Home

Bluesky · LinkedIn

Category: Critical review

  • Making Sense of Progestogens in HRT: What I Learned When I Went Back to the Evidence

    One of the areas I have found most challenging in menopause care is choosing the right progestogen. Not because options are lacking — but because there are several, each with subtly different properties, and the differences are often poorly explained in everyday practice.

    I realised I was not as clear as I wanted to be on how the commonly used progestogens really differ from one another. So I went back to the evidence. This post is a summary of what I found when I looked more closely at three widely used options in hormone replacement therapy (HRT): micronised progesterone (often prescribed as Utrogestan although other versions are available), dydrogesterone, and drospirenone.

    Why the Progestogen Matters

    In women with a uterus, progestogens are essential in HRT to protect the endometrium from unopposed oestrogen stimulation. But endometrial protection is only part of the story.

    Different progestogens have different effects on:

    – mood and sleep

    – bleeding patterns

    – metabolism and fluid balance

    – breast tissue

    – cardiovascular and thrombotic risk

    Understanding these differences matters — particularly in the perimenopause, where women may be more sensitive to hormonal effects and more likely to stop treatment if side effects are problematic.

    Micronised Progesterone: Closest to Physiology

    Micronised progesterone is chemically identical to endogenous progesterone. The “micronised” part simply refers to the mechanical process used to improve absorption by reducing the particle size.

    What stands out when reviewing the literature is its receptor selectivity. Micronised progesterone acts primarily at progesterone receptors, with minimal off-target effects. This likely explains its relatively favourable profile in relation to mood, lipids and cardiovascular risk.

    Orally, it undergoes significant first-pass metabolism, which reduces bioavailability but also produces metabolites such as allopregnanolone. Clinically, this often translates into a sedative effect, which some women find helpful for sleep — particularly when taken at night — while others find it limiting.

    When used in evidence-based doses, micronised progesterone provides reliable endometrial protection, although bleeding patterns can be variable and sometimes require adjustment.

    Dydrogesterone: Targeted and Well Tolerated

    Dydrogesterone is a synthetic progestogen, but one with a structure that closely resembles natural progesterone. It has high oral bioavailability and strong receptor selectivity, meaning effective endometrial protection can be achieved at relatively low doses.

    One of the consistent findings across studies is its predictable bleeding profile when used sequentially. Withdrawal bleeds tend to be more regular, with fewer episodes of unscheduled bleeding compared to some other synthetic progestogens.

    Importantly, dydrogesterone appears metabolically neutral. It is non-androgenic, does not adversely affect lipid or glucose metabolism, and is generally well tolerated in terms of mood and breast tenderness. Although often used off-label for HRT in the UK, its safety and efficacy data are reassuring.

    Drospirenone: Different by Design

    Drospirenone is structurally quite different from the other two. It is derived from spironolactone and has anti-mineralocorticoid and anti-androgenic properties.

    This gives it a distinct clinical niche. Its ability to counteract sodium and water retention can be particularly helpful for women troubled by bloating, fluid retention or raised blood pressure. Some women also benefit from its anti-androgenic effects on acne or hirsutism.

    Drospirenone has demonstrated effective endometrial protection in fixed-dose HRT preparations and is also licensed as a progestogen-only contraceptive (for example, the 4 mg 24/4 regimen). This makes it a useful option in the perimenopause, where contraception may still be required.

    However, long-term breast safety data are more limited, and caution is advised in women at risk of hyperkalaemia, particularly those taking other potassium-sparing medications.

    Breast and Cardiovascular Safety: What the Evidence Suggests

    Breast cancer risk remains one of the most common concerns around HRT. Observational data — particularly from large cohort studies — suggest that micronised progesterone and dydrogesterone are associated with a lower breast cancer risk compared with some older synthetic progestogens.

    These data are not from randomised trials and must be interpreted cautiously, but they are broadly reassuring. Thrombotic risk appears to be driven far more by the route of oestrogen administration than by progestogen choice, with transdermal oestrogen consistently favoured.

    Evidence around drospirenone and thrombotic risk in HRT is still evolving, but current data do not suggest a clear excess risk.

    Practicalities Matter Too

    Beyond pharmacology, practical considerations influence real-world prescribing. Cost, licensing, availability, and flexibility of dosing all matter — as does the woman’s own experience of side effects.

    It is also important to remember that oral progestogens are not the only option. The levonorgestrel-releasing intrauterine system provides highly effective endometrial protection with minimal systemic exposure and remains an excellent choice for many women, particularly those who want long-acting contraception alongside HRT.

    What This Changed for Me

    Looking back at the evidence helped me move away from thinking about progestogens as interchangeable. They are not. Each has strengths, limitations and a particular place in practice.

    For women with higher concern about breast or cardiovascular risk, micronised progesterone or dydrogesterone are often preferable. For those struggling with fluid retention, acne, or needing contraception, drospirenone may offer advantages. And for many, the “best” choice is the one that balances evidence with lived experience.

    Shared decision-making, grounded in up-to-date evidence and individual priorities, is key.

    Further Reading

    British Menopause Society. Progestogens and Endometrial Protection: Tools for Clinicians

    NICE Guideline NG23: Menopause: diagnosis and management

    Stevenson JC et al. Progestogens in menopausal hormone therapy. Drugs in Context

    Mueck AO et al. Dydrogesterone in HRT. Maturitas

    Palacios S et al. Drospirenone in hormone therapy. Maturitas

  • Enhanced Glucose Processing in Gestational Diabetes: Shifting the Diagnostic Landscape

    Jones DL, Kusinski LC, Barker P, Burling K, Halsall I, Turner E, et al. Enhanced glucose processing in gestational diabetes diagnosis: Effects on health equity and clinical outcomes. Diabet Med. 2024 Dec 17;e15476.

    The diagnosis of gestational diabetes mellitus (GDM) has always been a fraught territory. Relying on the oral glucose tolerance test (OGTT), we know the test is inconvenient, variably reproducible, and often poorly tolerated by women. What Jones et al. (2024) add with their OPHELIA study is a careful look at what happens when the pre-analytical handling of blood samples is tightened up: putting samples on ice, rapid centrifugation, and freezing within 2.5 hours. This stops the metabolism of glucose by red cells, leading to. Greater accuracy. The result? Glucose values rise by about 0.6 mmol/L – and the rate of GDM diagnosis leaps from 9% to 22% .

    This is an important finding. The additional women picked up weren’t just at the margins. They were, on average, younger, had higher BMIs, and gave birth to significantly more large-for-gestational-age (LGA) infants (37% vs. 22% under standard testing) . In other words, women with clinically meaningful risk were slipping through the diagnostic net when standard processing was used.

    The equity dimension

    What makes this paper particularly important for those of us in primary care is the way diagnosis intersects with equity. Women most likely to be missed on standard processing were often from higher BMI groups and with differing ethnic profiles. This matters because we already know attendance at OGTT appointments is lower in women from deprived and minoritised ethnic groups . So, the current pathway risks a double inequity: first, some women are less likely to attend, and second, those who do attend may have their hyperglycaemia under-recognised if the sample processing is suboptimal.

    As GPs, we often see the knock-on effects of these diagnostic gaps. Babies born large-for-gestational-age, women with unrecognised hyperglycaemia who may face higher risks of future type 2 diabetes, and families who shoulder the longer-term metabolic consequences.

    But what about overdiagnosis?

    Of course, increasing the diagnosis rate so dramatically raises another concern: are we at risk of overmedicalising pregnancy? Some women identified by enhanced processing required no treatment beyond lifestyle advice, and their risk profile was arguably milder. Jones et al. acknowledge this, but importantly they found the undiagnosed group were not uniformly “low risk” – they had comparable fasting glucose levels to the standard GDM group and higher rates of adverse outcomes.

    For primary care, this tension between under- and over-diagnosis is familiar territory. Just as with hypertension thresholds or cholesterol risk calculators, the line between early intervention and unnecessary burden is a fine one. The challenge will be whether health systems can support the increase in GDM diagnoses with proportionate and person-centred management, without overwhelming services or fuelling unnecessary anxiety in women.

    Implications for practice

    For GPs, the study prompts some key reflections:

    Equity of access: If enhanced processing becomes standard, are we simultaneously addressing the barriers that keep some women from being tested in the first place? Otherwise, the inequity gap may actually widen. Holistic risk framing: Enhanced processing identifies women at higher risk of adverse outcomes – but diagnosis alone isn’t the endpoint. Supporting women through diet, activity, and psychosocial support may be more impactful than simply labelling. The long view: Diagnosing GDM is not just about pregnancy outcomes. It’s also about recognising long-term metabolic risk and ensuring women get follow-up beyond the six-week postnatal check.

    Ultimately, this paper reinforces a core truth: how we handle samples in the lab isn’t a technicality – it shapes who gets a diagnosis, who gets treatment, and who carries risk unnoticed. If we are serious about tackling health inequities in pregnancy, then perhaps the starting point is as simple (and as complex) as a tube of blood and some ice.

  • Improvements in Stress, Affect, and Irritability Following Brief Use of a Mindfulness-based Smartphone App: A Randomized Controlled Trial – Economides et al, 2018

    Available here – full text.

    One area which I reviewed as part of my foundation module in pain was Mindfulness and Mindfulness-Based Stress Reduction (MBSR) to see if there was any benefit for chronic pain sufferers. From what I found in a number of papers I reviewed was that pain scores do not change but acceptance of chronic pain improves.  Since reading about this, it is something I have mentioned to my patients as an option, or at least to investigate it.  I always add the caveat ‘it is not for everyone’ but a surprising number of the young soldiers I see with pain (usually musculoskeletal or urological) engage with it.  I reviewed one paper which looked specifically at Headspace (as one of the smartphone app market leaders).  This was an RCT of Head Space, where patients were randomised to either the app or active control, to see if Head Space was superior (Economides et al., 2018).  My non-expert critical ‘take’ on the paper is summarised below. This study used validated outcome measures which demonstrated statistically improved scores in measures of irritability & anxiety.

    Aim / Type of study An RCT comparing Mindfulness to an active control.

     
    Methods A 3rd party recruiting agency (https://www.findparticipants.com) was used to recruit participants. They did NOT have chronic pain and were naïve to both meditation, mindfulness and the Headspace app. They had no psychological illness.  They had to have access to a smartphone. Using a statistical approach, 52 participants were required to achieve significance at the 0.05% level.

    The Headspace meditation mindfulness app was compared against a control group using Headspace audiobook. The intervention group (N=41) was exposed to the first 10 sessions of 10-minute sessions delivered by the Headspace app.  The control (N=28) was 10 sessions of 10 minutes of excerpts from a Mindfulness & Meditation audiobook.  To closely match the intervention, the audiobook was narrated by the same author in a similar manner.  Thus, the only difference between the two groups was the content.

    There were 4 outcome measures:  Stress Overload Scale (SOS) – personal vulnerability and event load, Scale of Positive and Negative Experience (SPANE) and Brief Irritability Test (BITe).  These were assessed by all participants in both groups and paired T-tests were undertaken between them. Dropouts were included in an intention to treat analysis.

    The outcome measures were all reductions in the 4 measures from baseline.  The reduction in scores in the two groups were assessed by an Analysis of Variance test (ANOVA) as well as post hoc t-tests to further characterise differences.  Intention to treat analysis was also included.
    Results / Data In two of the outcome measures (SOS event load and SPANE) there was significant difference between the groups favouring Head Space (P<=0.01).  SOS personal vulnerability was also different between the groups again favouring Head Space (P=<=0.05). There was no difference in the SOS Personal Vulnerability score between the two groups (P=0.09).
    Comments Whilst the size of the groups was different (41 in Headspace vs 28 in Audiobook), they were broadly similar demographically.  There were more females in the Headspace group and the percentage who agreed or strongly agreed meditation could be beneficial was higher (70.8% vs 57.2%), although the authors comment that demographics were not significantly different (x2 test >0.05).  After randomisation and allocation but before baseline assessment, a much higher number of audiobook participants dropped out (48 vs 33) resulting in a smaller group.

    The outcome measures were scores on validated questionnaires with good internal consistency.  All the tests have good test re-test reliability bar the BITe which has not been determined yet.  The participants were randomised by a rigorous approach and blinded to the intervention they were receiving but it is difficult to ascertain if the reviewers were blinded.  The study was all done on-line and were e-mailed the voucher code which restricted their access to the intervention or control content.  By assumption, this is a single-blinded study as the researcher would have known who was receiving the code.

    In terms of the strengths and weaknesses of the study, two of the researchers were involved in the development of the Head Space app.  The possibility of funding bias is raised by this given a potential conflict of interest with a commercial product.  There are three other areas for critical review in the context of the population researched:

    Area of Reflection Implication for chronic pain patients
    The patients involved did not have chronic pain. The findings of this study may not be generalisable.
    The sample may not represent the general population.  In both groups, those who agreed or strongly agreed meditation can be beneficial is over 50% (29/41 and 16/28 for Head Space and control respectively).  This compares to a large survey which found a lifetime prevalence of 5.2% of the use of meditation for health reasons (Cramer et al., 2016). Patients who have previously done well with psychoeducational pain courses (ie an acceptance of MBSR) may well do better with Mindfulness.
    The demographics of the sample cohort are predominantly white/Caucasian and college/university education.  All three of these reduce the applicability of this study to the wider population, a valid point raised by the researchers when assessing the strengths/weakness of their work. Again the generalisability may be challenged.  The Army has a mixed ethnic demography but is still predominantly Caucasian.  Future work I am considering is to see if commonwealth soldiers with chronic pain can get similar benefits.

    To summarise, MBSR can improve affect and reduce depression scores but may not significantly reduce pain scores. It can be delivered successfully via a smartphone app. It is a low-risk intervention which may have some positive benefits.  This paper is a small snapshot with some methodological weaknesses, but it otherwise seems well constructed and I liked the active control.  To the uninitiated who had not used MBSR before, it seems like a good comparator.  It has certainly prompted some discussion amongst our primary care team about the role of apps in the rehabilitation of our injured soldiers.  We hope to look at two or three of these (including Headspace) in this context and get both objective results as well as the qualitative opinion of what the soldier actually thought.

    CRAMER, H., HALL, H., LEACH, M., FRAWLEY, J., ZHANG, Y., LEUNG, B., ADAMS, J. & LAUCHE, R. 2016. Prevalence, patterns, and predictors of meditation use among US adults: a nationally representative survey. Scientific reports,6,36760.

    ECONOMIDES, M., MARTMAN, J., BELL, M. J. & SANDERSON, B. 2018. Improvements in Stress, Affect, and Irritability Following Brief Use of a Mindfulness-based Smartphone App: A Randomized Controlled Trial.Mindfulness,1-10.