Physiological versus Synthetic Oestrogens for Bone Mineral Density in Premature Ovarian Insufficiency

By Eileen Chen

My interest in female reproductive health and fertility led to this research project with Professor Jane MacDougall at Addenbrooke’s Hospital in Cambridge, to help guide treatment options for premature ovarian insufficiency.

What is premature ovarian insufficiency, and why is it important?

Premature ovarian insufficiency (POI) is a loss of ovarian function before the age of 40, affecting around 1% of women. It is not simply ‘early menopause’, although many of the symptoms caused by lack of ovarian hormone production (including hot flushes, night sweats and vaginal dryness) are common for women with POI. Some women never have functioning ovaries, whilst for others premature ovarian insufficiency arises later in life.

POI is important is due to the significant impacts it may cause, and its ability to affect women of different ages. In many cases, the cause remains unknown. However, we do know a whole host of environmental and genetic factors can cause POI, including chemoradiotherapy for cancer treatment, autoimmune associations, and rarer genetic diseases like Turner’s syndrome. The effects of POI are both physical and psychological, including a reduction in fertility, day-to-day symptoms of hormone deficiency, and long-term consequences for health such as bone density reduction, osteoporosis and associated fragility fractures (oestrogen acts on receptors to enhance bone deposition within the bone remodelling process).

What are the hormone replacement options in premature ovarian insufficiency?

Oestrogen and progesterone hormones, which are normally produced by ovaries, are exogenously replaced in POI. The synthetic oestrogen in the combined oral contraceptive pill (COCP) is one method, as well as hormone replacement therapy (HRT), which contains physiological oestrogen.

Patients have a choice to make, guided by clinical advice and personal preference, regarding the type of hormone replacement they wish to receive. HRT and COCPs come in different doses, delivery methods (transdermal or oral) and delivery regimes (cyclical, continuous or intermittent). A potential benefit of the COCP for patients is its contraceptive effect, because although POI is associated with infertility, there is still risk of pregnancy and so contraception is recommended. Also, some younger patients find the ‘stigma’ of taking HRT difficult to overcome, as it is also given to menopausal women.

Nevertheless, studies have suggested that HRT may be beneficial for long term bone density and cardiovascular health in women with POI. This is thought to be due to the more ‘natural’ form of the physiological oestrogen in HRT. Existing evidence, comparing the effect of synthetic versus physiological oestrogen on bone mineral density, is somewhat limited in terms of the number of studies carried out and on small patient datasets.

How did we carry out the study?

Our study aimed to see whether physiological or synthetic oestrogens are better for bone mineral density in patients with POI.

We carried out a retrospective study on 30 women with POI who had been referred to the gynaecology services at Addenbrooke’s Hospital, Cambridge. Patients had received either synthetic or physiological oestrogens prior to their bone density scans. Bone mineral density Z scores of the spine and hip were obtained from dual energy x-ray absorptiometry (DXA) scans via online database reports. Z score is the number of standard deviations of the BMD measurement above or below that of adults of the same sex and age. We chose to use Z scores, instead of T scores, to control for age differences between patients. Both patient groups had been taking the therapy for similar lengths of time (4.7 years for physiological oestrogen versus 4.0 years for synthetic oestrogen).

What did the study find?

We found that the bone mineral density at the lumbar spine was significantly improved with physiological oestrogen compared to synthetic oestrogen therapy (p <0.05). Interestingly, we did not find a significant difference in bone mineral density at the hip when comparing the effect of both treatments.

What are the implications for future management of POI?

The idea that physiological oestrogen may have beneficial impacts for bone density at the lumbar spine has already been alluded to [1] and is supported by our study. HRT, providing physiological oestrogens, may result in improved bone density in women with POI when compared to COCPs containing synthetic oestrogen. What’s more, our study also supports a notion that physiological oestrogen may have a beneficial impact on bone density in comparison to synthetic oestrogens, even when given in COCP form. This is an exciting addition to the limited evidence base for management of premature ovarian insufficiency. If newer COCPs containing physiological oestrogen can provide the same benefits as HRT on bone mineral density, patients may have a wider choice of options for oestrogen replacement when it comes to bone health.

Physiological oestrogen seems to have beneficial impact on the bone density of the spine, but not the hip. Previous randomised controlled trials have echoed this finding [2] [3]. The reason for this is currently unclear, but previous authors have suggested this may be due to factors such as differences in response to oestrogen, and a higher turnover rate of the type of bone which forms more of the spine than the hip [3].

We hope that the findings of this study will help clinicians to guide better-informed patient choices when it comes to replacing oestrogen with HRT or the COCP. However, we recognise that a small patient cohort limits the power of our study. Importantly, our study only looked at women with a 46 XX karyotype and did not include patients with Turner’s syndrome (who have a 45 XO karyotype). These patients should be considered separately due to different disease progression and management. Further research into the methods of delivery of hormone replacement, different types of progesterone therapy and therapy regimes is needed to fully inform the management of this condition.


Eileen Chen is a fifth-year medical student at the University of Cambridge. She has a keen interest in fertility and reproductive health, and is passionate about women’s health. Her academic interests include the study of the immune system, and the ability to manipulate viruses in future therapeutics.



[1]          J. Sassarini, M.A. Lumsden, H.O.D. Critchley, Sex hormone replacement in ovarian failure – new treatment concepts, Best Pract. Res. Clin. Endocrinol. Metab. 29 (2015) 105–114. doi:10.1016/J.BEEM.2014.09.010.

[2]          B. Cartwright, J. Robinson, P.T. Seed, I. Fogelman, J. Rymer, Hormone Replacement Therapy Versus the Combined Oral Contraceptive Pill in Premature Ovarian Failure: A Randomized Controlled Trial of the Effects on Bone Mineral Density, J. Clin. Endocrinol. Metab. 101 (2016) 3497–3505. doi:10.1210/jc.2015-4063.

[3]          P.M. Crofton, N. Evans, L.E. Bath, P. Warner, T.J. Whitehead, H.O.D. Critchley, C.J.H. Kelnar, W.H.B. Wallace, Physiological versus standard sex steroid replacement in young women with premature ovarian failure: effects on bone mass acquisition and turnover, Clin. Endocrinol. (Oxf). 73 (2010) 707–714. doi:10.1111/j.1365-2265.2010.03868.x.

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