for cervical cancer screening with a major change that it recommends either cervical cytology (CC) or high-risk HPV (hrHPV) test as a screening procedure every 3 years for women aged 30-65 years, and not both ( Grade A)  

https://obgynupdated.blogspot.com/2017/09/uspstf-simplifies-cervical-cancer.html

ACOG issues clinical practice guidelines for Gestational Diabetes Mellitus

The American College of Obstetricians and Gynecologists (ACOG) has issued clinical practice guidelines for the diagnosis and treatment of gestational diabetes mellitus (GDM).

Although prevalence of GDM is directly proportional to prevalence of type 2 DM in a given population, it is estimated that GDM accounts for 90% of cases diabetes in pregnancy. The prevalence of DM in pregnancy is around 6-9%.

https://obgynupdated.blogspot.com/2017/09/acog-issues-clinical-practice.html

ASRM guidelines update: Metformin alone is not the first line of treatment for ovulation induction in women with PCOS

Practice Committee of the American Society for Reproductive Medicine does not recommend Metformin alone for ovulation induction as a first line therapy in women with PCOS. The guidelines were published in Journal Fertility and Sterility Epub ahead of print.

Metformin is a biguanide used as an oral insulin lowering agent in type2 diabetes, but also used enthusiastically in women with PCOS because of shared pathophysiology of insulin resistance in both.

https://obgynupdated.blogspot.com/2017/09/asrm-guidelines-update-metformin-alone.html

Oral Nifedipine parallels IV hydralazine in lowering down BP in acute hypertensive emergency in pregnancy

Intravenous hydralazine and oral nifedipine both exhibit the same efficacy in lowering the blood pressure in acute hypertensive emergency of pregnancy reports the results of small randomized trial published online in journal American Journal of Obstetrics and Gynecology.

https://obgynupdated.blogspot.com/2017/09/oral-nifedipine-parallels-iv.html

Oral diclofenac potassium plus cervical lidocaine cream eases the pain during hysterosalpingography

Oral diclofenac potassium tab 30 minutes before hysterosalpingography (HSG) and cervical lidocaine cream 5% significantly relieves pain and eases patient anxiety during the procedure and for half an hour after reports the results of a randomized trial published in September issue of journal Fertility and Sterility.

https://obgynupdated.blogspot.com/2017/09/oral-diclofenac-potassium-plus-cervical.html 

ACOG issues clinical practice guidelines for Gestational Diabetes Mellitus

Courtesy: YouTube.

The American College of Obstetricians and Gynecologists (ACOG) has issued clinical practice guidelines for the diagnosis and treatment of gestational diabetes mellitus (GDM).

Although prevalence of GDM is directly proportional to prevalence of type 2 DM in a given population, it is estimated that GDM accounts for 90% of cases diabetes in pregnancy. The prevalence of DM in pregnancy is around 6-9%.

The prevalence of GDM globally is on the rise because of increasing obesity, delayed childbearing and sedentary lifestyle.

The document provides a brief overview of GDM, one of the most common complication of pregnancy, identifies the disease process, its diagnosis and management based on current research and identifies the lacunae for future research.

Screening for GDM is done by various methods and there is still no standardized method. ACOG supports the two-step process most commonly used in USA. It involves first screening with the administration of a 50-g oral glucose solution followed by a 1-hour venous glucose determination. 

Women whose glucose levels meet or exceed an institution’s screening threshold then undergo a 100-g, 3-hour diagnostic OGTT. Gestational diabetes mellitus is most often diagnosed in women who have two or more abnormal values on the 3-hour OGTT.

Other institutions and private practitioners use International Association of Diabetes and Pregnancy Study Group (IADPSG) recommended one step, universal 75-g, 2-hour OGTT to diagnose GDM.

The summary of recommendations by ACOG:

Recommendations based on good scientific evidence (Level A):

All women diagnosed with GDM should first be treated with adequate nutritional and exercise counselling, before starting any pharmacological treatment.

If lifestyle modifications fail to control glucose levels, Insulin is the first line of drug for controlling blood sugar in pregnancy.

Recommendations based on limited or inconsistent scientific evidence (Level B):

All pregnant women should be screened for GDM with a laboratory based blood glucose level testing.

Women who refuse to take insulin, or who are unable to safely administer insulin, metformin is a reasonable second-line choice.

Glyburide is not be recommended as a first-line pharmacologic treatment because, in most studies, it does not yield equivalent outcomes to insulin.

All women should be counselled about limitations of safety data regarding oral hypoglycemic agents.

Women should also receive counselling regarding the risks and benefits of a scheduled cesarean delivery when the estimated fetal weight is 4,500 g or more.

Recommendations based primarily on consensus and expert opinion (Level C):

In the absence of clear evidence and comparative trials, no single value of blood glucose can be taken as cutoff over another for 1-hour glucose test nor one set of diagnostic criteria for the 3-hour OGTT can be clearly recommended over the other. Practitioners should select a single set of criteria and use it consistently with their patients.

Women should be advised dietary guidance and 30 minutes of moderate physical activity, 5 days a week or 150 minute/week.  

In women, whose GDM is well controlled by diet and exercise, delivery is not indicated before 39 weeks of gestation, in absence of other obstetric indication. She can be safely managed expectantly up to 40 6/7 weeks of gestation, with antepartum fetal surveillance.

In women, whose GDM is well controlled by medications, delivery is recommended at 39 0/7 to 39 6/7 weeks of gestation.

All women with GDM should be screened at 4–12 weeks postpartum to identify women with diabetes, impaired fasting glucose levels, or impaired glucose tolerance, with an appropriate referral to medical practitioner.

The American Diabetic Association (ADA) and ACOG recommend repeat testing every 1–3 years for women who had a pregnancy affected by GDM and normal postpartum screening test results.

Full Text 

In case you missed it: Here are the top 5 posts this month

Clinical review: Updates on Cesarean Section

A roundup of the latest research on Cesarean Section

https://obgynupdated.blogspot.com/2017/08/clinical-review-updates-on-cesarean.html

ACOG releases Committee Opinion for Prenatal Corticosteroid Therapy for Fetal Maturation

An updated committee opinion from the American College of Obstetricians and Gynecologists (ACOG), was published in the August issue of Obstetrics & Gynecology.

https://obgynupdated.blogspot.com/2017/08/acog-releases-committee-opinion-for.html

Vaginal cleaning before cesarean delivery significantly reduces infection: A Systematic Review and Meta-analysis.

A simple and inexpensive intervention of vaginal cleaning with an antiseptic solution before cesarean delivery brings down the rate of endometritis note the results of a Systematic Review and Meta-analysis published August 4 in Journal of Obstetrics and Gynecology.

https://obgynupdated.blogspot.com/2017/08/vaginal-cleaning-before-cesarean.html

Adjunct Metformin helps reversal of atypical endometrial hyperplasia

Adjunct metformin treatment help reversal of atypical endometrial hyperplasia (AEH) and improves overall survival in endometrial cancer reports the result of a systematic review and meta-analysis published ahead of print in Journal of Gynecologic Oncology.

https://obgynupdated.blogspot.com/2017/08/adjunct-metformin-helps-reversal-of.html

Society for Maternal-Fetal Medicine (SMFM) issues guidelines for HCV in pregnancy

The Society for Maternal-Fetal Medicine (SMFM) has issued guidelines for screening and management of Hepatitis C infection in pregnancy.  

The guidelines were published ahead of print in American Journal of Obstetrics and Gynecology.

https://obgynupdated.blogspot.com/2017/08/society-for-maternal-fetal-medicine.html

Adjunct Metformin helps reversal of atypical endometrial hyperplasia

Adjunct metformin treatment help reversal of atypical endometrial hyperplasia (AEH) and improves overall survival in endometrial cancer reports the result of a systematic review and meta-analysis published ahead of print in Journal of Gynecologic Oncology.

Metformin is named as ‘Magic Bullet’ by some researchers because of its new-found role in reversing aging to improving survival in many cancers, besides being in use as antidiabetic and cardioprotective drug since nearly 60 years.

Metformin was introduced for use as antidiabetic in UK in 1958.

Endometrial cancer (EC) is one of the most common gynecological cancer. The American Cancer Society estimates that about 61,380 new cases of EC of the uterus (uterine body or corpus) will be diagnosed in 2017 and about 10,920 women will succumb to the disease.

This systematic review and meta-analysis searched Cochrane, LILACS, PubMed, Scopus and Web of Science in January 2017 and included 19 eligible studies that included information about reversal of atypical endometrial hyperplasia, cellular proliferation biomarkers expression and overall survival in metformin-users compared to non-users.

In 5 studies, metformin led to reversion of AEH to a normal histology and decreased cell proliferation biomarkers staining, from 51.94% to 34.47%.

Patients on adjunct metformin had 18% increased odds of survival as compared to patients who were not diabetic and not on metformin. (HR = 0.82; CI: 0.70–0.95; p = 0.09, I2 = 40%).

Type 2 diabetes mellitus and insulin resistance is involved in the etiology of endometrial cancer (EC), so metformin may have both direct and indirect effect on tumor regression.

There was considerable heterogenicity observed between the studies but, despite that metformin was shown to be beneficial in reversal of AEH and improving overall survival in EC.

The authors call  upon future need of prospective trials regarding the anticancer effect of metformin and improving the clinical outcomes in EC.  

Primary source: Effects of metformin on endometrial cancer: Systematic review and meta-analysis

Meireles, Cinthia G. et al.

Gynecologic Oncology , Volume 0 , Issue 0 ,

Polycystic ovarian syndrome increases the risk of subsequent early ovarian aging later in life.

Women with polycystic ovarian syndrome (PCOS) have 8.64 fold increase in risk of developing premature ovarian failure as compared to women who did not have PCOS according to a population based study in forthcoming issue of Journal Menopause. Metformin was found to be effective in reducing such risk. 

The study authors reviewed data across a period of 14 years (1998 to 2012) from Taiwan National Health Insurance Research Database.

The study group consisted of women with PCOS (exposure group; n=7,049), each woman with PCOS was age matched with 10 other women without PCOS. (contrast group; n = 70,490).

The cohort was followed up for 10 years. The diagnosis of POI and PCOD was confirmed by blood test and ultrasonography.

Polycystic ovary syndrome (PCOS) is an endocrinopathy that affects approximately 10% of reproductive-aged women throughout their lives and POI affects 1-3% of women by age 40.

It was seen that POI was nearly 8 times more common in women with PCOD. Kaplan-Meier survival analysis showed that POI free survival rates of women were significantly more in contrast group than exposure group (P < 0.001).

After adjustment of covariates, it was seen that women with PCOD have 8.31 fold increase in risk of developing premature ovarian failure, this was 9.93 fold for women who did not receive metformin treatment for PCOS.

Metformin was significantly effective in lowering the risk to nearly half (5.66).

However, well-designed, prospective, long-term, large-scale, randomized clinical trials are necessary to elucidate the efficacy and safety of long term metformin in patients with PCOS.  

The results of this study are in contrast to the earlier hypothesis that women with polycystic ovaries (PCO) are protected against POI because they may have actually been born with a larger pool of resting follicles.

Currently, PCOS and POI are both being investigated as diseases of autoimmune origin.

Metformin or Oral Contraceptives for treatment of Polycystic Ovarian Syndrome in Adolescents: A Meta-analysis

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorder in adolescent and adult women affecting 1 in 15 women worldwide and have important metabolic and reproductive implication.  

The diagnosis of PCOS is challenging specially in adolescent as normal pubertal changes can mimic the signs of PCOS. The Rotterdam criteria are widely in use for diagnosis. These criteria require that patients have at least two of the following conditions: ovulatory dysfunction, androgen excess, and polycystic ovaries. It is also necessary to rule out other causes of androgen excess and ovulatory dysfunction before a diagnosis of PCOS is made. 

The treatment approach varies according to the age of the patient, desire for pregnancy and the presenting symptoms.  

The Endocrine Society guidelines for the treatment of adults with PCOS recommends using oral contraceptive pills (OCPs) to control symptoms of androgen excess, while reserving metformin for cases with impaired glucose tolerance or features of metabolic syndrome.

However, evidence is sparse to support the best first-line medication in adolescents with PCOS.

Investigators Dr. Reem A. Al Khalifah and colleagues of King Saud University in Saudi Arabia published a metaanalysis and systemic review of randomized, controlled trials (RCTs) to evaluate the use of metformin versus OCPs for the treatment of PCOS in adolescents ages 11 to 19 years in the Pediatrics, online April 28.

The team searched the literature through Ovid Medline, Ovid Embase, Cochrane Central Register of Controlled Trials, and gray literature resources, up to January 29, 2015. Only four RCTs met the inclusion and exclusion criteria’s amounting to 170 patients in total. 

It was seen that OCP treatment resulted in improvement in menstrual irregularities with a modest improvement in the acne scores.  On the other hand, metformin improved the BMI, decreased dysglycemia prevalence and improved total cholesterol and low-density lipoprotein levels. Both treatment modalities have a similar effect on hirsutism. 

However, the evidence quality was very low, so "treatment choice should be guided by patient values and preferences, while balancing potential side effects" said Dr. Al Khalifah

But, as PCOS is a spectrum with many girls presenting with obesity and hairiness while others have normal body weight and just have menstrual irregularities. So, depending upon the symptoms, the treatment is tailored according to the patient need, with either OCP or metformin being the first line of treatment. 

Concurrently, the importance of life style modification and statin is also stressed to provide long term cardiac protection in these patients.

References:
http://womenshealth.gov/publications/our-publications/fact-sheet/polycystic-ovary-syndrome.html#b
http://www.ncbi.nlm.nih.gov/pubmed/26280343
http://press.endocrine.org/doi/abs/10.1210/jc.2013-2350

Wonderdrug ' Metformin', the next breakthrough in anti-aging.

Common Diabetes drug Metformin could be next breakthrough in Anti-aging.

Gestational Diabetes Mellitus Revisited

Gestational Diabetes Mellitus Revisited 

Today is world diabetes day. The International Diabetes Federation has released new data in support of its campaign against Diabetes quoting that “1 in 7 births is affected by gestational diabetes” and “One quarter of all births are affected by high blood glucose during pregnancy in South-East Asia.”

 This article is based on The International Federation of Gynecology and Obstetrics (FIGO) Initiative on gestational diabetes mellitus: A pragmatic guide for diagnosis, management, and care.

• The International Diabetes Federation (IDF) estimates that one in six live births (16.8%) are to women with some form of hyperglycemia in pregnancy.

• While 16% of these cases may be due to diabetes in pregnancy (either preexisting diabetes—type 1 or type 2—which antedates pregnancy or is first identified during testing in the index pregnancy), the majority (84%) is due to gestational diabetes mellitus (GDM).

• The definition of GDM is still evolving.

• Hyperglycemia first detected at any time during pregnancy should be classified either as diabetes mellitus in pregnancy (DIP) or GDM.

• When the level of hyperglycemia first detected by testing at any time during the course of pregnancy meets the criteria for diagnosis of diabetes in the nonpregnant state, the condition is called DIP. Those criteria are:

      1) Fasting plasma glucose ≥7.0 mmol/L (126 mg/dL); and/or

      2) 2-hour plasma glucose ≥11.1 mmol/L (200 mg/dL) following a 75-g oral glucose load; or

      3)Random plasma glucose ≥11.1 mmol/L (200 mg/dL) in the presence of diabetes   symptoms.

• DIP may either have been pre-existing diabetes (type 1 or type 2) antedating pregnancy, or diabetes first diagnosed during pregnanc.

• When hyperglycemia detected during routine testing in pregnancy (generally between 24 and 28 weeks) does not meet the criteria of DIP it is called GDM.

            To address the global burden of GDM, FIGO recommendations:

• Universal testing-- All pregnant women should be tested for hyperglycemia during pregnancy using a one-step procedure and FIGO encourages all countries and its member associations to adapt and promote strategies to ensure this.

• As per the recommendation of the IADPSG (2010) and WHO (2013), the diagnosis of GDM is made using a single-step 75-g OGTT when one or more of the following results are recorded during routine testing specifically between weeks 24 and 28 of pregnancy or at any other time during the course of pregnancy:

     1)Fasting plasma glucose 5.1−6.9 mmol/L (92−125 mg/dL);

     2)1-hour post 75-g oral glucose load ≥10 mmol/L (180 mg/dL);

     3)2-hour post 75-g oral glucose load 8.5–11.0 mmol/L(153−199 mg/dL)

• Asian Indians are considered to be at the highest risk of gestational diabetes. Based on studies from India and keeping in mind the already high burden and rising prevalence of diabetes and the realities of resource constraints within the health system in India, as well as the high rate of deliveries (27 million each year), the Diabetes in Pregnancy Study Group in India (DIPSI) developed the following guideline for diagnosis of GDM in the community. This guideline has been endorsed by the Ministry of Health, Government of India, the Federation of Obstetrics and Gynecological Societies of India (FOGSI), and the Association of Physicians of India (API)
• For Asian Indians Testing for GDM is recommended twice during prenatal care. The first testing should be done during first prenatal contact as early as possible in pregnancy. The second testing should be done ideally during 24−28 weeks of pregnancy if the first test is negative. If women present beyond 28 weeks of pregnancy, only one test is to be done at the first point of contact.

• The management of GDM should be in accordance with available national resources and infrastructure even if the specific diagnostic and treatment protocols are not supported by high-quality evidence, as this is preferable to no care at all.

• Life style modification is the corner stone in management of DIP and GDM.

• Nutritional therapy includes an individualized food plan to optimize glycemic control. Medical nutritional therapy in pregnancy can be described as “a carbohydrate-controlled meal plan that promotes adequate nutrition with appropriate weight gain, normoglycemia, and the absence of ketosis.

• Daily energy intake of approximately 2050 calories (minimum of 175 g carbohydrates/day) in all BMI categories in women with GDM was reported to reduce weight gain, maintain euglycemia, avoid ketonuria, and achieve average birth weights of 3542 g.

• Oral antidiabetic agents  Insulin, glyburide, and metformin are safe and effective therapies for GDM  during the second and third trimesters, and may be initiated as first-line treatment after failing to achieve glucose control with lifestyle modification. Among OADs, metformin may be a better choice than glyburide.

• Insulin should be considered as the first-line treatment in women with GDM who  are at high risk of failing on OAD therapy, including some of the following factors

       • Diagnosis of diabetes <20 weeks of gestation

             • Need for pharmacologic therapy >30 weeks

       • Fasting plasma glucose levels >110 mg/dL

       • 1-hour postprandial glucose >140 mg/dL

       • Pregnancy weight gain >12 kg

• The postpartum period is crucial, not only in terms of addressing the immediate perinatal problems, but also in the long term for establishing the basis for early preventive health for both mother and child, who are at a heightened risk for future obesity, metabolic syndrome, diabetes, hypertension, and cardiovascular disorders.

• Progression to diabetes is more common in women with a history of GDM compared with those without a GDM history. 
• Both “intensive lifestyle” and metformin have been shown to be highly effective in delaying or preventing diabetes in women with IGT and a history of GDM.

• The current EBCOG proposal is to screen women with a history of GDM at 6−12 weeks postpartum using the 2-hour 75-g OGTT with nonpregnancy diagnostic criteria. Women with a history of GDM should have lifelong screening for the development of diabetes or prediabetes at least every 3 years.

     References:

• http://www.ijgo.org/article/S0020-7292%2815%2930033-3/pdf

http://www.ijgo.org/article/S0020-7292%2815%2930033-3/pdfhttp://www.ijgo.org/article/S0020-7292%2815%2930033-3/pdfhttp://www.ijgo.org/article/S0020-7292%2815%2930033-3/pdf