A cross-sectional national questionnaire survey assessing the clinical attitudes of members of the British Menopause Society to the management of women with premature ovarian insufficiency

Main findings

Over half the respondents indicated that HRT was their preferred means of hormone replacement, while a fifth had the combined oral contraceptive pill (COCP) as their preferred option. Of the former group, the majority indicated a preference for transdermal over oral preparations. A quarter of practitioners mentioned they did not carry out a bone density scan as part of their management, while half did not routinely counsel their women about testosterone replacement. The majority recommended continuation of hormone replacement until the average age of the natural menopause.

Strengths and limitations

This survey, despite being a subjective analysis of current clinical practices, provides a view of the current trends of management of women with POI within the United Kingdom. The survey assessed the main aspects involved in the management of women with POI as highlighted in previously published literature on this topic,^2,9 and included the views of practitioners’ who are specialists or had a special interest in this field.

Interpretation

Studies have shown that women with POI have a higher incidence of ischaemic heart disease (IHD), mortality secondary to IHD and an increased overall mortality.^10,11 Women with POI have also been shown to have reduced bone mineral density (BMD) and an increased incidence of fractures compared to controls. ¹² Estrogen replacement has been shown in observational studies to lower the risks of cardiovascular disease, osteoporosis and fractures. Most international guidance documents recommend continuing hormone replacement until the natural age of the menopause.^13–15 However, there is lack of data from randomised controlled trials (RCTs) to demonstrate the benefits of the various treatment regimens and this may explain the large variations noted amongst practitioners. More research is required to further assess this and guide clinical practice.^10,11

Vega et al., ¹⁶ reported on the loss of bone mass and the risk of fractures in relation to the age of onset of the menopause. Women who suffered an early menopause had significantly lower spinal bone density (4%) compared to controls and femoral neck bone density (7%), as well as a threefold higher incidence of hip fractures by the age of 66 years (9.4% for early menopause compared with 3.3% in woman who had a normal menopause and none in the late menopause group).

Gallagher ¹² reported a summary of the published literature on the risk of bone loss and fractures in women with early menopause. The review included large well-designed observational studies, and concluded that an early menopause, usually before age 45 years, leads to a higher risk of osteoporosis and a higher incidence of fractures, while a reduction in the incidence of fractures was noted with the use of hormonal therapy. The author concluded that women who experience an early menopause at an age younger than 45 years should undergo BMD measurements within 10 years of the menopause as the evidence indicates a higher incidence of serious osteoporotic fractures such as spinal and hip fractures in this group. In this survey, we noted a varied approach among respondents to carrying out BMD assessments in women with POI, with a third indicating that they only carried it out selectively, while a quarter indicated that they did not carry it out at all. It can be argued that women taking adequate HRT until the average age of the menopause, specifically those in whom treatment is commenced early, will be at lower risk of having low bone density, and this may partly explain some of the varied practices seen regarding the performance of bone density assessment. Furthermore, access to bone density assessment may not be readily available to all practitioners looking after women with POI. In contrast, in women with untreated POI, BMD assessment can act as a tool in emphasising the benefits of HRT.

The women’s health initiative study revealed an overall increased incidence of stroke in women who commenced oral estrogen and progestogen therapy or oral estrogen alone between the ages of 50 and 79 years. This risk was age related and was noted to be lower in women between ages 50 and 59 years.^17,18 These data should, however, not be extrapolated to include women with POI, as this group represents a different cohort with a different pathophysiology. A review of seven observational studies showed an increased risk of all stroke including ischaemic stroke in women who underwent an early menopause before the age of 50 years, with the risk reduced in women who received hormone therapy. ¹⁹

All routes of estrogen administration can effectively treat menopausal symptoms and provide cardiovascular and bone protection in women with POI. However, the different routes of administration follow different metabolic pathways and as a result can have different advantages and disadvantages. Oral estrogen administration follows a first-pass hepatic metabolism pathway and this can adversely affect the coagulation cascade and pro-inflammatory markers, including C-reactive protein, compared to transdermal administration. There is a lack of evidence assessing the effects of the route of estradiol administration in women with POI. Two large nested case–controlled studies that reviewed the UK’s General Practice Research Database have shown a reduced risk of stroke and venous thrombosis in naturally menopausal women between the ages of 50 and 79 years receiving transdermal estradiol compared to oral preparations.^20,21 These findings cannot be extrapolated to include women with POI, and further research is needed to assess this effect in women with POI. In our survey, it was noted that the majority of practitioners had a preference for transdermal estradiol administration over the oral route. More research is needed to determine the optimal regimen and route of HRT administration in women with POI. The views assessed in our survey were those of the clinicians looking after women with POI. The choice of hormonal therapy being HRT or the COCP, and route of administration, however, will ultimately be decided by the woman’s preferences, contraceptive and fertility needs, but is likely to be influenced by the advice and guidance provided by their supervising practitioner.

Micronised progesterone has also been shown to have a better safety profile when compared to its synthetic counterparts. Observational studies in women beyond the natural age of the menopause have reported a lower risk of breast cancer compared with synthetic progestogens, ²² in addition to having a neutral effect on the vasculature and therefore, a lower risk of venous thromboembolic disease and cardiovascular disease compared with synthetic progestogens. ²³ There is a lack of evidence on the effect of various progesterone preparations in women with POI. Our survey showed that approximately a fifth of practitioners preferred micronised progesterone while the majority showed a preference for synthetic progestogens. A currently ongoing RCT is assessing the cardiovascular effects, effects on lipid and coagulation profiles of micronised progesterone versus medroxyprogesterone acetate in combination with transdermal estradiol in women with POI. ²⁴

Panay et al. ²⁵ reported a questionnaire survey that assessed UK and international practices on the management of POI. The survey included 50 health professionals and reported varied practices in both diagnosis and management. Various terminologies were used with 54% using premature ovarian failure, 16% using POI and 14% primary ovarian dysfunction. 48% routinely carried out BMD assessment at diagnosis. 92% indicated they would use HRT while 68% would consider the COCP, the latter being more common in the UK than elsewhere. UK practitioners were more likely to use transdermal HRT compared to European practitioners and the majority recommended continuation of therapy until the natural age of the menopause. The authors concluded that there was little consensus on nomenclature with much geographic variations in clinical practice particularly with the route of estrogen replacement.

Rebar and Connolly ²⁶ reported that 55% of women with POI and primary amenorrhoea were noted to have chromosomal abnormalities compared to 13% of women with secondary amenorrhoea who developed POI before the age of 30 years. It has been reported that 10–20% of women with POI have some evidence of autoimmunity with thyroid autoimmune disorders being the commonest. However, the pathogenic role of anti-ovarian antibodies in POI remains questionable. In this survey, approximately three quarters of practitioners indicated that they would carry out karyotype analysis either routinely or selectively on women with POI, a third indicated they would routinely perform an autoantibody screen, a third did it selectively while a further third would not perform an autoantibody screen, again showing little consensus among practitioners.^27,28

In this survey, future fertility potential was reported by clinicians to be a major concern for a significant proportion of their patient population. Being faced with an early menopause can be a devastating event and a life altering diagnosis for many women. Spontaneous ovulation may occur sporadically and it has been reported that 5–10% of women with POI conceive at sometime after the diagnosis. However, assisted reproductive techniques with donated oocytes remains the most realistic means to achieve a pregnancy in women with POI. ²⁸ With such a high percentage of women expressing concerns regarding their fertility, recourse to counselling and fertility clinics offering egg donation treatment becomes important. A multidisciplinary approach to the management of these women will enable these aspects of care to be addressed.