The menopause transition can have a significant impact on many women, with more than 75 % experiencing menopausal symptoms, and a quarter describing severe symptoms. Symptoms on average last 7 years and a third of women experience long-term symptoms. Menopausal hormone therapy (MHT), compared with placebo, has consistently shown improvements in menopausal symptoms and overall quality of life. Furthermore, MHT has a significant protective effect against osteoporosis and cardiovascular disease in women initiating MHT under the age of 60 [
[1]
,[2]
]. Approximately 10 % of European women aged 45–69 were reported as taking MHT [[3]
]. Estradiol in MHT is generally delivered orally or transdermally while progestogens include synthetic progestogens or body similar micronised progesterone.Transdermal estradiol is unlikely to increase venous thrombosis or stroke risk above that in non-users and has a lower risk compared with oral administration. Micronised progesterone and dydrogesterone may also be associated with a lower breast cancer and venous thrombosis risk compared with other progestogens [
[2]
]. MHT should therefore not be viewed as one intervention with set risks and side effects.Access to different MHT preparations is essential to optimise treatment and meet women’s needs. However, in various parts of the world, lack of availability of licenced MHT products, commercial discontinuation of products and manufacturing and supply shortages impact on such access.
MHT preparations containing transdermal estradiol are licenced in most European countries, North America, Australia, New Zealand, Asia (including China, India and Pakistan) and certain African countries. However, limited access remains an issue in many countries worldwide, restricting choice and access to the advantages of transdermal estradiol.
Some MHT products have also been discontinued for commercial reasons either globally or in selected countries. For example, testosterone patches were discontinued in Europe in October 2012, restricting availability to testosterone gel preparations manufactured for male use, used off-licence in female replacement doses. Globally, estradiol implants were discontinued in July 2011 and testosterone implants in November 2012.
Other MHT preparations selectively discontinued in some countries are still marketed in other countries around the world. Dydrogesterone (a synthetic progestogen with a neutral metabolic profile and less adverse effect on breast tissue and thrombotic risk) as a stand-alone preparation but usable in combination with estrogen replacement was withdrawn from the UK market from March 2008 for commercial reasons, although still currently marketed in certain European countries. Dydrogesterone, however, is marketed in the UK within combined MHT preparations. Other regional discontinuations of MHT products include drospirenone with estradiol (the former a spironolactone analogue with anti-androgenic/anti-mineralocorticoid properties offering an alternative in women with progestogen intolerance), discontinued for commercial reasons in the UK early 2019 and the tissue selective estrogen complex [TSEC] (containing conjugated equine estrogen and the selective estrogen-receptor modulator bazedoxifene offering selective anti-estrogenic activity on the uterus and breast thus avoiding the need for a progestogen), discontinued for commercial reasons in the UK August 2018, but continues to be marketed in other countries.
Pharmaceutical companies may discontinue certain MHT products for commercial reasons, depending upon availability of other competing products. However, it is unclear why certain MHT preparations discontinued in some countries remain available in neighbouring countries with similar access to MHT products.
Shortages in availability of licenced MHT products related to manufacturing and supply issues have also affected access to MHT products in many countries. The Netherlands and Greece have experienced transdermal estrogen preparation shortages, despite these being officially marketed there. In the UK, MHT shortages were first noted in late 2018 and continue to the present day. Initially, supply problems were reported due to manufacturing issues caused by regulatory action at one contractor’s manufacturing site. Subsequently, shortages were noted with the main estradiol patch line which supplied 40 % of the UK market. The manufacturing company indicated this resulted from increased demand, whereby in the six months up to June 2019 the amount the company sold was greater than the entire year of 2018. The UK was the largest market for this particular transdermal estradiol patch line globally and this has been cited as a further contributory cause of the UK shortages. Pharmaceutical manufacturers of most other transdermal preparations have indicated no production issues.
It is difficult to ascertain how much of the overall shortages in MHT supplies that followed in the UK was a domino effect to the shortages of the main estradiol patch product and the resulting increased demand on other products or direct manufacturing/supply issues.
The UK’s Department of Health and Social Care (DHSC) indicated that uncertainties surrounding Brexit negotiations are an unlikely contributory factor. In view of the shortages, the UK government in October 2019 issued restrictions on exporting certain MHT products seeking to prevent medicine wholesalers from parallel exporting. Media reports suggested possible shortages in MHT ingredient imports from China as a factor. However, other large markets namely France, Spain and Mexico appear unaffected by MHT shortages (unlikely if shortages of ingredients from China had been a significant factor). Media reports also speculated whether inclusion of some MHT products on the National Health Service (NHS) drug tariff (the amount the NHS repays pharmacies for generic prescription medications) in 2018 may have contributed. The DHSC however refuted this, and the price of UK MHT patch preparations remains higher than in most European countries. Furthermore, many MHT products on the NHS tariff list are unaffected by the shortages.
In October 2019 the main estradiol patch product affected by the shortages in the UK was sold to a different manufacturer and is expected to be back in supply in February 2020. We await to see the impact this has on resolving the current shortages.
As clinicians, whilst our first step is to offer help and advice regarding suitable MHT alternatives, beyond this we need to understand the reasons behind the shortages and what measures can be taken to resolve the issue and prevent a reoccurrence.
The fact remains that due to companies making commercial decisions regarding what products they are prepared to market in particular countries, and a secondary factor of supply shortages (the reasons behind which are difficult to ascertain) women do not have equal access to MHT products around the world. This could result in women being denied access to preparations that are more suitable to their particular needs, but which are no longer available to them as a result of these marketing decisions or supply shortages.
Contributors
Haitham Hamoda is the sole author.
Conflict of interest
The author declares that he has no conflict of interest.
Funding
No funding was received for the preparation of this editorial.
Provenance and peer review
This article was commissioned and not externally peer reviewed.
References
- Menopause: Clinical Guideline – Methods, Evidence and Recommendations, (NG23), 12 November, Version 1.5.2020www.nice.org.uk/guidance/ng23/evidence/fullguideline559549261
- The British Menopause Society & Women’s Health Concern 2016 recommendations on hormone replacement therapy in menopausal women.Post Reprod. Health. 2016; 22: 165-183
- Menopausal hormone therapy use in 17 European countries during the last decade.Maturitas. 2014; 79: 287-291https://doi.org/10.1016/j.maturitas.2014.07.002
Article info
Publication history
Published online: February 07, 2020
Received:
January 26,
2020
Identification
Copyright
© 2020 Elsevier B.V. All rights reserved.
