sign in sign up
<<
Home , Menstrual disorder, Precocious puberty

Human Reproduction Update, Vol.9, No.5 pp. 493±504, 2003 DOI: 10.1093/humupd/dmg038

Menstrual disorders in : investigation and management

Martha Hickey1,3 and Adam Balen2

1Department of Obstetrics and , School of Women's and Infants' Health, University of Western Australia, King Edward Memorial Hospital, 374 Bagot Road, Subiaco, WA 6008, Australia and 2Clarendon Wing, Leeds General In®rmary, Leeds LS2 9NS, UK Downloaded from https://academic.oup.com/humupd/article/9/5/493/727661 by guest on 06 October 2021

3To whom correspondence should be addressed. E-mail: [email protected]

Menstrual disorders in adolescence may present diagnostic and management challenges for the gynaecologist. This review will describe the common and uncommon menstrual disorders that may arise in early reproductive life, together with guidance on their investigation and management.

Key words: adolescence/amenorrhoea/dysfunctional uterine bleeding//PCOS

Introduction gynaecological and intersex conditions. In 2003 the UK Royal College of Obstetricians and Gynaecologists (RCOG) has also Adolescence is a time of enormous physical and psychological approved a special training module in Paediatric and Adolescent change for young women. Serious gynaecological pathology is Gynaecology. The ACOG has recently released a `tool kit' rare in this age group, but menstrual disturbances are not designed to facilitate the inclusion of adolescents into a general uncommon and may add further disruption to this dif®cult phase ob-gyn practice (http://www.acog.org) which may be of use to for adolescents and their families. practitioners in other countries treating adolescents. It is likely that many adolescents with menstrual disturbances Embarrassment about discussing menstruation, fear of disease never present to their family doctor or gynaecologist. The and ignorance about available services are likely to mean that American College of Obstetrics and Gynecology (ACOG, 1996) many problems are not discussed or present following maternal takes a proactive stance in adolescent health by recommending an pressure. Alternatively, presentation with a menstrual disturbance initial visit to a gynaecologist for health guidance, screening and may disguise other issues, such as those relating to contraception, the provision of preventative services around the age of 13±15 , sexually transmitted (STI) or even sexual years. This is an opportunity for clinicians to advise the adolescent assault, and the gynaecologist should ensure that the young woman on what is `normal' for girls of her age regarding pubertal is given the opportunity to raise other concerns. Adolescents do not development, and menstrual cyclicity and would not access health services in the same manner as adults and effective normally include a . This anticipatory guidance services must recognize these patterns and plan accordingly. A and information to young girls and their parents may help ease the recent survey of 248 obstetric and gynaecology units in the UK transition from childhood through and a healthy adoles- indicated that adolescents constitute up to 5% of new gynaeco- cence (Adams Hillard, 2002). Such guidelines do not exist in the logical referrals and, whilst it was recognized by most that UK and it is unlikely that an adolescent would encounter a adolescents had special needs, the majority did not provide gynaecologist without the clinical suggestion of pathology. specialized services (Balen et al., 2002). Effective history-taking from an adolescent requires particular Con®dentiality is a primary ethical and professional duty for skills and sensitivities. Adolescents may have dif®culty raising doctors, and a crucial issue in adolescent health care. In the USA, issues of menstruation with their doctors (Malus et al., 1987) and the ACOG, American Academy of Pediatrics and the American may present with complaints of minor symptoms rather than their Medical Association have endorsed the principle of con®dentiality primary concerns (Patton, 1999). Neither the British nor in adolescent health care. In the UK and Australia the legal Australian colleges of Obstetrics and Gynaecology recognize precedence of the Gillick case (Gillick versus West Norfolk and training in adolescent gynaecology as part of their core curriculum Wisbech Area Health Authority, UK) allows the practitioner to and there are no UK guidelines for the management and referral of determine whether an adolescent has reached suf®cient under- specialized problems (Balen et al., 2002). Since the formation of standing and intelligence to be capable of making up her own mind the British Society of Paediatric and Adolescent Gynaecology, on the matter requiring decision. Adolescents are unlikely to there is now a UK course for the management of adolescent access sexual and reproductive health services unless they can be

Human Reproduction Update Vol. 9 No. 5 ã European Society of Human Reproduction and Embryology 2003; all rights reserved 493 M.Hickey and A.Balen assured of con®dentiality (Rogstad et al., 2002), hence the menarche. Most cycles still range from 21 to 45 days, even in the gynaecologist should ensure that s/he maintains con®dentiality ®rst year after menarche, with an upper limit of normal (i.e. 2 SD) and that the patient is assured of this. of 40±45 days (Southam and Richart, 1966; Flug et al., 1984; World Health Organization, 1986). By the third year after menarche, 60±80% of cycles are 21±34 days long, a pattern Menarche similar to that seen in adults (Widholm and Kantero, 1971; Flug The involves the coordination of many events by et al., 1984). Cycles >90 days represent the 95th percentile for the hypothalamic±pituitary±ovarian axis and is readily in¯uenced length, even in the ®rst gynaecological year. Thus consideration by physiological, pathological and psychological changes occur- should be given to a gynaecological evaluation in girls whose ring during the reproductive lifespan. The age of menarche is cycles are longer than this interval, since amenorrhoea of this determined by general health, genetic, socio-economic and interval or longer may have important implications for long-term nutritional factors. The mean age of menarche is typically between bone and cardiovascular health (Treloar et al., 1967). 12 and 13 years (Flug et al., 1984; World Health Organization, does not necessarily underlie prolonged or irregu- Downloaded from https://academic.oup.com/humupd/article/9/5/493/727661 by guest on 06 October 2021 1986; Herman-Giddens et al., 1997). The oft-quoted statement that lar cycles and some cycles are ovulatory with a long follicular there has been a decrease in the mean age of menarche in recent phase (Venturoli et al., 1987). Early menarche is associated with decades has not been substantiated by large population studies, early onset of ovulatory cycles. When menarche occurs at <12 either in the USA (Chumlea et al., 2003) or in the UK (Whincup years, 50% of cycles are ovulatory in the ®rst year and virtually all et al., 2001). However, the UK study observed that almost one girl by the ®fth year. By contrast, it takes 8±12 years for all cycles to be in eight reaches menarche while still at primary school. There ovulatory in girls with later onset of menarche (Vihko and Apter, appears to be a relationship between body weight and the onset of 1984). This has important clinical implications for advising menarche, supported by earlier menarche seen in obese girls adolescents on the `normality' of their menstrual pattern relative (World Health Organization, 1986). to their age at menarche and likely patterns in the future. Nutrition and body weight play an important role in pubertal After menarche, pregnancy can occur. It is impossible and development. Chronic disease, malnutrition, eating disorders and unwise to try to separate menarche from sexual health education in high levels of physical activity can delay menarche. The mech- adolescent girls. Guidance about contraception and STI is anism for this relationship has not been conclusively de®ned. essential, regardless of whether she is currently sexually active. Insulin has been suggested as a modulator of the tempo of pubertal The teenage birth rate in the UK is second only to that in the USA development through regulation of insulin-like growth factor and a high percentage of adolescent occurs in the binding protein (IGFBP-1) and sex binding globulin initial months of sexual activity. Early menarche is associated with (SHBG; Ibanez et al., 1997). States of over-nutrition and earlier age of sexual debut, increased rates of STI and cervical are associated with increased serum concentrations of insulin. atypia and is hence an important indicator for continued risk Therefore if excessive nutritional intake persists during childhood, behaviour regarding reproductive health (Andersson-Ellstrom it is possible that hyperinsulinaemia resulting from obesity may et al., 1996). UK teenagers have high rates of STI (Creighton lead to lower levels of IGFBP-1 and reduced SHBG concentra- et al., 2002) and younger age is the strongest risk factor for tions, thus enhancing IGF-I and sex steroid bioavailability. trachomatis infection, across a broad range of popu- associated with PCOS may augment this lations (Burstein et al., 1998). Effective prevention strategies must situation. The converse would be true in states of malnutrition, include the younger adolescent population, ideally before they where low levels of insulin would allow for the development of become sexually active. increased IGFBP-1 and SHBG levels. However, it is still unclear whether hyperinsulinaemia in childhood is a result of obesity, or if Disorders of puberty it is the cause of obesity. The role of genetic factors, which may determine insulin production and obesity risk in childhood, have Precocious puberty also yet to be clearly explained. Well-described physical and anatomical changes of puberty, Serum concentrations of relate to body fat mass, and classi®ed according to Tanner (1962) are evident from 9 to 13 leptin appears to act on the to control calorie intake, years and follow the increase in adrenal from 6 to 8 decrease thermogenesis, increase levels of serum insulin, and years. Precocious puberty has been de®ned by Marshall and increase pulsatility of GnRH (Mann and Plant, 2002), hence Tanner (1969) as `Any secondary sex characteristic appearing regulating the onset of puberty (Mantzoros et al., 1997). This may in a girl before the age of 8 years (9 years for boys) or the onset explain the observed relationships between body fat and ovarian maturation observed by Frisch and Revelle (1970). Homozygous of menstruation prior to 10 years of age'. The de®nition of mutation of the leptin gene results in early-onset morbid lower limit for the onset of pubertal development in girls is obesity, and the absence of pubertal development in association controversial and pubertal growth may be occurring earlier with reduced growth hormone secretion (Clement et al., 1998). than had previously been described, despite the age of Menstrual bleeding lasts 2±7 days in 80±90% of adolescent girls menarche remaining constant. Racial variations are well (Flug et al., 1984). As a rule of thumb, changing three to six pads established and pubertal development occurs earlier in girls per day without soiling from oversaturated pads suggests a normal from an Asian and Afro-Caribbean background than in white ¯ow (Adams Hillard, 2002). Whilst adolescent menstrual cycles girls (Datani and Brook, 1998; Chumlea, 2003). A US study of may initially be variable this does not mean that `anything goes' >17 000 girls suggests that pubertal development is seen in and cycles tend to regulate over the ®rst 2±3 years following 15% of white girls aged under 8 years and 48% of black girls

494 Menstrual disorders in adolescence

Table I. Causes of precocious puberty and development as well as timing and sequence of physical milestones should be considered. This assessment might be Gonadotrophin dependent (`true' or `central' precocious puberty) most appropriately performed by a paediatrician. It is import- Idiopathic (family history, overweight/obese) ant that parents and girls are aware that menarche is likely to Intracranial lesions (tumours, , irradiation, trauma) Gonadotrophin secreting tumours occur in the 2 years following initial pubertal development. Hypothyroidism Bone maturation is accelerated in precocious puberty, leading Variants to premature epiphyseal closure and curtailed stature. Pituitary Premature (and thelarche variant) suppression with GnRH agonists is frequently indicated to Gonadotrophin independent delay puberty. Therapy with GnRH agonists does not substan- Congenital adrenal hyperplasia tially affect adult height in girls who enter puberty between Sex steroid secreting tumours (adrenal or ovarian) ages 6 and 8 years (Leger et al., 2000; Root, 2000). McCune±Albright syndrome

Exogenous ingestion/administration e.g. child ingesting oral Downloaded from https://academic.oup.com/humupd/article/9/5/493/727661 by guest on 06 October 2021 contraceptive pills Delayed puberty is de®ned as absence of onset of puberty by >2 SD later than the average age, i.e. >14 years in females. Delayed puberty may be idiopathic/familial or due to a number of general conditions resulting in undernutrition. Absence of (Herman-Giddens et al., 1997), although the average age of puberty may also be due to gonadal failure (elevated menarche did not differ between these groups. Hence, US gonadotrophin levels), or due to impairment of gonadotrophin guidelines advise that investigation of or secretion. development is justi®ed in white girls aged <7 years and black Although some cases of delayed puberty in girls may be due girls <6 years (Kaplowitz and Oberfeld, 1999). Similar to constitutional delay and require only reassurance, the patient population ®gures for the UK are not available, hence the requires review within 6 months, at which point investigation is de®nition of precocious puberty remains unchanged. likely to be indicated. Delayed puberty due to chronic disease Early signs of pubertal development are likely to cause may respond to improved control of the associated condition. alarm in parents and may lead to social and psychological Eating disorders such as anorexia nervosa and bulimia affect dif®culties for the girl aware that her body is becoming 0.5±1% of young women in developed countries with long- markedly different from that of her peers. In girls, 90% of cases term mortality rates approaching 20% (Tamburrino and are constitutional, secondary to premature release of gonado- McGinnis, 2002). The classic triad of presenting symptoms is trophins, without any organic lesion and puberty often weight loss >15% of ideal body weight, behavioural changes proceeds slowly in these girls (Root, 2000). and amenorrhoea (secondary or primary). Delayed puberty In 10% of cases, precocious puberty is secondary to an associated with low body mass index (BMI) should be intercranial lesion causing premature gonadotrophin release carefully questioned about eating disorders, as amenorrhoea such as meningitis or cerebral tumour. The rare McCune± may precede signi®cant weight loss. Bulimia is associated with Albright syndrome (characterized by ®brous dysplasia of the and can occur in girls of normal weight. skeletal system, cafe-au-lait spots, and endocrine dysfunction) Intense exercise, such as long-distance running, ballet, rowing, is also associated with precocious puberty. In primary long-distance cycling and gymnastics, is associated with hypothyroidism increased circulating thyrotrophin-stimulating delayed menarche in young girls, and with amenorrhoea in hormone and consequent increased thyroid-stimulating hor- older women (Frisch et al., 1981). These `endurance' sports are mone may also elevate FSH and hence lead to premature associated with lower bodyweight and percentage fat. The ovarian activity (Duncan et al., 1998). Feminizing estrogen- extent to which menarche is `delayed' is related to the age at secreting ovarian tumours are rare and the majority are benign. which participation in the sport begins, and to the intensity of When precocious puberty presents under the age of 6 years an training. Promotion of very thin women as `ideal' role models underlying disturbance affecting ovarian development is more through media and fashion has contributed to an increase in likely. When these features occur closer to the time of normal in adolescent girls. In addition, there are future puberty it is more likely that that problem is one of general implications for ovarian function, fertility and sexuality and advance of the maturational process (Adams Hillard, 2002). psychological support may be required at an early stage. Rarely, anomalous puberty may arise when there is When chromosomal or structural abnormalities are sus- inappropriate hormonal secretion with . Causes pected, or premature ovarian failure, the patient should be include gonadal dysgenesis with a functioning tumour, referred directly to a tertiary referral centre offering tailored congenital adrenal hyperplasia and adrenal tumours. services for young women, preferably with the results of Precocious adrenarche has been associated with an increased preliminary investigations. risk of subsequent insulin resistance and hyperandrogenism/ Gonadal failure presenting as delayed puberty requires PCOS (Ibanez et al., 2000; Pathomvanich et al., 2000). specialist assessment and management. Clinicians should be The causes of precocious puberty are summarized in Table I. aware that several studies indicate long delays in both In assessing precocious puberty, the child's previous growth recognition of premature ovarian failure as abnormal and

495 M.Hickey and A.Balen

Table II. Causes of delayed puberty

General Constitutional delay of growth and puberty Underweight (due to severe dieting/anorexia nervosa, over-exercise or competitive sports, malabsorption such as coeliac disease or in¯ammatory bowel disease) Other chronic disease Gonadal failure (hypergonadotrophic ). Ref: http://www.emedicine.com/med/topic117.htm Prodromal premature ovarian failure: this is a state of ovarian insuf®ciency in which FSH levels are elevated and menses are irregular but not to the degree required to make a diagnosis of premature ovarian failure. It is also referred to as overt ovarian insuf®ciency. Karyotypically normal (idiopathic) spontaneous premature ovarian failure Turner's syndrome Pure gonadal dysgenesis: The term `pure' here refers to the fact that the syndrome seems to have purely affected the . No associated dysmorphic ®ndings exist as are noted in Turner syndrome, which is often referred to as gonadal dysgenesis. Pure gonadal dysgenesis can occur with either a 46,XX or a 46,XY karyotype

Autoimmune Downloaded from https://academic.oup.com/humupd/article/9/5/493/727661 by guest on 06 October 2021 17,20-Desmolase de®ciency or 17-hydroxylase de®ciency Radiation or chemotherapy Galactosaemia FSH receptor mutation Gonadotrophin de®ciency Congenital hypogonadotrophic hypogonadism (6 anosmia) Hypothalamic/pituitary lesions (tumours, post radiotherapy) Rare inactivating mutations of genes encoding LH, FSH or their receptors

diagnosis by a clinician (Alzubaidi et al., 2002) and that ogistÐwhose role is to help co-ordinate the transition from delayed diagnosis may have serious implications for longer- childhood through adolescence and then womanhood and help term health. with issues relating to sexual function and sexual identity, In subjects with hypergonadotrophic hypogonadism, puberty and fertility. It is during the dif®cult time of may be induced from any age; however, in Turner's syndrome adolescence that the patient usually ®rst realizes that there are delay in induction to ~14 years old possibly permits maximal serious problems and it is often the specialist gynaecologist who response to growth . Low-dose estrogen helps her to understand the diagnosis and requirements for therapy (2±5 mg/day) is given to promote breast development management. The support of a skilled nurse and clinical psych- and cyclical estrogen plus is then used as ologist is invaluable at this time. The Department of Health in the maintenance therapy. There is some evidence that transdermal UK is currently reviewing the national provision of services for the therapy may be preferred although it is too early for any management of intersex. Those units that have the skills to manage con®dent recommendation. Ankarberg-Lindgren et al. (2001) intersex conditions usually also have the appropriate facilities to induced puberty in 15 girls with hyper- or hypogonadotrophic treat complex anatomical anomalies of the MuÈllerian tract (for hypogonadism using low doses of transdermal example cervical and vaginal agenesis). Disorders of sexual development may result in ambiguous patches attached only during the night and compared the genitalia or anomalies of the internal genital tract and may be due estradiol concentrations obtained with those in healthy girls. A to genetic defects, abnormalities of steroidogenesis and dysyn- transdermal matrix patch of 17b-estradiol (25 mg/24 h; Evorel, chrony during organogenesis. Age of presentation will depend Janssen Pharmaceuticals±Cilag) was cut into pieces corres- upon the degree of dysfunction caused. Ambiguous genitalia occur ponding to 3.1, 4.2 or 6.2 mg/24 h initially and attached to the in ~1:30 000 newborns. Issues concerning genital surgery for buttock. After 4±14 months, the dose was increased gradually. intersex are controversial and data on long-term outcomes are Serum 17b-estradiol concentrations were measured every 2 h. lacking. However, the effects on sexual function of surgical This regimen appeared to mimic the spontaneous levels as well removal of parts of the are largely unknown. A recent UK as the diurnal pattern of serum 17b-estradiol in early puberty. study by Minto et al. (2003) of 39 adults with intersex conditions In most of the girls, breast development occurred within 3±6 and ambiguous genitalia and found markedly increased rates of months of the start of treatment. The causes of delayed puberty in those who had undergone genital surgery are summarized in Table I. compared with those who had not had surgery. These risks should be discussed when counselling parents regarding genital surgery in infants or children, and provide further evidence that delaying Intersex disorders surgery until individuals can make their own decision is preferable It is imperative that intersex conditions are managed in centres by when possible. a multi-disciplinary team that includes paediatric surgeons, Sensitivity is paramount in dealing with young women found to urologists (often paediatric and adult), surgeons, endocri- have genetic or hormonal abnormalities with profound implica- nologists, specialist nurses, psychologists and also the gynaecol- tions for their future sexual and reproductive heath. The physician

496 Menstrual disorders in adolescence should aim to provide access to counselling, further information a urethral ®stula which may require careful repair at the time of about their condition and contact details for support groups an introitoplasty. If clitoral reduction is imperative it should be undertaken with care to preserve the neurovascular bundle and insensitivity syndrome sensation. Surgery may be undertaken during the neonatal Girls who are phenotypically normal but have absent pubic and period and may be required again during adolescence. As with axillary hair in the presence of normal breast development are all surgery for intersex disorders, the precise timing is open to likely to have complete androgen insensitivity syndrome debate, as is the degree to which the patientÐrather than her (CAIS, previously known as testicular feminization syndrome). parents and physiciansÐis involved in the decision-making In this condition, the karyotype is 46,XY and, whilst testes are process. In the rare situation of 17a-hydroxylase de®ciency, present, there is an end-organ insensitivity to secreted replacement corticosteroids normalizes the adrenocortico- androgens because of abnormalities in the . trophic hormone axis and then estrogen and progestogen The incidence is ~1:60 000 genotypic male births and is replacement can be prescribed. inherited as an X-linked trait (the androgen receptor is on the Downloaded from https://academic.oup.com/humupd/article/9/5/493/727661 by guest on 06 October 2021 short arm of the X chromosome). Anti-MuÈllerian factors Congenital absence of the vagina prevent the development of internal MuÈllerian structures and Structural disorders of the reproductive tract during embry- the Wolf®an structures also fail to develop because of the ological development (MuÈllerian disorders) are usually asso- insensitivity to testosterone. The external genitalia appear ciated with normal ovarian development and therefore do not female. In ~10% the defect is incomplete (PAIS: partial require sex steroid therapy, but for those with an absent vagina androgen insensitivity syndrome); the external genitalia may an arti®cial vagina needs to be developed when the young be ambiguous at birth, with labio-scrotal fusion and virilization woman is `appropriately mature' to understand the diagnosis may sometimes occur before puberty. Partial androgen and the options regarding intervention. Surgical `neo vaginas' insensitivity syndrome covers a wide spectrum of under- are now rarely advised since vaginal dilators provide excellent virilized phenotypes ranging from clitoromegaly at birth to results and are now ®rst line therapy for vaginal agenesis infertile men. (ACOG, 2002). The renal tract should be imaged in those with Diagnosis is con®rmed by identi®cation of the androgen MuÈllerian abnormalities to rule out an associated structural receptor gene mutation. Although patients with complete variation. androgen insensitivity syndrome are raised as females, patients Women with Mayer±Rokitansky±Kuster±Hauser syndrome with partial androgen insensitivity syndrome should be man- (MRKH or Rokitansky syndrome) have a 46,XX genotype and aged according to age at diagnosis, response to treatment with a normal female phenotype with spontaneous development of exogenous androgens, and the presence of an androgen gene secondary sexual characteristics, as ovarian tissue is present mutation. and functions normally. The MuÈllerian ducts have failed to fuse AIS should be distinguished from other forms of male and so there is vaginal agenesis. The incidence is ~1:5000 pseudohermaphroditism such as 17b-hydroxysteroid dehydro- female births and may be associated with renal tract anomalies genase type 3 de®ciency, leydig cell hypoplasia due to (15±40%) or anomalies of the skeletal system (10±20%). The inactivating LH receptor mutations or 5a-reductase type 2 external genitalia have a normal appearance, but the vagina is de®ciency. short and blind-ending, such that either surgery or gradual AIS may be diagnosed in infancy if a testis is found in either dilation is necessary to achieve a capacity appropriate for the labia or an inguinal hernia, in which case both testes should normal sexual function. Hormone treatment is not required as be removed at this time because of the potential risk of ovarian estrogen output is normal. Indeed occurs and malignancy. If not diagnosed in infancy, CAIS may only ovarian stimulation followed by oocyte retrieval can be present at puberty with primary amenorrhoea and removal of performed in order to achieve a `biological' pregnancy via abdominal/inguinal testes should then be performed. surrogacy. Gonadectomy should be performed whenever there is a Y The vaginal dimple can vary in length from just a slight chromosome or Y chromosome remnant because of the depression between the labia to up to 5±6 cm. Vaginal dilators, theoretical risk of malignancy developing in the dysfunctional made of plastic or glass, are used ®rst to stretch the vaginal skin gonad. This is probably best delayed until after puberty and the patient is encouraged to apply pressure for 15 min because in the case of AIS the testosterone is converted to twice daily with successive sizes of dilator. An adequately estrogen and can help to initiate some normal breast develop- sized vagina is usually formed by 6 months but this may take ment. Exogenous estrogen should then be prescribed. longer and long-term use of dilators may be requiredÐ Progestogens are not required because the is absent. depending upon the frequency of . The diagnosis of Rokitansky syndrome can usually be made Congenital adrenal hyperplasia without the need for a . Sometimes, however, an The commonest cause of `female pseudohermaphroditism' is scan will reveal the presence of a uterine remnant congenital adrenal hyperplasia. Androgenization of the female (anlagan) which is usually small and hardly ever of suf®cient external genitalia may lead not only to clitoral enlargement but size to function normally. If there is active endometrial tissue also fusion of the labio-scrotal folds. There may in addition be within the uterine anlagan the patient may experience cyclical

497 M.Hickey and A.Balen

Table III. Causes of primary amenorrhoea with two cervices or a partial septum causing a unilateral obstruction. Excision is required both to prevent retention of Uterine causes uterine secretions and to permit sexual intercourse. MuÈllerian agenesis (e.g. Rokitansky syndrome) Transverse fusion abnormalities usually present with pri- Ovarian causes Polycystic ovary syndrome mary amenorrhoea and require careful assessment before Premature ovarian failure (usually genetic, e.g. Turner's syndrome) surgery. The commonest presentation is of cyclical lower Hypothalamic/pituitary causes (hypogonadotrophic hypogonadism) abdominal pain and a visible haematocolpos with a bulging Weight loss purple/blue hymen. The surgery required is a simple incision. Intense exercise (e.g. ballerinas) Delayed diagnosis may lead to haematometra and consequent Idiopathic Consitutional delay or secondary increased risk of (secondary to retrograde menstruation). A transverse vaginal septum due to failure of Hypopituitarism fusion or canalisation between the MuÈllerian tubercle and sino-

Causes of hypothalamic/pituitary damage (hypogonadism) vaginal bulb may present similarly but is associated with a pink Downloaded from https://academic.oup.com/humupd/article/9/5/493/727661 by guest on 06 October 2021 Tumours (craniopharyngiomas, gliomas, germinomas, dermoid cysts) bulge at the introitus as the septum is thicker. Great care must Cranial irradiation, head (rare in young girls) Systemic causes be taken during surgery to prevent annular constriction rings Chronic debilitating illness and the procedure should only be performed in dedicated Weight loss centres by experienced surgeons. Endocrine disorders (thyroid disease, Cushing's syndrome etc.) Primary amenorrhoea The failure to menstruate by the age of 16 years in the presence of normal secondary sexual development, or 14 years in the absence Table IV. Classi®cation of secondary amenorrhoea of secondary sexual characteristics, warrants investigation. This distinction helps to differentiate reproductive tract anomalies from Uterine causes Asherman's syndrome, cervical stenosis gonadal quiescence and gonadal failure. Primary amenorrhoea TB may be a result of congenital abnormalities in the development of Ovarian causes ovaries, genital tract or external genitalia or a disturbance of the Polycystic ovary syndrome normal endocrinological events of puberty. Overall it is estimated Premature ovarian failure (genetic, autoimmune, infective, that endocrine disorders account for ~40% of the causes of primary radio/chemotherapy) amenorrhoea, the remaining 60% having developmental abnor- Hypothalamic causes (hypogonadotrophic hypogonadism) Weight loss, exercise, chronic illness, psychological distress, idiopathic malities. For an excellent review of this topic see http:// Pituitary causes www.emedicine.com/med/topic117.htm and for a summary see Hyperprolactinaemia Table III. Hypopituitarism Sheehan's syndrome Causes of hypothalamic/pituitary damage (hypogonadism) Secondary amenorrhoea Tumours (e.g. craniopharyngiomas) Cranial irradiation Secondary amenorrhoea is the absence of menstruation, which Head injuries may be temporary or permanent and of >6 months duration, Sarcoidosis although 6 months is largely an arbitrary de®nition and Tuberculosis amenorrhoea should be considered within its clinical context. Systemic causes Any cause of secondary amenorrhoea may also cause primary Chronic debilitating illness (such as mellitus or lupus), weight loss, amenorrhoea. PCOS and pregnancy may both present with endocrine disorders (thyroid disease, Cushing's syndrome etc.) secondary amenorrhoea in early reproductive life. A prolonged Drugs causing amenorrhoea Cocaine and opioids have central effects that may disrupt the menstrual cycle hypoestrogenic state carries the risk of bone demineralization, Psychotrophic drugs osteoporosis and fracture. Therefore, secondary amenorrhoea Progestogens associated with low estrogen levels requires estrogen supplemen- Drugs interfering with the HPO axis such as GnRH analogues tation to maintain bone density. The causes of secondary amenorrhoea are summarized in Table IV. HPO = hypothalamic±pituitary±ovarian; TB = tuberculosis. Examination and investigation of amenorrhoea in adolescence pain and the anlagan should be excised (usually laparoscopi- Taking a gynaecological history from an adolescent should include cally). questions about sexual activity and risk-taking behaviour. However, pregnancy should be ruled out with laboratory testing Fusion abnormalities of the vagina in cases of oligoamenorrhoea or amenorrhoea even if sexual Longitudinal fusion abnormalities may lead to a complete activity is denied, since adolescence may feel unable to con®de in septum that may be associated with two complete uterine horns a clinician about this (Adams Hillard, 2002).

498 Menstrual disorders in adolescence

Table V. The investigation of amenorrhoea secondary amenorrhoea in adolescence and is associated with osteopenia or osteoporosis. Colao et al. (2000) observed that Method although prolactin levels were normalized by dopamine antagonist History therapy, bone density did not return to normal, emphasizing the Physical examination importance of early diagnosis and longer-term follow-up of these Note body mass index, pubertal development, Stigmata of PCOS and other patients. A moderate and transient elevation in prolactin may Acne and hirsutism occur in response to `stress' or even a recent breast examination. A Endocrine assessment more permanent but still moderate elevation (>700 mIU/l) is Pregnancy test if suspected associated with hypothyroidism and is also a common ®nding in FSH, LH, prolactin, thyroid function tests women with PCOS. Testosterone (if stigmata of PCOS) Amenorrhoea in women with PCOS is secondary to acyclical Further endocrinology only if above do not provide diagnosis ovarian activity and continuous estrogen production. A positive Ultrasound response to a progestogen challenge test, which induces a

Morphology of ovaries and endometrial thickness (for estrogenization) Downloaded from https://academic.oup.com/humupd/article/9/5/493/727661 by guest on 06 October 2021 Pelvic imaging withdrawal bleed, may distinguish patients with PCOS-related MRI if suggestion of complex anatomical problem hyperprolactinaemia from those with polycystic ovaries and Pituitary/hypothalamic imaging unrelated hyperprolactinaemia, because the latter causes estrogen As indicated clinically de®ciency and therefore failure to respond to the progestogen Bone mineral densitometry challenge. However, a positive withdrawal bleed may also be If hypoestrogenic Karyotype associated with weight gain in a previously underweight subject. If premature ovarian failure Amenorrhoea may also have long-term metabolic and physical consequences. In women with PCOS and prolonged amenorrhoea, there is a risk of and adenocarcinoma. For PCOS = polycystic ovary syndrome. this reason, endometrial shedding should be encouraged at least every 3 months, either via therapy with a low-dose contraceptive pill or cyclical progestogens, or via intermittent progestogens. The need for a bimanual examination in a young woman who has never been sexually active should be carefully considered. The Premature ovarian failure majority of adolescents can be assessed using an examination of the external genitalia and imaging studies such as ultrasound if Premature ovarian failure may present as primary or secondary needed. However, a cooperative adolescent, even if never sexually amenorrhoea in adolescents. Karyotyping is indicated to exclude active, can often be evaluated with a single ®nger bimanual Turner's syndrome (45X, or 46XX/45X mosaic) or other sex examination, allowing her mother to be present if the patient chromosome mosaicisms. Thyroid-stimulating hormone, fasting wishes. Examination may identify a blind ending or absent vagina glucose and adrenal antibodies should be checked and repeated or haematocolpos, and the visualization of the . annually, due to the association with autoimmune disease in those Transabdominal ultrasound may indicate whether the uterus and with a normal karyotype. Idiopathic familial POF is also well ovaries are present. In the USA, magnetic resonance imaging is the recognized and may be associated with a mutation of the inhibin a primary investigation of preference and can provide information gene (Marozzi et al., 2002). Ovarian antibodies are rarely useful. additional to ultrasound. Examination under anaesthesia (EUA) is Measurement of bone mineral density is indicated in amenorrhoeic the ®nal step in diagnosis which might rarely need to be combined women who are estrogen de®cient. A total of 8% of bone mass is with laparoscopy, for example in complicated MuÈllerian lost in the ®rst year after and thereafter between 1 and abnormalities (Letterie et al., 1995). 2% (Luisetto et al., 1993). The vertebral bone is more sensitive to A transabdominal ultrasound examination of the is an estrogen de®ciency and vertebral fractures tend to occur in a excellent non-invasive method of obtaining valuable information younger age group (50±60 years) than fractures at the femoral neck in these patients. An examination under anaesthetic is sometimes (>70 years). For review see Bakalov and Nelson (2001). Dual- indicated for cases of intersex with primary amenorrhoea; it is energy X-ray absorptiometry (DEXA) is valuable in predicting rarely required in cases of secondary amenorrhoea. patients at risk of fracture. However, DEXA scans of adolescents The investigative techniques for amenorrhoea are listed in require normal values for this population that may not be routinely Table V. Signs of hyperandrogenism (acne, hirsutism, alopecia) included with the scanner software (http://www-stat-class.stanfor- are suggestive of the polycystic ovary syndrome (PCOS, see d.edu/pediatric-bones/). below). Hyperandrogenism must be distinguished from viriliza- tion, where high circulating androgen levels are associated with Oligomenorrhoea deepening of the voice, increase in muscle bulk and cliteromegaly. A baseline assessment of the endocrine status should include Oligomenorrhoea may be de®ned as menses occurring less measurement of serum prolactin and gonadotrophin concentra- frequently than every 35 days. The commonest cause of tions and an assessment of thyroid function. Elevated gonado- oligomenorrhoea is PCOS and other causes include either trophin (FSH and LH) concentrations indicate ovarian failure temporary disturbances of menstrual cycle control, body weight whilst suppressed levels suggest hypogonadotrophic hypogonad- (obesity or underweight) and hyperprolactinaemia as well as ism. Hyperprolactinaemia due to prolactinoma may present with developing causes of secondary amenorrhoea.

499 M.Hickey and A.Balen

PCOS in adolescence hair. Laser therapy works best in women with dark hair on fair PCOS appears to underlie irregular menses in up to one-third of skin, but is expensive and not permanent (despite claims to the girls (Venturoli et al., 1986). Menarche is not usually delayed, contrary). Electrolysis is the only permanent method of hair but bleeding is then persistently irregular. In adolescents, removal and should be delayed until androgens are effectively PCOS can present with primary or secondary amenorrhoea, suppressed. acne, hirsutism or merely irregular periods, as set out in Hyperandrogenism can be treated by a combination of an Table IV. estrogen (such as ethinylestradiol, or a combined contraceptive Ovarian dysfunction leads to the main signs and symptoms pill), and the anti-androgen acetate (CPA, 50±100 of the PCOS and the ovary is in¯uenced by external factors, in mg). lower circulating androgens by a combination particular the gonadotrophins and insulin, which are them- of a slight inhibition of gonadotrophin secretion and gonado- selves dependent upon both genetic and environmental in¯u- trophin-sensitive ovarian steroid production and by an increase ences. Approximately 20±33% of women of reproductive age in hepatic production of -binding globulin result- will have polycystic ovaries on ultrasound scan (Polson et al., ing in lower free testosterone. The CPA is taken for the ®rst 10 Downloaded from https://academic.oup.com/humupd/article/9/5/493/727661 by guest on 06 October 2021 1988; Michelmore et al., 1999); while perhaps 75±80% of days of a cycle (the `reversed sequential' method) and the these will have symptoms consistent with the diagnosis of estrogen for the ®rst 21 days. After a gap of exactly 7 days, PCOS. Menstrual disturbance is likely to be the main issue for during which menstruation usually occurs, the regimen is adolescents with PCOS but the established long-term risks of repeated. As an alternative, the preparation Dianetteâ obesity, subfertility and diabetes as well as the possible risks of (Schering, UK) contains ethinylestradiol in combination with endometrial hyperplasia and carcinoma (Hardiman et al., 2003) CPA, although at a lower dose (2 mg). CPA acts as a and cardiovascular disease (recently reviewed by Rajkowha competitive inhibitor at the androgen receptor. CPA can rarely et al., 2000) and breast (Balen, 2001) require consid- cause liver damage and liver function should be checked after 6 eration. Obesity also compounds the clinical manifestations of months and then annually. Combined oral contraceptive pills PCOS and weight loss may lead to symptom improvement. (COCP) have the added advantage of providing effective PCOS may ®rst manifest in adolescence but its origins are contraception for adolescents, given the high rates of likely to be much earlier. PCOS is associated with increased unintended pregnancy in this group. If contraception is needed, weight gain during puberty (Balen and Dunger, 1995). Genetic counselling should include the information that COCP will not study of PCOS has identi®ed links with insulin secretion and protect against STI and additional barrier contraception is action as well as increased ovarian androgen secretion). advised. However, the COCP has the disadvantage of increas- Association has been reported with common allelic variation ing insulin resistance (Morin-Papunen et al., 2000). However, at the variable number of tandem repeat locus (VNTR) in the this effect on insulin sensitivity has not been observed with the promoter region of the insulin gene (Waterworth et al., 1997). norgestimate-containing OCP in non-obese PCOS subjects This locus has been variably associated with the risk of obesity, (Cibula et al., 2002). insulin resistance and type 2 diabetes. The identi®ed associ- , a potassium sparing diuretic, has anti- ation has been with the class III/III genotype, particularly in androgenic properties and is useful in women for whom the women who have anovulatory cycles and are hyperinsulinae- is contra-indicated (e.g. because of mic (Waterworth et al., 1997; Michelmore et al., 2001). hypertension). Spironolactone, at a dose of 50±200 mg daily, may result in erratic menstrual bleeding and should be Management of PCOS in adolescence combined with reliable contraception. A new COCP, The clinical management of young women with PCOS should Yasminâ (Shering UK), contains the progestogen, drospir- be focused on her individual problems. Obesity worsens both enone, which is a derivative of spironolactone, with potential symptomatology and the endocrine pro®le and so obese girls anti-androgenic properties and bene®ts for women with PCOS. (BMI >25 kg/m2) should be encouraged to lose weight, and Although diet is the ®rst line treatment for improving insulin they should also have a test of fasting glucose tolerance (e.g. 2 sensitivity in overweight adolescents with PCOS, insulin- h GTT) and fasting insulin to assess the glucose:insulin ratio. sensitizing agents, such as , are becoming increas- Impaired glucose tolerance has been seen in up to one-third of ingly popular in the management of PCOS as they act directly adolescents with PCOS (Palmert et al., 2002). on insulin resistance and help correct both metabolic and Hyperandrogenism and hirsutism are distressing symptoms endocrine problems. Although initial studies suggest an for young women and the clinician should be aware that improvement in menstrual regularity in PCOS, the role of cosmetic measures may disguise the extent of the problem. insulin-sensitizing medications in adolescents with PCOS is Optimally treatment combines cosmetic and medical therapies. unclear. Primary prevention of diabetes mellitus and cardio- Medical regimens stop further progression of hirsuitism and vascular disease by lifestyle modi®cation, including regular slow the rate of hair growth. However, drug therapies may take exercise and a balanced diet, is particularly important in 6±9 months or longer before any bene®t is perceived and so adolescents, who have the opportunity to establish healthy laser, electrolysis, waxing and bleaching may be helpful in the habits before entering adulthood. The ®ndings of diabetes interim. Medical therapy is aimed at slowing the rate of hair prevention trials suggest that these interventions may be more growth whilst cosmetic treatments attempt to remove existing ef®cacious than pharmacological therapy (Legro, 2002;

500 Menstrual disorders in adolescence

Table VI. The spectrum of clinical manifestations of polycystic ovary syndrome

Signs and symptoms Endocrine disturbances Possible late sequelae (% patients affected)

Obesity (38%) ­ Insulin Dyslipidaemia ¯ Sex hormone-binding globulin ­ LDL, ¯ HDL, ­ triglycerides Menstrual disturbance (66%) Oligomenorrhoea 47% Amenorrhoea 19% Regular cycle 30% Hyperandrogenism (48%) ­ androgens (testosterone and Diabetes mellitus androstenedione) Cardiovascular disease (PCOS underlies 73% of anovulatory infertility) ­ LH Hypertension Downloaded from https://academic.oup.com/humupd/article/9/5/493/727661 by guest on 06 October 2021 Asymptomatic: 20% of those with polycystic ovaries ­ prolactin Endometrial carcinoma

Kaufman et al., 2002; Kiess et al., 2003). However, the be collected. In the majority of cases, no signi®cant underlying implications of PCOS for long-term health remain unclear, pathology will be found and reassurance of the patient and her and, although mortality rates have not conclusively been shown parents is the most appropriate management. to be elevated in PCOS patients, concerns exist that women General physical examination should search for evidence of with this syndrome cluster risk factors for premature morbidity pelvic and systemic pathology that may account for heavy and/or and mortality (Wild, 2002). irregular bleeding. Investigations may include abdominal ultrasound scan and, if necessary, examination under anaesthesia. An estima- tion of circulatory haemoglobin levels should be performed on all Management of amenorrhoea females complaining of menorrhagia. Immune thrombocytopaenia purpura (ITP) may also present with menorrhagia in the adolescent The general principle of treatment is to replace estrogen when (associated with bruising, petechiae and mucosal bleeding) requir- hypoestrogenaemia is demonstrated in order to prevent the ing specialist haematological assessment (Bevan et al., 2001). The consequences of long-term estrogen de®ciency. Even short-term incidence of these disorders in the UK has not been reviewed estrogen de®ciency leads to bone loss, increasing the risk of recently, but a 9 year audit of paediatric cases in the USA from 1971 osteoporosis. More prolonged de®ciency may also increase to 1980 revealed that a primary coagulation disorder was found in cardiovascular risk. When a uterus is present, progestogens should almost 20% of 59 patients admitted to a children's hospital for acute also be given to avoid endometrial hyperplasia. Longitudinal studies are needed to determine the optimum replacement needed menorrhagia, where genital tract pathology had been excluded. One- for young hypoestrogenic women such as those with Turner's quarter of those with severe menorrhagia (haemoglobin <10 g/100 syndrome. In these patients, growth hormone supplements may ml), one-third of those requiring transfusion, and one-half of those also be used to increase stature. presenting at menarche had such an underlying disorder (Claessens et al., 1981). Red blood cell indices and serum ferritin levels may be indicated if there is iron de®ciency anaemia. In anovulatory DUB, Management of dysfunctional uterine bleeding in serum LH and FSH changes may indicate PCOS or a premature peri- adolescence menopausal state. Transabdominal ultrasound and serum androgens will provide additional information in the diagnosis of PCOS. If The term `dysfunctional uterine bleeding' (DUB) is taken to mean there is irregular and acute bleeding, complications of pregnancy `excessively heavy, prolonged or frequent bleeding of uterine should be excluded. origin, which is not due to pregnancy or to recognizable pelvic or systemic disease'(Fraser, 1985). Ovarian cycles associated with bleeding may be ovulatory or anovulatory, and the condition may Management of DUB be acute or chronic. In later reproductive life, DUB is regular and ovulatory in ~80% of cases, but in adolescence and early Management of DUB in the adolescent is medical in almost all reproductive life, anovulatory DUB with irregular cycles is circumstances. Modern low-dose oral contraceptive pills can be relatively common, up to 50% of cycles in the ®rst year of safely prescribed to most young women, provided that they are not menarche. known to have contraindicating factors. The combined oral Young women presenting with ovulatory DUB are occasionally contraceptive pill has been shown by objective measurement to found to have underlying coagulopathies. If there is a family reduce menstrual blood loss in ovulatory and anovulatory DUB history of coagulopathy or a history of heavy bleeding at surgery or (Nilsson et al., 1971). tooth extraction, it is worth discussing with a haematologist which In the treatment of anovulatory DUB, progestogens may be special investigations may be indicated and how the blood should suitable for women who are unable or unwilling to take estrogen-

501 M.Hickey and A.Balen

Table VII. Differential diagnosis of dysmenorrhoea and in adolescence (data derived from Quint, 2002)

Cyclical, or associated with bowel and bladder Uterus and ovaries Endometriosis symptoms, if sexually active Ovarian pathology Adhesions Infection MuÈllerian abnormalities Related to bowel motions, associated with bloating Gastrointestinal tract IBS, ulcerative colitis, Crohn's disease Dysuria Genitourinary system Recurrent cystourethritis, renal abnormality such as pelvic kidney, interstitial cystitis Associated with back pain Musculoskeletal system Skeletal abnormality such as scoliosis, kyphosis, spondylosis, spondylolithesis, myofascial syndrome Variable pattern Psychosocial Consider family stress, sexual and physical abuse

IBS = irritable bowel syndrome. Downloaded from https://academic.oup.com/humupd/article/9/5/493/727661 by guest on 06 October 2021

containing compounds. Oral progestogens are only effective if Endometriosis and pelvic pain given for >21 out of 28 days and low-dose Dysmenorrhoea is a common gynaecological complaint among progestogens are not an effective treatment for menorrhagia adolescent girls. Traditional teaching has distinguished pri- (Lethaby et al., 2000). mary (or spasmodic) and secondary dysmenorrhoea, but there In the adolescent with anovulatory DUB, cyclical oral is little objective evidence that these are distinct conditions progestogens may be required until spontaneous regular ovulation with differing pathologies. It is likely that many cases of occurs. endometriosis in young women have been put down to The disadvantages of oral progestogen regimens for DUB `spasmodic' dysmenorrhoea and persistent, disruptive and include the need for long-term oral medication and the possibility severe dysmenorrhoea unresponsive to non-steroidal anti- of unwanted `pre-menstrual symptoms' including: bloating, edema, headache, depression and reduced libido; androgenic in¯ammatory drugs (NSAID) and COCP warrants investiga- effects (depending on the progestogen used), such as acne and tion and treatment. Endometriosis may also present with non- hirsutism; irregular breakthrough bleeding and a change in cyclic pain, bowel and urinary symptoms. carbohydrate tolerance and lipid balance. The contraceptive The differential diagnosis of chronic pelvic pain in the depot preparation of medroxyprogesterone acetate (such as adolescent (>6 months) is extensive (see Table VII). History Depo-Proveraâ) will induce amenorrhoea in 50% of users at 1 should include questioning about bowel symptoms suggestive year. For those who can accept the 15±20% rate of irregular or of irritable bowel syndrome or in¯ammatory bowel disease as prolonged breakthrough bleeding, this may provide a safe and well as a social and sexual history. effective treatment regimen. The Mirenaâ intrauterine implant Pelvic examination may be helpful if the young woman is system (IUS) releasing 20 mg of levonorgestrel/day (LNG-IUS 20) sexually active, and may reveal uterosacral tenderness or is a highly effective long-term treatment for both ovulatory and nodularity suggestive of endometriosis, or cervical excitation anovulatory DUB (Anderson and Rybo, 1990). The system also suggestive of infection. Pelvic ultrasound is more sensitive for provides reversible contraception. The Mirena has a place in the ovarian pathology. It is reasonable to offer an empirical 3 management of refractory DUB in young women but the physician month trial of COCP, taken continuously for dysmenorrhoea. should consider insertion of the device under general anaesthetic. Failure to respond to this therapy and persistent gynaecological at the same time may also be indicated to exclude symptoms is an indication for laparoscopy. The patient's (rare) intrauterine pathology if a general anaesthetic is planned. consent should be obtained before laparoscopy to excise visible Irregular `breakthrough' bleeding is the main unwanted effect of endometriosis. all progestogen preparations and the main reason why women choose to discontinue these preparations, despite their other Menstrual disorders in adolescents with intellectual disability advantages. Historically there has been a tendency to aim for amenorrhoea in institutionalized women with intellectual disability, using Menstrual disturbances in PCOS continuous progestogens or by surgery. This has arisen from In obese girls with PCOS, weight loss may lead to resumption concerns about the ability of a young intellectually disabled of ovulation (Kiddy et al., 1992). Cyclical progestogen woman to cope with menstruation and the risks of sexual abuse treatment for 10 days every 6 weeks will generally lead to and unplanned pregnancy. Common menstrual disorders in this withdrawal bleeding and prevent hyperplasia. The COCP is an group include dysmenorrhoea (or behavioural changes thought alternative method of producing a regular withdrawal bleed, to re¯ect pain), amenorrhoea associated with delayed puberty but concerns about effects on insulin resistance must be or secondary to low weight, menorrhagia and cyclic exacer- considered (see above). bation of conditions such as epilepsy (Grover, 2002).

502 Menstrual disorders in adolescence

Endometrial ablation has been reported as an option for References managing heavy and irregular bleeding in this population (Wing®eld et al., 1994) but little is known about the medium to AdamsHillard, P.J. (2002) Menstruation in young girls: a clinical perspective. Obstet. Gynecol., 99, 655±662. long-term ef®cacy of this treatment in young women. In Alzubaidi, N.H., Chapin, H.L., Vanderhoof, V.H., Calis, K.A. and Nelson, addition, since does not guarantee L.M. (2002) Meeting the needs of young women with secondary contraception and subsequent pregnancy is associated with and spontaneous premature ovarian failure. Obstet. Gynecol., 99, 720±725. very poor fetal outcome, tubal ligation is usually recommended American College of Obstetrics and Gynecology (1996) Guidelines for at the same time. In a case series of >100 adolescents with Women's Health Care. ACOG, Washington, DC. signi®cant intellectual disability and moderate to high support American College of Obstetrics and Gynecology (2002) Committee opinion. Nonsurgical diagnosis and management of vaginal agenesis. Number 274, needs requiring specialist advice for menstrual disorders, July 2002. Committee on Adolescent Health Care. American College of Grover (2002) encountered only two young women requiring Obstetrics and Gynecology. Int. J. Gynaecol. Obstet., 79, 167±170. or endometrial ablation for menstrual disorders. Andersson, J.K. and Rybo, G. (1990) The levonorgestrel releasing intra-

uterine contraceptive device in the treatment of menorrhagia. Br. J. Downloaded from https://academic.oup.com/humupd/article/9/5/493/727661 by guest on 06 October 2021 Alternative management included providing information about Obstet. Gynecol., 97, 690±694. menstrual hygiene training, and improvement of family Andersson-Ellstrom, A., Forssman, L. and Milsom, I. (1996) Age of sexual support services including respite care. The capacity of debut related to life-style and reproductive health factors in a group of Swedish teenage girls. Acta Obstet. Gynecol. Scand., 75, 484±489. women with disabilities, even those with high support needs, Ankarberg-Lindgren, C., Elfving, M., Wikland, K.A. and Norjavaara, E. to gain additional skills in their personal menstrual manage- (2001) Nocturnal application of transdermal estradiol patches produces ment may often be underestimated (Grif®n et al., 1994). levels of estradiol that mimic those seen at the onset of spontaneous puberty in girls. J. Clin. Endocrinol. Metab., 86, 3039±3044. Effective medical managements for menstrual disorder in Bakalov, V. and Nelson, L.M. (2001) Ovarian Failure. eMedicine. http:// intellectually disabled girls and women were essentially the www.emedicine.com/med/topic1700.htm same as those for non-disabled women and included NSAID Baldaszti, E., Wimmer-Puchinger, B. and Loschke, K. (2003) Acceptability of for dysmenorrhoea and COCP or DMPA for menorrhagia. the long-term contraceptive levonorgestrel-releasing intrauterine system (Mirena): a 3-year follow-up study. Contraception, 67, 87±89. Surgery was only performed as a `last resort'. Since this study Balen, A.H. (2001) Polycystic ovary syndrome and cancer. Hum. Reprod. the Mirena (Schering, UK) intrauterine system has become Update, 7, 522±525. widely available. It is likely that Mirena will have a major Balen, A.H. and Dunger, D. (1995) Pubertal maturation of the internal genitalia (Commentary). Ultrasound Obstet. Gynecol., 6, 164±165. impact on menstrual management in this population, and may Balen, A.H., Fleming, C. and Robinson, A. (2002) Health needs of adolescents obviate the need for surgery with its attendant risks and loss of in secondary gynaecological care: results of a questionnaire survey and a reproductive potential in these vulnerable women. Mirena has review of current issues. Hum. Fertil. (Camb.), 5, 127±32. Bevan, J.A., Maloney, K.W., Hillery, C.A., Gill, J.C., Montgomery, R.R. and demonstrated an 86% reduction in menstrual blood loss at 3 Scott, J.P. (2001) Bleeding disorders: a common cause of menorrhagia in months and a 97% reduction at 12 months in women with adolescents. J. Pediatr., 138, 856±861. ovulatory dysfunctional uterine bleeding (Anderson and Rybo, Burstein, G.R., Gaydos, C.A., Diener-West, M., Howell, M.R., Zenilman, J.M. and Quinn, T.C. (1998) Incident Chlamydia trachomatis among 1990), which continues over a 5 year period. Nearly 50% of inner-city adolescent females. J. Am. Med. Assoc., 280, 521±526. Mirena users experience amenorrhoea during 3 years of use Chumlea, W.C., Schubert, C.M., Roche, A.F., Kulin, H.E., Lee, P.A., Himes, (Baldaszti et al., 2003). Menstrual blood loss is also reduced in J.H. and Sun, S.S. (2003) Age at menarche and racial comparisons in US girls. Pediatrics, 111, 110±113. anovulatory bleeding. The system also acts as a highly Cibula, D., Fanta, M., Hill, M., Sindelka, G., Skrha, J. and Zivny, J. (2002) effective and reversible contraceptive. Insertion under general Insulin sensitivity in non-obese women with polycystic ovary syndrome anaesthetic may be preferable in women with intellectual during treatment with oral contraceptives containing low-androgenic progestin. Hum. Reprod., 17, 76±82. disability. Claessens, E.A. and Cowell, C.A. (1981) Acute adolescent menorrhagia. Am. J. Obstet. Gynecol., 139, 277±280. Clement, K., Vaisse, C., Lahlou, N., Cabrol, S., Pelloux, V., Cassuto, D., Summary Cassuto, D., Gourmelen, M., Dina, C., Chambaz, J. et al. (1998) A mutation in the human leptin receptor gene causes obesity and pituitary Adolescent menstrual disorders are relatively common and it dysfunction. Nature, 392, 398±401. is unclear who these young women present to and what Colao, A., Di Somma, C., Loche, S., Di Sarno, A., Klain, M., Pivonello, R., Pietrosante, M., Salvatore, M. and Lombardi, G. (2000) Prolactinomas in information is provided to them. The issues of when to talk, adolescents: persistent bone loss after 2 years of prolactin normalization. how to talk and what to say to young girls and their Clin. Endocrinol. (Oxf.), 52, 319±327. families regarding the processes of early maturation and Creighton, S., Edwards, S., Welch, J. and Miller, R. (2002) News from the frontline: sexually transmitted infections in teenagers attending a menstruation are unresolved. These discussions will inevitably genitourinary clinic in south east London. Sex. Transm. Infect., 78, stray into issues of self-con®dence, body image and sexuality 349±351. and it is possible that many gynaecologists may not feel Dattani, M.T. and Brook, C.G.D. (1998) Precocious puberty. In Fraser, I.S., suf®ciently comfortable or experienced in these areas. Those Jansen, R.P.S., Lobo, R.A. and Whitehead, M.I. (eds), Estrogens and Progestogens in Clinical Practice. Churchill Livingstone, London, pp. adolescents who do attend the gynaecologist will often attend 495±506. with a mother or friend and sensitivity in dealing with even minor Duncan, S.L.B. (1998) Disorders of puberty. In Shaw, R., Soutter, P. and disorders is paramount. Referral to specialized centres for rarer Stanton, S. (eds), Gynaecology. Churchill Livingstone, Edinburgh, chap. but serious endocrine or structural abnormalities is necessary. 12, pp. 173±189. Flug, D., Largo, R.H. and Prader, A. (1984) Menstrual patterns in adolescent Liaison with paediatricians or psychosexual counsellors may also Swiss girls: a longitudinal study. Ann. Hum. Biol., 11, 495±508. be required. Fraser, I.S. (1985) The dysfunctional uterus: dysmenorrhoea and dysfunctional

503 M.Hickey and A.Balen

uterine bleeding. In Shearman, R.P. (ed.), Clinical Reproductive Michelmore, K.F., Ong, K., Mason, S., Bennett, S., Perry, L., Vessey, M.P., Endocrinology. Churchill Livingstone, Edinburgh, pp. 579±598. Balen, A.H. and Dunger, D.B. (2001) Clinical features in women with Frisch, R.E., Gotz-Welbergen, A.V., McArthur, J.W., Albright, T., Witschi, J., polycystic ovaries: relationships to insulin sensitivity, insulin gene VNTR Bullen, B., Birnholz, J., Reed, R.B. and Hermann, H. (1981) Delayed and birth weight. Clin. Endocrinol., 55, 439±446. menarche and amenorrhea of college athletes in relation to age of onset of Minto, C.L., Liao, L.M., Woodhouse, C.R., Ransley, P.G. and Creighton, S.M. training. J. Am. Med. Assoc., 246, 1559±1563. (2003) The effect of clitoral surgery on sexual outcome in individuals Frisch, R.E. and Revelle, R. (1970) Height and weight at menarche and a who have intersex conditions with ambiguous genitalia: a cross-sectional hypothesis of critical body weights and adolescent events. Science, 169, study. Lancet, 361 (9365), 1252±1257. 397±399. Morin-Papunen, L.C., Vauhkonen, I., Koivunen, R.M., Ruokonen, A., Grif®n, J., Carlson, G., Taylor, M. and Wilson, J. (1994) Menstrual Martikainen, H.K. and Tapanainen, J.S. (2000) Endocrine and management and intellectual disability: new perspectives. Occup. Ther. metabolic effects of metformin versus ethinyl estradiol-cyproterone Int., 1, 141±157. acetate in obese women with polycystic ovary syndrome: a randomized Grover, S.R. (2002) Menstrual and contraceptive management in women with study. J. Clin. Endocrinol. Metab., 85, 3161±3168. an intellectual disability. Med. J. Aust., 176, 108±110. Palmert, M.R., Gordon, C.M., Kartashov, A.I., Legro, R.S., Emans, S.J. and Hardiman, P., Pillay, O.S. and Atiomo, W. (2003) Polycystic ovary syndrome Dunaif, A. (2002) Screening for abnormal glucose tolerance in and endometrial carcinoma. Lancet, 361 (9371), 1810±1812. adolescents with polycystic ovary syndrome. J. Clin. Endocrinol. Herman-Giddens, M.E., Slora, E.J., Wasserman, R.C., Bourdony, C.J., Metab., 87, 1017±1023. Downloaded from https://academic.oup.com/humupd/article/9/5/493/727661 by guest on 06 October 2021 Bhapkar, M.V., Koch, G.C. and Hasemeier, C.M. (1997) Secondary Pathomvanich, A., Merke, D.P. and Chrousos, G.P. (2000) Early puberty: a sexual characteristics and menses in young girls seen in of®ce practice: a cautionary tale. Pediatrics, 105, 115±116. study from the Pediatric Research in Of®ce Settings network. Pediatrics, Nilsson, L. and Rybo, G. (1971) Treatment of menorrhagia. Am. J. Obstet. 99, 505±512. Ibanez, L., Potau, N., Zampolli, M., Rique, S., Saenger, P. and Carrascosa, A. Gynecol., 110, 713±720. (1997) Hyperinsulinemia and decreased insulin-like growth factor- Patton, G. (1999) A Brie®ng Paper for the National Public Health Partnership. binding protein-1 are common features in prepubertal and pubertal girls In National Public Health Partnership, Australian Government with a history of premature . J. Clin. Endocrinol. Metab., 82, Publication, Australia. 2283±2288. Polson, D.W., Adams, J., Wadsworth, J. and Franks, S. (1988) Polycystic Ibanez, L., Dimartino-Nardi, J., Potau, N. and Saenger, P. (2000) Premature ovariesÐa common ®nding in normal women. Lancet, 1, 870±872. adrenarcheÐnormal variant or forerunner of adult disease? Endocr. Rev., Quint, E.H. (2002) Pelvic pain in an adolescent. J. Pediatr. Adolesc. Gynecol., 21, 671±696. 15, 115±116. Kaplowitz, P.B. and Ober®eld, S.E. (1999) Reexamination of the age limit for Rajkowha, M., Glass, M.R., Rutherford, A.J., Michelmore, K. and Balen, A.H. de®ning when puberty is precocious in girls in the United States: (2000) Polycystic ovary syndrome: a risk factor for cardiovascular implications for evaluation and treatment. Drug and Therapeutics and disease? Br. J. Obstet. Gynecol., 107, 11±18. Executive Committees of the Lawson Wilkins Pediatric Endocrine Rogstad, K.E., Ahmed-Jushuf, I.H. and Robinson, A.J. (2002) MSSVD Society. Pediatrics, 104, 936±941. Adolescent Sexual Health Group. Standards for comprehensive sexual Kaufman, F.R. (2002) Type 2 diabetes mellitus in children and youth: a new health services for young people under 25 years. Int. J. STD AIDS, 13, epidemic. J. Pediatr. Endocrinol. Metab., 15 (Suppl. 2), 737±744. 420±424. Kiddy, D.S., Hamilton-Fairley, D., Bush, A., Short, F., Anyaoku, V., Reed, Root, A.W. (2000) Precocious puberty. Pediatr. Rev., 21, 10±19. M.J. and Franks, S. (1992) Improvement in endocrine and ovarian Southam, A.L. and Richart, A.M. (1966) The prognosis for adolescents with function during dietary treatment of obese women with polycystic ovary menstrual abnormalities. Am. J. Obstet. Gynecol., 94, 637±637. syndrome. Clin. Endocrinol., 36, 105±111. Tamburrino, M.B. and McGinnis, R.A. (2002) Anorexia nervosa. A review. Kiess, W., Bottner, A., Raile, K., Kapellen, T., Muller, G., Galler, A., Paschke, Panminerva Med., 44, 301±311. R. and Wabitsch, M. (2003) Type 2 diabetes mellitus in children and Tanner, J.M. (1962) Growth at Adolescence, 2nd edn. Blackwell, Oxford. adolescents: a review from a European perspective. Horm. Res., 59 Treloar, A.E., Boynton, R.E., Behn, B.G. and Brown, B.W. (1967) Variation (Suppl. 1), 77±84. of the human menstrual cycle through reproductive life. Int. J. Fertil., 12, Leger, J., Reynaud, R. and Czernichow, P. (2000) Do all girls with apparent 77±126. idiopathic precocious puberty require gonadotrophin-releasing hormone Venturoli, S., Porcu, E., Fabbri, F., Paradisi, R., Ruggeri, Bolelli, S., Orsini, agonist treatment? J. Pediatr., 137, 819. L.F., Gabbi, D. and Flamigni, C.L. (1987) Menstrual irregularities in Legro, R.S. (2002) Detection of insulin resistance and its treatment in adolescents: hormonal pattern and ovarian morphology. Horm. Res., 24, adolescents with polycystic ovary syndrome. J. Pediatr. Endocrinol. 269±279. Metab., 15 (Suppl. 5), 1367±1378. Vihko, R. and Apter, D. (1984) Endocrine characteristics of adolescent Letterie, G.S., Haggerty, M. and Lindee, G. (1995) A comparison of pelvic menstrual cycles: impact of early menarche. J. Steroid Biochem., 20, 213± ultrasound and magnetic resonance imaging as diagnostic studies for 216. mullerian tract abnormalities. Int. J. Fertil. Menop. Stud., 40, 34±38. Waterworth, D.M., Bennett, S.T., Gharani, N., McCarthy, M.I., Hague, S., Luisetto, G., Zangari, M., Nardi, A., Ramazzina, E., Adami, S. and Galuppo, Batty, S., Conway, G.S., White, D., Todd, J.A., Franks, S. and P. (1993) In¯uence of aging and menopause in determining vertebral and Williamson, R. (1997) Linkage and association of insulin gene VNTR distal forearm bone loss in adult healthy women. Bone Min., 22, 9±25. regulatory polymorphism with polycystic ovary syndrome. Lancet, 349, Malus, M., LaChance, P., Lamy, L., Macaulay, A. and Vanasse, M. (1987) 986±990. Priorities in adolescent health care: a teenagers view-point. J. Fam. Pract., 25, 159±162. Whincup, P.H., Gilg, J.A., Odoki, K., Taylor, S.J. and Cook, D.G. (2001) Age Mann, D.R. and Plant, T.M. (2002) Leptin and pubertal development. Semin. of menarche in contemporary British teenagers: survey of girls born Reprod. Med., 20, 93±102. between 1982 and 1986. Br. Med. J., 322, 1095±1096. Mantzoros, C.S., Flier, J.S. and Rogol, A.D. (1997) A longitudinal assessment Widholm, O. and Kantero, R.L. (1971) A statistical analysis of the menstrual of hormonal and physical alterations during normal puberty in boys. V. patterns of 8,000 Finnish girls and their mothers. Acta Obstet. Gynecol. Rising leptin levels may signal the onset of puberty. J. Clin. Endocrinol. Scand., 14 (Suppl.), 1±36. Metab., 82, 1066±1070. Wild, R.A. (2002) Long-term health consequences of PCOS. Hum. Reprod. Marozzi, A., Porta, C., Vegetti, W., Crosignani, P.G., Tibiletti, M.G., Dalpra, Update, 8, 231±241. L. and Ginelli, E. (2002) Mutation analysis of the inhibin alpha gene in a Wing®eld, M., McClure, N., Mamers, P.M., Weigall, D.T., Paterson, P.J. and cohort of Italian women affected by ovarian failure. Hum. Reprod., 17, Healy, D.L. (1994) Endometrial ablation: an option for the management 1741±1745. of menstrual problems in the intellectually disabled. Med. J. Aust., 160, Marshall, W.A. and Tanner, J.M. (1969) Variations in pattern of pubertal 533±536. changes in girls. Arch. Dis. Child., 44, 291±303. World Health Organization Task Force on Adolescent Reproductive Health Michelmore, K.F., Balen, A.H., Dunger, D.B. and Vessey, M.P. (1999) (1986) World Health Organization multicenter study on menstrual and Polycystic ovaries and associated clinical and biochemical features in ovulatory patterns in adolescent girls. I. A multicenter cross-sectional young women. Clin. Endocrinol. (Oxf.), 51, 779±786. study of menarche. J. Adolesc. Health Care, 7, pp. 229±235.

504