A clinical dilemma: the potential use of egg freezing to preserve fertility in a young patient at risk of developing premature ovarian failure

Introduction

It is recognized that many cases of spontaneous premature ovarian failure (POF) appear to be inherited. Estimates of the rates have varied widely, from approximately 4% to 31%. ^1,2 One well-designed study reported 13% of POF cases to be familial. ² While causative mutations in some genes have been identified, for example in the FMR1, FOXL2, FSH receptor and LH receptor genes, ³ it is likely that there are many more which are as yet undiscovered. A family history of POF causes anxiety and presents an interesting clinical dilemma in terms of fertility preservation. This case report discusses such a case and illustrates the importance of multidisciplinary management.

A 15-year-old girl with blepharophimosis ptosis epicanthus inversus syndrome type 2 (BPES2), an autosomal-dominant condition inherited from her father, attended the POF clinic with her mother. Her mother was concerned because of the known association between BPES1 and POF and because her daughter has irregular periods. A cousin with BPES2 was diagnosed with POF at the age of 18. There was no further information on the reproductive status of other affected family members.

The patient experienced normal pubertal development, with menarche at the age of 13. She initially had a 28-day cycle but after six months this became irregular, occurring every one to three months, with bleeding lasting up to four weeks. An untimed follicle-stimulating hormone (FSH) was normal (FSH 6.6, leuteinizing hormone [LH] 2.9, estradiol not performed). Testosterone, TSH and prolactin were also normal. Her body mass index (BMI) was 18, with no recent changes. She had never been sexually active. A trans-abdominal ultrasound scan performed in clinic revealed ovaries of a normal size and appearance. Unfortunately, the view was inadequate to perform a full antral follicle count.

She had already undergone genetic testing for BPES. An insertion mutation was found in the FOXL2 gene. The geneticist advised the family that this type of mutation is not usually associated with POF; it is FOXL2 mutations with truncation and deletion which cause POF. ⁴

The family wanted to find out more information about egg freezing, having read about it on a BPES website. They were able to discuss this with a fertility doctor in the clinic.

It was explained to the family that in the immediate years following menarche, irregular periods are common and a borderline low BMI may exacerbate this. Given the normal ultrasound and untimed FSH, the current ovarian reserve was considered to be normal. We plan to perform a day 2–4 FSH, LH and estradiol to confirm this. The patient may then wish to consider the combined oral contraceptive pill to regularize her cycles.

Following discussion with the fertility specialist, the patient and her mother decided that egg freezing was not an option they wished to pursue at the moment. They had not realized that it would be such a demanding and invasive process, or that the success rates were so low. It was agreed that given the current normal investigations, the risk of developing POF in the imminent future is low and there is plenty of time for the patient to consider her options. These would include doing nothing, considering starting a family earlier rather than later or considering egg or embryo freezing at a later date. A follow-up appointment was arranged for three months' time.

Discussion

BPES is a rare autosomal dominant disorder. Eyelid manifestations occur in both type 1 and type 2 BPES but only type 1 is associated with POF. The conditions are caused by mutations in the FOXL2 gene, which is expressed in the developing eyelids, the ovary and the pituitary. Many different mutations have been described. ⁴ Although the mutation in this case is not associated with POF, it is recognized that there may be intra- and interfamilial variations in the expression of POF with FOXL2 mutations. ⁵ The possibility of two separate mutations, or another familial cause of POF, also exists.

This case illustrates the difficult situation faced when there is a family history of POF. Due to the presence of the BPES2 syndrome, this family had an increased awareness of the significance of young family member experiencing POF. In the rare cases of a known mutation causing the POF, an individual can choose to be tested for it. However, in the vast majority of cases this is not an option. How should such families be advised? Many clinicians would advise the individual to consider starting a family earlier rather than later, but there is currently increasing interest in egg freezing as a method of preserving fertility. One case in which a woman with mosaic Turner's syndrome opted to have egg freezing is described in the literature. ⁶

Serum anti-Müllerian hormone (AMH) is another test for ovarian reserve that could have been considered in this case. AMH is produced by developing antral follicles from the stage of primordial follicle recruitment until they have reached the size to be selected for dominance. AMH appears to be an intraovarian signal for the size of the antral follicle pool and enables its regulation. ⁷ As it is only produced by growing antral follicles, it is a measure of their number, ⁸ which is considered to be related to the total number of oocytes. AMH is used as a marker of ovarian reserve to predict response to ovarian stimulation in assisted reproduction, ⁹ and levels are related to age at menopause. ¹⁰ A potential advantage of using AMH to evaluate ovarian reserve in this case is that it is independent of the time of the menstrual cycle. ¹¹ It could also continue to be monitored during combined oral contraceptive pill use. ^11,12 However, the use of regular AMH assessments in patients at risk of developing POF has not yet been thoroughly evaluated. Apart from difficulties recommending a specific course of action based on results, due to a lack of research in this area, another limitation is that AMH is not always routinely available in National Health Service (NHS) clinics (including ours).

Egg freezing is a demanding process, involving multiple visits to an in vitro fertilization centre, transvaginal scans and hormone injections. It also carries a small but significant risk of potentially life-threatening complications such as ovarian hyperstimulation. ¹³ As non-essential medical treatment, many would feel that it is inappropriate for a 15-year old who is still in full-time education and not yet sexually active. Some of the ethical issues to be considered before embarking on treatment would be as follows:

Her understanding of egg freezing including the procedures involved, risks and likely success rates.

Limited data are available on the success rates of egg freezing. The Human Fertility and Embryology Authorisation report only a small chance of delivering a healthy baby following egg freezing (5–10%) and to date only five babies have been born in the UK following the technique. ¹⁴ Success rates may improve with the use of vitrification (rapid freezing); ¹⁵ however, at present this method is not widely used in the UK. Although funding can be applied for in special circumstances (for example, prior to cancer treatment), it is not generally funded by the NHS. Recent guidance from the British Fertility Society and Association of Clinical Embryologists notes that egg freezing is a relatively new treatment, with value limited by low success rates and that there is a need for further, large clinical trials to inform us of the best techniques. ¹⁶ Patients' perceptions of egg freezing, having heard about it for example on the Internet (as in this case), may be very different from the reality and it is often perceived as an easy, harmless and effective way to preserve fertility. This is why a multidisciplinary POF clinic, at which experts in fertility can provide counselling, is vital.

Competing interests

None declared.