Management

Although Sheila was initially referred for fertility treatment, it is important that her overall reproductive and psychological health is considered. This includes advice on the use of adequate hormone replacement therapy (HRT) in the longer term to maintain her bone mass, and to prevent sexual dysfunction, as well as treating the vasomotor symptoms associated with estrogen deficiency. In younger women, hormone replacement can be provided from the use of the combined oral contraceptive pill or more conventional biphasic HRT. However, psychologically in a woman recently diagnosed with POI presenting with infertility, the use of the combined oral contraceptive pill may seem counterintuitive. This would prevent the small but recognized chance of spontaneous pregnancy seen in 5–10% of women with POI. Furthermore, recent evidence has suggested that the use of biphasic conventional HRT, mimicking a more normal endocrine environment, may have a more beneficial uterine effect, helping create a thicker endometrium [3]. The unfortunate media hype surrounding the risks of long-term HRT, and in particular breast cancer, need to be carefully managed, and the true risks in premature ovarian failure need to be explained to avoid lack of compliance. The lack of ovarian androgens may cause a noticeable decrease in libido and an additional small dose of testosterone replacement has been shown to be helpful [4]. This can be administered transdermally as a gel. It is important to monitor for adverse side effects of androgens such as hirsutism, acne and changes in the HDL cholesterol. A full discussion on the choice of HRT is beyond the scope of this chapter; please refer to Chapters 17 and 25.

Associated medical disorders, which may have been found on the initial assessment, should be addressed to ensure that pregnancy is safe and outcome optimized. These include normalization of endocrine disorders such as thyroid and adrenal dysfunction. Women with Turner’s syndrome often have cardiac and renal abnormalities, and need to have a cardiac assessment of their aorta due to the high risk of coarctation. Appropriate psychological support is essential with referral to a trained counselor, not only for support following the diagnosis but also to talk through the implications of egg donation.

Fertility treatment

Sheila has a small chance of natural ovulation and spontaneous pregnancy, estimated to be between 5% and 10%. Reassuringly, if a spontaneous pregnancy does occur, the risk of miscarriage is no greater than women with normal ovarian function. Although numerous interventions have been attempted to increase the likelihood of spontaneous ovulation, including a short-term course of the oral contraceptive pill (pill rebound), HRT, steroids and gonadotropin-releasing hormone agonists (GnRHa), there is no substantiated evidence that any of these are better than expectant management. One small study suggested that the use of GnRHa in combination with gonadotropins with high-dose steroid therapy may be beneficial in women with POI and a normal karyotype, but much larger studies are needed confirm this potential benefit [5]. It is impossible to predict if Sheila’s spontaneous ovulation will return, although normalization of serum endocrinology can occur as disease levels fluctuate. Ovarian tissue cryopreservation is a possible option for women who are about to lose their ovarian function through ablative chemotherapy, but it has no role to play in Sheila’s case as her oocyte numbers are already depleted at the time of diagnosis. The best option for pregnancy is egg donation, which is discussed in detail in the following section.

Egg donation

Egg donation allows the patient to carry and deliver her husband’s genetic child. Although the child is not genetically linked, the woman is responsible for the child’s existence, nurturing the embryo from conception to delivery, and in the UK, her name is recorded as the mother on the child’s birth certificate. The use of egg donation has increased substantially as a treatment option in Europe, almost doubling from 13,609 in 2008 [6] to 25,187 in 2010 [7].

Regulation

The regulations governing egg donation vary substantially around the world. In the UK, where in vitro fertilization (IVF) treatment has been closely regulated by the Human Fertilisation and Embryology Authority (HFEA) since 1991, information on donors, including a description of themselves, their ethnic group, marital status, the number and gender of their current children, their physical characteristics, details of screening tests and medical history as well as a goodwill message for potential children, are held by the HFEA. A change in the HFEA Act saw anonymity removed from all gamete donation from April 1, 2005. Since that time, at the age of 18 a child can contact the HFEA and be provided with identifying information about their genetic origins, including contact information. The HFEA will inform the donor that a request has been received, prior to releasing information. This loss of anonymity did not receive uniform approval, and there was a fall off in those coming forward as egg donors in 2006, although this has now recovered almost completely [8]. Furthermore, in a recent survey, up to 34% of recipients travel overseas for egg donation to avoid the anonymity rules [9]. Donors who donated prior to 2005 can apply to the HFEA to remove anonymity. However, no donor has the legal right to contact their donor-conceived child, although they can find out how many children were born as a result of their donation.

Egg donors in the UK have to be under the age of 36, unless there are exceptional documented reasons to use older women, such as known donation. Donors are encouraged to allow the clinic to verify their medical and psychological history with their general practitioner. When selecting donors, clinics need to take into account the implications of the donation for the donor’s family and her future fertility. Donors can put conditions on the use and storage of their gametes, but these need to be compatible with the Equality Act 2010. Donors and recipients need to be aware that the donors can withdraw their consent to the use of their gametes and to the use of embryos created from their gametes at any stage in the treatment process. It is therefore mandatory that all gamete donors and recipients are provided with the opportunity to receive appropriate implications counseling. In the UK, couples are encouraged to reveal to their donor-conceived child their genetic origins. The emphasis placed on telling the child following egg donation relates to the extensive psychological literature outlining the experiences of adopted children and their perceived need to find out about their genetic origins.

Source of egg donors

Egg donors in the UK are recruited from two clear groups. The first are women who donate altruistically, principally to help others, responding to stories in the media or who have friends or family who have had difficulty conceiving. The recipient can use a family friend or relative directly, or by agreeing to donate to others, allowing the recipient access to the “donor pool,” in a cross-over arrangement. A common example is a sister donating to the other sister, although recent evidence suggests that this can at times prove difficult, as ovarian insufficiency may unknowingly be unearthed in the sibling [10]. Altruistic donors account for less than half (43% in 2010) of all UK donors [7]. Ethically, altruistic donors are showing an unselfish concern for the welfare of others, and make the donation voluntarily without payment in return, or compensation. From the child’s perspective it is known that the donor’s motives are hugely relevant, and that those donating altruistically are likely to be more committed, rather than those donors potentially donating for monetary gain, as the latter are less likely to think about the long-term consequences. In 2012, the HFEA changed the rules on compensation, and now UK donors can be paid reasonable expenses up to the value of £750. This encouraged some to come forward where the primary motive is monetary gain rather than altruistic donation.

The second, and largest, group of donors in the UK is those who receive benefit in kind, including free or subsidized fertility treatment by donating a proportion of their gametes during their own fertility treatment. Egg-sharing started in the UK nearly 20 years ago and now accounts for 57% of all UK donors in 2010. In these circumstances, patients who require in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) treatment, donate a set number of their oocytes to a recipient. Careful selection is essential to ensure that the donor will produce sufficient oocytes to make the process worthwhile for both parties. In general, if the assessment ultrasound suggests that the donor will not produce sufficient oocytes, clinics usually favor canceling the recipient cycle. It is not allowed by law to continue with the cycle and donate all the oocytes to the recipient, then the donor start a fresh cycle for her own use. This process known as “egg giving” was outlawed by the HFEA [8]. It is essential the clinic have a clear policy of whether a charge will apply if this situation were to occur. Egg-sharers mainly consist of women not eligible for NHS-funded treatment, often as their partners have had children in previous relationships. Research has shown that in comparison to altruistic donors the chance of a successful outcome is similar, and that both the donor and the recipient have an equal chance of a successful outcome [11]. However, there is some evidence that some unsuccessful egg-sharing donors feel regret in the knowledge that another couple may become the parents of a child genetically related to them [12]. The full extent of the implications of the change in the UK regulations with anonymity on those unsuccessful egg-sharing donors will not be known until 2023 when the first child is 18 and is able to trace their genetic parent.

The major drawback of egg donation in the UK has been the shortfall in egg donors, and as a consequence many patients now choose to travel overseas.

Recruitment of donors overseas is variable, and some countries like Sweden manage almost entirely on altruistic donation. However, those countries, which incidentally perform the majority of egg donation in Europe, pay their donors a financial incentive to donate. The largest exponent in Europe is Spain who performed 12,928 cycles in 2010. Other countries within Europe performing a large number of cycles include the Czech Republic (2,365), Russia (2,147), the UK (1,891) and Belgium (1,412). In some countries such as Turkey, egg donation is not permitted on religious grounds, and as a result services have developed in neighboring states or provinces where the rules permit, such as Northern Cyprus, which now has a flourishing egg donation program. Across the world, egg donation programs are well developed in North America, with payment of donors established practice. In 2007 the American Society of Reproductive Medicine recommended a limit on the payment to donors to $50,00, and no more than $10,000 could be justified [13]. A recent survey of agencies and clinics offering egg donor matching and donation respectively in the USA demonstrated that these guidelines are being flaunted. Furthermore, many of these agencies and clinics are paying additional amounts for certain characteristics [14]. Paid oocyte donation has potential concerns, and there is a risk that where money is involved donors may be encouraged to donate three or more times, which may ultimately have an impact on their own health and fertility.