Frontiers in Gynecological Endocrinology: Volume 1: From Symptoms to Therapies (ISGE Series)

11. Premature Ovarian Insufficiency and Its Fertility Implications

Michael Savvas¹ and Haitham Hamoda¹

(1)

The Assisted Conception Unit, King’s College Hospital, London, UK

Michael Savvas

Email: Mike.savvas@nhs.net

11.1 Terminology

Premature menopause is defined as the complete loss of ovarian function occurring before the age of 40 and is a diagnosis that is usually made retrospectively when a woman presents with oestrogen deficiency symptoms, amenorrhoea of more than 1 year, an elevated FSH and reduced serum oestradiol.

Premature ovarian failure or premature ovarian insufficiency is that phase when there is some loss of ovarian function associated with impaired fertility and impaired hormone production. While a woman may have normal periods and be able to conceive, this phase is often associated with some degree of infertility and irregular menstrual cycles. There is no agreed precise definition of POI and it may be regarded as the initial phase of a continuum that ultimately results in premature menopause.

11.2 Causes

There are many causes of premature ovarian insufficiency (Table 11.1), but in the majority of cases the cause remains unknown. An increasing number of young women and girls are surviving cancer treatment and there is, therefore, a growing number of women with iatrogenic ovarian failure. It is estimated that 5 % of women will experience the menopause by the age of 45, 1 % before the age of 40 and 0.1 % before the age of 30.

Table 11.1

The causes of premature ovarian insufficiency

11.3 Clinical Presentation

Women with premature ovarian insufficiency may present with oligo or amenorrhoea in association with climacteric symptoms, hot flushes or night sweats. Sometimes these symptoms first become apparent when a woman discontinues the oral contraception pill in order to try for a pregnancy. In many cases, the diagnosis is made by the fertility specialist, when investigating a woman with infertility but normal menstrual cycles. The blood test may reveal an elevated FSH, reduced oestradiol or an abnormally low AMH. Indeed, it is likely that many cases of unexplained infertility are in fact due to undiagnosed premature ovarian failure.

11.4 Clinical Symptoms

The symptoms of premature ovarian infertility include irregular periods, amenorrhoea and the typical menopausal symptoms.

In the long term, women with premature ovarian insufficiency are also at risk of osteoporosis, heart disease and there is also an associated increase in overall mortality (Table 11.2).

Table 11.2

Symptoms and long term consequences of premature ovarian insufficiency

The most distressing symptom of premature ovarian failure is often loss of fertility with 54 % of women reporting this as the most distressing consequence of their diagnosis [1].

11.5 Pregnancy After Premature Ovarian Insufficiency

It is thought that around 5 % of women with this diagnosis will go on to conceive but this is variable, a younger woman with a diagnosis is more likely to conceive than a woman in her late 30s with the same diagnosis. There is no effective intervention to enhance the likelihood of spontaneous or natural conception. One study [2] has shown that 24 % of women with premature ovarian insufficiency experienced intermittent ovarian function and 4 % went on to conceive. The vast majority of those who conceived did so in the first year indicating that the longer the period of amenorrhoea, the less likely it is that a woman will conceive naturally. Women who present with premature ovarian failure and primary amenorrhoea are also very unlikely to conceive as compared to those who present with secondary amenorrhoea.

The average age at which women give birth has been rising in the recent decades and in the UK the average age of a woman having giving birth is 29.7 years with nearly half of women being over the age of 30 (Fig. 11.1). The average age of first birth is currently 27.9 compared to 26.6 in 2001 (Office for national statistics 2013). An increasing number of women who have delayed having children will therefore not be able to do so due premature ovarian insufficiency occurring in the third or fourth decade of life.

Fig. 11.1

The mean maternal age at time of giving birth. Adapted from National Statistics Office (2012)

11.6 Predicting POI

Most women are aware of the biological advantages in having children earlier but are prevented from doing so because of complex economic, educational and social factors.

Many women, therefore, wish to be reassured or at least want to know the state of their ovarian function and how much longer they have before their fertility is significantly reduced. The clinical history, assessment of ovarian reserve and response to ovarian stimulation may be used for this.

11.6.1 Clinical History

The clinical predictions tend not to be very helpful as there may already be some degree of decline of ovarian function before this is suspected clinically as when a woman presents with a history of oligomenorrhoea associated climacteric symptoms. A history of autoimmune disease, particularly Addison’s and autoimmune thyroiditis may also increase the likelihood that a woman will develop premature ovarian failure.

Family history can sometimes be helpful particularly if the mother or any older sisters had an early menopause.

A recent study from Denmark revealed that women whose parents had an early menopause were more likely to have reduced AMH and antral follicle count. Interestingly, there was no significant association with elevated FSH, serum oestradiol or ovarian volume [3].

11.6.2 Assessment of Ovarian Reserve

Ovarian reserve can be defined as the size of the ovarian follicle pool as associated with the quality with the oocytes. These naturally decline with age resulting in reduced fertility. Fertility specialists employ a number of methods to assess ovarian reserve as a way of predicting outcome to treatment, in particular in predicting response to ovarian stimulation and therefore helping decide on the appropriate dose of FSH to be used for stimulation. Assessment of ovarian reserve is typically carried out in the early follicular phase FSH. An elevated FSH indicating some degree of ovarian failure. Antral follicle count has also been used, however, its reliability is very much operator dependent. Recently, AMH has been used and appears to be more reliable than FSH or AFC. A further advantage is that AMH can be carried out at any time during the cycle; however, while ovarian reserve tests are useful in predicting response to ovarian stimulation, they cannot predict menopause because follicular atresia does not occur as a constant and uniform rate. It has been suggested that the rate of decline in AMH rather than absolute AMH levels may be useful in predicting the age of the menopause [4]. However, this is of limited clinical value as the average age of women in this study was 41 and the shortest time interval required was 3.5 years. These findings may therefore not hold for younger women and in any case a 3.5-year interval makes it impractical as a test for women wishing to predict the time of the menopause.

11.6.3 Poor Ovarian Response to Stimulation

A history of poor response to ovarian stimulation is a further indicator of increased risk of ovarian failure.

Nikolaou et al. [5] reported that women who had poor response to ovarian stimulation were likely to develop menopausal symptoms within 7 years. Lawson et al. reported that poor ovarian response was a stronger predictor of ovarian failure than an elevated FSH [6].

11.7 Fertility Treatment

Treatment with donor eggs remains very successful with very good pregnancy rates. The difficulty with this treatment, however in many countries, remains the lack of donors; this issue is discussed elsewhere in this publication.

A further aspect of the treatment is oocyte (or embryo) cryopreservation; it is widely used for women prior to cancer treatment and there is an increasing demand for social egg freezing.

11.7.1 Egg Freezing

Egg freezing was first carried out more than 25 years ago. However, in recent years, the success rate of egg freezing has improved with the introduction of vitrification or fast freezing, which is a technique that avoids ice formation within the cell. A recent study has shown that the pregnancy rate using fresh eggs is not better than that of using frozen eggs from donors with pregnancy rates of around 50 % in both groups. It must be pointed out however that in this study the egg donors in both groups were very young at 26 year so age [7].

11.7.2 Social Egg Freezing

There is increasing demand for social egg freezing. One of the largest reports from Brussels [8] reported that the mean age of women who store eggs for social reasons was 37. The reason for this presumably is that women in their middle to late 30s who realise that they will not be having children in the very near future are wishing to preserve fertility as an insurance policy. The majority of women in this report indicated that they expected never to have to use these frozen eggs. However, experience of thawing is limited, particularly in this age group and only one woman thawed her treatment with frozen/thawed eggs. She was 39 and unfortunately did not conceive. There is more experience with post-chemo therapy and the success here is likely to be related to the woman’s age and health prior to any chemo or radiotherapy. Data regarding the successful thawing of fertility treatment for women who have chemotherapy is lacking due to the fact that women who freeze eggs prior to chemotherapy may not be in a position to undergo fertility treatment until many years later.

11.7.3 Ovarian Tissue Freezing

More recently, there have been reports of successful ovarian tissue freezing with autologous transplantation. However, very few pregnancies have occurred with this treatment and this remains experimental. The advantages, however, are obvious in that a large number of oocytes can be stored, whereas oocyte preservation will only be applicable for a limited number of eggs.

11.7.4 Fertility Chemo Protection

GnRH treatment prior to chemotherapy has been proposed as a way of reducing the likelihood of ovarian damage and a recent Cochrane review confirms that this can reduce the likelihood of amenorrhoea and increase the likelihood of spontaneous ovulation. However, there does not appear to any increase in the incidence of pregnancy [9].

11.8 Conclusion

Loss of fertility is often the most distressing consequence of premature ovarian insufficiency and premature ovarian menopause and indeed this diagnosis may first be identified by infertility specialists. As women delay motherhood, an increasing number of women with this diagnosis will require fertility treatment. There is an increasing demand for social egg freezing but while the results of freezing donor eggs is encouraging, there is little data regarding the outcome of social egg freezing where women are usually older. Women needing chemotherapy or radiotherapy may benefit from pre-treatment with Gonadotropin Releasing Hormone. As yet there is no reliable predictor of POI.

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