Quality improvement project - Reducing the inadvertent prescribing of unopposed estrogen in primary care Dr Liz Horrocks Banstead PCN.

OBJECTIVE: The aim of the project was to reduce the risk of patients using the estrogen only part of their hormone replacement therapy (HRT) inadvertently in Banstead PCN. Although understanding about the risk of unopposed estrogen is well understood by prescribers, there are numerous flash points where this exposure can occur which was highlighted by several cases encountered during a study period of 3 months. STUDY DESIGN: Cases encountered revealed numerous reasons for this exposure which were split into three areas: Prescribing factors, dispensing checks and patient understanding. MAIN OUTCOME MEASURES: Quality improvement suggestions were tailored to the factors involved. IT system changes to EMIS, our main computer software provider, were proposed to enable safer prescribing. Following discussion with key stakeholders, increased education for pharmacists was proposed alongside an alert sticker system at the dispensing end point. Patient understanding and education for all parties was delivered through various routes. RESULTS: The IT system alterations required are complex and still awaited. Funding was obtained and stickers distributed. The results from a re-audit from this intervention are awaited. Interim education measures at an individual level were meantime explored and the impact of them assessed. Patient education and the role of social media were explored. I produced a short video which was circulated to doctors with the plan to distribute via other clinician social media accounts. CONCLUSIONS: A key discovery through this study is that many of the flash points identified can be difficult to detect and many are not measurable. The increasing number of HRT prescriptions, time pressures in primary care and the known risk from using unopposed estrogen of endometrial cancer means these changes are of potential great value.

A retrospective audit of general practitioner's referrals to Guys and St Thomas' specialist menopause clinic between 2021 and 2022.

Purpose: We performed a retrospective audit of General Practitioners' (GPs) referrals to the specialist Menopause Clinic at Guys and St Thomas's (GSTT) between 2021 and 2022. We aim to establish the indication for the referrals and whether they were compliant with the National Institute for Health and Care Excellence Guidance NICE.Background: GSTT is a teaching hospital in central London that educates gynaecologists in training as well as (GP) for specialist certification in Menopause. The menopause clinic receives approximately 580 GP referrals per month from South East London practices. The current waiting time for an initial appointment is up to 1 year. This delay reflects an increase in demand for menopause care and a deficit in service provision in many areas of the UK.NICE has recommended that GPs refer complicated cases to menopause specialists, with 11 specific criteria.Study Sample and Data Collection: We randomly selected 50 patients referred to the GSTT clinic by a GP between 2021 and 2022. Patient data were collected, including patient demographics, date of referral, indication for referral, date of consultation, waiting time, past medical history, investigations, and treatment instigated during the appointment.Results: The majority of referrals to the GSTT menopause Specialist clinic met the NICE guidelines (76%). One-sixth of the referrals could have been prevented or managed through alternative routes. Finally, although this is a small study, some patient unmet needs (PUNS) and GPs' educational needs have been identified.

Review of menopause advice given to patients undergoing bilateral oophorectomy.

The NICE Guideline (NG23) 2015 Menopause: Diagnosis and Management states that 'women who are likely to go through the menopause as a result of medical or surgical treatment should be offered support and information about the menopause and fertility before they have their treatment, and a referral to a Health Care Professional with expertise in the menopause'. To investigate whether discussion about the surgery causing the menopause, and advice on possible treatments had been documented, I conducted a retrospective study of women undergoing bilateral oophorectomy at a central London teaching hospital from 1st April 2018 to 30th September 2018. Only 30% of women (8 out of 27) in this study had documentary evidence of having received menopause advice around the time of bilateral oophorectomy.

Estrogen and COVID-19 symptoms: Associations in women from the COVID Symptom Study.

It has been widely observed that adult men of all ages are at higher risk of developing serious complications from COVID-19 when compared with women. This study aimed to investigate the association of COVID-19 positivity and severity with estrogen exposure in women, in a population based matched cohort study of female users of the COVID Symptom Study application in the UK. Analyses included 152,637 women for menopausal status, 295,689 women for exogenous estrogen intake in the form of the combined oral contraceptive pill (COCP), and 151,193 menopausal women for hormone replacement therapy (HRT). Data were collected using the COVID Symptom Study in May-June 2020. Analyses investigated associations between predicted or tested COVID-19 status and menopausal status, COCP use, and HRT use, adjusting for age, smoking and BMI, with follow-up age sensitivity analysis, and validation in a subset of participants from the TwinsUK cohort. Menopausal women had higher rates of predicted COVID-19 (P = 0.003). COCP-users had lower rates of predicted COVID-19 (P = 8.03E-05), with reduction in hospital attendance (P = 0.023). Menopausal women using HRT or hormonal therapies did not exhibit consistent associations, including increased rates of predicted COVID-19 (P = 2.22E-05) for HRT users alone. The findings support a protective effect of estrogen exposure on COVID-19, based on positive association between predicted COVID-19 with menopausal status, and negative association with COCP use. HRT use was positively associated with COVID-19, but the results should be considered with caution due to lack of data on HRT type, route of administration, duration of treatment, and potential unaccounted for confounders and comorbidities.

Minimising menopausal side effects whilst treating endometriosis and fibroids.

Medical management of endometriosis and fibroids involves manipulation of the hypothalamic-pituitary-gonadal axis to alter the balance of sex hormones thereby inhibiting disease progression and ameliorate symptoms. Unfortunately, resultant menopausal symptoms sometimes limit the tolerability and duration of such treatment. The use of gonadotrophin-releasing hormone agonists to treat these diseases can result in short-term hypoestrogenic and vasomotor side effects as well as long-term impacts on bone health and cardiovascular risk. The routine use of add-back hormone replacement has reduced these risks and increased patient compliance, making this group of drugs more useful as a medium-term treatment option. The estrogen threshold hypothesis highlights the concept of a 'therapeutic window' in which bone loss is minimal but the primary disease is not aggravated. It explains why add-back therapy is appropriate for such patients and helps to explain the basis behind new developments in the treatment of hormonally responsive gynaecological conditions such as gonadotrophin-releasing hormone antagonists and progesterone receptor modulators.

The use of hormone therapy and its alternatives in women with a history of hormone dependent cancer.

OBJECTIVE: Treating the effects of menopause in women with history of oestrogen-dependent cancers presents a clinical dilemma. Endocrine adjuvant agents like tamoxifen and other cancer treatments, often induce premature menopause. Vasomotor, psychological and somatic symptoms may be more severe in these women. The risk of hormone therapy (HT) and its efficacy must be balanced. Currently, there are no consensus guidelines for the management of these patients. STUDY DESIGN: This is a retrospective study carried out between 10/01/2011 and 27/01/2012 in a tertiary referral menopausal clinic. MAIN OUTCOME MEASURES: Data was collected about cancer type and treatment, symptoms, prior use of T, bone density analyses and menopause treatments. RESULTS: 590 patient records were scanned and 146 patients (24.7%) had a history of cancer. Of these, 45.9% were younger than 50 years old. 67.1% comprised breast cancer patients, of which 69.4% were on adjuvant endocrine agents. 24.7% consisted of gynaecological cancer patients who were predominantly treated with surgery in conjunction with adjuvant therapies. 90.4% of the women had at least one menopause-related symptom, vasomotor symptoms being most prevalent, followed by psychological and vaginal symptoms. Women used a variety of HT and non-HRT therapies for their symptoms. Of the 77 women who had a personal history of oestrogen receptor positive cancers, 19.5% chose to take HT in spite of it being contraindicated. CONCLUSIONS: Prescribing HT to women with a history of hormone dependent cancer remains controversial. Patient 'Quality of Life' must be considered. More research is required in this area.

Gonadotrophin receptor hormone analogues in combination with add-back therapy: an update.

Gonadotrophin receptor hormone analogues (GnRHa) have been used in a range of sex hormone-dependent disorders. In the management of premenstrual syndrome, they can completely abolish symptoms. The success of GnRHa in the treatment of endometriosis and adjuvant therapy in the management of fibroids is proven. This efficacy does not come without a cost and the side-effects of the hypo-estrogenic state have limited their application. The use of add-back therapy to counter these effects has enabled wider application, longer durations of treatment and an increase in compliance. This review article is an update on the evidence supporting gonadotrophin receptor hormone analogues in combination with add-back therapy.

Treatment of premature ovarian failure trial: description of an ongoing clinical trial.

Premature ovarian failure is a relatively common clinical condition, and carries important long-term health consequences. Estrogen replacement is recommended to alleviate unpleasant hypo-estrogenic symptoms and reduce long-term health risks. However, the most suitable form of estrogen replacement, and the exact effects of no treatment, is unknown. Surprisingly, little research has been carried out in this area. We describe the design of an ongoing clinical trial that will address these issues so that we can begin to provide evidence-based care for affected women.

Symptoms of the menopause.

Numerous symptoms can be attributed to the lack of oestrogen at the time of the menopause. Some of the mechanisms for this are still unclear. However, while there is substantial evidence that many of the symptoms that women encounter during the menopausal period can be directly attributed to oestrogen deficiency, others are less well supported. An up-to-date review of the literature is provided.

Reversibility of the effects of acute ovarian hormone suppression on verbal memory and prefrontal function in pre-menopausal women.

BACKGROUND: Whilst acute loss of ovarian function is associated with memory deficits, the biological basis of this is poorly understood. We have previously reported that acute loss of function during Gonadotropin Hormone Releasing Hormone agonists (GnRHa) treatment is associated with impaired verbal memory and a disruption of corresponding left inferior frontal gyrus (LIFG) during the encoding stage. In the current study, we provide a critical extension to this work by determining whether this memory deficit is reversible following normalization of ovarian function. To do this we carried out a further imaging study using the same verbal memory recognition task after cessation of GnRHa-induced ovarian suppression. METHOD: We used event-related fMRI to study verbal episodic memory performance and brain activation at the LIFG in 13 healthy pre-menopausal women pre-, during, and post-acute ovarian hormone suppression using GnRHa. RESULTS: Following resolution of acute GnRHa-induced ovarian suppression, verbal recognition scores returned to their initial levels and this restoration was associated with a restored level of left frontal activation during successful encoding of words. CONCLUSIONS: Our findings suggest that the memory deficits associated with acute ovarian suppression are reversed following resolution of normal ovarian function and are associated with reversible attenuation of LIFG activation during encoding. These findings lend further support to the hypothesis that memory difficulties reported by some women following acute ovarian hormone withdrawal are reversible and may have a clear neurobiological basis.

A study of visuospatial working memory pre- and post-Gonadotropin Hormone Releasing Hormone agonists (GnRHa) in young women.

Gonadotropin Hormone Releasing Hormone agonists (GnRHa) produce an acute decline in ovarian hormone production leading to a 'pseudo' menopause. This is therapeutically useful in the management of a variety of gynaecological conditions but also serves as a powerful model to study the effects of ovarian hormones on cognition. Animal and human behavioral studies report that memory is particularly sensitive to the effects ovarian hormone suppression (e.g. post GnRHa). Further, it has recently been reported that ovariectomy in young women increases the risk of cognitive impairment in later life. However, the underlying brain networks and/or stages of memory processing that might be modulated by acute ovarian hormone suppression remain poorly understood. We used event-related fMRI to examine the effect of GnRHa on visual working memory (VWM). Neuroimaging outcomes from 17 pre-menopausal healthy women were assessed at baseline and 8 weeks after GnRHa treatment. Seventeen matched wait-listed volunteers served as the control group and were assessed at similar intervals during the late follicular phase of the menstrual cycle. We report GnRHa was associated with attenuation of left parahippocampal (BA 35) and middle temporal gyri (BA 21 ,22, 39) activation, with a significant group-by-time interaction at left precuneus (BA 7) and posterior cingulate cortex (PCC) (BA 31) at encoding, and with cerebellar activation at recognition in the context of unimpaired behavioral responses. Our study suggests that acute ovarian hormone withdrawal following GnRHa, and perhaps at other times, (e.g. following surgical menopause and postpartum) alters the neural circuitry underlying performance of VWM.

Physiological variation in estradiol and brain function: a functional magnetic resonance imaging study of verbal memory across the follicular phase of the menstrual cycle.

Women frequently complain of memory problems at times in their reproductive lives that are associated with changes in estrogen concentration (e.g. around menopause and childbirth). Further, behavioural studies suggest that memory performance may fluctuate across the menstrual cycle. For example, performance on verbal tasks has been reported to be greatest during phases associated with high estrogen concentrations whereas the opposite has been reported with visuo-spatial tasks. The biological basis of these reported effects remains poorly understood. However, brain imaging studies into the effects of estrogen therapy in postmenopausal women suggest that estrogen modulates the metabolism and function of brain regions sub-serving memory. Furthermore, we have recently reported that acute suppression of ovarian function in young women (with a Gonadotropin Hormone Releasing Hormone agonist) is associated with decreased activation in left prefrontal cortex, particularly the left inferior frontal gyrus (LIFG), during successful verbal memory encoding. We therefore investigated whether physiological variation in plasma estradiol concentration is associated with differences in activity of the LIFG during successful verbal encoding. We hypothesised that higher plasma concentrations of estradiol would be associated with increased brain activity at the LIFG and improved recall performance. Although we did not find a significant relationship between plasma estradiol concentration and verbal recall performance, we report a positive correlation between brain function and estradiol concentration at the LIFG.

Efficacy of tibolone as "add-back therapy" in conjunction with a gonadotropin-releasing hormone analogue in the treatment of uterine fibroids.

OBJECTIVE: To assess the efficacy of tibolone add-back therapy with Goserelin treatment of uterine fibroids. DESIGN: Randomized placebo-controlled study. SETTING: Gynecology department of an inner-city teaching hospital. PATIENT(S): Seventy-five women of reproductive age with uterine fibroids. INTERVENTION(S): All women were given monthly SC implants of 3.6 mg goserelin and were randomized to take 3 months of placebo followed by 3 months of tibolone 2.5 mg daily (delayed administration), tibolone 2.5 mg daily for 6 months, or placebo for 6 months. MAIN OUTCOME MEASURE(S): Changes in bone mineral density (BMD) at the hip and spine, fibroid and uterine size, and patient symptomatology. RESULT(S): In the tibolone group, 2% loss of BMD at the spine was observed compared with 5.5% loss in the placebo group. For total hip, tibolone led to a 0.7% gain in BMD compared with a loss of 1.7% in the placebo group. Tibolone did not affect GnRH analogue-induced fibroid shrinkage. Vasomotor symptom scores in women taking tibolone were 2.2 and were significantly lower than those taking placebo or in the delayed administration groups (mean scores 2.9 and 2.7, respectively). CONCLUSION(S): Tibolone appears to be a safe and effective add-back therapy which can be given from the commencement of GnRH analogue treatment for fibroids.

Gonadotropin hormone releasing hormone agonists alter prefrontal function during verbal encoding in young women.

Gonadotropin hormone releasing hormone agonists (GnRHa) are commonly used in clinical practice to suppress gonadal hormone production in the management of various gynaecological conditions and as a treatment for advanced breast and prostate cancer. Animal and human behavioural studies suggest that GnRHa may also have significant effects on memory. However, despite the widespread use of GnRHa, the underlying brain networks and/or stages of memory processing that might be modulated by GnRHa remain poorly understood. We used event-related functional magnetic resonance imaging to examine the effect of GnRHa on verbal encoding and retrieval. Neuroimaging outcomes from 15 premenopausal healthy women were assessed at baseline and 8 weeks after Gonadotrophin Releasing Hormone analogue (GnRHa) treatment. Fifteen matched wait-listed volunteers served as the control group and were assessed at similar intervals during the late follicular phase of the menstrual cycle. GnRHa was associated with changes in brain response during memory encoding but not retrieval. Specifically, GnRHa administration led to a change in the typical pattern of prefrontal activation during successful encoding, with decreased activation in left prefrontal cortex, anterior cingulate, and medial frontal gyrus. Our study suggests that the memory difficulties reported by some women following GnRHa, and possibly at other times of acute ovarian hormone withdrawal (e.g. following surgical menopause and postpartum), may have a clear neurobiological basis; one that manifest during encoding of words and that is evident in decreased activation in prefrontal regions known to sub-serve deep processing of to-be-learned words.

Effects of acute ovarian hormone suppression on the human brain: an in vivo 1H MRS study.

A previous proton magnetic resonance spectroscopy ((1)H MRS) study carried out by our group indicated that post-menopausal women who started taking oestrogen therapy (ET) at or around the menopause had a significantly lower choline (Cho) concentration in the hippocampus and parietal lobe than those who were ET naïve, suggesting that long-term ET positively modulates neuronal/glial membrane turnover in older females. The objective of the current study was to determine whether neuronal membrane turnover is modulated by sex hormones in younger women following a pharmacologic challenge that induced acute ovarian hormone suppression. We carried out an in vivo(1)H MRS study in a group of 10 premenopausal women pre- and post-8 weeks of acute ovarian suppression with a Gonadotrophin Releasing Hormone analogue (GnRHa) (two Zoladex 3.6 mg implants). We report that young women, post-ovarian suppression, had a significant increase in Cho concentration (and Cho/Cr ratio) in the dorsolateral prefrontal cortex (DLPFC). They also showed a trend to a significant increase in Cho concentration in the hippocampus. This supports our previous findings and adds to the evidence that neuronal/glial membrane metabolism is affected by sex hormones in women.

Tibolone histology of the endometrium and breast endpoints study: design of the trial and endometrial histology at baseline in postmenopausal women.

OBJECTIVE: To address the endometrial safety of tibolone. DESIGN: The Tibolone Histology of the Endometrium and Breast Endpoints Study (THEBES) is a randomized, double-blind, parallel-group trial of tibolone compared with continuous combined conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA). SETTING: Multi-country, multi-center ambulatory care setting. PATIENT(S): A total of 5,185 subjects were screened, and biopsies were obtained from 4,446 women. INTERVENTION(S): Participants were randomized in a 1:1:2 ratio, to tibolone (1.25 or 2.5 mg/d) or CEE-MPA. MAIN OUTCOME MEASURE(S): The one-sided 95% confidence intervals for the incidence of hyperplasia or cancer were evaluated for tibolone compared with CEE-MPA. RESULT(S): Endometrial biopsy results at baseline: atrophic (87.29%), inactive (0.25%), proliferative (6.12%), secretory (2.86%), menstrual type (0.40%), and hyperplasia (0.18%). Only subjects with atrophic or inactive endometrium were eligible for this study, and 3% of the women at screening either had no tissue (0.18%) or had an amount of tissue that was insufficient for diagnosis (2.72%). Three thousand two hundred forty postmenopausal women with a mean (+/-SD) age of 54.4 +/- 4.4 years and a mean time since menopause of 4.5 +/- 3.6 years were randomized. CONCLUSION(S): The Tibolone Histology of the Endometrium and Breast Endpoints Study is a prospective, randomized clinical trial, designed to provide evidence of the endometrial safety of tibolone compared with estrogen and progestogen. Screening endometrial histology shows a low prevalence of endometrial hyperplasia (0.18%) and no carcinoma.