ARTICLE IN PRESS

Current Obstetrics & Gynaecology (2004) 14, 254260

www.elsevier.com/cuog

Amenorrhoea: investigation and treatment

William L. Ledger*, Jonathan Skull
Department of Obstetrics and Gynaecology, Jessop Hospital for Women, University of Shefeld, Level 4, The Jessop Wing Tree Root Walk, Leavygreave Road, Shefeld S3 7RE, UK

KEYWORDS
Amenorrhoea; Anovulation; Ovarian failure; Oligomenorrhoea

Summary Amenorrhoea and severe oligomenorrhoea are frequently seen in gynaecological practice. Appropriate investigation and treatment are best organised from an anatomical standpoint, with rapid and cost-effective assessment of each level of the hypothalamopituitaryovarianuterine axis. Investigation should also be tailored to meet the needs of the patientFa young woman with primary amenorrhoea and little secondary sexual development has very different concerns and potential diagnoses from an anovular infertile 30-year-old with secondary amenorrhoea. Whilst the commoner diagnoses of polycystic ovary syndrome (PCOS), premature ovarian failure and prolactinoma are easily made and involve evidencebased treatment, the rarer causes of amenorrhoea may escape diagnosis unless the clinician is sufciently alert to detect anomalous results of investigations. Treatment of amenorrhoea depends on the causeFkey areas are the induction and maintenance of menstruation in young women with amenorrhoea, and induction of ovulation for the infertile amenorrhoeic patient. Premature ovarian failure warrants consideration of hormone replacement therapy up to the age of natural menopause. & 2004 Elsevier Ltd. All rights reserved.

Introduction
Regular, cyclical menstruation is an obvious aspect of normality for women in their reproductive years. For teenage girls, if periods fail to appear by age 1416 years most girls and their parents will seek medical advice. Similarly, if a womans menses cease, or if there is signicant change in menstrual pattern, this will trigger consultation with a clinician. Regular menstruation indicates that the hypothalamopituitaryovarian axis is intact. Those who experience monthly menstrual bleeds spaced 2735 days apart are almost certainly ovulatory. Primary failure to begin menstrual periods during the midteen years can be due to a problem at any level of
*Corresponding author. Tel.: 44-114-2268317; fax: 44114-2752153. E-mail address: o.g.jessop@shefeld.ac.uk (W.L. Ledger).

the axis, as can secondary loss of regular cycles later in reproductive life. Treloars classic studies showed that each woman has her own intrinsic cycle length during the years of ovulation, and that after irregularity during the early years of onset of menses, cycles settled into a regular rhythm until the onset of perimenopause in their mid- to late forties. Amenorrhoea describes complete absence of mensesFno menstrual bleeds for greater than 6 months in the absence of pregnancy. Primary amenorrhoea is dened as absence of onset of menses by 16 years of age, and secondary amenorrhoea as absence of periods for at least 6 months if the patient has previously had regular periods, and 12 months if she has previous had oligomenorrhoea. In contrast, oligomenorrhoea describes infrequent periods, with bleeds less than every 6 weeks but at least one bleed in 6 months.

0957-5847/$ - see front matter & 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.curobgyn.2004.04.004

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Amenorrhoea: investigation and treatment 255

The causes of amenorrhoea are best remembered by reference to the levels within the hypothalamo pituitaryovarian axis, at which problems can develop. These are listed in Table 1.

oid disorder, weight loss or gain, hirsutism or menopausal symptoms.

Examination
Examination of the amenorrhoeic patient is performed to exclude an anatomical cause. Stigmata of chromosomal conditions should be sought and the development of secondary sexual characteristics evaluated. The body mass index (BMIFweight in kg/height in m2) should be calculated. Signs of virilisation or hirsutism may be seen. It should be remembered that a young patient presenting with primary amenorrhoea may not be sexually active and therefore vaginal examination should be avoided in these cases, although inspection of the external genitalia should exclude vaginal hypoplasia or an imperforate hymen. Abdominal ultrasound may be a useful alternative to pelvic examination in young, anxious patients.

Assessment of the amenorrhoiec patient

The evaluation of amenorrhoea requires a careful history and physical examination followed by appropriate further investigations. The possibility of pregnancy must always be considered and a urine pregnancy test performed.

History
History can often be helpful in reaching a diagnosis. Care should be taken to seek evidence of psychological dysfunction or emotional stress, family history of possible genetic anomalies or diabetes, the presence of galactorrhoea, symptoms of thyr-

Basic investigations
Traditionally, amenorrhoea has been investigated using a stepwise approach. Whilst this may minimise the number of investigations required, it can lead to an increased number of visits to complete each stage of investigation. This in turn can lead to delays in diagnosis and result in greater expense. Therefore, an approach that involves a number of initial investigations performed in one visit is preferable and will usually allow a diagnosis to be made by the following visit. Efciency can be further improved in the secondary care setting by performing initial investigations before the rst attendance at clinic. These can be organised by the General Practitioner (GP) or ordered on the basis of information provided in the referral letter. The initial investigations required are:
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Table 1

Causes of amenorrhoea.

Level 1Fhypothalamic CongenitalFKallmans syndrome AcquiredFpituitary stalk disconnection syndromes (e.g. craniopharyngioma), excessive weight loss, excessive exercise, cranial radiotherapy Level 2Fpituitary TumourFprolactinoma, non-functional tumour InfarctionFSheehans syndrome InfectionFtuberculosis Radiotherapy, surgery Level 3Fovarian Polycystic ovary syndrome Ovarian failure (premature menopause) Resistant ovary syndrome Ovarian agenesis/dysgenesis Chemo/radiotherapy and surgery Level 4Futero-vaginal Uterine agenesis Testicular feminisation Imperforate hymen Ashermans syndrome Radiotherapy Level 5Fextrinsic to the HPO axis Thyroid and adrenal disorders Systemic disease Physiological Pregnancy and lactation

FSH; LH; thyroid function tests; prolactin; pelvic ultrasound (preferably transvaginal).

Possible further investigations

Further investigations will be determined by the suspected diagnosis. For example, a suspicion of a uterine abnormality might prompt hysteroscopy and/or laparoscopy. If hyperandrogenism is suspected then tests for polycystic ovary syndrome, adrenal androgen excess and late onset congenital adrenal hyperplasia should be performed, involving measurement of

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testosterone, androstenedione, sex hormone binding globulin, 17-hydroxyprogesterone and dehydroepiandrosterone sulphate. Suspicion of a pituitary prolactinoma should prompt magnetic resonance imaging of the pituitary. A progestogen challenge test is a useful means of evaluating the level of endogenous oestrogen and the competence of the outow tract, and can be performed after the initial evaluation. A course of a progestational agent is administered (e.g. oral medroxyprogesterone acetate, 10 mg daily for 5 days). Within 27 days after completing the course, the patient should bleed. If she does, the presence of a functional outow tract and a uterus lined by reactive endometrium sufciently prepared by endogenous oestrogen is conrmed. If the progestogen challenge test does not result in a bleed, there is either an abnormality of the outow tract or preliminary oestrogen proliferation of the endometrium has not occurred. Further evaluation may be performed by administering oestrogen (e.g. oestradiol valerate 2 mg) for 21 days with the terminal addition of progestogen for the last 5 days. In the absence of withdrawal bleeding, a second course is recommended for conrmation. If bleeding occurs the outow tract must be intact and the problem is oestrogen deciency. Whilst the progestogen challenge test is very useful in determining hypo-oestrogenic states, there are rare conditions when withdrawal bleeding will not occur despite adequate levels of endogenous oestrogen. This can happen where the endometrium is decidualised in response to high levels of androgens (e.g. with polycystic ovaries), or high progesterone levels associated with a specic adrenal enzyme deciency.

Hypothalamic amenorrhoea
Hypothalamic amenorrhoea is frequently a diagnosis of exclusion, reached once defects at other levels have been sought but not found. A decrease in GnRH neuronal activity leads to a slowing of GnRH pulses at the pituitary. Reduction in the frequency and possibly amplitude of GnRH pulses results in failure to stimulate sufcient synthesis and secretion of FSH and LH by the pituitary gonadotroph cells, leading to a degree of hypogonadal hypogonadism. Slowing of pulse frequency to a rate of less than one pulse per 2 h is sufcient to prevent normal follicle development and ovulation. Whilst complete failure of gonadotrophin secretion should be detectable in peripheral blood samples,

many hospital clinical chemistry laboratories use assays for FSH and LH that are imprecise when measuring low concentrations (since they are designed to assess menopausal levels of gonadotrophins). Patients with hypothalamic amenorrhoea may therefore appear to have low normal concentrations of FSH and LH in their circulation. The common causes of hypothalamic amenorrhoea in the West are excessive weight loss and exercise. Amenorrhoea is one of the cardinal clinical signs of anorexia nervosa in women, but low BMI in the absence of signicant psychological disease may also lead to amenorrhoea. This can occur if BMI falls below 19, or if the total body fat mass falls below about 20%. Weight loss related amenorrhoea is seen more frequently if weight is lost rapidly. Young women frequently achieve their desired body habitus by a combination of dieting and exercise. Intense sustained exercise leads to cessation of GnRH pulses and amenorrhoea, but less intense exercise in combination with dieting seems to produce similar effects. Many elite female athletes are amenorrhoeic and it is clear that their high level of exercise does not maintain integrity of bone density. Amenorrhoeic athletes or those with weight related amenorrhoea should be advised to consider hormone replacement therapy if their condition is persistent. However, reduction in intensity of exercise or improvement in calorie intake will frequently result in resumption of hypothalamic activity and regular menstrual cycles. Desire for fertility frequently leads to lifestyle alteration and correction of these defects. A number of rare hypothalamic space occupying lesions can present with amenorrhoea. Other tumours causing pituitary stalk compression prevent delivery of GnRH to the pituitary, again causing amenorrhoea. This most frequently occurs around onset of puberty, resulting in primary amenorrhoea. Calcied or cystic lesions can be seen on cranial CT or magnetic resonance imaging (MRI) scans, and require neurological and neurosurgical assessment. Kallmans syndrome describes rare (1: 50 000) congenital absence of development of GnRH neurons between the hypothalamus and pituitary. The condition may be sporadic or an autosomal dominant or X-linked recessive disorder, and may be seen in association with anosmia. Failure of the GnRH message reaching the pituitary prevents initiation of FSH and LH synthesis, with primary amenorrhoea. Replacement of FSH and LH by injection, or pulsatile infusion of GnRH to reinstitute endogenous secretion of gonadotrophins, will restore ovulation and offer the possibility of pregnancy.

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Pituitary conditions
Hyperprolactinaemia arising from a prolactin secreting tumour (macro or micro adenoma) accounts for approximately 15% of secondary amenorrhoea and may present as primary amenorrhoea. Prolactin is the only pituitary hormone to be under negative control by its hypothalamic regulator, prolactin inhibitory factor (PIF). The discovery that the inhibitory factor is in fact dopamine allowed explanation of the actions of many drugs on prolactin secretion. Drugs that inhibit dopamine secretion by the hypothalamus produce amenorrhoea by increasing circulating levels of prolactin due to pituitary disinhibition. This occurs when patients are treated with a variety of psychotropic anti-dopaminergic medications, and also after use of other common agents including Cimetidine, methyldopa and metaclopramide. Circulating concentrations of prolactin may also be moderately increased in polycystic ovary syndrome and by stress, leading to possible diagnostic confusion. Cannulated venous samples can be collected during bedrest if stress related hyperprolactinaemia is suspected. The elevation in prolactin is unlikely to interfere with ovulation or menstrual cyclicity in such cases. Pathological hyperprolactinaemia will be associated with amenorrhoea and, in most but not all cases, galactorrhoea. Bitemporal hemianopia should always be sought at rst presentation, since it may indicate the need for urgent imaging of the pituitary to exclude an expanding macroadenoma. About 10% of patients with hyperprolactinaemia and amenorrhoea will have a macroadenoma. It is important to diagnose these lesions since they can expand and cause damage to the optic nerves at the level of the optic chiasma. MRI with gadolinium enhancement has widely replaced traditional pituitary X-ray for this purpose. Some macroadenomas, and most microadenomas will respond to drug therapy with dopaminergic agents such as bromocriptine and cabergoline. Bromocriptine has been in use for many years and is effective, but associated with high incidence of gastrointestinal side effects. The more recent introduction of cabergoline has reduced GI side effects and allowed a less frequent and more convenient dosing regime. Resistant cases and some macroadenomas will require hypophysectomy. The pituitary can also be damaged by pituitary surgery or cranial radiotherapy, with consequent amenorrhoea as one feature of pan-hypopituitarism. Sheehans syndrome, pituitary infarction following major obstetric haemorrhage, is now very uncommon in the UK following improvements in obstetric practice.

Ovarian disorders
As the target organ for pituitary gonadotrophins, the ovary will fail to produce ovarian follicles in response to insufcient plasma concentrations and pulses of FSH and LH. However, the majority of cases of secondary amenorrhoea and oligomenorrhoea result from primary ovarian disease, most commonly PCOS.

Polycystic ovary syndrome (PCOS)

Understanding of the pathophysiology of PCOS has advanced over the past 15 years since the introduction of transvaginal ultrasound and rapid, accurate hormone assays. Whilst traditionally diagnosed as Stein Leventhal syndrome, with obesity, oligo/amenorrhoea, hirsutism and acne, this is now seen as one end of the spectrum of this disorder. In many patients, menstrual disturbances and other manifestations of the syndrome are triggered by weight gain, and can be treated by weight loss and exercise. However other patients have normal body habitus but exhibit features such as oligomenorrhoea and infertility. Patients with PCOS may have endocrine disturbances including raised LH and LH: FSH ratio, hyperandrogenism with elevated total and free testosterone and other androgens and low sex hormone binding globulin and hyperprolactinaemia. There is also strong evidence of insulin resistance, with risk of development of type II diabetes in later life. The central role of disordered glucose metabolism in PCOS helps to explain the impact of weight gain and the recent success of insulin sensitising agents such as metformin in the treatment of PCOS related oligomenorrhoea and anovulation. Polycystic ovary syndrome is a common condition with a variety of clinical presentations. It has been dealt with in detail elsewhere in Current Obstetrics and Gynaecology (2003; 13(5)). The burgeoning literature on long-term health effects of PCOS has recently been reviewed in an RCOG Green Top Guideline. From the point of view of investigation of amenorrhoea, a restricted number of endocrine investigations combined with transvaginal ultrasound should allow a diagnosis to be reached in most cases. Treatment will depend on the clinical presentation. Infertility requires ovulation induction with medical (clomiphene citrate, gonadotrophin injection, metformin), or surgical (laparoscopic ovarian diathermy) means. If fertility is not desired then menstrual regulation with cyclical oestrogen/gestagen or the oral contraceptive pill may be needed. It is important to

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recognise that although women with PCOS are not usually hypo-oestrogenic with the risk of osteoporosis, infrequent menses can lead to endometrial hyperplasia and malignancy. It is therefore mandatory to induce menstrual bleeds in amenorrhoeic or severely oligomenorrhoeic patients every 34 months, even if regular menses are not desired.

patients to ovulate, and it is questionable whether laparoscopic ovarian biopsy is justiable, since it carries risk and is unlikely to lead to effective treatment. Gonadotrophin injection is unlikely to provoke an ovarian response, and patients should be treated as for POF.

Premature ovarian failure (POF)

The ovary contains a nite number of primordial follicles, which form the womans lifetime store of potential ovulations. The number of primordial follicles in this pool varies from individual to individual, and can be depleted by medical interventions including chemo and radiotherapy. There is frequently a family history in such patients, or there may be manifestations of auto-immune disease leading to auto-immune oophoritis. Rarer causes include galactosaemia (even in treated patients), and Turners syndrome mosaicism leading to early secondary amenorrhoea. Girls with nonmosaic Turners syndrome generally exhibit primary amenorrhoea. The nal result of all these processes is loss of ovarian reserve and early onset of menopause. Cessation of periods will be preceded by several years of irregular or more frequent menses, with hot ushes, sweats and other hypo-oestrogenic symptoms. Although ovarian failure is diagnosed as premature if it occurs before the age of 40 years, many women over this age still desire fertility, and this diagnosis is frequently very distressing. Such patients can be offered treatment with donated oocytes, although recent changes in UK law on donor anonymity have reduced the numbers of women willing to donate spare oocytes after IVF treatment. The high-risk of early onset osteoporosis in early POF, combined with the distressing effects of lack of oestrogen on general and sexual health, mandate the use of oestrogen replacement therapy in such patients. Consideration should also be given to monitoring of bone mineral density, with secondary intervention where necessary, in a dedicated long-term follow-up clinic.

Disorders of the uterus and vagina

Abnormalities of the uterus or outow tract are relatively rare when all causes of amenorrhoea are considered, but are more common in cases of primary amenorrhoea. Generally, congenital anomalies will present with primary amenorrhoea and acquired conditions with secondary amenorrhoea. Congenital anomalies can arise from embryological failure of canalisation or complete lack of development of the Mullerian duct. Alternatively, failure of development of the upper vagina and uterus may result from androgen insensitivity (testicular feminisation).

Mullerian anomalies
Failure of canalisation of the Mullerian duct at any level will result in primary amenorrhoea. The presentation will depend upon the level at which the tract is blocked. An imperforate hymen presents in a teenage girl with normal sexual development. She may also have intermittent abdominal pain, difculty with micturition and a palpable lower abdominal swelling. Examination will reveal a bulging, bluish membrane at the lower end of the vagina. The treatment involves surgical incision of the membrane. If there is obstruction of the vagina or cervix at a higher level associated with a normal functioning uterus this will be compounded by the painful distension of haematocolpos, haematometra or haemoperitoneum. In all cases surgery should be performed to re-establish continuity of the genital tract. In some circumstances, the distension and damage to otherwise healthy reproductive organs will necessitate their removal. MRI and ultrasound are both useful in reaching an accurate diagnosis and preoperative preparation.

Resistant ovary syndrome

A resistant ovary has a normal or near normal number of primordial follicles on biopsy but does not respond to FSH by follicle growth and ovulation. This may merely represent incipient POF in most cases, although defects in the FSH receptor have been described which may render the ovary nonresponsive. Little can be done to induce such

Mullerian agenesis
Primary amenorrhoea with no apparent vagina occurs due to a lack of Mullerian development and is the second most common cause of primary amenorrhoea after gonadal dysgenesis. These patients have an absence or hypoplasia of the

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vagina. The uterus may be normal or there may only be rudimentary bicornuate cords present. Ovarian function, growth and development are normal. The peripheral karyotype is normal 46, XX female in contrast to testicular feminisation. There is a high association with other anomalies and appropriate investigations should be performed. Renal tract abnormalities (ectopic kidney, renal agenesis, horseshoe kidney and abnormal collecting ducts) are present in 30% of cases and skeletal abnormalities (mostly involving the spine) in 12%. Ultrasound and MRI can be used to diagnose the anatomical problem. Laparoscopy is only indicated if there is uncertainty. Surgical removal of Mullerian remnants is not necessary unless they are causing a problem due to broid growth, haematometra or endometriosis. Many patients with an absent vagina may be treated effectively by progressive dilatation using the Frank method. The use of progressively larger dilators can create a functional vagina in 612 weeks. Operative treatment should be reserved for patients in whom the Frank method is unacceptable, fails or when a well-formed uterus is present and fertility might be preserved. If the cervix is atretic or there is complete vaginal agenesis, most would recommend against trying to preserve fertility and suggest removal of the Mullerian structures at the time of construction of a neovagina.

The testes may be intra-abdominal, but are often in an inguinal hernia. There is no spermatogenesis. The incidence of malignancy is high and the gonads should be surgically removed. However, this is best left until after puberty because tumours do not occur prior to this and development is achieved with endogenous hormones. This is in contrast to other cases where gonads with a Y chromosome should be removed as soon as a diagnosis is made. Following removal, oestrogen replacement therapy should be commenced. Rare cases of incomplete testicular feminisation do occur and have variable degrees of masculinisation. Since treatment is the same, precise diagnosis is not essential.

Ashermans syndrome
Secondary amenorrhoea may result following destruction of the endometrium. This generally occurs as a result of an overzealous post-partum curettage resulting in intrauterine adhesions, but may also occur after uterine surgery (Caesarean section, myomectomy or metroplasty), or following intrauterine device-related infections and severe generalised pelvic infections. The multiple synechiae are clearly seen on either hysterosalpingography or hysteroscopy. Patients with Ashermans syndrome can present with other problems besides amenorrhoea, including abortions, dysmenorrhoea, hypomenorrhoea, infertility or recurrent pregnancy loss. The mainstay of treatment is hysteroscopic lysis of adhesions using scissors, diathermy or laser. The insertion of an intrauterine device or a paediatric Foley catheter may help prevent adhesions from recurring. Subsequent stimulation of the endometrium with high doses of oestrogens combined with cyclical progestogens can restore menstruation in the majority, although repeated treatments are often required. Following this treatment, the prognosis is good with pregnancy rates of 7080%. However, premature labour, placenta accreta, placenta praevia and post-partum haemorrhage may complicate the pregnancy. Destruction of the endometrium can also be caused by tuberculosis, although this is rare in the developed world. This diagnosis is made by culture of endometrial biopsy or menstrual discharge. The prognosis for pregnancy in these patients is very poor. Uterine schistosomiasis is another rare cause and eggs may be found in urine, faeces, rectal scrapings, menstrual discharge or endometrium.

Androgen insensitivity (testicular feminisation)

This is the third most common cause of primary amenorrhoea after gonadal dysgenesis and Mullerian agenesis. A blind vaginal canal is found with an absent uterus. The gonadal sex is male and the patient has testes and an XY karyotype, but the genitalia are the opposite of the gonads, thus the patients is a male pseudohermaphrodite and phenotypically female, but with absent or sparse pubic and axillary hair. Growth and development are normal. They are often taller than average, and whilst breasts are large, glandular tissue is sparse, nipples are small and areolae are pale. Labia minora are usually underdeveloped. The underlying condition is an androgen receptor defect. Thus circulating androgens are normal or slightly elevated, but the critical steps in sexual differentiation which require androgens fail to take place and development is totally female. The uterus, tubes and upper vagina are absent because anti-Mullerian hormone is present.

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Practice points
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Aims: prompt and efcient diagnosis of the cause of amenorrhoea leading to appropriate treatment directed towards the patients current needs. Investigations: the level of disorder in the hypothalamicpituitaryovarian axis needs to be identied. Initial investigations are: FSH, LH, thyroid function tests, prolactin and pelvic ultrasound. The progestogen challenge test can be used to assess the degree of oestrogenisation. Further investigations depend upon these results, but may include karyotype and autoimmune screens in cases of ovarian failure or imaging of the pituitary in cases of hypogonadotrophic hypogonadism or hyperprolactanaemia. Management: treatment depends upon the patients current needs, which may be fertility, deciency or delayed puberty. Particular attention should be paid to correcting states of oestrogen deciency to prevent the long-term sequelae of osteoporosis, or delayed puberty. In cases of ovarian failure excellent pregnancy rates can be achieved with oocyte donation.

Long-term implications of PCOS association with risk of diabetes, cardiovascular and cerebrovascular disease are emerging. Should PCOS patients have long-term treatment with insulin sensitising agents? How best to produce weight loss and physical tness in obese PCOS patients?

Further reading
Zacharias L, Rand WM, Wurtman RJ. A prospective study of sexual development and growth in American girls: the statistics of menarche. Obstet Gynecol Survey 1976; 31: 325. Frank RT. Formation of articial vagina without operation. Am J Obstet Gynaecol 1938; 35: 1053. Jones GS, DeMoraes Ruehsen M. A new syndrome of amenorrhoea in association with hypergonadotropism and apparently normal ovarian follicular apparatus. Am J Obstet Gynecol 1979; 104: 597. Trounson A, Leeton N, Besanko M, Wood C, Conti A. Pregnancy established in an infertile patient after transfer of a donated embryo fertilised in vitro. Br Med J 1983; 286: 8358. Bukulmez O, Yareli H, Gurgan T. Total corporal synechiae due to tuberculosis carry a very poor prognosis following hysteroscopic synechialysis. Hum Reprod 1999; 14: 196096. Van kasteren YM, Schoemaker J. Premature ovarian failure: a systematic review on therapeutic interventions to restore ovarian function and achieve pregnancy. Hum Reprod Update 1999; 5: 48392. Treloar A et al. Variation of the human menstrual cycle throughout reproductive life. Int J Fertility 1967; 12: 77126. Sharma A, Atiomo W. Recent developments in polycystic ovary syndrome. Curr Obstet and Gynaecol 2003; 13(5): 2816. Ledger W. Long term consequences of the polycystic ovary syndrome. Royal College of Obstetricians and Gynaecologists. Clinical Guideline Number 33, 2002. The Rotterdam ESHRE/ASRM sponsored Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome, Fertil Steril, 2004; 81: 1925. Critchley HOD Amenorrhoea and oligomenorrhoea, and hypothalamicFpituitary disfunction. In: Shaw RW, Soutter WP, Stanton SL, editors. Gynaecology, 3rd ed. Edinburgh: Churchill Livingstone; 2003.

Research directions

Regulation of ovarian apoptosis: improved knowledge will explain many cases of premature ovarian failure and may allow preservation of female fertility beyond the age of 40 years. Oocyte cryopreservation: egg freezing may allow future fertility for patients about to undergo chemo/radiotherapy.