AHRQ Report: Comparative Effectiveness and Safety of Treatments for Common Causes of Infertility

SUMMARY:

The AHRQ released a systematic review with the goal of evaluating the comparative effectiveness and safety of treatments for common causes of infertility. Previous studies often did not separate outcomes based on diagnoses. This systematic review focuses on the following clinical scenarios

• Women ages 18–44, with infertility due to
  • PCOS
  • Endometriosis
  • Unknown reasons
  • Tubal or peritoneal factors
• Couples with male factor infertility

Findings

• 151 studies
  • 56 for PCOS | 7 for endometriosis | 50 for
    infertility secondary to unknown causes | 8 for tubal/peritoneal factor | 23
    for male factor | 5 for outcomes in male and female gamete donors
  • 21 studies where findings were relevant across
    all infertility diagnose

PCOS

• Letrozole vs clomiphene results in (moderate strength
  evidence)
  • Higher live birth rates
  • Reduced multiple births
  • No difference in ectopic pregnancies
• Metformin vs clomiphene (moderate strength
  evidence)
  • No differences in outcomes when used as primary
    therapies
• Laparoscopic ovarian drilling vs oral agents
  (moderate strength evidence)
  • No difference in live birth rates

Couples with unexplained infertility

• Immediate IVF vs starting clomiphene and IUI or gonadotropins and IUI, followed by IVF as necessary (moderate strength evidence)
  • Shorter time to pregnancy
  • Likely no differences for other outcomes including
    • Live birth | Multiple births | Ectopic pregnancy | Miscarriage | Low birthweight | Ovarian hyperstimulation syndrome

Couples with Male factor infertility

• ICSI vs and intracytoplasmic morphological sperm injection (not used in the US)
  • No difference in live birth rate (moderate strength evidence)
  • No difference in miscarriage rate (low strength evidence)

Oocyte donors

• GnRH agonist trigger vs hCG trigger (low strength
  evidence)
  • Lower incidence of ovarian hyperstimulation syndrome

KEY POINTS:

Additional Findings

• Limited evidence regarding specific comparisons for tubal factor or endometriosis-related infertility
• Lower live birth rates for African-Americans compared with other racial/ethnic groups (low strength evidence)
• Single embryo transfer (low strength evidence)
  • Lower live birth rates 
  • Significant reductions in multiple birth rates
• Maternal cancers and ART (low strength evidence)
  • No increase in most maternal cancers after ART treatment after adjustment for infertility in general or specific causes
• Children born after ART (low strength evidence)
  • Possible increased risk of neurodevelopmental disorders after ICSI compared with IVF alone
  • No difference in overall cancer incidence
• The Evidence Summary states

In general, our current review’s findings are consistent with the NICE and ASRM guidelines— there is a general consensus that the overall body of evidence for many aspects of infertility treatment across all patient groups is limited. One consistent limitation is the relative paucity of studies utilizing live birth per couple as the primary outcome

Learn More – Primary Sources:

Management of Infertility

PCOS: Targeting Treatments to Improve Reproductive Outcomes and Reduce CVD

SUMMARY:

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy affecting reproductive aged women, with a prevalence of 10-13%. It is a heterogeneous and poorly understood condition characterized by varying degrees of hyperandrogenism, ovarian dysfunction and polycystic ovaries.  Due to insulin resistance, women with PCOS are at increased risk for metabolic syndrome and consequent diabetes, cardiovascular events, and sleep disorders.  Unopposed estrogen from chronic anovulation may result in premenopausal endometrial cancer even though the absolute risk remains low. Once identified, women need to be counseled and treated appropriately to reduce their risk of these complications, while optimizing fertility, and reducing preconception risk factors throughout their lifetimes.

Treatment for Menstrual Disorders

Not Attempting to Conceive

• Combined oral contraceptives suppress luteinizing hormone secretion, ovarian androgen secretion and increase circulating sex hormone binding globulin (SHBG)
  • Recommended for primary treatment of menstrual disorders
  • May also be used to treat hirsutism
  • No clinical advantage of using high-dose ethinyl estradiol (≥30 μg) vs low-dose (<30 μg) when treating hirsutism
• Progestin-only contraceptives or progestin containing IUDs protect the endometrium but lead to abnormal bleeding patterns in over 50% of patients
• Metformin
  • Should be considered in adults with a BMI ≥25 kg/m2
  • Can be considered for adolescents
    • Starting at 500 mg increments with extended release may improve compliance
    • Maximum dose 2.5 grams in adults and 2 grams in adolescents
• Metformin can be used over OCP for metabolic indication
• OCP can be used over metformin for menstrual regulation and/or hirsutism
• Combination of metformin and OCP can be more effective than either medication alone
• Bariatric surgery
  • Should be considered to improve weight loss, ovulation, pregnancy rates, diabetes, hirsutism      
  • Given the rapid return of fertility, effective contraception is indicated prior to surgery

Note: Weight should be stable for a year prior to conception to decrease pregnancy and newborn complications

Treatment for Hirsutism

• Combined with effective contraception, anti-androgens could be considered to treat hirsutism if there is a suboptimal response after a minimum of 6 months of COCP and/or cosmetic therapy
• Spironolactone
  • Diuretic | Aldosterone antagonist | Androgen receptor antagonist
  • Dose: 25 to 100 mg twice daily
  • May take up to 6 months to be effective
• Flutamide
  • Androgen-receptor antagonist
  • Dose: 125 to 250 mg/day
  • Increased risk of severe liver toxicity
  • Teratogenic
• Finasteride
  • 5-alpha-reductase inhibitor
  • Dose: 1 to 5 mg/day
  • Increased risk of liver toxicity
  • Teratogenic
• Topical eflornithine
  • Inhibitor of ornithine decarboxylase
  • Twice daily application for facial hair
• Cyproterone acetate
  • antiandrogen and progestin medication
  • ≥10 mg is not advised due to risk for meningioma
• Mechanical hair removal
  • Electrolysis | Laser vaporization | Shaving | Plucking | Waxing | Depilatory creams

Treatment to Reduce Cardiovascular and Diabetes Risks

Not Attempting to Conceive

• Lifestyle modification (e.g. regular exercise and weight loss)
  • Weight loss is the primary therapy in PCOS
  • As little as 5% reduction in weight can restore regular menses and improve response to fertility medications
  • No advantage in any particular diet – caloric restriction is the key factor
  • Women should be informed that metformin and active lifestyle intervention have similar efficacy.
• Statins lower testosterone, total and LDL cholesterol levels but do not improve menses, hirsutism or acne
• No evidence that combined hormonal contraceptives or progestins will increase the risk of diabetes or CVD in women with PCOS
• All women with PCOS should have
  • A lipid profile at diagnosis and thereafter based on CVD risks, regardless of age and BMI
  • Blood pressure measured annually and when planning pregnancy or seeking fertility treatment

Treatment for Women with PCOS Planning to Conceive

First-Line Interventions

• Letrozole
  • Letrozole (aromatase inhibitor) is considered a first-line treatment for ovulation induction in infertile anovulatory women with PCOS, with no other infertility factors
• Letrozole starting dose is 2.5 mg/day for 5 days starting day 3, 4 or 5 of cycle and increase to 5 mg/day for 5 days with a maximum dosage of 7.5 mg/day if ovulation does not occur at lower, initial dose

• Letrozole should be used rather than clomiphene citrate in women with PCOS with anovulatory infertility and no other infertility factors to improve ovulation, clinical pregnancy and live birth rates
• Clomiphene Citrate
  • Improved performance compared to metformin alone or placebo
  • Over 50% of those who conceive do so on 50 mg/day dose and 20% on 100 mg/day dose
  • Most pregnancies occur within 6 months
• Second-Line Interventions
• If clomiphene citrate or letrozole fails
  • Gonadotropins
  • Laparoscopy with ovarian drilling

Third-Line Intervention 

• The International Guideline considers IVF to be a third line intervention for PCOS

PCOS in Pregnancy

• PCOS women have higher risk pregnancies
• Women with PCOS are not at increased risk of large for gestational age babies, macrosomia, and instrumental delivery
• Assisted reproductive technology in women with PCOS will not add additional risk of miscarriage, preterm birth, impaired fetal growth, and caesarean section, over that observed in women without PCOS
• Metformin in pregnant women with PCOS has not been shown to prevent Gestational diabetes | Late miscarriage between 12 to 22 weeks | Hypertension in pregnancy | Preeclampsia | Macrosomia

Diabetes Assessment

Screening for Diabetes

• Assess glycemic status at baseline in all women with PCOS at time of diagnosis, when planning pregnancy or seeking fertility treatment and repeat every 1 to 3 years depending on other risk factors
• To assess glycemic status, use one of the following tests
  • 75-g Oral glucose tolerance test (OGTT)
  • If an OGTT cannot be performed then Fasting plasma glucose or HbA1C can be done, noting significantly reduced accuracy
  • OGTT is the most accurate test regardless BMI
• In pregnancy
  • If not performed preconception, offer OGTT at first prenatal visit
  • Offer all pregnant women with PCOS an OGTT at 24 to 28 weeks gestation

KEY POINTS:

• Letrozole outperforms clomiphene citrate for ovulation induction
  • Higher live-birth rate
  • Higher ovulation rate
  • Higher clinical pregnancy rate
• Before starting medical/surgical ovulation induction therapies, counsel about lifestyle modification including
  • Stop smoking
  • Reduce weight and increase exercise especially in setting of overweight/obesity
  • Reduce alcohol consumption
• Both letrozole and clomiphene citrate are contraindicated in pregnancy
• Management goals include
  • Protecting the endometrium from the effects of unopposed estrogen
  • Reestablishing a regular menstrual cycle
  • Preventing the metabolic syndrome and cardiovascular sequelae of PCOS
  • Providing support for ovulatory dysfunction for those anticipating pregnancy

Learn More – Primary Sources:

Recommendations From the 2023 International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome 

Monash University PCOS Program

ACOG Practice Bulletin No 194: Polycystic ovary syndrome

Screening and Diagnosis of Obstructive Sleep Apnea  – PcMED Project

CMAJ Review: Diagnosis and management of polycystic ovarian syndrome

Polyendocrine Metabolic Ovarian Syndrome (formerly PCOS): Making the Diagnosis

SUMMARY: 

Polyendocrine metabolic ovarian syndrome, also known as polycystic ovary syndrome (PCOS), is a complex disorder characterized by varying degrees of ovulatory dysfunction, hyperandrogenism, and metabolic dysfunction, with associated risks including cardiovascular disease, diabetes, and endometrial cancer. In 2026, an international global consensus recommended renaming the condition polyendocrine metabolic ovarian syndrome (PMOS) to better reflect its multisystem endocrine, metabolic, and ovarian features and to avoid the misleading implication of ovarian cysts. During this transition in nomenclature, existing diagnostic guidance remains anchored in the 2023 International Guideline. Developed through an international advisory panel via the Centre for Research Excellence in Polycystic Ovary Syndrome (CREPCOS), funded by the Australian National Health and Medical Research Council of Australia (NHMRC), in partnership with Monash University, several European societies on reproductive health, and the ASRM, the guideline provides updated definitional criteria to support accurate diagnosis. There is a plan underway to integrate the name change into the 2028 update of the International Guidelines.

Diagnostic Criteria 

The International Guideline Endorses the Rotterdam Criteria  

• The Rotterdam Criteria requires two out of three of the following (after other causes are excluded):
  • Clinical/biochemical signs of hyperandrogenism
  • Ovulatory dysfunction
  • Polycystic ovaries on ultrasound or elevated anti-mullerian hormone (AMH) levels

Note: If hyperandrogenism is present in the setting of irregular menses, ultrasound or AMH are not necessary  

• Adolescents   
  • Ultrasound and AMH are not recommended  
  • Adolescents with PCOS-like features not meeting diagnostic criteria should be considered at “increased risk” for PCOS 
    • Reassessment advised around 8 years post-menarche 
    • Applicable to those with PCOS features pre/post combined OCP use, persistent symptoms, or significant weight gain in adolescence 

Clinical Diagnosis 

Hyperandrogenism  

• Findings consistent with diagnosis of hyperandrogenism include
  • Acne
  • Alopecia
  • Hirsutism
• In adolescents, clinical findings must be severe
• Reported unwanted excess hair growth and/or alopecia should be considered significant regardless of observed severity

Anovulation 

• Consider PCOS when irregular menstrual cycles are present
• Irregular Menses should be defined as follows
  • Normal if occurring in year 1 post menarche (considered part of pubertal transition)
  • 1 to <3 years post menarche: <21 or >45 days
  • 3 years post menarche to perimenopasuse: <21 days or >35 days or <8 cycles per year
  • 1 year post menarche: >90 days for any one cycle
  • Primary amenorrhea: By age 15 or >3 years post thelarche (breast development)

Note: Ovulatory dysfunction can still occur with regular cycles | Confirm anovulation with serum progesterone levels | Nonclassic congenital adrenal hyperplasia (CAH) can mimic PCOS 

Imaging  

Ultrasound and Polycystic Ovarian Morphology (PCOM) 

• Do not use for <8 years post menarche
• High incidence of multifollicular ovaries
• Transvaginal approach preferred
  • 8 MHz transducer
• Follicle number per ovary is the most effective sonographic marker for PCOS
• Threshold
  • ≥20 follicles/ovary and/or
  • Ovarian volume ≥10 ml in either ovary

Laboratory Diagnosis 

Androgens 

• Use one of the following
  • Total and Free testosterone
  • Calculated bioavailable testosterone
• Consider androstenedione and dehydroepiandrosterone sulfate (DHEAS) if total or free testosterone are not elevated
  • Note that additional information provided will be limited
• Lab tests for hyperandrogenism unreliable for women using hormonal contraception
  • If lab testing important/required, withdraw hormonal contraception for at least 3 months and use alternate contraceptive during that time
• If androgen results are very high compared to lab reference ranges, consider neoplasia
• Routine screening for Cushing Syndrome in patients with hyperandrogenic chronic anovulation not indicated
  • Only screen if patients have coexisting signs
    • Buffalo hump | Abdominal Striae | Centripetal fat distribution | Hypertension

Note: Lab testing for hyperandrogenism most useful when clinical findings unclear or absent 

AMH 

• Should not be the only indicator of a PCOS diagnosis 
• Either AMH or ultrasound can be used to PCOM (polycystic ovarian morphology) 
• AMH should not be used in adolescents 
• Factors that influence AMH levels  
  • Peaks age 20 to 25 
  • Inversely proportional to maternal weight 
  • May be suppressed by recent combined oral contraceptive use 
  • Varies during the menstrual cycle 

Other Clinical Considerations at Time of Diagnosis  

Consider Patients at Increased Risk for Metabolic Syndrome  

• Physical exam 
  • Blood pressure | BMI | Waist circumference 
• Look for additional signs of hyperandrogenism and insulin resistance 
  • Acne | Hirsutism | Male pattern hair growth | Acanthosis nigricans | Clitoromegaly 
• Laboratory (may be considered in addition to androgen levels depending on clinical scenario) 
  • TSH | Prolactin | 17-OH progesterone 
  • Consider screening for Cushing syndrome / acromegaly 
  • 2-hour oral glucose tolerance test (fasting glucose, 75 g oral glucose load, 2 hour glucose level) 
  • Fasting lipid and lipoprotein levels 

Metabolic Syndrome Implications 

• Obesity
  • Weight reduction: As little as 5% will have improved pregnancy rates, glucose and lipid levels and reduced hirsutism
• Women with PCOS have a 2- to 5-fold increased risk of diabetes
  • Fasting glucose levels are poorly predictive of risk
  • The 2 hr 75 gram glucose tolerance test above should be utilized instead
• Screen women with PCOS for cardiovascular risk with BMI, fasting lipid and lipoprotein levels, metabolic syndrome risk factors
  • Rescreen periodically as impaired glucose tolerance can develop over time
• Recommend healthy lifestyle behaviors for all women with PCOS
  • Focus on healthy eating and physical activity.
  • Aims to improve general health, quality of life, body composition, and weight management.
  • Goals include maintaining weight, preventing weight gain, and achieving modest weight loss

Obstructive Sleep Apnea (OSA) 

• PCOS associated OSA independent of BMI 
• Screen with simple questionnaire (find more information in Related Topics below)  
• Definitive diagnosis via sleep study 

Endometrial Hyperplasia and Cancer Risk 

• PCOS is associated with higher risk for endometrial hyperplasia and cancer 
• Routine screening is not recommended as absolute risk is low  
• Prevention strategies 
  • Weight management 
  • Menstrual cycle regulation 
  • Progestogen therapy 
• If increased endometrial thickness, treat as per guidelines including biopsy and withdrawal bleeding  

Psychological Features 

• PCOS may be associated with the following  
  • Depression 
  • Altered body image 
  • Eating disorders 

Pregnancy Risks 

• Increased risk for  
  • Gestational diabetes 
  • Preterm birth 
  • Hypertension 
  • Cesarean delivery 
  • Growth restriction 
• No increased risk  
  • LGA infants 
  • Instrumental deliveries 
  • Macrosomia 

 Learn More – Primary Sources: 

Recommendations From the 2023 International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome  

Polyendocrine metabolic ovarian syndrome, the new name for polycystic ovary syndrome: a multistep global consensus process

Monash University PCOS Program 

ACOG Practice Bulletin No 194: Polycystic ovary syndrome 

Screening and Diagnosis of Obstructive Sleep Apnea  – PcMED Project 

CMAJ Review: Diagnosis and management of polycystic ovarian syndrome