Endometrial Hyperplasia: Symptoms, Types, Causes and Treatment

Endometrial hyperplasia is a condition that can strike women at various stages of life, yet it remains underrecognized despite its close association with endometrial cancer. Understanding the symptoms, types, causes, and latest treatment options is essential for early detection and effective management. Below, we break down the key aspects of endometrial hyperplasia using the latest research and clinical guidelines.

Symptoms of Endometrial Hyperplasia

Endometrial hyperplasia often goes unnoticed until symptoms become bothersome or even alarming. Recognizing these symptoms early can prompt evaluation and timely intervention, preventing progression to more serious conditions such as endometrial carcinoma.

Symptom	Description	Prevalence/Notes	Sources
Abnormal Bleeding	Unusual uterine bleeding (heavy, irregular)	Most common symptom; includes menorrhagia, metrorrhagia	1 2 3 4 5
Heavy Periods	Increased flow or prolonged menstruation	Often significantly more common in EH patients	3 5
Amenorrhea	Absence of menstruation	Occasional; seen in about 1 in 6 cases	3
Blood Clots	Passage of clots during menstruation	Not unusual	3

Table 1: Key Symptoms

Understanding the Symptoms

Abnormal uterine bleeding is the hallmark symptom of endometrial hyperplasia. This can manifest in several ways:

• Menorrhagia: Excessive menstrual bleeding, both in quantity and duration, is a frequent complaint among affected women. This can become a source of distress, impacting daily activities and quality of life. Notably, the prevalence of heavy periods is over twice as high in women with endometrial hyperplasia compared to those with other uterine conditions or healthy controls 3 5.
• Metrorrhagia: Irregular bleeding that doesn’t follow the expected menstrual cycle is another common presentation, sometimes occurring between periods 3.
• Amenorrhea: While less common, some women experience a complete absence of menstruation, with about 16% of cases reporting this symptom 3.
• Blood Clots: Many women also notice the passage of clots during menstruation, reflecting the severity of bleeding 3.

Additional Clinical Features

Although abnormal bleeding is the most common symptom, a minority of women may experience no menstrual changes until hyperplasia is well-established. In postmenopausal women, any uterine bleeding is abnormal and should prompt evaluation 1 2. Women with a history of endocrine disorders or risk factors (discussed below) may be at increased risk and should be vigilant for these symptoms 5.

Types of Endometrial Hyperplasia

The classification of endometrial hyperplasia has evolved, but understanding the different types is crucial for assessing cancer risk and guiding treatment.

Type	Description	Cancer Risk	Sources
Hyperplasia without Atypia	Increased glands, normal cells	Low (1–5% progression)	1 6 7 8 14
Atypical Hyperplasia/EIN	Glandular crowding + abnormal cell appearance	High (up to 30–60% progress/coexist)	2 6 7 8 14
Simple vs Complex (Old WHO)	Degree of gland crowding (simple: mild; complex: marked)	Outdated; now merged into above two categories	2 6 8

Table 2: Types of Endometrial Hyperplasia

Modern Classification (WHO 2014)

The 2014 World Health Organization (WHO) classification simplified previous systems into two main categories 8 14:

• Hyperplasia without Atypia: This form shows a proliferation of endometrial glands but no abnormal cellular features. It is considered benign, with a very low risk (about 1–5%) of progression to cancer, especially if the hormonal imbalance that caused it is corrected 8.
• Atypical Hyperplasia/Endometrial Intraepithelial Neoplasia (EIN): This type shows both glandular crowding and cytologic atypia (abnormal cell features). It is considered premalignant, with up to 30% risk of progression to endometrial carcinoma if untreated, and up to 60% of cases may already have concurrent cancer at diagnosis 2 6 7 8.

Previous Classifications

Earlier systems, such as the 1994 WHO classification, subdivided hyperplasia into four groups (simple vs. complex, with or without atypia) based on glandular architecture and cellular features 2 8. However, due to poor reproducibility and clinical utility, these have largely been replaced by the two-category system 6 8.

Clinical Implications

• Non-atypical hyperplasia is generally managed conservatively.
• Atypical hyperplasia/EIN requires more aggressive management due to the high risk of cancer 7 8 14.

Causes of Endometrial Hyperplasia

Understanding what drives the development of endometrial hyperplasia helps inform both prevention and treatment. The primary cause relates to hormonal imbalance, but other contributing factors play important roles.

Cause	Mechanism/Pathway	Risk Enhancers	Sources
Unopposed Estrogen	Estrogen stimulates endometrial growth without progesterone opposition	Obesity, PCOS, anovulation, HRT, tamoxifen	1 7 8 13
Obesity	Increased peripheral estrogen production (aromatase)	Metabolic syndrome	8 9
Age >45	Increased risk with advancing age	Especially with abnormal bleeding	9
Infertility/Nulliparity	Associated with chronic anovulation	PCOS, other ovulatory disorders	9
Family History	Colorectal cancer (Lynch syndrome)	Genetic predisposition	8 9
Inflammation	Cytokine-driven promotion of hyperplasia	Chronic endometrial inflammation	10
Medications	Long-term tamoxifen, unopposed estrogen HRT	Breast cancer therapy, menopause	1 8

Table 3: Causes and Risk Factors

Hormonal Imbalance

The most significant cause of endometrial hyperplasia is prolonged exposure to estrogen without sufficient progesterone 1 7 8 13. Estrogen stimulates the endometrial lining to proliferate, while progesterone counteracts this growth and promotes shedding. In the absence of ovulation (as in polycystic ovary syndrome or perimenopause), progesterone levels remain low, and the endometrium becomes excessively thickened.

Key Risk Factors

• Obesity: Fat tissue converts androgens to estrogens, increasing estrogen exposure. Women with a BMI ≥90 kg are at significantly higher risk 8 9.
• Polycystic Ovary Syndrome (PCOS): Characterized by chronic anovulation, PCOS leads to persistent unopposed estrogen 8.
• Hormone Replacement Therapy (HRT): Postmenopausal women on estrogen-alone therapy are at risk; combined estrogen-progesterone therapy is protective 1 8.
• Tamoxifen Use: While effective for breast cancer prevention, tamoxifen acts as an estrogen agonist in the uterus, increasing hyperplasia risk 1 8.

Additional Contributing Factors

• Age: Incidence rises with age, particularly after 45 years and in postmenopausal women 9.
• Infertility/Nulliparity: Women who have never been pregnant or who have a history of infertility are at higher risk, likely due to more cycles of unopposed estrogen 9.
• Genetic Syndromes: Lynch syndrome (hereditary nonpolyposis colorectal cancer) increases the risk 8 9.
• Inflammation: Recent studies indicate that chronic inflammation and elevated cytokines (such as IL-1β, IL-6, TNF-α) promote the progression of hyperplasia to more severe forms, especially atypical hyperplasia 10.

Treatment of Endometrial Hyperplasia

Treatment aims to reverse abnormal endometrial proliferation, relieve symptoms, and reduce cancer risk. The approach depends on the type of hyperplasia, patient age, comorbidities, and desire for fertility preservation.

Type/Patient Group	First-line Treatment	Alternatives / Notes	Sources
Without Atypia	Progestin therapy (oral or IUD)	Weight loss, treat cause, monitor	1 4 7 8 13 14
With Atypia/EIN	Hysterectomy (total)	High-dose progestins if fertility desired + close monitoring	1 7 8 14
Fertility Preservation	High-dose progestins, LNG-IUS	Regular biopsy follow-up	7 11 14
Refractory/recurrent	Surgery	Investigational therapies	13 14

Table 4: Treatment Overview

Management of Hyperplasia Without Atypia

• Progestin Therapy: The mainstay of treatment is progestin, administered orally, via injection, or with a levonorgestrel-releasing intrauterine system (LNG-IUS). This therapy is highly effective, leading to regression in most cases 1 4 7 8 13 14.
• Lifestyle Modification: Weight loss and treatment of underlying endocrine or ovulatory disorders enhance efficacy 8.
• Surveillance: Regular follow-up with endometrial sampling (biopsy) is recommended to ensure resolution 14.

Management of Atypical Hyperplasia/EIN

• Hysterectomy: Due to the high risk of coexistent or future cancer, total hysterectomy is recommended for most women who do not desire future fertility 1 7 8 14.
• Fertility-Preserving Options: For younger women wishing to maintain fertility, high-dose progestin therapy (oral or LNG-IUS) can be considered, but only with close histological monitoring. Response rates are lower and risk of progression higher than for non-atypical cases 7 11 14.
• Surgical Details: When surgery is chosen, total (not supracervical) hysterectomy is essential to remove all at-risk tissue 8.

Special Considerations

• Persistent or Recurrent Disease: Women who do not respond to medical treatment or who have recurrent hyperplasia may require surgery 13 14.
• Other Treatments: Investigational therapies targeting estrogen receptors, growth factor pathways, or using agents like metformin are being explored, particularly for women with metabolic syndrome 13.
• Role of Biomarkers: Emerging research suggests that assessing hormone receptor status (estrogen/progesterone receptors) may help predict response to therapy, but this is not yet standard 6 12.

Conclusion

Endometrial hyperplasia is a common and clinically significant condition, serving as a precursor to endometrial carcinoma. Early recognition and appropriate classification are crucial for effective management and cancer prevention.

Key Takeaways:

• Abnormal uterine bleeding—especially heavy or irregular periods—is the most common symptom.
• Types are now classified as hyperplasia without atypia (low cancer risk) and atypical hyperplasia/EIN (high cancer risk).
• Causes center on unopposed estrogen, with risk increased by obesity, PCOS, certain medications, and genetic factors.
• Treatment depends on type and patient goals: progestins for non-atypical, hysterectomy for atypical (unless fertility preservation is needed), with lifestyle and risk-factor modification always important.

Timely diagnosis and personalized management can prevent progression to cancer and preserve quality of life and fertility for many women. If you or someone you know is experiencing abnormal uterine bleeding or has risk factors, prompt medical evaluation is essential.