Introduction

Abnormal uterine bleeding (AUB) such as heavy or irregular vaginal bleeding of any cause, is the most common reason for referral to a gynecologist, and frequently leads to an invasive diagnostic test such as endometrial biopsy or hysteroscopy. In a large study of premenopausal women with AUB referred for an endometrial biopsy, the prevalence of complex endometrial hyperplasia or cancer was 3.0%.

Endometrial hyperplasia is a precursor to endometrial cancer and is thought to result from persistent, prolonged, unopposed estrogenic stimulation of the endometrium, the most common cause being a succession of anovulatory cycles. Anovulation occurs most often during the perimenopause, or in women with polycystic ovarian syndrome or obesity. An important distinction in the evaluation of hyperplasia is whether or not nuclear atypia is present. Women with complex hyperplasia with atypia are at risk of progression to endometrial cancer and as many as 28% of cases will progress over time to cancer and up to 43% of cases have unrecognized concurrent carcinoma at the time of biopsy.

Commonly recognized risk factors for endometrial cancer include age, obesity, nulliparity, infertility, and late-onset menopause. Family history of hereditary nonpolyposis colorectal cancer is another risk factor. Diabetes and hypertension are frequently associated with endometrial cancer, while smoking and use of combined oral contraceptive pill are thought to be protective.

Over the past 2 decades there has been global recognition of increasing levels of obesity. At the same time, there is epidemiological evidence of increased incidence of endometrial cancer. Several systematic reviews have shown an association between obesity and endometrial cancer. However, given that the majority of endometrial cancer occurs in postmenopausal women, it has not been widely recognized that obesity is a significant risk factor for endometrial hyperplasia and cancer in young, symptomatic, premenopausal women.

Developing a greater understanding of the leading risk factors for premenopausal women would lead to improved clinical pathways from primary to secondary care and improved targeting of invasive diagnostic testing. The objective of the current study was to evaluate the association of body mass index (BMI) and endometrial complex hyperplasia or cancer in premenopausal women with AUB who had an endometrial biopsy, adjusting for clinical and demographic factors. We hypothesized that obese women would be more likely to have complex hyperplasia or cancer compared to normal-weight women.

Materials and Methods

This was a retrospective cohort study including women age ≤55 years who had an endometrial biopsy at Auckland District Health Board from 2008 through 2014. Women were included if they had a history of AUB (clinical diagnosis by the referring doctor, including structural and nonstructural causes) and were not menopausal (either recorded as menopausal in the clinical record, or amenorrhea ≥6 months, or serum follicle-stimulating hormone level >20 IU/L). Women were excluded if they were known prior to 2008 to have had endometrial cancer. Women who were not residents of Auckland District Health Board were also excluded due to the referral pattern of surrounding district health boards to Auckland for tertiary cancer services. The primary study outcome was histologic diagnosis of endometrial biopsy of complex hyperplasia, complex atypical hyperplasia, or endometrial cancer, as stated in the pathology report.

Participants were identified from the hospital laboratory database of all inpatient and outpatient samples. The National Health Identifier was used to directly link with the hospital electronic medical records and clinical and demographic data were collected. The following clinical variables were collected: age, BMI, parity, self-reported use of hormone therapy, menstrual history, infertility (>12 months), medical history (smoking, diabetes, breast cancer, colorectal cancer), and family history (breast, colorectal, or endometrial cancer). Recent investigations (hemoglobin, pelvic ultrasound scan) and subsequent hysterectomy were also recorded.

Endometrial biopsy was performed by Pipelle (Pipelle De Cornier, Laboratoire CCD, Paris, France), sharp curettage, or both. If >1 biopsy was performed within 6 months, the one resulting in the most serious diagnosis was considered the final outcome. If a hysterectomy was performed within 6 months of the biopsy, the hysterectomy histology was considered the final outcome. The exception to this was in the setting where the biopsy reported hyperplasia, there was clear documentation that the patient was treated with progestogen in the interim, and the hysterectomy histology was normal. In that case, due to the known effectiveness of progestogen in treating endometrial hyperplasia, then the original biopsy result was considered the final outcome.

Self-reported ethnicity was collected at hospital registration with a standard New Zealand (NZ) census question. The concept of ethnicity adopted by Statistics NZ is a social construct of group affiliation and identity. The present statistical standard for ethnicity states that ethnicity is the ethnic group or groups that people identify with or believe they belong to; thus, ethnicity is self-perceived and people can belong to >1 ethnic group. If >1 ethnicity was reported, it was prioritized using the NZ Ministry of Health protocol.

Height and weight measurements used for calculating BMI were measured within 1 year of biopsy. Standard World Health Organization criteria were used to categorize BMI (normal 18.5–24.9 kg/m ² , overweight 25–29.9 kg/m ² , obese ≥30 kg/m ² ). Socioeconomic status was estimated using the NZ deprivation score based on recorded maternal place of residence. Deprivation centiles (1–10) were condensed into quintile scores from 1 (least deprived) to 5 (most deprived).

Materials and Methods

This was a retrospective cohort study including women age ≤55 years who had an endometrial biopsy at Auckland District Health Board from 2008 through 2014. Women were included if they had a history of AUB (clinical diagnosis by the referring doctor, including structural and nonstructural causes) and were not menopausal (either recorded as menopausal in the clinical record, or amenorrhea ≥6 months, or serum follicle-stimulating hormone level >20 IU/L). Women were excluded if they were known prior to 2008 to have had endometrial cancer. Women who were not residents of Auckland District Health Board were also excluded due to the referral pattern of surrounding district health boards to Auckland for tertiary cancer services. The primary study outcome was histologic diagnosis of endometrial biopsy of complex hyperplasia, complex atypical hyperplasia, or endometrial cancer, as stated in the pathology report.

Participants were identified from the hospital laboratory database of all inpatient and outpatient samples. The National Health Identifier was used to directly link with the hospital electronic medical records and clinical and demographic data were collected. The following clinical variables were collected: age, BMI, parity, self-reported use of hormone therapy, menstrual history, infertility (>12 months), medical history (smoking, diabetes, breast cancer, colorectal cancer), and family history (breast, colorectal, or endometrial cancer). Recent investigations (hemoglobin, pelvic ultrasound scan) and subsequent hysterectomy were also recorded.

Endometrial biopsy was performed by Pipelle (Pipelle De Cornier, Laboratoire CCD, Paris, France), sharp curettage, or both. If >1 biopsy was performed within 6 months, the one resulting in the most serious diagnosis was considered the final outcome. If a hysterectomy was performed within 6 months of the biopsy, the hysterectomy histology was considered the final outcome. The exception to this was in the setting where the biopsy reported hyperplasia, there was clear documentation that the patient was treated with progestogen in the interim, and the hysterectomy histology was normal. In that case, due to the known effectiveness of progestogen in treating endometrial hyperplasia, then the original biopsy result was considered the final outcome.

Self-reported ethnicity was collected at hospital registration with a standard New Zealand (NZ) census question. The concept of ethnicity adopted by Statistics NZ is a social construct of group affiliation and identity. The present statistical standard for ethnicity states that ethnicity is the ethnic group or groups that people identify with or believe they belong to; thus, ethnicity is self-perceived and people can belong to >1 ethnic group. If >1 ethnicity was reported, it was prioritized using the NZ Ministry of Health protocol.

Height and weight measurements used for calculating BMI were measured within 1 year of biopsy. Standard World Health Organization criteria were used to categorize BMI (normal 18.5–24.9 kg/m ² , overweight 25–29.9 kg/m ² , obese ≥30 kg/m ² ). Socioeconomic status was estimated using the NZ deprivation score based on recorded maternal place of residence. Deprivation centiles (1–10) were condensed into quintile scores from 1 (least deprived) to 5 (most deprived).

Results

The study cohort comprised 916 women who met the inclusion and exclusion criteria ( Figure 1 ). Half of the women were obese. Obese women were more likely to be <40 years old, of Māori and Pacific ethnicity, and residing in areas of high deprivation. Characteristics of participants are shown in Table 1 .

Flow chart of participants

Flow diagram of participant selection. Some participants may have had >1 exclusion criteria.

ADHB , Auckland District Health Board.

Wise et al. BMI and endometrial pathology in premenopause. Am J Obstet Gynecol 2016 .

Table 1

Characteristics of participants

	BMI <30		BMI ≥30
	N = 465	%	N = 451	%
Demographic characteristics
Age, y
Mean ± SD	43.7 ± 6.4		42.0 ± 7.2
<40	87	18.7	137	30.4
40–44	139	29.9	119	26.4
45–49	163	35.0	137	30.4
50–55	73	15.7	57	12.6
Ethnicity
European	158	34.0	82	18.2
Māori	36	7.7	80	17.8
Pacific	18	3.9	213	47.3
Indian	83	17.8	35	7.8
Asian	112	24.1	22	4.9
Other	58	12.5	18	4.0
NZ deprivation score
1–2	44	12.6	16	4.9
3–4	65	18.7	52	15.9
5–6	78	22.4	56	17.1
7–8	87	25.0	88	26.9
9–10 a	74	21.3	115	3
Weight, kg
Mean ± SD	65.9 ± 10.2		104.8 ± 24.5
Clinical characteristics
Menstrual history
Mean duration of AUB, y (mean ± SD)	3.4 ± 4.1		3.8 ± 5.4
Menstrual cycle regularity
Regular	203	44.7	157	35.4
Irregular	209	46.0	254	57.2
Menstrual cycle duration, d
<7	211	47.0	170	38.6
7–14	83	18.5	78	17.7
>14	53	11.8	80	18.2
Intermenstrual bleeding
Yes	131	28.8	82	18.6
Hormonal therapy (current, recent)
COCP	29	6.2	15	3.3
Progestogen	112	24.1	170	37.7
Tamoxifen	3	0.6	2	0.4
Pregnancy history
Nulliparity	69	14.8	67	14.9
Infertility	20	4.5	33	7.6
Medical history
Diabetes	26	5.7	63	14.0
Breast cancer	8	1.7	7	1.6
Colorectal cancer	1	0.2	1	0.2
Smoking (current)	50	10.9	92	20.7
Family history of cancer
Endometrial	10	2.2	14	3.1
Breast	21	4.5	24	5.3
Colorectal	19	4.1	10	2.2
Anemia
Yes	148	32.9	202	46.6
Pelvic ultrasound scan
Submucous fibroid	35	7.5	18	4.0
Polyp	33	7.1	32	7.1
Endometrial thickness, mm
Mean	16.5 ± 44.6		26.0 ± 126.5
≥12 mm	117	38.0	156	49.8

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