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REVIEW Nonmenstrual bleeding in The Obstetrician & Gynaecologist women under 40 years of 2004;6:153–158 age Keywords intermenstrual Anne Connolly and Siân Esther Jones bleeding, , cervical The complaint of nonmenstrual bleeding, either intermenstrual or ectropion, pelvic postcoital, is a common symptom among women. This complaint is inflammatory often the result of minor alterations of physiological events caused by disease (PID), the influence of endogenous or exogenous hormones. It is often also hysteroscopy associated with a high degree of anxiety. This review briefly outlines the causes of this symptom in this younger age group of women and recommends an evidence-based approach to their investigation and subsequent management. It is important to ensure that the investigations are rational, relevant and streamlined in order to give reassurance or to begin appropriate treatment without undue delay. Premature ovarian failure is not included in this review. Women in this group who present with bleeding should be investigated as for postmenopausal bleeding.

Introduction initially restrain blood loss but later haemostasis is due to vasoconstriction of the spiral arterioles.2 Sporadic vaginal bleeding not related to menses is a common symptom in women under 40 Classification and causes years.While it often causes concern, it is rarely a sign of sinister pathology in this age group but, Nonmenstrual bleeding may be classified as as cervical and endometrial cancers commonly either: present with nonmenstrual bleeding, the first : bleeding arising principle of management must be to exclude • Author details from the genital tract in a woman with a malignancy. It is also essential in women of regular menstrual cycle, not occurring at reproductive age that a pregnancy-related menstruation or following sexual complication is excluded. intercourse • postcoital bleeding: genital tract bleeding Pathophysiology occurring after . In order to appreciate the complaint of In order to determine the cause of non- nonmenstrual bleeding, the physiology of the menstrual bleeding, a history (see Box 1) and Anne Connolly DRCOG MRCGP, menstrual cycle must be understood. The examination (see Box 2), with particular con- General Practitioner at The Ridge Medical Practice, Bradford, UK. duration of the normal menstrual cycle is sideration of the woman’s age, hormonal status, between 21 and 35 days. It consists of a sexual history and general health, are necessary. proliferative and a secretory phase, followed by The common causes of nonmenstrual bleeding menstruation. Oestrogen initially promotes are outlined in Box 3. proliferation of the .The secretory phase commences after ovulation, when the Assessment thicker endometrium stabilises under the com- bined influences of oestrogen and progesterone. When women present in the clinic or surgery Siân Esther Jones FRCOG, Menstrual bleeding follows, as the secretion of with intermenstrual or postcoital bleeding, they Consultant Obstetrician and oestrogen and progesterone falls, and lasts are usually very concerned about their problem. Gynaecologist, Bradford Royal Infirmary, Department of between 2 and 6 days. The average menstrual A good history and examination will often elicit Obstetrics and , blood loss occurring in approximately two- the cause and allow the anxious woman to be Duckworth Lane, Bradford, BD9 6RJ, UK. email: thirds of adult women is between 20 ml and reassured without unnecessary or extensive [email protected] 60 ml.1 During menstruation, thrombin plugs investigations. (corresponding author)

153 © 2004 Royal College of Obstetricians and Gynaecologists REVIEW Box 1. Points on history taking The Obstetrician & Gynaecologist • Duration, frequency and amount of bleeding • Menstrual history, including normal bleeding pattern and last menstrual period 2004;6:153–158 • Possibility of pregnancy • Relationship of the nonmenstrual bleeding to normal menstruation and sexual intercourse • Exogenous hormone therapy: i.e. the use of oral or transdermal contraceptives, intrauterine system or long-acting progestogen contraception • Nature and quantity of any associated vaginal discharge and any recent changes to this symptom • Possibility of a bleeding disorder • Any trauma to the genital tract

Speculum examination of the is Aetiology and management important to exclude any obvious abnormality such as a cervical polyp or ectopy. Appropriate swabs should be taken for microbiology. A cervical smear should be taken if one is due, with Physiological events referral for colposcopy and cervical biopsy if The fluctuating oestrogen levels expected there is clinical suspicion of invasive neoplasia or through the menstrual cycle are usually adequate if the smear is reported as abnormal. Bimanual to maintain the stability of the endometrium, pelvic examination will assess uterine size and except during menstruation. Sometimes there is tenderness and any gross adnexal pathology. an excessive fall in oestrogen levels following the follicular phase peak and resulting ovulation, allowing shedding of the endometrium, causing Box 2. Examination intermenstrual bleeding to occur. The sub- • General examination, including assessment for anaemia sequent corpus luteal formation allows a rise in • Abdominal palpation oestrogen and progesterone production, further • Vulval inspection stimulating the endometrium and preventing • Pelvic examination: further bleeding.This physiological anomaly is a i Cuscoe’s speculum examination to examine the cervix and common cause of intermenstrual bleeding in and assess any abnormal discharge younger women. ii bimanual examination to palpate the cervix and assess any abnormal uterine or adnexal pathology Box 3. Causes of nonmenstrual bleeding Transvaginal ultrasound is a useful tool for providing information about pelvic structures • Minor complications of physiological and their pathology. It can be used to assess the events size, number and location of fibroids and • Hormonal contraception measure endometrial thickness; a useful indicator • Pelvic inflammatory disease to determine the need for further endometrial • Pregnancy-related assessment. In some units, endometrial thicken- • Benign endometrial or cervical ing can be further clarified by the use of saline pathology instillation, allowing better definition and • Cervical ectopy and ectropion increased confidence in the diagnosis of fibroids, • Malignant lesions polyps or more sinister pathology. • Haematological abnormalities • Vaginal or vulval lesions Hysteroscopy is currently the standard investi- • Other gation for evaluation of the . It allows direct visualisation of the entire endometrium and directed biopsy of any suspicious lesions. This investigation is ideally Management consists of reassurance after the performed during the proliferative phase of the exclusion of pathological causes. If a woman cycle when the endometrium is thinnest and requests treatment then cyclical progestogens or easiest to evaluate and is ideally performed in the use of the combined oral contraceptive (COC) outpatient setting. pill should be discussed.

154 © 2004 Royal College of Obstetricians and Gynaecologists Hormonal contraception irregular bleeding with the progestogen-only pill REVIEW may not subside spontaneously and the choice The Obstetrician Intermenstrual bleeding is often experienced for the woman will lie between accepting the & Gynaecologist when starting any type of oral contraception, irregularity, changing brand or using an occurring in 30–40% of COC users during the alternative method of contraception. first 3 months. This may be due to insufficient 2004;6:153–158 sex-steroid concentrations to maintain the endometrium or due to inconsistent pill-taking, Infective causes with adolescents missing three pills per month Many women who suffer from chlamydial or on average.3 The newer, third-generation COCs gonorrhoeal infection will develop , have been designed to contain less androgenic which in turn may cause intermenstrual or post- progestogen and often lower doses of oestrogen coital bleeding. As adolescents have a high rate than the older, second-generation preparations, of chlamydial infection this must be considered thereby giving more acceptable bleeding and excluded early as a cause of nonmenstrual patterns.4 bleeding when dealing with younger, sexually active women. Irregular bleeding is a more frequent occurrence with use of the progestogen-only preparations, Infection of the upper genital tract, causing presumably due to partial suppression of ovarian endometritis and/or salpingitis, may also cause activity, allowing a periodic variation of the nonmenstrual bleeding. Women with salpingitis circulating oestradiol level and resulting in loss of are often systemically unwell with a febrile stability of the endometrium.With perseverance illness, abdominal or pelvic pain and, on examin- the bleeding irregularity usually subsides. ation, a purulent vaginal discharge may be found as well as abnormal bleeding. However, an endo- Users of the long-acting progestogen contracept- metritis can occur with few signs or symptoms. ive preparations, depot medroxyprogesterone It should be considered in sexually active young acetate, etonogestrel implant or the levonor- women with a menstrual calendar suggesting gestrel-releasing intrauterine system, can also ovulatory menstruation but with superimposed experience irregular vaginal bleeding, particularly nonmenstrual bleeding. during the first few months. Cervicitis or endometritis is usually a clinical It is important to differentiate the initial men- diagnosis but cervical and chlamydia swabs are strual irregularities experienced when starting routinely taken to detect a specific cause and any hormonal method of contraception from the allow recommendations of appropriate anti- women who suffer prolonged problems or who microbial therapy, ensuring adequate contact develop nonmenstrual bleeding after a period of tracing if indicated, as recommended in the UK stability.These women should be investigated to national guidelines for the management of exclude any alternative pathology, such as sexually transmitted infections.6 cervicitis caused by a chlamydial infection or the coincidental development of an endocervical Pregnancy-related bleeding polyp.5 A possible pregnancy-related complication must When starting any type of hormonal contra- be considered in a woman of reproductive age ceptive method, it is essential that the user because of the serious nature of several of these counsels the woman adequately about the disorders. Pregnancy complications include likelihood of nonmenstrual bleeding in the first threatened, incomplete or missed miscarriages, few months of use, thereby preventing un- ectopic pregnancy, trophoblastic disease and necessary anxiety and improving understanding subinvolution of the placental site. It is therefore and compliance. If bleeding persists in a COC imperative that a pregnancy test is included in user,then change to a COC with a higher dose of the initial evaluation of any woman of the progestogen component initially, then reproductive age. One study of 550 pregnancies consider a phasic pill or a third-generation pill,or found that bleeding occurred before the 20th change to a COC with a higher dose of the week in 117 (21%) of women and 67 (12%) of oestrogen component. the total ended in a miscarriage.7

Prolonged, irregular bleeding caused by the use If there is any suspicion of an ectopic pregnancy of any of the progestogen methods may be or trophoblastic disease, then a pregnancy test managed using a short course of a COC (if not and urgent transvaginal ultrasound scan should contraindicated) or an oestrogen-only prepar- be arranged. Management then depends on the ation, such as oral oestradiol. Unfortunately, results of these investigations.8

155 © 2004 Royal College of Obstetricians and Gynaecologists REVIEW Benign endometrial or cervical including dyspareunia as well as excessive vaginal discharge and postcoital bleeding. The Obstetrician pathology & Gynaecologist Women with submucous fibroids, endometrial Symptomatic lesions may be treated by polyps or endometrial hyperplasia may experi- outpatient cryotherapy but ablative treatment 2004;6:153–158 ence intermenstrual bleeding but these are under local or general anaesthesia may be infrequent findings in women under the age of needed if symptoms persist after cryotherapy or 40 years. The bleeding from these lesions arises where the lesion is inflamed. Prior to performing from the erratic and irregular endometrial any treatment, it is essential to ensure that the shedding that they may cause. Sometimes woman has had a recent, normal cervical smear women with endometrial or fibroid polyps and that sexually transmitted infection has been experience dysmenorrhoea-like pain in assoc- excluded. iation with their intermenstrual bleeding. This can be diagnostic. Malignancy Hysteroscopy is the standard investigation for Gynaecological malignancies are uncommon in direct endometrial evaluation if the nonmen- women under 40 years but may arise from any strual bleeding pattern suggests that more part of the genital tract, such as the endo- detailed endometrial investigation is indicated. metrium or cervix, or more rarely the vagina, This is best undertaken in the outpatient setting, , or .Any of these may proceeding to operative hysteroscopy for small present with nonmenstrual bleeding. benign lesions in a one-stop setting.9 The incidence of has decreased Endocervical polyps are a cause of postcoital in the UK, notably since the introduction of the bleeding and are easily identified on speculum call/recall system in 1988 and since screening examination. In women under the age of 40 targets were encouraged. However, it is still a rare years, when concurrent endometrial disease is but important cause of nonmenstrual bleeding, unlikely, they can easily be avulsed in the out- particularly postcoital bleeding, in younger patient or primary-care setting. If nonmenstrual women; 85–95% of cervical cancers are bleeding continues after this, formal endometrial squamous, with the incidence decreasing by 7% assessment must be undertaken. per annum.There is a bimodal peak incidence of squamous-cell carcinomas occurring between Where facilities permit, hysteroscopic removal of the ages of 35–39 and 60–64 years, with cervical small polyps (less than 3 cm) and fibroids (less intraepithelial neoplasia grade 3 (CIN3) than 2 cm) can be undertaken in the outpatient incidence peaking at 35 years.11 setting but larger lesions require hysteroscopic removal under general anaesthesia. Adenocarcinomas derived from the endo- cervical form the remainder. The prevalence of this is increasing, arising in a Cervical ectopy and ectropion younger group of women, often under the age Cervical ectopy is a normal physiological of 35 years.12 occurrence and is the result of higher oestrogen exposure that occurs at certain times, such as Women with invasive cervical cancer often puberty, pregnancy or with anovulation. In the present with intermenstrual or postcoital 1970s, ‘pill erosions’ were common with the bleeding or excessive seropurulent discharge. higher-dose COC. In the 21st century, ectopy is However, in cases of early stromal invasion there rarely due to the COC and does not resolve are often no symptoms and the problem may when the COC is discontinued. only be identified by cervical screening. In one UK study, all the women who suffered from A cervical ectropion is defined as the presence of cervical cancer aged under 65 years presented everted endocervical columnar epithelium on with postcoital bleeding.13 Conversely,only 3.8% the ectocervix. It requires no treatment if of women who complained of postcoital asymptomatic but 5% of women with a cervical bleeding were subsequently found to have an ectropion report postcoital bleeding.10 Ectopy invasive cervical carcinoma.14 Postcoital bleeding and ectropion can produce significant mucoid must therefore be regarded as absolute indication discharge without being inflamed. Inflammation of the need for cervical inspection. Cervical tends to give rise to postcoital bleeding. examination may demonstrate a small exophytic Secondary infection of cervical ectopy or or ulcerated cervical lesion, which bleeds readily ectropion may involve both epithelium and on contact. stroma, producing symptoms of cervicitis,

156 © 2004 Royal College of Obstetricians and Gynaecologists Cervical cytology is indicated in the absence of These tumours often produce oestrogen and REVIEW a negative smear in the previous 3 years but it may therefore present with intermenstrual The Obstetrician must be remembered that a smear is not a bleeding due to the resulting endometrial & Gynaecologist reliable test for invasive cancer. It should only be hyperplasia. regarded as a screening test for CIN before 2004;6:153–158 invasive cancer causes abnormal signs or Ovarian tumours of epithelial origin rarely symptoms. A smear may be taken from an present with abnormal bleeding. The most abnormal cervix in addition to a biopsy of the common presenting complaint is abdominal lesion but, if relied upon alone, it will at best distension, which presents late in the disease delay a diagnosis and at worst be falsely process.The initial investigations include a pelvic reassuring. When cervical cancer is suspected, ultrasound examination to confirm the presence early referral for colposcopic examination is of a pelvic mass and detect any ascites before it mandatory.15 becomes clinically apparent. In conjunction with the tumour marker serum CA125, an estimated Endometrial cancers are rare in women aged ‘risk of malignancy score’ can be determined under 40 years but 20–25% of cases of prior to laparotomy. endometrial carcinoma occur before the menopause.16 These women usually present with Women should be referred to a gynaecological intermenstrual bleeding but up to one-third oncologist for appropriate treatment. complain initially of menorrhagia. Haematological disorders The risk of developing endometrial hyperplasia or neoplasia is increased in women with Women with coagulation disorders usually conditions allowing elevated circulating present with menorrhagia but occasionally will oestrogen levels, such as obesity, polycystic complain of nonmenstrual bleeding problems. ovarian syndrome, impaired glucose tolerance, These disorders may be related to a platelet nulliparity, functioning ovarian tumours and in deficiency (e.g. idiopathic thrombocytopenic women with a family history of breast, ovarian purpura) or to a defect of platelet activity (Von or colonic cancers. Hysteroscopic assessment Willebrand’s disease).20 A platelet count, a coagu- with endometrial sampling should be considered lation screen and measurement of coagulation in younger women with chronic anovulation or factors are necessary investigations if these an accumulation of the risk factors outlined problems are suspected. above, who complain of nonmenstrual bleeding, in order to exclude hyperplastic endometrial Management consists of referral to a haema- disease.17 tologist followed by joint management.

The histology of most endometrial biopsies falls Benign vaginal and vulval lesions into one of the four categories and helps dictate future management: Trauma to the lower genital tract, such as is seen with postcoital vaginal lacerations or foreign- proliferative, secretory, benign or atrophic • body injuries, may be the cause of an acute endometrium presentation of nonmenstrual bleeding. Scratch- simple or complex (adenomatous) • ing due to vulval irritation may also cause hyperplasia without atypia localised bleeding. Causes include: • simple or complex (adenomatous) hyperplasia with atypia • allergic dermatitis, with common irritants • endometrial adenocarcinoma.18 being perfumed soap or washing powder generalised skin disorders such as psoriasis, The presence of atypia is the most important risk • intertrigo, lichen planus or scabies factor in the development of endometrial vaginal infection due to candidiasis or cancer.19 Women who have hyperplasia but no • Trichomonas vaginalis. evidence of atypia may be treated with progestogens and surveillance endometrial biopsies performed at regular intervals. Atypical Other causes hyperplasia is best managed surgically. It is not unusual for a young woman to forget to Ovarian tumours, which are most frequently of remove a tampon after menstruation has epithelial origin, are rare in younger women. finished. These women present with an Less than 3% of ovarian cancers are found in offensive, bloodstained, purulent discharge. The women under the age of 35 years and most of cause of this problem is easily identified and dealt these are germ-cell or sex-cord stromal tumours. with on speculum or vaginal examination.

157 © 2004 Royal College of Obstetricians and Gynaecologists REVIEW Forty percent of women fitted with a copper- colposcopy with biopsy of suspicious containing intrauterine contraceptive device will • The Obstetrician cervical lesions have intermittent bleeding during the first & Gynaecologist • hysteroscopy with endometrial sampling – month with the following menses being heavier directed or global but regular. The bleeding is caused by a local 2004;6:153–158 transvaginal ultrasound scan. increase in fibrinolytic activity of the • endometrium, believed to be due to the device causing distortion and abrasive injury to the Summary endothelium. Counselling prior to fitting the Sporadic nonmenstrual bleeding either as device and reassurance in the early months is the intermenstrual or postcoital bleeding in women only management that is necessary. under the age of 40 years is a common present- ing complaint but rarely it has a sinister cause. Investigations The role of primary-care clinicians is to identify The history of the nonmenstrual bleeding those women who have a significant cause of pattern helps dictate the initial investigations their nonmenstrual bleeding and then to arrange necessary. appropriate investigations and specialist referral. • Intermenstrual bleeding Those women who do not need specialist input Disease of the or lower genital tract should be identified and managed as outlined should be investigated accordingly. above without the need for unnecessary inter- • Postcoital bleeding vention. Disease of the lower genital tract specifically requiring speculum examination. The challenge for secondary-care clinicians is the need to provide a rapid and accurate diag- These investigations should be performed as nosis for those women referred to them, with the indicated and may include: minimum number of investigations and un- • cervical cytology in the absence of a recent necessary invasive procedures. The development negative result of one-stop gynaecological assessment services is • triple swabs: high vaginal swab for culture, being driven by the demands of patients, and 2 endocervical swabs for gonorrhoea clinicians and managers in order to streamline culture and chlamydia analysis this process.This will reduce costs to the health • pregnancy test or serum bHCG if there is service and to the public. any possibility of pregnancy

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158 © 2004 Royal College of Obstetricians and Gynaecologists