European Journal of Cardiovascular Medicine

Abnormal uterine bleeding (AUB) is defined as bleeding from the uterine corpus that is abnormal in regularity, volume, frequency or duration, and includes bleeding between menstrual periods and bleeding after menopause [1,2]. According to the International Federation of Gynecology and Obstetrics (FIGO), normal menstruation in non-pregnant women of reproductive age recurs every 24 to 38 days, lasts up to 8 days, and shows a cycle-to-cycle variation of not more than 7 to 9 days [3]. The traditional objective threshold for heavy menstrual bleeding is a monthly blood loss exceeding 80 mL [4], although in everyday practice the diagnosis rests mainly on the woman's own perception of excessive loss that interferes with her physical, social and emotional well-being.

AUB is among the most frequent reasons for gynaecological consultation, and it accounts for a large share of endometrial sampling procedures and hysterectomies performed worldwide [5,6]. A considerable proportion of women experience symptoms of excessive menstrual loss at some time during their reproductive life [7]. Beyond the physical morbidity, which includes iron-deficiency anaemia, AUB is associated with reduced health-related quality of life, absenteeism from work and substantial health-care costs [8,9]. In low- and middle-income settings, where nutritional anaemia is already highly prevalent, the consequences of chronic blood loss are expected to be even more pronounced.

For many years the studies used overlapping and confusing terms such as menorrhagia, metrorrhagia, polymenorrhoea and dysfunctional uterine bleeding (DUB), the last being a diagnosis of exclusion applied when no structural or systemic cause could be identified [10]. To standardise nomenclature, FIGO introduced the PALM-COEIN system in 2011, which divides the causes of AUB into structural entities that can be defined by imaging or histopathology (Polyp, Adenomyosis, Leiomyoma, Malignancy and hyperplasia) and non-structural entities (Coagulopathy, Ovulatory dysfunction, Endometrial, Iatrogenic, and Not yet classified. The American College of Obstetricians and Gynecologists has likewise recommended that the older terminology be abandoned in favour of descriptive terms [11].

Normal endometrial bleeding depends on a delicate balance between ovarian steroid hormones, endometrial vascular integrity, local haemostatic mechanisms and the regulation of endometrial repair [12,13]. When this balance is disturbed, as in anovulation with persistent unopposed oestrogen stimulation, the endometrium may show disordered proliferation, hyperplasia and, ultimately, neoplastic transformation [14,15]. The pattern of underlying pathology varies markedly with age: anovulatory cycles are common in adolescents and in the perimenopause, structural lesions such as leiomyoma and polyp predominate in the middle reproductive years, and atrophy or malignancy account for most cases of postmenopausal bleeding [16].

In India, AUB is a leading cause of gynaecological outpatient attendance, and many women present late, with advanced anaemia, after prolonged self-medication or after failure of treatment at peripheral centres [17]. Several hospital-based histopathological studies from different regions of the country have documented the pattern of endometrial pathology in AUB [18-22]. These studies broadly agree that the fourth and fifth decades are the most affected, that functional endometrial patterns are the commonest findings, and that hyperplasia and carcinoma, though less frequent, are not negligible; however, the proportions vary with the age mix of the study population, the method of tissue sampling and the referral pattern of the institution.

Endometrial sampling, followed by histopathological examination, continues to be the reference method for excluding hyperplasia and endometrial carcinoma in women with AUB [23,24]. The American College of Obstetricians and Gynecologists recommends tissue sampling in women aged 45 years or older with AUB, and in younger women with unopposed oestrogen exposure, failed medical management or persistent bleeding. In postmenopausal bleeding, transvaginal sonographic measurement of endometrial thickness may help to select women for biopsy [25,26], but histology remains decisive.

Because the clinical and histopathological profile of AUB differs between populations and institutions, local data are valuable for planning investigation and management protocols. The present study was therefore undertaken to describe the clinical profile of women with AUB attending a tertiary care hospital, to determine the spectrum of endometrial and associated uterine histopathology, and to correlate the histological findings with age and the pattern of bleeding.

1.1 Aim and objectives

To study the demographic and clinical profile of women presenting with abnormal uterine bleeding. To determine the histopathological spectrum of endometrium in endometrial biopsy and hysterectomy specimens. To correlate the histopathological findings with age and bleeding pattern, and to categorise the aetiology by the FIGO PALM-COEIN system.

.1 Study design, setting and period

This was a hospital-based, cross-sectional observational study conducted jointly by the Department of Obstetrics and Gynaecology and the Department of Pathology of a tertiary care teaching hospital in India over a period of 12 months, from January 2015 to December 2015. The study was approved by the Institutional Ethics Committee and written informed consent was obtained from every participant.

2.2 Sample size

The sample size was calculated using the formula n = Z²pq/d², taking an anticipated proportion of a given pathology of 20%, an absolute precision (d) of 5% and a confidence level of 95%, which gave a minimum of 246 women. To allow for inadequate or unsuitable samples, 300 consecutive eligible women were enrolled.

2.3 Inclusion and exclusion criteria

Inclusion criteria: women of any age presenting with abnormal uterine bleeding as defined by FIGO [3], who underwent endometrial sampling (dilatation and curettage or endometrial aspiration biopsy) or hysterectomy for the same complaint, and who gave informed consent.

Exclusion criteria:

• Pregnancy-related bleeding (abortion, ectopic pregnancy, gestational trophoblastic disease) and postpartum bleeding.
• Visible organic lesions of the vulva, vagina or cervix on speculum examination, including cervical carcinoma.
• Women who had received hormonal therapy or anticoagulants during the preceding three months.
• Known case of endometrial carcinoma on treatment, and women with pelvic malignancy of non-uterine origin.

2.4 Data collection

A pre-designed proforma was used to record age, parity, menopausal status, pattern and duration of bleeding, associated symptoms, past medical and gynaecological history, and use of an intrauterine contraceptive device (IUCD). General and systemic examination, followed by abdominal, speculum and bimanual pelvic examination, was performed. Body mass index (BMI) was calculated, and obesity was defined as BMI of 25 kg/m² or more, as appropriate for Asian populations. The bleeding patterns were labelled according to the operational definitions shown in Table 1.

Table 1: Operational definitions of bleeding patterns used in the study

Investigations included complete blood count with haemoglobin estimation, platelet count, bleeding and clotting time, thyroid-stimulating hormone (TSH), urine pregnancy test and random blood sugar. Anaemia was defined as a haemoglobin level below 12 g/dL [27] and graded as mild (10-11.9 g/dL), moderate (7-9.9 g/dL) or severe (<7 g/dL). Transvaginal or transabdominal ultrasonography was performed in all women to assess endometrial thickness and to detect uterine and adnexal pathology.

2.5 Tissue sampling and histopathological examination

Endometrial tissue was obtained by dilatation and curettage or endometrial aspiration biopsy in women who fulfilled the indications for sampling (age 40 years or above, postmenopausal bleeding, failed medical treatment, or persistent bleeding), and from the uterus in women who underwent hysterectomy for AUB with or without fibroids. Hysterectomy specimens were opened, the endometrium and myometrium were examined grossly, and representative sections were taken from the endometrium, myometrium, cervix and any focal lesion. All tissue was fixed in 10% neutral buffered formalin, processed routinely, embedded in paraffin, and sections of 4-5 µm thickness were stained with haematoxylin and eosin.

Slides were examined independently by two pathologists, and disagreements were resolved by consensus. Cyclical endometrium was dated according to the criteria of Noyes and colleagues [28]. Endometrial hyperplasia was classified into simple and complex hyperplasia, with or without atypia, as per the World Health Organization classification [29,30], and atypical hyperplasia was considered equivalent to endometrial intraepithelial neoplasia (EIN). Specimens with scanty tissue insufficient for a reliable opinion were labelled as inadequate. The cause of AUB in each woman was assigned a single primary category according to the PALM-COEIN classification based on a combination of clinical, imaging and histological findings.

2.6 Statistical analysis

Data were entered into Microsoft Excel and analysed with SPSS software (version 20.0, IBM Corp., Armonk, NY). Categorical variables are expressed as numbers and percentages, and continuous variables as mean ± standard deviation. The chi-square test (or Fisher's exact test when expected cell counts were less than five) was used to compare proportions, and a p value of less than 0.05 was considered statistically significant.

A total of 300 women with AUB who satisfied the eligibility criteria were included. Endometrial tissue was available from curettage or endometrial biopsy in 216 women (72.0%) and from hysterectomy specimens in 84 women (28.0%).

3.1 Demographic profile

The age of the women ranged from 15 to 62 years, with a mean of 38.6 ± 9.8 years. As shown in Table 2 and Figure 1, the maximum number of women belonged to the 40-49 year age group (34.0%), closely followed by the 30-39 year group (32.0%); together these two decades accounted for two-thirds of all cases. Adolescents (<20 years) formed only 4.0% of the sample. Most women were multiparous, and 276 (92.0%) were still in the reproductive or perimenopausal period, while 24 (8.0%) were postmenopausal.

Table 2: Demographic profile of women with abnormal uterine bleeding (n=300)

Mean age 38.6 ± 9.8 years (range 15-62 years).

3.2 Clinical presentation

Menorrhagia was the most frequent presenting complaint (35.0%), followed by menometrorrhagia (16.0%), metrorrhagia (14.0%) and polymenorrhoea (13.0%). Postmenopausal bleeding was the presenting complaint in 24 women (8.0%) (Table 3). The duration of symptoms was less than six months in 42.0% of women, but 28.0% had been symptomatic for more than one year (Table 4).

Table 3: Pattern of abnormal uterine bleeding (n=300)

Anaemia (haemoglobin <12 g/dL) was present in 246 women (82.0%), and 168 women (56.0%) had moderate or severe anaemia. Only 18.0% had a normal haemoglobin level. Details are provided in Table 4.

Table 4: Duration of symptoms and haemoglobin status (n=300)

3.3 Associated factors and ultrasonographic findings

Obesity was the commonest associated factor (37.0%), followed by polycystic ovarian syndrome (PCOS) in 11.0% and hypertension in 10.0% of women. Hypothyroidism was found in 9.0% and a copper IUCD was in situ in 7.0% (Table 5). Ultrasonography was normal in 38.0% of women. The commonest abnormal findings were thickened endometrium (22.0%) and uterine fibroids (14.0%), whereas polyps and adenomyosis were suspected in 7.0% and 6.0%, respectively (Table 6).

Table 5: Associated medical and gynaecological factors (n=300)

More than one factor may be present in the same woman.

Table 6: Ultrasonographic findings (n=300)

3.4 Histopathological spectrum of the endometrium

The histopathological diagnoses are listed in Table 7 and Figure 2. Normal cyclical endometrium (proliferative 22.0% and secretory 18.0%) accounted for 40.0% of cases, making it the largest group. Disordered proliferative endometrium was seen in 14.0%, irregular shedding in 4.0% and endometrial hyperplasia in 54 women (18.0%), of whom 48 (16.0%) had hyperplasia without atypia (simple 10.0%, complex 6.0%) and 6 (2.0%) had atypical hyperplasia/EIN. Endometrial adenocarcinoma was diagnosed in 9 women (3.0%), all of the endometrioid type. Atrophic endometrium (7.0%), endometrial polyp (6.0%) and chronic endometritis (5.0%) were the other notable findings. Nine samples (3.0%) were inadequate for opinion.

Table 7: Histopathological spectrum of endometrium in abnormal uterine bleeding (n=300)

3.5 Age-wise distribution of histopathological findings

The histological pattern changed significantly with age (Table 8). Normal cyclical endometrium and disordered proliferative patterns predominated in women below 40 years, whereas hyperplasia, atrophy and carcinoma were concentrated in women aged 40 years and above. Hyperplasia was present in 36 of 138 women aged 40 years or older (26.1%) compared with 18 of 162 younger women (11.1%), a statistically significant difference (χ² = 11.32, df = 1, p < 0.001). All nine carcinomas occurred in women aged 40 years or more: three in the 40-49 year group and six in women aged 50 years or above. The overall risk of carcinoma in premenopausal women was 1.1% (3 of 276).

Table 8: Age-wise distribution of histopathological diagnoses (n=300)

χ² test for hyperplasia, ≥40 vs <40 years: χ² = 11.32, p < 0.001.

3.6 Correlation of bleeding pattern with histopathology

Menorrhagia was associated mainly with normal cyclical endometrium (54.3%) and hyperplasia (20.0%), while menometrorrhagia showed the highest proportion of hyperplasia (43.8%) and included three of the carcinomas (Table 9). Polymenorrhoea and oligomenorrhoea were chiefly associated with cyclical or disordered proliferative endometrium. All six carcinomas in the postmenopausal group presented with postmenopausal bleeding.

Table 9: Correlation of bleeding pattern with histopathological diagnosis

Cyc., normal cyclical endometrium; Func., disordered proliferative/irregular shedding; Hyp., hyperplasia; Atr., atrophic; Endo., chronic endometritis; Pol., polyp; Ca, adenocarcinoma; Inad., inadequate.

3.7 Postmenopausal bleeding

Twenty-four women (8.0%) presented with postmenopausal bleeding. Atrophic endometrium was the commonest cause (62.5%), followed by adenocarcinoma in six women (25.0%) and endometrial polyp in three (12.5%) (Table 10).

Table 10: Histopathology in women with postmenopausal bleeding (n=24)

3.8 Uterine pathology in hysterectomy specimens

Eighty-four women underwent hysterectomy. Leiomyoma was found in 45 specimens (53.6%), either alone (39.3%) or associated with adenomyosis (14.3%), and adenomyosis was present in 33 specimens (39.3%) in all (Table 11). Six hysterectomy specimens (7.1%) showed endometrial carcinoma, and the myometrium was unremarkable in 12 (14.3%).

Table 11: Myometrial and other uterine pathology in hysterectomy specimens (n=84)

3.9 Aetiology according to the PALM-COEIN classification

When the women were classified according to PALM-COEIN, the structural group (PALM) accounted for 53.0% of cases, with malignancy and hyperplasia (21.0%) and leiomyoma (15.0%) being the largest components. Among the non-structural causes (COEIN), ovulatory dysfunction was the leading category (25.0%), followed by endometrial causes (12.0%), including chronic endometritis and atrophy (Table 12).

Table 12: Classification of the cause of AUB by the FIGO PALM-COEIN system (n=300)

Atrophic endometrium in postmenopausal women is included under category E.

Abnormal uterine bleeding is a heterogeneous condition whose causes range from normal-variant anovulation to endometrial carcinoma. This study of 300 women in a tertiary care hospital describes its clinical profile and histopathological spectrum, and shows that although functional and benign causes account for most cases, hyperplasia and malignancy form a significant minority that cannot be identified without tissue diagnosis.

The mean age of our patients was 38.6 years, and the fourth and fifth decades together contributed 66.0% of cases, with the 40-49 year group the largest. A similar concentration of AUB in the late reproductive and perimenopausal years has been reported by several Indian authors  and in studies from neighbouring countries [31,32]. This age distribution has a sound biological explanation. In the perimenopausal years, follicular depletion leads to frequent anovulatory cycles, with persistent oestrogen and inadequate progesterone, and the resulting endometrium is prone to irregular shedding, hyperplasia and heavy bleeding. Adolescents were few in our series (4.0%), which probably reflects the tertiary referral nature of the hospital, because most adolescent anovulatory bleeding settles with medical management at primary or secondary level. Multiparity (72.0%) was a feature of the majority of our patients, as in other Indian series and is consistent with the social setting in which women complete their families early and present when menstrual problems begin in the fourth decade.

Menorrhagia was the most common presentation (35.0%) in our study, and it is also the leading complaint in many hospital-based Indian and South Asian studies [18,19,31]. Menometrorrhagia (16.0%) and metrorrhagia (14.0%) came next. The fact that menometrorrhagia and metrorrhagia carried the highest rates of hyperplasia and carcinoma in the present study agrees with the long-standing teaching that irregular, unpredictable bleeding in a woman over 40 deserves a lower threshold for endometrial sampling than cyclical heavy bleeding.

Anaemia was extremely common (82.0%), and more than half of the women had moderate or severe anaemia. This reflects the cumulative effect of chronic menstrual blood loss on a background of nutritional iron deficiency, and the fact that 28.0% of women had been symptomatic for over a year before seeking tertiary care. Such delay is well recognised in Indian practice [17], and the impact of AUB on quality of life, working capacity and health-care expenditure is considerable. These findings highlight the need for early detection and iron supplementation at the primary-care level, and for community education that heavy menstrual bleeding is not a normal condition to be tolerated.

Obesity (37.0%) and PCOS (11.0%) were the commonest associated conditions, and both are mechanisms of chronic anovulation and increased peripheral conversion of androgens to oestrone, leading to unopposed oestrogenic stimulation of the endometrium. The occurrence of hypothyroidism in 9.0% of our patients underlines the value of routine thyroid function testing in women with AUB, since thyroid dysfunction is a treatable systemic cause that may be missed otherwise. Ultrasonography was normal in 38.0%, which is not surprising, because functional causes of AUB do not produce structural abnormalities on imaging. Thickened endometrium and fibroids were the commonest abnormal findings. Sonography is an excellent first-line tool for structural lesions and, in postmenopausal bleeding, a thin endometrium of 4-5 mm or less has a very high negative predictive value for carcinoma [25,26]; nevertheless, it cannot replace histology in women with persistent or high-risk bleeding.

In the present study normal cyclical (proliferative and secretory) endometrium formed the largest single group (40.0%), followed by disordered proliferative endometrium (14.0%). Predominance of proliferative-phase and secretory-phase endometrium has been described in many Indian histopathological audits of AUB [18-21]. Several explanations are possible: a normal endometrium may be obtained when the bleeding is due to a structural lesion elsewhere in the uterus, to a coagulation or local haemostatic disturbance, or to ovulatory heavy menstrual bleeding in which the endometrium itself is histologically unremarkable. The biopsy may also have been timed in a phase that does not capture the lesion. The finding of a normal secretory endometrium underscores that a normal biopsy does not exclude AUB, and further evaluation of the myometrium, coagulation profile and local prostaglandin or fibrinolytic mechanisms may be required.

Disordered proliferative endometrium and irregular shedding together accounted for 18.0% of our cases, and they are regarded as the morphological expression of anovulation with an imbalance of oestrogen and progesterone [33]. They were concentrated in younger women and in the perimenopause, which fits the endocrine background just described. Because disordered proliferative endometrium lies on a continuum with simple hyperplasia, and the distinction depends on gland architecture and the degree of glandular dilatation, interobserver variation in its diagnosis is well recognised [34]. We attempted to reduce this problem by using two independent observers.

Endometrial hyperplasia was identified in 18.0% of women, of whom 16.0% had no atypia and 2.0% had atypical hyperplasia/EIN. Several Indian series report hyperplasia in a broadly similar, clinically important proportion of AUB biopsies, most often in the fifth decade. In our study hyperplasia was significantly more frequent in women aged 40 years or more than in younger women (26.1% vs 11.1%, p<0.001), and it was most strongly associated with menometrorrhagia. The clinical importance of hyperplasia lies in its risk of progression. In the classic long-term study of Kurman and colleagues, the progression to carcinoma was about 1% for simple and 3% for complex hyperplasia without atypia, but 8% for simple atypical and 29% for complex atypical hyperplasia. For this reason, the detection of atypical hyperplasia or EIN in six of our patients had immediate management implications, and the identification of such lesions is a principal justification for histological evaluation in AUB.

Endometrial adenocarcinoma was found in 3.0% of all women, all of them aged 40 years or above, and the risk in premenopausal women was 1.1%. By contrast, 25.0% of women with postmenopausal bleeding had carcinoma. This is higher than the figure usually quoted for unselected postmenopausal bleeding, and probably reflects the referral bias of a tertiary hospital and the small number of postmenopausal cases. Nevertheless, it reinforces the universal recommendation that every woman with postmenopausal bleeding must be investigated for endometrial malignancy. Atrophic endometrium was the commonest finding in this subgroup (62.5%), as reported in other series, and was benign, but the diagnosis of atrophy should only be accepted after carcinoma has been excluded by adequate sampling or imaging.

Endometrial polyps were found in 6.0% of women, and they are a well-established structural cause of intermenstrual and heavy bleeding. Their importance relates to a small but definite risk of malignancy, which is higher in symptomatic and postmenopausal women [35]; a polyp in a woman with postmenopausal bleeding should therefore be removed and examined histologically. Chronic endometritis was recorded in 5.0% of women, which is somewhat comparable with the proportion reported in Indian studies, and may be related to IUCD use, previous abortions or pelvic infection. Identification of plasma cells in the endometrial stroma is the key diagnostic feature and justifies appropriate antimicrobial treatment.

In the 84 hysterectomy specimens, leiomyoma was present in 53.6% and adenomyosis in 39.3%, with coexistence in 14.3%. Leiomyoma is the commonest benign tumour of the female genital tract and a major indication for hysterectomy in India, whereas adenomyosis is frequently underdiagnosed pre-operatively because its clinical and sonographic features overlap with those of fibroids and functional bleeding. The high proportion of adenomyosis in our hysterectomy series is in keeping with the experience of other Indian institutions that have studied hysterectomy specimens in AUB and it supports careful examination of the myometrium in every specimen.

4.6 PALM-COEIN categorisation

Using the PALM-COEIN system, structural causes accounted for 53.0% of cases, and ovulatory dysfunction (25.0%) was the single largest non-structural cause. Application of a standard classification offers important advantages. It allows direct comparison between centres, and focuses the clinician on a systematic evaluation, with imaging and histology used to identify structural lesions and endocrine and haematological tests to define non-structural ones. The 3.0% of our women who could not be classified because of inadequate sampling illustrates the practical limitation of blind endometrial sampling, whose sensitivity for carcinoma is high but whose accuracy for focal lesions such as polyps is lower than that of hysteroscopy-guided biopsy.

4.7 Strengths and limitations

The strengths of this study are the prospective collection of clinical data, the use of a standard classification and independent double reporting of the slides. The limitations include its single-centre, hospital-based design, which limits generalisation to the community and probably overestimates the frequency of serious pathology; the inclusion of hysterectomy specimens, which introduces selection towards structural lesions; the lack of hysteroscopic correlation and of hormonal assays; and the absence of follow-up to assess treatment outcome. Larger multicentre studies with follow-up are required to refine the risk stratification of women with AUB in the Indian population.

Abnormal uterine bleeding is most common in women between 30 and 49 years of age, with menorrhagia the principal complaint and anaemia a near-universal consequence. Functional endometrial patterns, namely normal cyclical and disordered proliferative endometrium, accounted for over half of the histological diagnoses, but endometrial hyperplasia was found in nearly one-fifth of the women and carcinoma in 3.0%, being confined to women aged 40 years and above and strikingly common in postmenopausal bleeding. Leiomyoma and adenomyosis were the main myometrial causes in women undergoing hysterectomy.

On the basis of these findings, we recommend that (i) endometrial sampling with histopathological examination should be performed in all women with AUB aged 40 years or above, in every woman with postmenopausal bleeding, and in younger women with risk factors or failure of medical therapy; (ii) haemoglobin, thyroid function and ultrasonographic evaluation should form part of the routine work-up; (iii) the PALM-COEIN classification should be used uniformly for reporting and planning treatment; and (iv) iron supplementation and early referral should be promoted at the primary-care level to reduce the burden of anaemia.

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