Premature Ovarian Insufficiency- where do we stand now?

Dr. Panay kicked off this morning’s BMS symposium by explaining the work done with the premature ovarian insufficiency registry.

Premature ovarian insufficiency (POI) is defined as the accelerated loss of ovarian follicles which results in ovarian reserve in a woman before she reaches the age of forty. POI is known to lead to menstrual disturbance, elevated gonadotrophins and estrogen deficiency. This in turn can have an impact on climacteric symptoms, cardiovascular disease, bone density and fertility. Observational data suggests a 7% incidence but some countries have reported this can be as high as 20%! POI can also be difficult to diagnose, Dr. Panay highlighted the importance of confirming diagnosis with two FRSH occurrences higher than 25, 4-6 weeks apart.  

With POI known to have an impact on estrogen deficiency, work was done by Tao X-Y et al. to analyse the impact of POI and early menopause on mortality. Data showed that two cohorts of women who had POI and experienced early menopause both experienced higher mortality rates, suggesting there is a link that needs to be further investigated.

With more research needed, guidelines were developed which included a recommendation to pre-menopause registry in the UK. Nelson’s group in Harvard are also building an extensive registry with hopes that the two can be merged in time.

Work is already being done by Cloke et al. in the Genomics England Collaborative UK study where targeted gene sequencing has enabled identification of likely causative mutations in a modest proportion of POI families. Large scale whole genome sequencing is also being looked at as a potential method of identification of novel causative genome factors.

So what are the aims of the registry?

  • Characterise various presentations of POI
  • Identify what markers can be used to precisely predict the course and timing of ovarian insufficiency
  •  Create a global bio bank for generic studies
  • Determine long term response to interventions (analysing effective of oral contraceptives vs MHT vs no treatment)
  • Identify if the type of MHT has an impact
  • Quantify precise risks e.g. psychological/osteoporosis/breast/cardiovascular disease/cognitive dysfunction

Data in the registry has been collected for over a decade, but more data is always needed so it’s important to sign up and collaborate where possible!

Whilst diagnosis of POI can be difficult, significant delay in diagnosis should be avoided. More than 50% of women with the condition visited more than 3 clinicians before a diagnosis, with a quarter of conditions taking more than 5 years to be diagnosed. This delays means that a period of estrogen deficiency can go untreated which has been sighted as a contributor to low bone density.

When a successful diagnosis has been made, Dr. Panay believes estrogen replacement should be the first line treatment until the average age of menopause. This is not a view shared by all as many believe the combined oral contraceptive (COC) is a simple choice. However with this treatment option, symptom resurgence can occur during the pill free week. So far three small randomised clinical trials have looked at a comparison of MHT vs COC, with data confirming that MHT leads to lower hyperinsulineamia, increased bone formation markers and improved LS BMD.

When it comes to choosing the dose of MHT, data shows that women with POI require higher doses of estrogen than older women. Dr. Panay also suggests that androgen replacements should also be considered as an additional treatment.

When discussing treatment, patient’s choice about conceiving will play an important part. Data from a survey done by Singer et al. 2011 shows that fertility is the biggest concern for women with POI. Options for fertility issues include IVF with donator oocytes (this has the highest chance of pregnancy up to 60% per cycle but is avoided by many women), adoption, surrogacy and child free living. More research is being done in this area to with stem cells in adult ovaries and we hope more options will be available to women with POI in the near future.

For now there is still a lot more data that needs to be collected, we need to focus on ensuring diagnosis is timely and treated in the most appropriate way for the patient. Sign up for the registry at https://poiregistry.net/ and play you part in addressing remaining questions.