The initial assessment of an adolescent with DUB requires an accurate summary of the patient’s medical history, both familiar (in order to exclude haemorrhagic diatheses) and personal (previous surgery, trauma with ecchymosis, epistaxis or gingival bleeding, previous or current pathologies, use of drugs, accurate menstrual and sexual history), in addition to an objective medical examination (body mass index, stage of puberty, inspection of external genitalia with an eventual gynaecological examination for sexually active patients, abdominal examination). It can sometimes be useful, although not strictly necessary, to perform a pelvic ultrasound (abdominal/transrectal or transvaginal in a sexually active patient) (Tables 6.3 and 6.4).

Although the Italian situation differs from that of the USA, where around 62% of 17–18-years-old teenagers are sexually active [9], it is important to exclude pregnancy or a related complication (miscarriage or ectopic pregnancy): this can only be done through an accurate anamnesis of the adolescent. In the USA, statistics have drawn further attention to the fact that around 25% of adolescents will contract a sexually transmitted infection. Since cervicitis and endometritis are both frequent causes of heavy menstrual flow [10], if they are confirmed, it would be advisable to investigate (or to confirm) the presence of N. Gonorrhoea and of Chlamydia trachomatis.

A laboratory assessment should therefore be performed in accordance with the clinical history and physical examination of the patient. The initial laboratory tests should include pregnancy test, complete blood count (CBC), fibrinogen, Prothrombin Time (PT) and Partial Thromboplastin Time (PTT) [11, 12]. In adolescents with a history of heavy and prolonged bleeding, immunological dosage of von Willebrand factor (vWF:Ag), dosage of factor VIII coagulant activity (FVIII:C), factor XI (FXI:Ag) and ristocetin cofactor activity (VWF:RCo) could be required [11, 13]. In suspect cases, it is good practice to request a haematological consultation. In adolescents who have a medical history indicative of anovulation, plasma levels of follicle-stimulating hormone (FSH) and Thyroid-Stimulating Hormone (TSH) should be evaluated, while in those with DUB and evident hirsutism, prolactin levels (PRL), total testosterone, dehydroepiandrosterone sulphate (DHEA-S), 17-OH progesterone (17-OHB) and androstenedione levels should be measured in association with an oral glucose tolerance test (2 h OGTT) and the dosage of fasting insulin and lipids [11, 13]. In order to better quantify the extent of blood loss, some authors have suggested to use a simple and reliable semiquantitative method at home (Pictorial Blood Loss Assessment Chart: PBAC score) [14–16], besides the above-mentioned CBC, serum iron and ferritinemia. The daily menstrual graphic is based on the scores that are attributed to each tampon or sanitary towel used, in relation to the different levels of saturation observed (one use >3 towels/day in the first 3 days of cycle, with/without blood clots, together with a menstrual loss >80 mL/day) [17] (Table 6.5).

Adolescents who are not pregnant and do not have a sexually transmitted infection can reveal in around 20% of cases an underlying coagulopathy [18–20], especially if they suffer from a heavy menstrual flow. In particular, haematological causes of DUB can be divided into two groups:

However, the most known haematological cause is vWD, whose prevalence in the general European and American populations is estimated to be near 1% [21, 22]. Not only is menorrhagia mainly prevalent in women who show blood clotting disorders, but these are also mainly prevalent in patients with menorrhagia. A prevalence of 3–36% of vWD has been reported in adolescents with menorrhagia [23]. Similarly, it has been shown that an alteration in coagulation was present in 25% of adolescents with severe bleeding or haemoglobin levels <10 g/dL [24]; such levels reached 50% in cases of adolescents with menorrhagia already present in successive cycles after the menarche [25]. Depending on the severity of symptoms and laboratory test results, the different variants of vWD have been classified by the International Society on Thrombosis and Haemostasis into three different subgroups: type 1, the less severe form of factor vW deficiency (70% of cases); type 2, in turn divided into four variants and the form due to a qualitative defect (20–30% of cases); and type 3, the most severe and rare form of factor vW deficiency (<5%) [26].

Chronic renal impairment can cause menstrual irregularities. In particular, it has been showed that around 80% of women with chronic renal impairment suffer from menorrhagia [27]. There are several factors that can cause the condition to arise: (a) an increase in azotaemia often leads to irregular secondary cycles, to central inhibition of gonadotropins and to a consequent reduction in serum oestradiol levels [28]; (b) elevated levels of prolactin, that occur in around 50% of patients undergoing dialysis (due to reduced clearance), can cause DUB in adolescents with renal impairment [27, 29, 30]; and (c) haematological alterations subsequent to renal impairment (normochromic anaemia, normocytic anaemia due to a reduction in erythropoietin production; increased bleeding time due to a reduction in fibrinogen, platelets and associated uraemia) can cause prolonged and severe bleeding [23, 27, 31].

Similarly, hepatic impairment, either chronic or slowly progressive, can be linked to blood clotting disorders (reduction in vitamin K-dependent blood clotting factors: factors II, VII, IX and X; reduction in levels of protein S, protein C, fibrinogen and platelets) [32] or alterations in hormonal levels.

Menstrual irregularities, including amenorrhoea, oligomenorrhoea and menometrorrhagia, have been observed in adolescents with diabetes [33, 34]. In fact, hyperglycaemia seems to have an effect on the hypothalamic-pituitary axis, leading to a progressive slowing-down of gonadotropin-releasing hormone (GnRH) pulsatility and a consequent reduction in the pulsatile production of luteinizing hormone (LH) [33–35]. DUB has been observed more frequently in adolescents with poor glycaemic control, especially in those with haemoglobin A1c levels above 12.8 mg/dL or glycaemia above 240 mg/dL [33–35]. In adolescents with insulin-resistant diabetes, DUB is the result of increased peripheral conversion of androstenedione into oestrone, which leads to an excessive oestrogenic response in the endometrium. Similarly, the stimulatory effects of insulin on the ovary increase androgen production, resulting in irregular bleeding of the endometrial mucosa.

Alterations of the menstrual cycle have been described in patients affected by inflammatory intestinal diseases. In fact, menstrual alterations (oligomenorrhoea, polymenorrhoea, menorrhagia and metrorrhagia) were observed in a group of 360 women suffering from Crohn’s disease and 251 suffering from ulcerative colitis in 60% and 53% of the cases, respectively [36, 37]. The aetiology of DUB associated with enteric pathologies is not well understood even though there is a recognised link with the severity of the illness, stress and malabsorption.

Menstrual cycle disorders have also been described in women with rheumatic diseases. When compared with healthy subjects, women with juvenile chronic arthritis have a higher incidence of metrorrhagia: in particular, menstrual disorders generally appear after the onset of the disease [38]. Alterations in the menstrual cycle have also been observed in around 53% of women with Systematic Lupus Erythematosus (SLE) [39]. Increased serum levels of LH and PRL were also frequent in these subjects.

In adolescents, another pathological condition that has been associated with DUB is the cyanotic congenital heart disease [40, 41]. The mechanism through which other alterations of the menstrual cycle are induced is currently unknown, although surgical correction time with respect to the menarche period seems to be key. In fact, subjects under 10 years of age at the time of corrective surgery show higher regularity of the menstrual cycle than subjects undergoing correction post-menarche (menstrual cycle become regular only after 6 months following the surgery) [42]. In subjects where the surgical repair is postponed until 6–10 years post-menarche there is an elevated incidence of menstrual cycle alterations, with a predominance of amenorrhoea.

Polycystic Ovary Syndrome (PCOS) has been increasingly described in adolescents suffering from Temporal Lobe Epilepsy (10–25%) in comparison with control subjects (4–6%) [43, 44]. Furthermore, numerous studies have reported that around 40% of adolescents treated with valproic acid suffer from PCOS and 30% have alterations in the menstrual cycle compared to adolescents treated with other anticonvulsants [43–46]. It is believed that an increase in PCOS and DUB incidence is a direct effect of epileptogenic lesions on the hypothalamic-pituitary axis in addition to the known effects of some antiepileptic drugs. The exact mechanism involved is not understood, although weight gain linked to treatment with valproic acid could play a role, since it is associated with a reduction of sex hormone-binding globulin (SHBG) and insulin-like growth factor binding protein, which thereby leads to an increase in androgen and PCOS [44–47].

It has long been known that thyroid disorders are linked with menstrual cycle abnormalities. An increase in SHBG levels occurs during hyperthyroidism, which leads to a similar increase in serum levels of oestradiol, testosterone and androstenedione [48]. In subjects with DUB, hypomenorrhoea occurs in 52% of cases, polymenorrhoea in 32.5%, oligomenorrhoea in 11% and hypermenorrhoea in 4.5%. Conversely, in subjects with hypothyroidism a reduction in SHBG occurs, leading to a reduced elimination of androstenedione and oestrone and an increase of aromatase activity. The most frequently observed menstrual disorder is menorrhagia, due probably to irregular endometrium growth secondary to an excess of oestrogens [48]. In other cases, it can be caused by reduced levels of factors VII, VIII, IX and XI, thereby further increasing the risk of menorrhagia [48, 49].

It is widely known that androgen excess can cause DUB in adolescents. Sometimes, the presence of menstrual alterations can be the first sign of PCOS or other hyperandrogenic conditions. The most frequent cause of androgen excess in adolescents is PCOS: although the exact prevalence in this population is not known, it occurs in 3–6% of adult women [50, 51]. In addition to insulin resistance, often related to PCOS, two other extreme conditions of PCOS can occur (albeit more rarely): hyperthecosis of the ovary (a condition of hyperandrogenism in which androgen levels are higher while those of LH are lower), and hyperandrogenism, insulin-resistance and acanthosis nigricans syndrome (HAIR-AN) [52]. In addition to PCOS, other rare conditions of hyperandrogenism in adolescents are also recognised as a cause of DUB: late-onset Congenital Adrenal Hyperplasia (CAH), Cushing syndrome, androgen-secreting tumours, and hyperprolactinaemia.

Elevated levels of PRL are able to inhibit GnRH secretion: intermittent secretion of this peptide initially causes luteal phase deficiency together with polymenorrhoea, while amenorrhoea appears when the secretion of GnRH is completely suppressed. As mentioned above, a hyperandrogenic condition is secondary to hyperprolactinaemia, but it is also possible for prolactin to have a direct effect on the adrenal gland and ovary.

The treatment of DUB is mainly dependent on the cause (endocrine or non-endocrine). The simple correction of the cause is often enough to improve and correct menstrual alteration: it is widely known, for example, that treatment of thyroid disorders leads to a swift return to the normal menstrual cycle. The estimation and consequent correction of blood loss represents the second and crucial therapeutic objective. The most frequently proposed drugs for this specific purpose are listed in Table 6.6.

Oestrogens have long been used as initial therapy against acute DUB, especially since 1982 when a randomised controlled trial showed that 72% of patients who underwent two doses of oestrogen i.v. (12 h apart) stopped bleeding compared to 38% who received a placebo [53]. The single parenteral oestrogen therapy definitely has the advantage of inducing endometrial vasospasm, regenerating the endometrial mucosa and increasing blood clotting factors. Actually, at least in Italy, it is not possible to use it since more than a decade, due to its commercial unavailability. The alternative is the administration of an association of combined oral contraceptive (COC) containing at least 30 mcg of ethinylestradiol, starting with 2–3 pills per day and subsequently reducing it to one pill per day, when bleeding has reduced (after 3–4 days, on average). A review of six randomised controlled trials comparing cyclic and continuous administration of a COC has demonstrated their equivalent efficacy and compliance; however, a significantly reduced menstrual loss was observed in the group who underwent continuous treatment with COC [19, 54]. To date, there are no available data regarding the choice of a COC over another [23].

In patients with contraindications to oestrogens, progestogen is the only available option. Actually, according to Cochrane, the administration of oral progestogens from the 15th to 26th day of the cycle in subjects with ovulatory cycles does not offer advantages over other medical therapies [tranexamic acid, non-steroidal anti-inflammatory drugs (NSAIDs), Danazol, medicated intrauterine devices (IUD)]. However, their administration can be more effective if prolonged for at least 21 days, despite we should consider their side effects (swelling, weight gain, fatigue, headaches/migraines, mood changes and depression) that limit to three cycles their use [55]. According to National Institute for Health and Care Excellence guidelines, this last method of administration is particularly effective in women with anovulatory cycles and should represent a potential option after non-use of other medical therapies, as a result of intolerance or their failure [56].