Endometrial Hyperplasia – Current Nomenclature and Treatment

SUMMARY: 

Endometrial intraepithelial neoplasia (EIN) is the precursor of type I endometrioid adenocarcinoma. Distinguishing between hyperplasia and a precancerous lesion is important in optimizing management. 

Disease Categories  

• Benign endometrial hyperplasia (benign), a diffuse condition due to prolonged estrogen effect 
  • Treatment is hormonal therapy 
• Endometrial intraepithelial neoplasia (EIN) 
  • Premalignant 
  • Focal abnormality progressing to diffuse involvement  
  • Treatment can be hormonal therapy or surgery 
• Endometrial adenocarcinoma, endometrioid type, well differentiated (malignant), a focal abnormality progressing to diffuse 
  • Treatment is surgical 

Note: the above is the system developed by the International Endometrial Collaborative Group | Other classification systems exist and ACOG does not endorse a particular EIN classification system

Criteria Used for diagnosing EIN 

• Architectural change with area of glands greater than stroma 
• Cytologic abnormality in area of architectural change 
• Size of abnormal area  
• Not a polyp, area of repair, secretory endometrium (excludes mimics) 
• Not carcinoma (excludes cancer) 

Detecting Concurrent Carcinoma  

• Risk of endometrial cancer in hysterectomy specimens is 30% to 50%   
• Methods for Detecting Concurrent Carcinoma  
  • Hysteroscopic-guided uterine sampling is recommended for diagnosis  
  • In-office suction endometrial sampling may miss pathology  
• Avoid methods yielding crushed or cauterized samples  

Surgical Management of EIN  

• Hysterectomy is the definitive treatment   
• Supracervical hysterectomy is not advised   

Considerations for Oophorectomy  

• Oophorectomy decision should be patient-centered, weighing risks and benefits  
• Intraoperative assessment for occult carcinoma may guide surgical decisions  

Intraoperative Assessment  

• Assess uterine specimens for occult carcinoma   
• Assessment should be directed by qualified pathologists and experienced surgeons  
• Consultation with a gynecologic oncologist depending on clinical scenario and availability   

Morcellation – Proceed with Caution 

• If morcellation is required, use a contained environment such as a bag   
• Note that morcellation can affect pathology evaluation   

Endometrial Ablation  

• Not recommended   
• High persistence | Increased recurrence rates | May complicate evaluation of future bleeding episodes  

Nonsurgical Management of EIN 

Progestational Agents 

• Recommend progestational agents for patients not suitable for hysterectomy  
• LNG-IUD vs Oral Progestins  
  • Data on the superiority of administration methods are limited  
  • LNG-IUD may have a higher regression rate compared to oral progestins alone  
  • Combined intrauterine and oral progestins may be more effective  
• Oral Progestin Formulations  
  • No evidence favors one oral progestin formulation over another  
  • Megestrol acetate or medroxyprogesterone acetate are commonly used  
• Follow-up  
  • Repeat histologic assessment within 3 to 6 months for treatment response  
  • Long-Term Maintenance Therapy  
  • Consider long-term progestational agent maintenance for high-risk patients  
  • Consider risk factors (e.g., age, late menopause, and obesity)  
  • Optimal duration of maintenance therapy remains uncertain  

Future Fertility  

• Fertility-sparing therapy may be an option with assisted reproductive technology  
• Pregnancy rates range from 26.3% to 41.0% with progestational agents  
• Active management for achieving pregnancy should be discussed  

Counseling on Lifestyle Modifications  

• Weight Loss and Glycemic Control  
• Obesity is a significant risk factor   
• Lifestyle modification with weight loss and glycemic control improves overall health  
• Bariatric surgery can be an appropriate intervention among selected patients  
• Weight loss can enhance the response to progestin treatment  
• Telemedicine and Text-Based Interventions  

KEY POINTS: 

• The EIN system appears to increase reproducibility and reduce subjective, descriptive interpretation of pathology 
• Hysteroscopy with directed biopsy of any discrete lesions is the best way to confirm a premalignant endometrial lesion and to exclude endometrial carcinoma 
• Both suction curettage and dilation and curettage have significant sampling limitations 
• Hysterectomy is the definitive therapy for EIN: Abdominal, vaginal or minimally invasive, with or without removal of fallopian tubes and ovaries 
  • Supracervical hysterectomy is contraindicated 
  • Endometrial ablation should not be performed due to high recurrence rates and difficulty evaluating bleeding etiologies 
• Medical treatment, using progestins, can be offered to patients who wish to retain fertility, desire uterine retention, or have multiple medical comorbidities 
  • Medroxyprogesterone acetate and megestrol acetate are most commonly used 
  • The 52 mg levonorgestrel containing IUD provides another option 
  • Regression rates approach 90% with any of the above 
• Discussion of lifestyle changes particularly in the setting of obesity can be a part of management with shared decision making  
• Telemedicine and text-based interventions can assist patients with weight loss  

Learn More – Primary Sources 

Management of Endometrial Intraepithelial Neoplasia or Atypical Endometrial Hyperplasia | ACOG 

Is Progestin-Based Contraception Linked to Depression?

BACKGROUND AND PURPOSE: 

• Weight gain, acne, mood changes and depression have been listed as possible side effects of progestin-based contraceptive methods  
• Worly et al. (Contraception, 2018) performed a systematic review to measure the association between progestin-only contraception and depression 

METHODS: 

• Systematic Review 
• Search included progestin-only contraception and depression, focusing on externally validated depression measures 
• Study quality was evaluated using USPSTF and the Cochrane Risk of Bias Tools 
• Study questions were as follows 
  • Is there an association or causative link between progestin-only hormonal contraception and depression? 
  • Does the type of progestin or route of administration influence such an association? 
  • Are there certain populations (e.g., adolescents, postpartum patients or women with a history of depression) in which this association exists?

RESULTS: 

• 26 studies met inclusion criteria 
  • 5 randomized controlled trials 
  • 11 cohort studies 
  • 10 cross-sectional studies 
• There was minimal association between progestin-only methods and depression 
• Subdermal implants  
  • In five low-quality, high-risk-of-bias studies, there was no correlation between depression and subdermal implants  
• Levonorgestrel IUD  
  • Four out of five varying-quality and medium-risk-of-bias studies there was no association  
  • One large population based study found an association, but was retrospective with a weak association and “evidence is unimpressive”  
• Two progestin-only contraceptive pill studies with varying levels of quality and bias indicate no increase in depression scores 
  • One study demonstrated a lower depression scores but had a small sample size 
  • One larger population based study did find slight increased risk but retrospective and higher dose formulations   
• Medroxyprogesterone acetate intramuscular injection  
  • Trials had varying levels of quality and bias, but overall show no difference in depression 

CONCLUSION: 

• Difficult to derive definitive conclusions, but currently, there is no significant evidence to support an increased risk for increased depression with progestin contraception 
• A minority of users may experience depression, but this effect was not seen in more robust studies  
• Adolescents were likewise not found to have increased risk for depression  
• It is important to continue to measure associations between progestin contraception and mental health 

Learn More – Primary Sources:  

The relationship between progestin hormonal contraception and depression: a systematic review 

Short Cervix and Risk for Preterm Birth: Do Pessaries Work? 

PURPOSE:

This study by Xin-Hang et al. (Scientific Reports, 2017) sought to explore the effectiveness of using cervical pessaries to prevent preterm birth and perinatal morbidity and mortality in asymptomatic women with a singleton pregnancy and a short cervix (length ≤25 mm).

METHODS:

Systematic Review and Meta-Analysis

RESULTS:

A total of 1,412 women were analyzed. Cervical pessary placement was not shown to reduce the risk of spontaneous preterm birth <34 weeks’ gestation (RR 0.71; 95%CI, 0.21–2.43, P = 0.59). Cervical pessary placement was not associated with any maternal or neonatal adverse effects. The authors concluded that although analysis of these trials did not indicate that cervical pessaries decrease the risk of spontaneous preterm birth, large randomized controlled trials are needed to confirm the findings due to study limitations.  Such limitations include the potential bias due to inability to blind researchers and providers.  Furthermore, only 3 studies could be included and therefore the sample size does not allow for proper analysis of cofounding variable (for example BMI and varying cervical lengths). Finally, the use of progestogens in combination with pessaries remains to be determined.

Learn More – Primary Sources:

Cervical Pessary for Prevention of Preterm Birth: A Meta-Analysis