INTRODUCTION:

The ovarian function wanes during the perimenopause, ovulation becomes erratic and unpredictable, and results in not only reduced fertility but also unpredictable bizarre bleeding which is characteristic for this period [1].

The decrease in the number of oocyte-containing primordial follicles from 7 x 10000000 at 20 weeks gestational age to 2x 10000000 at the time of birth continues postnatally, so that at menarche there are only about 300000 oocytes and fewer than 0.001 % of the original follicles are ever ovulated [2]. It is estimated that during the perimenopause only a few thousands oocytes will remain, and most of them are resistant to the stimuli which ordinarily lead to ovulation [3].

At the time of the menopause, following an accelerated rate of decline during the last premenopausal decade, there are virtually no follicles left [4]. It is interesting that cycling perimenopausal females have almost 10 times the number of primordial follicles compared with the same-aged post-menopausal females [5].

Physiologically, it appears that there is a reproductive menopause which precedes the endocrine menopause by about 10 years [6]. Though the former is heralded by increasing FSH values which begins to be detectable in the early follicular phase in females more than 35 years of age (despite that they are still cycling regularly), the latter is clearly evident by cessation of menses [7]. The period bounded by the reproductive menopause and the endocrine menopause is the perimenopausal transition [8]. During this transition, episodes of ovarian activity is alternative with episodes of ovarian inactivity [7]. This results in variability in FSH/ LH ratio secretion and also in the values of ovarian steroids, leading to abnormal long and short cycles [9]. The follicular phase is prolonged in long cycles, indicating slow follicular development [10]. Estradiol (E2) levels continue to be low but constant till the end of the cycle when both FSH and E2 increase [11]. Ovulation might or might not occur, while endometrial proliferation continues during the long follicular phase, leading to a stage of prolonged and heavy bleeding [3].

In contrast, in a short cycle, there is little opportunity for endometrial proliferation, and at the end of the short cycle, the E2 level decreases and the level of FSH increases [10]. Ultimately, the estrogen levels are so low that endometrial proliferation can no longer be induced, so little or no visible menstrual bleeding occurs [11]. The FSH levels then rises 10 to 20 times reaching a peak level about one to three years after menopause and LH level is normal until this time, then it increases dramatically [12].

Perimenopausal bleeding is one of the commonest complaints in gynecological patients in primary care centers which accounts for one third of gynecologic office visits [13]. Abnormal uterine bleeding may be difficult to identify, because deviation from the normal to abnormal depends on individual woman menstrual pattern and her reproductive age which varies widely between different countries and races and many other affecting factors [14]. In pre-menopause, regular periods are the rule, and most deviations from that are probably due to pregnancy, birth control methods, structural pathologies such as fibroids, or a fluctuating hormone levels [15]. During the perimenopause (that is about four to eight years leading to menopause), irregular bleeding may occur which makes abnormal uterine bleeding difficult to recognize or define [7]. Following menopause, bleeding is always of concern and must be investigated and evaluated [16]. During perimenopause, menstrual cycles may become shorter, then longer, and blood flow may fluctuate from month to month [2]. Some ladies miss few periods and then have menstruation regularly [4]. The major causes are low hormone levels and declined frequency of ovulations [8]. Lesser ovulations lead to hormonal changes that makes the endometrium more thick than usual before sloughing off, leading to more heavy, erratic, and prolonged periods [5].

Despite that irregular menses is normal during perimenopause, some unusual bleeding could be a sign of a certain pathology which requires medical attention [17]. Of these signs are several menstrual cycles which are less than 21 days, bleeding or spotting between menstrual periods, bleeding after sexual relation, more than 3 months without a period and several periods that last three days more than usual [2,17-18]. There are many expected causes of abnormal uterine bleeding in perimenopausal ladies that include imbalanced hormones that can lead to absent periods, chronic failure of ovulation resulting in over growth of endometrial cell lining, which is a risk for unusual bleeding, and sometimes in liable women, it is a risk for endometrial cancer [16]. Fibroids can lead to heavy bleeding (i.e.menorrhagia), these benign tumors usually become larger during perimenopause and then shrink and subside after menopause [11]. Endometrial polyps may lead to heavy, prolonged or irregular bleeding (sometimes spotting), those benign ingrowths of the uterine endometrium may or may not require to be excised [18]. Hormonal contraceptive methods can cause many irregular bleeding patterns (missed or forgotten pills may cause break through or intermenstrual bleeding), hormone-treated intrauterine devices (IUDs) may reduce the flow while non-medicated IUDs may increase the menstrual flow [19]. Thyroid problems may be another cause of perimenopausal bleeding, in case of hypothyroidism there may be heavy bleeding, while absence of periods can occur both in hypo- and hyperthyroidism [20]. Clotting problems, such as inherited clotting diseases (like Von Willebrand Disease) that impair the clotting ability of the blood, which can lead to irregular vaginal bleeding [15]. In polycystic ovarian syndrome, which is an endocrine disorder characterized by absence of ovulation and a few or absent menstrual cycles, cycles that occur may be heavy due to abnormal proliferation of the uterine endometrium [6].

While postmenopausal women may develop a harmless episode of bleeding due to a single rogue ovulation after cessation of periods for more than a year, it is also normal for women who use hormone replacement therapy as continuous combined doses of estrogen and progesterone to develop spotting or bleeding during the first few months, and for women using cyclic hormone doses to have mild monthly bleeding [20, 4]. However, apart from that, bleeding in the postmenopausal period is abnormal and should be evaluated immediately without delay because about 10% of postmenopausal bleeding may be due to endometrial cancer (in this type of cancer, in almost all cases; bleeding is usually the first sign), if it is discovered and treated early, most probably it will be cured [21]. Fortunately, the most common causes of postmenopausal bleeding are much less serious, in most cases the problem is age-related due to atrophy of endometrium or vaginal lining due to decreased estrogen level [14]. They only require simple or even no treatment (although local vaginal estrogen cream may be helpful when atrophy leads to vaginal bleeding after sexual relationship) [7].

Uterine polyps are common possible source of uterine bleeding, it might or might not be necessary to excise them [22]. Bleeding could be a sign of a condition called endometrial hyperplasia (overgrowth of cells lining the uterus), it is not a malignancy but in certain conditions it leads to the growth of cells that turn into cancer (atypical hyperplasia) [21]. Endometrial hyperplasia is usually treated with medications [22].

Steps used for diagnosis begins with transvaginal ultrasound, passing through blind endometrial sampling and ending in some cases with hysteroscopy [23]. Since appropriate therapy depends on proper diagnosis of every case, luckily only small number of women with perimenopausal bleeding show premalignant or malignant changes in cells, when blood loss is sufficient to cause anemia then prompt intervention is necessary, in benign conditions some intervention is also required [24]. Many treatment choices are available like combined contraceptive pills with short hormone-free period, the application of levonorgestrel intrauterine device, antifibrinolytic agents and selective progesterone receptor modulators which are useful outpatient treatments [25]. Other women may need operative hysteroscopy and endometrium ablation which are therapeutic tools providing both short and long term improvement of abnormal uterine bleeding, in order to avoid or postpone hysterectomy [26].

There are new instruments to acquire endometrial biopsy but some gynecologists are still concerned about whether the sample obtained is adequate for histopathological examination or not, and whether some local intrauterine lesions are skipped during sampling. Accordingly, in this study we are aiming to compare the diagnostic accuracy of classical dilation and curettage (DandC) with sampling using the Pipelle device in patients having perimenopausal uterine bleeding.

MATERIAL AND METHODS:

Women with abnormal uterine bleeding more than 40 years of age attending Medical City consultation clinic during the period between January 2018 and January 2019 were included in this study. Thorough assessment of patients was done with pelvic ultrasound and laboratory investigations (CBC, thyroid function test, coagulation profile and liver function test). Pregnant ladies or those using hormonal contraception were excluded. Ninety-four women were included in this study, all had informed consent and the study procedures were fully explained to them. All women had normal liver function test and coagulation profile and all were euthyroid, then endometrial sampling was done by using the Pipelle device in the outpatient without cervical dilatation and samples gained were labeled as samples A. Afterwards, patients were sent to the theatre for DandC under general anesthesia and samples gained were labeled as samples B. Both samples were sent for histopathological examination without informing the pathologist about the method of sampling and patients medical history. The reports of histopathological examination were compared between Pipelle and DandC samples (group A and group B).

RESULTS AND DISCUSSION:

Ninety-four women having abnormal uterine bleeding were included in this study, with a median age of 46 years while their median age of menarche was 13 years. The median parity of the women was 3.5 and median thickness of endometrium was 10.5mm (Table 1).

Table 1: The characteristics of the studied patients

Variables	Median	Range
Age (years)	46	42-50
Age of menarche (years)	13	11-15
Parity	3.5	1-6
Endometrial thickness (mm)	10.5	10-11

The main symptoms of the patients were; menorrhagia (n= 25), metrorrhagia or irregular bleeding (n=22), polymenorrhagia (n=28) and postmenopausal bleeding (n=19). If the sample contained no endometrial tissue the sample was considered inappropriate by the histopathologist (several cases were excluded from the study because of inability to introduce the Pipelle; failure of the procedure, so we did for them DandC to diagnose the cause of vaginal bleeding but without including them in the study). All specimens obtained by DandC were adequate while 97.88 % of the specimens acquired by Pipelle method were adequate. The results of histopathological examination of 94 specimens obtained by DandC showed; endometrial hyperplasia in 31 specimens, endometrial polyps in 2 specimens, endometritis in 6 specimens, malignant endometrial features in 6 specimens, proliferative endometrium in 27 specimens and secretory endometrium in 22 specimens (Table 2).

Table 2: Histopathological diagnosis of both groups

Histopathological diagnosis	Histopathological results of the specimens obtained by conventional DandC	Histopathological results of the specimens obtained by the Pipelle device
Endometrial hyperplasia	31	31
Endometrial polyps	2	1
endometritis	6	5
Malignant endometrial changes	6	6
Proliferative endometrium	27	27
Secretory endometrium	22	22

DandC= Dilatation and Curettage

In this study, it was found that Pipelle was about 100% sensitive, 100% specific and had 100% predictive values for diagnosis of endometrial hyperplasia, endometrial carcinoma, proliferative and secretory endometrium. It was also 88.9% sensitive, 100% specific, and had 100% positive predictive value (PPV) and 99.2% negative predictive value (NPV) for diagnosis of endometritis. But it was only 60% sensitive, 100% specific, had 100% PPV and 89.6% NPV for diagnoses of endometrial polyps.

In this study, the Pipelle device had 100% accuracy in the diagnosis of endometrial hyperplasia, endometrial carcinoma, proliferation and secretory states of endometrium, and had accuracy of 99% in the diagnosis of cases with endometritis. While it had 98% accuracy in the diagnosis of endometrial polyps.

The backbone in the appreciation of perimenopausal bleeding is endometrial sampling principally to exclude endometrial carcinoma, so as to decide for next step management whether by medical treatment or conservative surgical procedure and trying to avoid radical surgery or keeping it as a last choice [27]. Many methods for endometrial sampling are available being invasive or non invasive which can be offered in the outpatient or inpatient clinics [11].

The traditional method of sampling is DandC which is a classical invasive inpatient procedure that requires general anesthesia [15]. The new method using Pipelle device which is non invasive outpatient method gives highly appropriate endometrial samples in about 98% of patients especially when the thickness of central endometrium is more than 5 mm [22]. So, if any patient had endometrial thickness less than 4 mm she was excluded from the study. We can do Pipelle sampling without anesthesia [17]. During this study we did routine pelvic examination and took Pipelle samples in the ward, then the patients were taken to the theatre and DandC was done under general anesthesia in order to synchronize the samples which is important in this comparative study.

The Pipelle is considered by many researchers as an accurate and reliable outpatient technique in comparison with DandC [28]. In this study Pipelle was almost 99% sensitive, 100% specific and had 99% predictive value. It had high accuracy in the diagnosis of endometrial carcinoma and endometrial hyperplasia. Clark et al. concluded that outpatient endometrial biopsy has modest accuracy in diagnosing endometrial hyperplasia and further assessment is needed to rely on this technique [19]. Demirkiran and his colleagues evaluated 673 patients using Cornier Pipelle for about two years, they found that the Pipelle method was easier to perform for surgeons compared to DandC and with the same sensitivity of DandC being 99% for both methods [29]. So it is a reliable method and can be used instead of DandC. Fakhar et al., in their study concluded that Pipelle endometrial sampling had 100% sensitivity for diagnosis of endometrial carcinoma, also it was sensitive and accurate for diagnosis of endometrial hyperplasia [4].

Svirsky et al. performed a meta-analysis to evaluate the accuracy of Pipelle in detecting endometrial carcinoma and atypical hyperplasia and deduced that this method was topmost to other techniques in recognition of endometrial carcinoma and atypical hyperplasia in pre and postmenopausal women, it was 89% sensitive, 99% specific and 98.5% accurate [16]. In our study the Pipelle had low sensitivity to diagnose endometritis and endometrial polyp. Polyp is the most histological diagnosis missed when the endometrial sampling is inadequate [30]. Several patients were excluded from the study because we couldn’t introduce or apply the Pipelle through the cervix to get an endometrial sample (failure of the procedure), but we did for them DandC to diagnose the cause of their vaginal bleeding without including them in the study.

We made a conclusion that taking an endometrial sample by using Pipelle could replace the traditional method of DandC, because it is accurate, safe and cheap outpatient procedure without the need for general anesthesia with high specificity and sensitivity in detecting endometrial carcinoma and endometrial hyperplasia.

CONCLUSION:

Pipelle is a simple, accurate, and safe procedure that can be performed in an outpatient clinic. Pipelle procedure do not require general anesthesia that is applied in DandC, this will prevent the complications that are associated with general anesthesia, as well as, less costly for the patient. The accuracy of this procedure is dependable and can be used as an alternative for DandC.

CONFLICT OF INTEREST:

The author declares that there is no conflict of interest relevant to this paper.

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Received on 05.12.2020 Modified on 08.01.2021

Research J. Pharm. and Tech 2021; 14(11):5764-5768.

DOI: 10.52711/0974-360X.2021.01002