Fig. 1 The number of germ cells in ovary over life determined by counting germ cells in the ovaries at post mortem.

Transcription

1 Gerard S Conway Department of Endocrinology, The Middlesex Hospital, London, UK On average, the menopause occurs at the age of 50 years, 1 with 1 % of women continuing to menstruate beyond the age of 60 years and 1% whose menopause occurs before 40 years. Arbitrarily, a menopause before the age of 40 years is defined as 'premature'. Premature ovarian failure may be caused by any process which reduces the number of oocytes within the ovary. In the embryo, germ cells first appear in the urogenital ridge. These germ cells then migrate to the primitive ovary. Once within the ovary, the germ cells multiply to form 3.5 million potential oocytes in each ovary (Fig. 1). From this time, oocytes are held in suspended animation - meiosis - until required for ovulation perhaps 40 years later. If a woman were to ovulate every month throughout her reproductive life, then she would use fewer than 500 eggs - a tiny proportion of the original 7 million (0.007%). Thus, if a woman were to prevent ovulation, say by taking the combined oral contraceptive Correspondence to Or Gerard 5 Conway, Consultant Endocnnologist The Middlesex Hospital, London WIN 8AA, UK "3T 1CO i s, o 100- i o Age (years) Fig. 1 The number of germ cells in ovary over life determined by counting germ cells in the ovaries at post mortem. British Medical Bulletin 000, 56 (No 3) C The British Council 000

2 Human reproduction: pharmaceutical and technical advances pill constantly, the age of the menopause would not be affected in any way. The timing of the natural menopause is inherited; daughters tend to follow their mothers and is also advanced by environmental factors such as smoking. Most germ cells are destroyed by the body through apoptosis. Before birth, two-thirds of the 7 million eggs are destroyed, presumably as part of quality control mechanism. Between infancy and the age of 40 years, eggs are gradually reduced from approximately 1 million to 10,000 in each ovary. Around the age of 40 years, the process of egg destruction is accelerated and few are left by the age of 50 years. If there is an abnormality of the X chromosome, such as in Turner's syndrome when one X chromosome is missing, then germ cell production is normal but the first phase of egg destruction is accelerated leaving very few eggs available at birth. 3 The missing X chromosome appears to make the suspended egg very unstable ensuring the early death of the ovary in individuals with Turner's syndrome. Aetiology of premature ovarian failure The cause of premature ovarian failure is unknown in the majority of women in whom the diagnosis is made. The psychological damage resulting from this disastrous diagnosis can be eased by a clear definition of the mechanism involved. Thus, even though investigation of the cause rarely leads to altered management, the dividends in terms of coping with the diagnosis is great. The known causes of premature ovarian failure can be categorised into genetic and environmental mechanisms (Table 1). Table 1 Causes of premature ovarian failure in 35 women attending the Middlesex Hospital, London, UK Idiopathic (including autoimmune) Turner's syndrome Chemotherapy Familial premature ovarian failure Pelvic surgery 46XY gonadal dysgenesis Galactosaemia Pelvic Irradiation n % Genetic causes Any defect of the female sex chromosome - the X chromosome - can cause ovary failure. The most common form of X chromosome defect is 644 British Medical Bulletin 000;56 (No 3)

3 Turner's syndrome. Women with Turner's syndrome have one X chromosome missing giving the chromosomal make-up of 45XO. For comparison, normal females are 46XX and normal males are 46XY. Women with Turner's syndrome are commonly of short stature and do not spontaneously enter puberty. The very early development of the ovary in women with Turner's syndrome appears normal, but all germ cells are lost by birth, giving a picture of gonadal dysgenesis. The paradigm of Turner's syndrome demonstrates that two intact X chromosomes are vital for normal ovarian function. 4 From the study of women with partial deletions of the X chromosome, it is clear that at least three loci are critical for ovarian development. 5 On a short arm of the X chromosome are genes responsible for the stigmata of Turner's syndrome and primary amenorrhoea. Particular interest has focused on Xp, where there are a series of genes that escape X-inactivation in humans. The smallest deletion of the X chromosome known to cause premature ovarian failure has identified Xq6-Xq8 as harbouring a gene that may cause premature ovarian failure. 6 The third area of the X chromosome that is thought to be critical for ovarian development is Xql3-. Recently, a collection of women with break points located in this region and who present with premature ovarian failure have been studied. 7 In a region covering 15 Mb, it was estimated that several premature ovarian failure genes must exist. In some instances, premature ovarian failure appears in several female members of the same family where no cytogenetic defect can be identified. 8 Occasionally, genetic markers can be found which can predict premature ovarian failure in future generations of such families. For this reason, a detailed family history is an essential part of the background when considering causes of ovary failure. In most mstances, the mode of inheritance of ovary failure in such families is not known and much research is directed at unravelling the genetic pattern in such pedigrees. From the published pedigrees, it is clear that familial premature ovarian failure has several modes of inheritance - autosomal dominant, autosomal recessive and X linked inheritance have all been reported Premature ovarian failure is also present in families with rare inherited conditions such as galactosaemia, fragile X syndrome and blepharophimosis. In each of these instances, the mechanism of ovarian damage is unknown. In galactosaemia, the vast majority of effected females present with primary amenorrhoea whereas male fertility appears to remain intact. 11 In blepharophimosis, only one-half of families exhibit ovarian failure, often with the clinical picture of resistant ovaries. 1 * 13 In Finland, an Alal89Val mutation affecting the extracellular domain of the FSH receptor gene was found to be associated premature ovarian failure in women from six families presenting with primary amenorrhoea. 14 British Medical BulleVn 000, 56 (No 3) 645

4 Human reproduction: pharmaceutical and technical advances Environmental causes Almost any surgery within the pelvis - such as ovary cyst removal or hysterectomy - might damage the ovary, probably by affecting the blood supply or causing inflammation in the area. The risk of ovary failure through pelvic surgery is unknown and thought to be very small indeed for most routine operations. Surgery on more distant organs, such as the appendix, is not reported to damage the ovary - even though related infections might cause infertility through the formation of adhesions between the fallopian tubes and surrounding structures. As more women survive childhood cancer or leukaemia, we realise that chemotherapy and radiotherapy commonly cause permanent damage to the ovary. 15 It is this group of women who are occasionally offered cryopreservation of ovary tissue before chemotherapy. Auto-immunity Examples of endocrine auto-immunity associated with premature ovarian failure are hypothyroidism, adrenal failure (Addison's disease) and type 1 diabetes mellitus. 16 Hypothyroidism occurs in women with premature ovarian failure more commonly than expected making it likely that, in some circumstances, the ovary is damaged by antibodies in the same way as the thyroid gland. By analogy, the ovary might also incur autoimmune damage even when no other gland seems to be affected. Unfortunately, current tests are not sufficiently sensitive to determine when this might be the case, but the refinement of these tests is a major drive in current medical research. Interest in this field arises from the possibility that an autoimmune marker might predict impending ovarian failure. Such a marker might enable prevention of complete ovarian failure if early immune suppression was applied. A very few pilot studies have suggested that treatment with prednisolone might reverse ovarian failure in some women. 17 ' 18 Toxins and viruses In most women with premature ovarian failure, the mechanism of damage is unknown - there is no family history, the chromosomes are normal and there is no sign of auto-immunity. We might guess that hidden environmental damage has occurred, perhaps in the distant past, leaving no trace by the time periods have stopped. In men, we know that viruses such as mumps can inflame the testicle, causing permanent 646 British Medial Bulletin 00Q56 (No 3)

5 damage and lack of sperm. Similarly, it is popular belief that sperm counts have fallen over recent years because of exposure of the testicle to environmental toxins or drugs. It is likely that the ovary is affected by viruses or toxins in a similar way to the testes. In particular, viruses are a likely cause of ovarian failure in women for whom no obvious cause is detected. Anecdotal reports of virus infections being quickly followed by ovarian failure add further support to a causal relationship. 19>0 Diagnosis of ovarian failure Ovary failure is diagnosed by measuring LH, FSH whose concentrations in the blood are raised and oestrogen which is reduced. The most sensitive of these hormones is the rise in FSH, which is the best early marker in ovarian failure. Successful pregnancy is rare if the FSH measurement is twice normal (0 U/l instead of 10 U/l). In fact, FSH rises throughout the latter half of reproductive life in parallel with the reduced fertility which occurs after the age of 30 years. 1 The first that an individual might know about ovarian failure is the onset of amenorrhoea. There are many reasons why periods stop - including pregnancy, weight loss and various hormone conditions; but ovary failure is the only cause of amenorrhoea which produces the hormone picture of raised FSH and LH concentrations and reduced oestrogen. Along with amenorrhoea, the low oestrogen concentrations in the circulation lead to symptoms of flushing, mood change and vaginal dryness - these are common to some of the other causes of amenorrhoea and do not necessary indicate a premature menopause. In most instances when a 'menopausal picture' is found on hormone measurements, the diagnosis is secure and permanent. Occasionally, however, ovaries go through a temporary phase of low activity and subsequently return to normal life. For this reason, at least two hormone measurements taken some weeks apart are necessary before the diagnosis of premature ovarian failure can be made. Further, it may be useful to monitor FSH measurements at monthly intervals over some months in order to establish to degree of variability of ovarian activity. Any attempts at fertility treatment might be focused on times which the serum FSH concentration 'dips' into the normal range. Conversely, the witnessing of persistently raised FSH measurements may help some women come to terms with the diagnosis of premature ovarian failure. As time passes, it becomes less likely that the ovaries will return to activity, although rare cases of pregnancy occurring long after premature ovarian failure has been diagnosed have been reported. The mechanism of this return of function is a mystery and, frustratingly, no medical treatment seems to make it more likely. British Medical Bulletin 000, 56 (No 3) 647

6 Human reproduction pharmaceutical and technical advances Opinions vary as to whether biopsy of the ovaries is useful. Most centres have abandoned biopsy in favour of ultrasound as a method of defining the degree of ovary damage. Ultrasound is able to detect ovaries in two-thirds of women with premature ovarian failure, whereas in the days of ovary biopsy only 10-15% of women were thought to have a normal remnant of ovary tissue. At the time of writing, knowledge of the appearance of the ovary is somewhat academic as even the best preserved ovary does not respond reliably to medical treatment if the FSH measurement is consistently raised. If and when immature eggs can be successfully nurtured in a test-tube to allow fertilisation, then knowledge of the appearance of the ovary will be important. At present, only mature eggs ready for ovulation can be used for in vitro fertilisation. Prognosis of premature ovarian failure The process of the menopause, whether natural or premature, is variable in timing. In some women, a completely regular menstrual cycle stops abruptly, while, in others, the transition from normal function to the complete menopause takes several years of fluctuating ovarian activity. When the menopause transition is long and drawn out, the fluctuating hormone levels can be particularly disturbing. Rarely, ovary damage appears to be partial, but stable, with no apparent progression to the complete menopause; this condition of raised serum FSH concentrations and infertility accounts for many women described as having resistant ovary syndrome. Once periods have ceased for 6 months and the diagnosis of premature ovarian failure is secure, fewer than 1:100 women experience a return to fertility and achieve a pregnancy in our experience. Spontaneous pregnancy is never impossible, but is it very unlikely. Several findings make the possibility of spontaneous pregnancy more likely - fluctuating FSH measurements, the ability to identify ovaries on ultrasound and the association with autoimmunity or chemotherapy. Young women who experience ovarian failure not only have to face the prospects of infertility, but also have to consider years of oestrogen replacement treatment. Women with long-term oestrogen deficiency have a reduced risk of breast cancer and probably of thrombosis. These benefits have to be balanced against the increased risk of osteoporosis and heart disease. As heart disease and osteoporosis are far more common than breast cancer, it seems likely that there is an overall benefit to long-term oestrogen replacement. The issue of HRT must be made, however, on an individual's balance of risk and benefit and blanket policies only form a guide to the process. 648 British Medical Bulletin 000,56 (No 3)

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