Nick Panay1
(1)
Queen Charlotte’s & Chelsea and Chelsea & Westminster Hospitals, Imperial College London, Du Cane Road, TW9 3BU London, UK
Nick Panay
Email: nickpanay@msn.com
Premature ovarian insufficiency (POI) remains poorly understood and under-researched [1]. It describes a syndrome consisting of early cessation of periods, sex steroid deficiency, and elevated menopausal levels of the pituitary hormones FSH and LH in women below the age of 40. POI can be primary (spontaneous POI) or secondary (induced by radiation, chemotherapy or surgery). Controversy persists over nomenclature with terms such ‘premature ovarian failure/dysfunction and ‘primary ovarian insufficiency’ still in usage.
POI has been estimated to affect about 1 % of women younger than 40, 0.1 % under 30 and 0.01 % of women under the age of 20. However, as cure rates for cancers in childhood and young women continue to improve, it is likely that the incidence of prematurely menopausal women is rising rapidly [2]. Recent data from Imperial College London suggest that the incidence of POI may be significantly higher than originally estimated. Cartwright and Islam [3] studied 4,968 participants from a 1958 birth cohort. They found that 370 (7.4 %) had either spontaneous or medically induced POI. Smoking and low socioeconomic status were predictive of POI and poor quality of life (SF 36) was twice as common in POI. The incidence of POI also appears to vary according to the population studied. It appears to be significantly higher, >20 %, in some Asian populations (personal communication from Indian Menopause Society).
In the past, the focus of medical care has been on improvement of survival rates. Very little attention has been given to the maintenance of quality of life in the short term and to the avoidance of the long-term sequelae of a premature menopause. One of the main reasons for this has been the bias of economic expenditure and medical endeavour to the prolongation of life (e.g. cancer treatments) rather than towards optimising quality of life in cancer survivors. Should this trend continue we are in danger of creating a population of young women who have been given back the gift of life but left without the zest to live it to its full potential. Maintenance of postmenopausal health is also of paramount importance if we are to minimise the economic impact on society in this and future generations.
Causes of spontaneous POI include idiopathic (no known cause), genetic, autoimmune and infective. The typical presentation of spontaneous POI is erratic or complete cessation of periods in a woman younger than 40 years, which may or may not necessarily be accompanied by symptoms. These symptoms may not be typical vasomotor in nature and include mood disturbances, loss of energy and generalised aches and pains. Our data and data from others [4–6] indicate that the next most disturbing aspect of POI after the loss of fertility is the adverse impact on sexual responsiveness and other psychological problems.
Thus, women with POI require integrated care to address physical, psychosocial and reproductive health as well as preventative strategies to maintain long-term health. However, there is an absence of evidence-based guidelines for diagnosis and management. POI is a difficult diagnosis for women to accept, and a carefully planned and sensitive approach is required when informing the patient of the diagnosis. A dedicated multidisciplinary clinic separate from the routine menopause clinic will provide ample time and the appropriate professionals to meet the needs of these emotionally traumatised patients. At the West London Menopause Centres, we have restructured our services and created a dedicated clinic for the POI patients. Counselling at this stage should include explanation that remission and spontaneous pregnancy can still occur in women with spontaneous or medical POI. Specific areas of management include the provision of counselling and emotional support, diet and nutrition supplement advice, hormone replacement therapy and reproductive health care, including contraception and fertility issues. There is an urgent need for large-scale long-term randomised prospective studies to determine the optimum routes and regimens of hormone replacement therapy. Outcome measures should include short-term symptoms, vasomotor, urogenital and psychosexual and the long-term effect on cardiovascular, cognitive and skeletal health.
12.1 Predictive Tests
As a minimum, the initial investigation of patients presenting with erratic periods, for which pregnancy should be excluded, include measurement of serum follicle-stimulating hormone (FSH), oestradiol and thyroid hormones. If FSH is in the menopausal range in a woman younger than 40, the test should be repeated along with oestradiol for confirmation as levels can fluctuate.
Evaluation of other hormones of ovarian origin, such as inhibin B and anti-Müllerian hormone (AMH), and the ultrasonographic estimation of the antral follicle count are also being used to predict ovarian reserve. Some studies suggest that the precise age of menopause transition can be predicted through the use of these biomarkers; this requires confirmation, especially in POI [7–9]. In the long term, the polygenic inheritance of a risk for spontaneous POI will be unravelled and banks of genes will be tested to give an individual the precise risk of suffering POI.
12.2 Counselling and Emotional Support
Women diagnosed with POI go through a very difficult time emotionally. The condition has been associated with higher than average levels of depression. Loss of reproductive capability is a major upsetting factor and this does not depend on whether the woman has already had children or not. Professional help should be offered to help patients cope with the emotional sequelae of POI. Adequate information should be given in a sensitive manner, including information about National self-support groups for POI, such as the Daisy Network in the UK (http://www.daisynetwork.org.uk).
12.3 Hormone Replacement Therapy
Young women with spontaneous POI have pathologically low oestrogen levels compared to their peers who have normal ovarian function. The global consensus on hormone therapy [10] and updated 2013 IMS recommendations [11] state that in women with POI, systemic hormone therapy is recommended at least until the average age of the natural menopause (51 years).
Hormone therapy is required not only to control vasomotor and other menopause symptoms but also to minimise risks of cardiovascular disease [12], osteoporosis [13] and possibly Alzheimer’s dementia [14], as well as to maintain sexual function. There is no evidence that the results of the Women’s Health Initiative study (a study of much older women) apply to this younger group. Hormone replacement therapy in POI patients is simply replacing ovarian hormones that should normally be produced at this age. It is of paramount importance that the patients understand this in view of the recent press on HRT. The aim is to replace hormones as close to physiological levels as possible.
Since spontaneous ovarian activity can occasionally resume consideration should be given to appropriate contraception in women not wishing to fall pregnant. Although standard oral contraceptive pills are sometimes prescribed, they contain synthetic steroid hormones at a greater dose than is required for physiological replacement and so may not be ideal. Low dose combined pills may be used to provide oestrogen replacement and contraception, although they are less effective in the prevention of osteoporosis and induce less favourable metabolic changes [15, 16]. The progestogen intrauterine system may also be offered in those who choose HRT and require contraception.
In our experience, the choice of HRT regimen and the route of administration vary widely among patients. In the absence of better data, treatment should therefore be individualised according to choice and risk factors. Where libido is a problem, testosterone replacement should be replaced, especially in surgically menopausal women. Although there is an absence of licensed androgenic preparations which can be used, off-label use of physiological female doses of transdermal testosterone appears efficacious and safe.
To complement the role of HRT for the long-term prevention of osteoporosis, supplementary intake of adequate dietary calcium (1,000 mg/day) and vitamin D (800–1,000 IU/day) should be encouraged, as should weight bearing exercises. The use of complementary therapies and non-oestrogen-based treatments such as bisphosphonates, strontium ranelate or raloxifene for the prevention of osteoporosis in women with POI has not been studied.
12.4 Fertility
Women with POI are not necessarily sterile unless surgically menopausal. There is however only a 5 % chance of spontaneous conception. Hence, women for whom fertility is a priority should be counselled to seek assisted conception by IVF using donor eggs or embryos. Future advances in the research of stem cells may make it possible for some women with POI to achieve pregnancy with their own oocytes [17]. Until such a time, oocyte/embryo donation remains the only real chance for these women to achieve pregnancy by assisted conception. Another family building option that should be discussed is adoption.
12.5 POI Registry
We urgently need to determine the scale of the POI problem, initially by the trawling of data from all clinics that manage women with POI. The data will undoubtedly demonstrate extreme variations in management and deficiencies will emerge. Armed with this information departments of health can then be petitioned to provide appropriate funding for the setting up of multidisciplinary units for the management of the particular psychological and physical needs of women with POI.
In the absence of prospective randomised controlled data, there is a need for high-quality observational data. There have been calls for a database/registry from our and other units to provide this information [18, 19].
Individual centres generally do not have sufficient exposure to women with POI to gather sufficient observational or RCT data to give meaningful results on disease characterisation and long-term outcomes. Cooper et al. make the point that fragmented research leads to fragmented patient care [19]. We are in total agreement that without definitive research, we are left to advise women with POI using inappropriate postmenopausal practice guidelines that are based on a different patient population.
The problems we need to overcome in setting up this database include a lack of established standards and design, quality of data, consistency of recruitment criteria, etc. Also, there has to be agreement as to the nature and quantity of the sample size required e.g. inclusion of women with iatrogenic POI as well as spontaneous. The collaborative effort of a cohort of international centres specialising in POI management can overcome many of these limitations.
It is vital that there is a sense of collective ownership of the data and any publications resulting from the research. We are currently in the process of data entry field modification through regular workshops with key collaborators to refine data capture fields and propose areas of data analysis and publication.
The potential benefits of such a database are many. It could be used to create not only an information database but also a global bio bank for genetic studies, with an ultimate goal of defining the specific pathogenic mechanisms involved in the development of POI e.g. unravelling the polygenic inheritance mechanism.
The database would have the potential to define and characterise the various presentations of POI along the lines of the STRAW + 10 Guidelines for natural menopause. The STRAW + 10 collaborators in their recent paper state that special groups, such as POI, warrant urgent attention for staging of reproductive aging [20]. It could also be used to further refine the role of biomarkers such as anti-Mullerian hormone to precisely predict the course and timing of natural and early ovarian insufficiency [7–9].
There is a desperate need to determine long-term response to interventions such as the contraceptive pill, hormone therapy and those not receiving treatment. This is particularly important in women with rare causes and hormone-sensitive cancers where randomised trials are unlikely to be ever performed.
Regarding treatment, questions which urgently need to be answered include, does the type of HRT matter, body identical versus other types of HRT, oral versus transdermal oestrogen, dosage of oestradiol, progesterone versus retroprogesterone versus androgenic progestogens and impact of androgens, on both short-term quality of life and long-term outcomes. The database will also give the opportunity for the role of unproven fertility interventions in POI to be studied such as DHEA, and the use of ultra low dose HRT and the contraceptive pill to suppress FSH levels to facilitate ovulation of any remaining oocytes.
As is the case with a number of other centres, we have been collecting data from our cohort of women with POI for a number of years (over 500 subjects to date) [21]. The next step is to amalgamate these data with those of our colleagues globally. We have already had verbal agreement from more than 30 international experts in POI who would be willing to contribute to such a database. An online website is currently being designed. All collaborators will have the opportunity to offer their views on ultimate database structure and data entry fields before real-time data entry commences in late 2013. The concept of the database has already been launched at the 15th World Congress of Gynecological Endocrinology 2012 and the 9th European Congress on Menopause and Andropause 2012 to the universal approval of experts and delegates [22, 23].
12.6 Conclusion
POI affects many young women globally. These women have unique needs that require special attention. There is an urgent need for standardised terminology and evidence-based guidelines upon which to establish the diagnosis and manage this difficult condition. These guidelines must be drawn up from population specific data to have any relevance. An international POI registry has the potential to provide such information. The problems and limitations of a disease database/registry can be minimised with adequate consensus, communication and collaboration. We hope this will ultimately lead to better understanding of the condition and the development of guidelines for the strategic optimisation of health and fertility in POI.
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