Mike Savvas’s research while affiliated with King's College Hospital NHS Foundation Trust and other places

Objective: To compare the impact of micronized progesterone (MP) or medroxyprogesterone acetate (MPA) in combination with transdermal estradiol (t-E2) on traditional coagulation factors and thrombin generation parameters in postmenopausal women diagnosed with premature ovarian insufficiency or early menopause. Method: Randomized prospective trial conducted in women diagnosed with premature ovarian insufficiency or early menopause and an intact uterus, recruited over 28 months. All participants were prescribed t-E2 and randomized to either cyclical MP or MPA using a web-based computer randomization software, Graph Pad. Thrombin generation parameters were measured at baseline and repeated after 3-months. Traditional hemostatic biomarkers were measured at baseline and repeated after 3, 6, and 12-months. Seventy-one participants were screened for the study, of whom 66 met the inclusion criteria. In total, 57 participants were randomized: 44 completed the thrombin generation assessment arm of the study, whilst 32 completed 12-months of the traditional coagulation factor screening component of the trial. Results: Thrombin generation parameters did not significantly change from baseline after 3-months duration for either progestogen component when combined with t-E2, unlike the traditional coagulation factors. Protein C activity, free Protein S, and Antithrombin III levels decreased with time in both treatment arms. Conclusion: Fluctuations in traditional hemostatic biomarkers were not reproduced by parallel changes in thrombin generation parameters that remained neutral in both groups compared with baseline. The absence of statistically significant changes in thrombin generation for the first 3-months of hormone therapy use is reassuring and would suggest a neutral effect of both progestogens on the global coagulation assay.

Objective To compare the difference between micronised progesterone (MP) and medroxyprogesterone acetate (MPA) in combination with transdermal oestradiol (t-E2) on cardiovascular disease (CVD) risk markers in women diagnosed with an early menopause and premature ovarian insufficiency (EMPOI). Background The European Society for Cardiology has identified carotid femoral pulse wave velocity (cfPWV) as the gold standard cardiogenic biomarker for risk stratification of arterial disease. Menopause has been shown to augment the age-dependent increase in arterial stiffness, with hormone replacement therapy (HRT) being the mainstay of management of women diagnosed with EMPOI. Study design A pilot randomised prospective open-label trial. Women were randomised to either cyclical MP (Utrogestan® 200mg) or MPA (Provera® 10mg) in conjunction with t-E2 (Evorel® Patches 50mcg/day) for 12 months. Seventy-one subjects were screened, and baseline data are available for 57 subjects. Main outcome measure Carotid-femoral pulse wave velocity (cfPWV). Results PWV did not significantly change from baseline in either treatment arm. MP + t-E2 demonstrated a positive effect on traditional CVD markers, with a significant improvement seen in cardiac output (CO) (0.71±1.01mL/min, 95% CI 0.20 to 1.21) and reduction in diastolic blood pressure (DBP) (-3.43±6.31mmHg, 95% Cl -6.57 to -0.29) and total peripheral resistance (TPR) (-0.15±0.19mmHg⋅min⋅mL⁻¹, 95% CI -0.24 to -0.05) after 12 months. MPA + t-E2, in contrast, did not demonstrate significant changes from baseline in traditional haemodynamic parameters. Conclusion The positive changes in traditional markers were not reflected in the cardiogenic biomarker, cfPWV, which has demonstrated a higher positive predictive value for cardiovascular events than traditional measurements.

The association between socioeconomic status and fertility is a subject that has received much attention. Yet, little is known as to whether the socioeconomic status has an impact on the outcomes of fertility treatment. This systematic review aims to assess any possible relationship between socioeconomic deprivation and treatment outcomes. A database search was conducted of all publications in this field up to March 2021. Eleven studies were identified and six of these specifically investigated the impact of socioeconomic status on fertility treatment outcomes. Children conceived following assisted conception are more likely to be born to mothers of a higher socioeconomic status than those conceived naturally. Of the few studies investigating the impact of socioeconomic status on fertility treatment outcomes and the results are conflicting , making it difficult to draw robust conclusions as to its effect. It is unknown which, if any, marker of socioeconomic status is the most significant for fertility patients: whether it is the characteristics of the individual or that of their surroundings. Further research is urgently needed. ARTICLE HISTORY

Executive summary • All women should be able to access advice on how they can optimise their menopause transition and the years beyond. • There should be a holistic and individualised approach in assessing and advising women, with particular reference to lifestyle advice and dietary modification. HRT for the management of menopausal symptoms Hormone replacement therapy (HRT) is the most commonly used treatment for managing menopausal symptoms and has been shown to be the most effective intervention in this context. The decision whether to take HRT, the dose of HRT used and the duration of its use should be made on an individu-alised basis after discussing the benefits and risks with each patient. Arbitrary limits should not be placed on the duration of usage of HRT. Long-term effects of HRT • HRT should be considered the first-line therapeutic intervention for the prevention and treatment of oste-oporosis in women with premature ovarian insufficiency (POI) and menopausal women below 60 years of age, particularly those with menopausal symptoms. • Cochrane analysis suggests that HRT started before the age of 60 or within 10 years of the menopause is associated with a reduction in atherosclerosis progression, coronary heart disease and death from cardiovascular causes as well as all-cause mortality. • Cochrane data-analysis as well as the long-term follow-up data from the Women's Health Initiative (WHI) showed no increase in cardiovascular events, cardiovas-cular mortality or all-cause mortality in women who initiated HRT more than 10 years after the menopause. • Women should be reassured that HRT is unlikely to increase the risk of dementia or to have a detrimental effect on cognitive function in women initiating HRT before the age of 60. • Current evidence suggests that estrogen alone HRT is associated with little or no change in the risk of breast cancer while combined HRT can be associated with an increased risk which appears duration dependent and may vary with the type of progestogen used. However, this risk is low in both medical and statistical terms, particularly compared to other modifiable risk factors such as obesity and alcohol intake, and this should be taken in the context of the overall benefits obtained from using HRT. Vaginal estrogen is not associated with an increased risk in breast cancer. Large observational trial data suggest that micronised proges-terone and dydrogesterone are likely to be associated

Objective: To assess the acceptability and perception of postmenopausal women, to two different hormone replacement therapy regimens, in relation to the control of their symptoms and development of adverse effects. Study design: Prospectively recruited postmenopausal women, <45 years, were randomised to one of two treatment arms for 12-months: cyclical micronised progesterone or medroxyprogesterone acetate in combination with transdermal oestradiol. A self-reported questionnaire with matrix rating scales was completed and repeated after 3, 6 and 12-months. Main outcome measures: Symptom control and development of adverse effects. Results: Seventy-one individuals were screened, with baseline data available for 67 subjects. A total of 190 questionnaires were returned. The most commonly reported symptoms were low energy levels, vasomotor symptoms and sexual dysfunction. The prevalence of adverse effects ranged between 57.89 and 87.50%, with a reduction seen in the transdermal oestradiol + micronised progesterone arm (73.91% at 3-months, decreasing to 57.89% at 12-months; p = 0.33), compared to the transdermal oestradiol + medroxyprogesterone acetate arm (76.92% at 3-months, increasing to 87.50% at 12-months; p = 0.69). The main reported adverse effects were bloating, weight change and psychological symptoms. A significant difference was documented between the groups after set intervals, with a greater proportion reporting breast tenderness after 3-months (p = 0.01), lower numbers reporting mood swings at 6-months (p = 0.01) and irritability at 12-months (p = 0.03) in the transdermal oestradiol + micronised progesterone arm compared to the transdermal oestradiol + medroxyprogesterone acetate arm. Conclusions: The acceptability of both regimens was high despite adverse effects, but tolerability of transdermal oestradiol combined with micronised progesterone appeared to be better with fewer women reporting psychological concerns.

Many cases of depression in women are due to endocrine factors and inappropriate treatment by antidepressants or mood-stabilizing drugs such as lithium. The syndrome reproductive depression includes premenstrual depression (PMDD), postnatal depression (PND) and climacteric depression which is more severe in the transitional phase 2 or 3 years before the periods cease rather than in the years after the menopause. Such patients are usually free of depression during pregnancy. The diagnosis cannot be made by measuring hormone levels but by a careful history relating depression to monthly cycles and the postnatal state. The range and aetiology of depression in women is different than in men and cannot be understood without knowledge of the effect that oestrogen, progesterone and androgens have upon mood. These frequent problems are usually treated badly by psychiatrists who have little knowledge and less interest in the effect of hormones on mood. Treatment should be by oestrogens preferably by the transdermal route possibly with the addition of testosterone and if necessary the addition of progesterone to protect the endometrium.

Introduction. The publication of the Womens Health Initiative study (WHI) in 2002 resulted in a significant change in the practice of prescribing hormone replacement therapy (HRT) and influenced the public perception on HRT. We carried out this review to assess the patterns of referral to a menopause service in a teaching hospital in the years following the publication of WHI. Methods. All new referrals between February 2008 and February 2011 were included. We assessed the source and indications for referral, presenting symptoms and the management options offered. Results. A total of 405 consecutive cases were included. The mean (SD) age of patients presenting with menopausal symptoms beyond the age of 45 years was 55 (7.73) years (range 45-82 years) while that for women presenting with premature ovarian failure (POF) was 37 (5.59) years (range 20-44 years). A total of 140 (34.6%) cases were referred to discuss HRT for menopausal symptoms; 79 (19.5%) had problems with their current HRT; 68 (16.8%) had POF; 10 (2.5%) had suspected POF; 26 (6.4%) had cyclical epilepsy; 22 (5.4%) wanted to discuss alternatives to HRT; 16 (4%) had amenorrhoea/oligomenorrhoea; nine (2.2%) hirsutism/ acne; seven (1.7%) were referred with osteoporosis; six (1.5%) had premenstrual syndrome while 22 (5.4%) had other indications (including cyclical migraine; infertility; irregular bleeding and HRT for gender re-assignment). The majority (328, 81%) were referred by their general practitioner (GP); while other referrals included external referrals from another hospital/consultant (34, 8.4%); internal referrals (23, 5.7%) and oncology referrals (4, 1%). A total of 210 (52%) were prescribed HRT; 136 (33.4%) were given advice on options (with no intervention); 26 (6.3%) opted for alternative therapies while six (1.5%) were prescribed bisphosphonates. Other interventions included referral for fertility advice; combined hormonal contraception and progestogen therapy in 27 (6.5%) cases. Conclusion. The majority of cases were referred by their GP to discuss symptomatic relief of menopausal symptoms or due to problems with their current HRT regimen. More than half were prescribed HRT, while approximately a third received advice but opted not to have active intervention. This information could be useful in counselling patients and planning the provision of service. Guidance and advice to GPs may allow a significant proportion of cases to be managed at primary care level.

Introduction: Polycystic ovarian morphology is quoted to be present in 16–25% of women. Some studies have shown IVF outcomes for women with PCOM to be comparable to women with other causes of subfertility. There is a lack of robust data looking specifically at IVF outcomes in women with PCOM. Objective: To evaluate IVF outcomes in women with polycystic ovarian morphology (PCOM) compared with women with nonpolycystic ovarian morphology (non-PCOM). Methods: This was a retrospective study looking at 484 consecutive women undergoing IVF at an Assisted Conception Unit in London, January-December 2016. 229 women with an Antral Follicle Count (AFC) of 24 or above and/or high AMH > 16.9 pmol/L were compared to 255 women with AFC < 24 and/or normal AMH (<16.9 pmol/L). Outcomes were compared between the two groups, looking at fertilisation rate, the number of good quality blastocysts, chemical and clinical pregnancy rate, embryos cryopreserved and incidence of OHSS. The mean age (±SD) in the PCOM and nonPCOM groups were 34 (±4.15) and 36 (±3.76), the fertilisation rate was 62% and 64% (p = 0.43), mean (±SD) number of good quality embryos was 3.7 (±3.23) and 1.4 (±1.92) (p < 0.01), the biochemical pregnancy rate was 35% and 34%, (p = 0.99), with a clinical pregnancy rate of 32% and 28%, (p = 0.51). In the PCOM and non-PCOM group, mean (±SD) number of embryos cryopreserved was 3.04 (±3.4) and 1.11 (±1.85), (p < 0.01), with OHSS incidence of 10% and 0.8%, (p < 0.0001) respectively with freeze all embryos occurring in 11% and 2% (p < 0.01) Discussion and conclusions: Women with PCOM have comparable outcomes to women with non PCOM in terms of biochemical and clinical pregnancy rates. However, they tend to have more surplus embryos for cryopreservation and have higher rates of OHSS requiring at times the avoidance of a fresh embryo transfer and cryopreservation of all embryos.

Objective: To compare the cumulative pregnancy rate (CPR) for experienced clinicians and trainees naive to the skill of embryo transfer (ET) during an assisted reproductive treatment (ART) cycle. To establish the minimum number of procedures required to achieve consistent outcomes. Method: A non-interventional retrospective observational cohort study looking at all consecutive ETs undertaken over a 5-year study period. The CPR was determined by a self-reported urinary home pregnancy test undertaken 16 days after oocyte retrieval. Results: The CPR did not differ between an experienced clinician (39%) and trainee (45%) for the first 50 (p=0.41) and last 50 (40.7% versus 42.7%) (p=0.81) ET procedures. The CPR for the individuals remained consistent with their peaks and troughs mirroring the overall success rate of the unit. This pattern continued when the data was further stratified for co-variables (age [≤37 years of age], catheter type [soft] and embryo quality [expanded blastocyst of grade ≥2]): CPRs for experienced clinicians was 65.7% (first 50 transfers) and 40.9% (last 50 transfers); CPR for trainees was 66.7% (first 50 transfers) and 53.6% (last 50 transfers); p=0.95 and p=0.37, respectively. The trainees, however, were more likely to use a stylet catheter with a 2-step transfer technique, with a cost over clinical implication. Furthermore, patients expressed a preference for an experienced clinician to perform their procedure, despite being informed that the grade of the clinician had no impact on the cycle outcome after an analysis of the unit’s data. Conclusion: The clinician's grade and duration of service have not been shown to significantly impact the outcome of the ART cycle. The findings, however, should be interpreted with caution, as they reflect the culture of training in the unit, where there is a strong emphasis on adequate direct and indirect supervision. Furthermore, the relationship between the volume of work and outcomes is established in postgraduate medical education, with the exact number required to achieve clinical competence being dependent on the procedure and intensity of the workload.