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

Polycystic ovary syndrome (PCOS) is poorly understood and is 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 and cardiovascular events.  Unopposed estrogen may result in endometrial cancer. Once identified, women need to be counseled and treated appropriately to reduce their risk of these health problems.

CLINICAL ACTIONS:

Treatment for Menstrual Disorders

Women with PCOS who are 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
  • Progestin-only contraceptives or progestin containing IUDs protect the endometrium but lead to abnormal bleeding patterns in over 50% of patients
  • Insulin sensitizing agents, including biguanides (metformin) and thiazolidinediones (pioglitazone, rosiglitazone)
    • The use of insulin sensitizers are associated with decrease in androgen levels, improved ovulation, improved glucose tolerance
    • Important to discuss contraception
    • The insulin sensitizing agents are not currently approved by the FDA for the treatment of PCOS
      • Metformin, according to ACOG has the “safest risk-benefit ratio”
      • The International Guideline recommends metformin for those women with metabolic features of glucose intolerance/ insulin resistance

Treatment for Hirsutism

Women with PCOS can be treated with the following:

  • Spironolactone, a diuretic, aldosterone antagonist, androgen receptor antagonist: 25-100 mg twice daily
    • May take up to 6 months to be effective
  • Flutamide, an androgen-receptor antagonist 125-250 mg/day: Teratogenic
  • Finasteride, a 5-alpha-reductase inhibitor, 1-5 mg/day: Teratogenic
  • Topical eflornithine, an inhibitor of ornithine decarboxylase, twice daily application for facial hair
  • Mechanical hair removal (electrolysis, laser vaporization, shaving, plucking, waxing, depilatory creams)

Treatment to Reduce Cardiovascular and Diabetes Risks

Women with PCOS who are 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
  • Insulin sensitizing agents such as metformin can delay development of diabetes in those at risk
    • Data currently insufficient to recommend insulin-sensitizing agents prophylactically for women at higher risk of diabetes due to PCOS
  • 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

Treatment for Women with PCOS Planning to Conceive

First-Line Interventions

  • Letrozole
    • Letrozole (aromatase inhibitor) is considered a first-line treatment due to data demonstrating increased ovulation rates, clinical pregnancy rates and live-birth rate vs clomiphene citrate
    • Counsel patients that letrozole is not approved by the FDA for ovulation induction
    • 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
  • Clomiphene Citrate
    • ‘Traditional’ first-line treatment with 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
  • Both clomiphene citrate and letrozole are associated with increase in multiple births, preterm birth, and hypertensive disorders

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

Diabetes Assessment

Screening for Diabetes

  • Assess glycemic status at baseline in all women at time of PCOS diagnosis and repeat every 1 to 3 years depending on other risk factors
  • To assess glycemic status, use one of the following tests
    •  Oral glucose tolerance test (OGTT)
    • Fasting plasma glucose
    • HbA1c
  • OGTT is recommended in women with PCOS and risk factors
    • BMI > 25 kg/m2
    • Asians > 23 kg/m2
    • History of impaired fasting glucose
    • Impaired glucose tolerance or gestational diabetes
    • Family history of diabetes mellitus type 2
    • Hypertension
    • High-risk ethnicity

Women considering fertility treatment or preconception planning 

  • Prior to fertility treatment and/or preconception planning
    • Offer all women a 75-g OGTT
  • In pregnancy
    • If not performed preconception, offer OGTT<20 weeks
    • Offer all pregnant women with PCOS an OGTT at 24-28 weeks gestation

SYNOPSIS:

Once diagnosed, treatment of PCOS should be tailored to patient’s risk factors and desires.  Lifestyle modifications including weight reduction and regular exercise have been shown to decrease the metabolic and hormonal effects of PCOS. Treatment regimens are based on protecting the endometrium from the effects of unopposed estrogen, reestablishing a regular menstrual cycle, preventing the metabolic syndrome and cardiovascular sequelae of PCOS, and providing support for ovulatory dysfunction in those anticipating pregnancy.

KEY POINTS:

  • ACOG Practice Bulletin updated based on recent data that letrozole outperforms clomiphene citrate for ovulation induction
    • Higher live-birth rate: 27.5% vs 10.1% (P=0.007) with odds ratio of 1.64 (95% CI, 1.32-2.04)
    • Higher ovulation rate: 61.7% vs 48.3% (P<0.001)
    • Higher clinical pregnancy rate: Odds ratio of 1.40 (95% CI, 1.18-1.65)
  • 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

Learn More – Primary Sources:

ACOG Practice Bulletin No. 194: Polycystic ovary syndrome

Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome

EJE: MANAGEMENT OF ENDOCRINE DISEASE: Morbidity in polycystic ovary syndrome

AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS, AMERICAN COLLEGE OF ENDOCRINOLOGY, AND ANDROGEN EXCESS AND PCOS SOCIETY DISEASE STATE CLINICAL REVIEW: GUIDE TO THE BEST PRACTICES IN THE EVALUATION AND TREATMENT OF POLYCYSTIC OVARY SYNDROME–PART 1

AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS, AMERICAN COLLEGE OF ENDOCRINOLOGY, AND ANDROGEN EXCESS AND PCOS SOCIETY DISEASE STATE CLINICAL REVIEW: GUIDE TO THE BEST PRACTICES IN THE EVALUATION AND TREATMENT OF POLYCYSTIC OVARY SYNDROME – PART 2

Polycystic Ovary Syndrome: Making the Diagnosis

An International Guideline for the diagnosis and management of polycystic ovary syndrome (PCOS) was released by the International PCOS Network (2018).  The International Guideline committees included participants from 37 societies and organizations covering 71 countries.  The International Guideline was developed through 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, ESHRE and the ASRM. This guideline provides needed definitional criteria to make an accurate diagnosis.

SUMMARY:

PCOS is a complex disorder characterized by varying degrees of ovulatory dysfunction, hyperandrogenism and metabolic disorders. It carries with it risk of cardiovascular disease and diabetes, as well as endometrial cancer.

KEY POINTS:

Diagnostic Criteria

The International Guideline Endorses the Rotterdam Criteria 

  • The Rotterdam Criteria requires two out of three of the following
    • Hyperandrogenism
    • Oligo or amenorrhea
    • Polycystic ovaries on ultrasound
  • Ultrasound not necessary for diagnosis when oligo/anovulation and hyperandrogenism present (however, will complete the phenotype)
  •  Adolescents
    • Both hyperandrogenism and oligo/anovulation must be present
    • Ultrasound not recommended

Diagnosing Hyperandrogenism

Clinical Diagnosis

  • History and physical exam findings of
    • 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

Laboratory Diagnosis

  • Use one of the following
    • Free testosterone
    • Free androgen index
    • 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
  • Lab testing for hyperandrogenism most useful when clinical findings unclear or absent
  • Routine screening for Cushing Syndrome in patients with hyperandrogenic chronic anovulation not indicated – should only occur if patients have coexisting signs
    • Buffalo hump | Abdominal Striae | Centripetal fat distribution | Hypertension
  • If androgen results are very high compared to lab reference ranges, consider neoplasia
  • The International Guideline recommends against  using AMH as a diagnostic marker for PCOS

Diagnosing Anovulation

  • When Irregular menstrual cycles are present, consider PCOS
  • 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

Ultrasound and Polycystic Ovarian Morphology

  • Do not use for <8 years post menarche
    • High incidence of multifollicular ovaries
  • Transvaginal approach preferred
    • 8 MHz transducer
  • Threshold (either ovary)
    • ≥20 follicles/ovary and/or
    • Ovarian volume ≥10 ml in either ovary

PCOS ICD10 Billing Code: E28.2

Other Diagnostic Considerations

Consider increased risk for metabolic syndrome and other causes of clinical findings  

  • 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

  • Obese women with PCOS who reduce their weight by 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 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
    • Strongly recommend weight loss, if appropriate, and regular exercise

Note: Nonclassic congenital adrenal hyperplasia (CAH) can mimic PCOS

  • Endocrine testing for nonclassic CAH
    • Screen for CAH with a fasting level of 17-OH progesterone in the morning in the follicular phase
    • If 17-OH progesterone is elevated (normal < 2 ng/mL) follow with an adrenocorticotropic hormone (ACTH) stimulation test
  • Genetic testing for nonclassic CAH
    • CAH is caused by mutations in both copies of the  CYP21A2 gene that codes for the 21-hydroxylase enzyme
    • Hundreds of mutations have been reported, with 12 pathogenic variants account for >90% of cases
    • 3 mutations  (p.V281L, p.P453S, p.P30L) are associated with the milder, nonclassic form
    • Nonclassic CAH is less severe because 20-50% of enzyme activity is still present and symptoms in women are similar to PCOS

Learn More – Primary Sources:

Monash University PCOS Program

ACOG Practice Bulletin No 194: Polycystic ovary syndrome

Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome

EJE: MANAGEMENT OF ENDOCRINE DISEASE: Morbidity in polycystic ovary syndrome

AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS, AMERICAN COLLEGE OF ENDOCRINOLOGY, AND ANDROGEN EXCESS AND PCOS SOCIETY DISEASE STATE CLINICAL REVIEW: GUIDE TO THE BEST PRACTICES IN THE EVALUATION AND TREATMENT OF POLYCYSTIC OVARY SYNDROME–PART 1

AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS, AMERICAN COLLEGE OF ENDOCRINOLOGY, AND ANDROGEN EXCESS AND PCOS SOCIETY DISEASE STATE CLINICAL REVIEW: GUIDE TO THE BEST PRACTICES IN THE EVALUATION AND TREATMENT OF POLYCYSTIC OVARY SYNDROME – PART 2