Incidence of venous thromboembolism in women receiving transdermal oestradiol/testosterone with micronised progesterone in accordance with NICE guidelines

Abstract

Background

Despite growing evidence supporting the long-term safety of hormone replacement therapy (HRT), concerns persist about certain adverse health outcomes, including venous thromboembolism (VTE). The aim of the study is to evaluate the risk of VTE in peri- and postmenopausal women treated with transdermal 17β-oestradiol with micronised progesterone or intrauterine progesterone (levonorgestrel) via the Mirena coil, in a real-world clinical setting.

Methods

The study included peri- and postmenopausal women attending a private menopause clinic between January 1, 2023, and December 31, 2023. Patients were actively undergoing treatment with transdermal oestradiol and progesterone in the form of micronised oral progesterone or the Mirena intrauterine system, prescribed either by the clinic or their general practitioner. The incidence of VTE was recorded at each clinical appointment, with descriptions of any precipitating factors potentially contributing to any thromboembolic event. Data concerning oestradiol dose and preparation, testosterone use, and age were extracted from medical records and analysed using descriptive statistical methods.

Results

A total of 13,026 women treated with transdermal oestradiol were included in the study. Of these, 11,071 women (85%) were also prescribed transdermal testosterone. The overall incidence of VTE in the cohort was 7/13,026 (0.054%).

Conclusions

These findings indicate that transdermal oestrogen combined with micronised progesterone/Mirena does not appear to increase the risk of VTE compared to the expected population risk for women of similar age.

Highlight box.

Key findings

• Our cohort included 13,026 patients treated with transdermal oestradiol and micronised oral progesterone. The incidence of venous thromboembolism in our cohort was 0.054%. 85% of these patients were also on transdermal testosterone.

What is known and what is new?

• Hormone replacement therapy (HRT) is a first line treatment for symptoms and prevention of long-term health associated with menopause. Formulation and route of hormone replacement has been shown to influence thromboembolism risk. Additionally, there is minimal research on the impact of testosterone in thromboembolism risk.

• Prior studies have primarily studied older formulations of hormone replacement which may have over-estimated thromboembolism risk. This study provides real-world data on thromboembolism incidence using modern formulations. Furthermore, we found no significant difference in venous thromboembolism risk in women treated with testosterone.

What is the implication, and what should change now?

• The low thromboembolism incidence supports the safety profile of transdermal oestrogen and micronized progesterone HRT. Clinicians can safely consider this treatment option in patients with menopausal symptoms.

Introduction

Background

Hormone replacement therapy (HRT) is the first-line treatment for symptoms associated with perimenopause and menopause (1). HRT not only treats menopausal symptoms, but continued exposure to key ovarian hormones contributes to the prevention of long-term health conditions such as osteopenia and osteoporosis (2,3), atherosclerosis and cardiovascular disease (4). HRT also likely slows early cognitive decline (5,6), prevents key components of the metabolic syndrome (7), and has been shown to reduce all-cause mortality in several large studies (8,9).

Venous thromboembolism (VTE) and hormone treatment

VTE encompasses two primary conditions, deep vein thrombosis (DVT) and pulmonary embolism (PE). DVT involves the formation of a thrombus within a deep vein, typically in the lower limbs, while PE occurs when part of the thrombus dislodges and travels to the lungs, obstructing one or more pulmonary arteries (1). Major complications of VTE include post-thrombotic syndrome and acute fatal PE, with mortality in 1–2% of affected patients (10).

VTE has an estimated incidence of 1 to 2 cases per 1,000 individuals annually, based on modelling of country-specific data from a population of over 300 million people (11). The risk of VTE increases significantly with age, approximately doubling with each decade after 40 years of age. One study observed a five-fold increase in VTE incidence among women aged 50 to 80 years (12). More recently, a Danish study reported cumulative incidences of VTE in women at 1.9% by age 50 and 4.3% by age 70 years (13).

The lifetime risk of VTE is slightly higher in women than in men (14). Factors such as the use of combined hormonal contraceptives (CHC), high body mass index (BMI) and pregnancy significantly increase this risk. In postmenopausal women, certain types of hormonal treatments have been associated with a reported increase in VTE risk, underscoring the importance of considering the type, dose, and route of hormone therapy administration when managing menopausal symptoms.

Type and route of oestrogen

The type of oestrogen used in HRT is a key determinant of VTE risk. Oral oestrogens, particularly conjugated equine oestrogens (CEE), have been associated with a higher VTE risk compared to transdermal oestradiol (15,16). This elevated risk with oral preparations is attributed to the first-pass hepatic metabolism of oral oestrogen, which increases the levels of coagulation factors such as factor VII and fibrinogen while reducing natural anticoagulants, including protein S. Early studies identified an increased risk of VTE in women using HRT formulations containing oral synthetic oestrogens and synthetic progestins, with older women experiencing a higher attributable risk.

The most influential study over the last 25 years, Women’s Health Initiative (WHI), has provided the most comprehensive dataset on the risks associated with older types of HRT, including the risk of VTE. The WHI consisted of two major arms: one investigating the effects of CEE alone in women without a uterus, and the other evaluating a combination of CEE with medroxyprogesterone acetate (CEE + MPA) in women with an intact uterus (9,17). There was an increased risk of both DVT and PE for the women receiving HRT compared to placebo. In the CEE + MPA group, the incidence of DVT was 22/8,506 (0.25%) compared to 61/8,102 (0.14%) in the placebo group [hazard ratio 1.87 (1.37–2.54), P<0.001]. The incidence of PE was 87/8,506 (0.09%) compared to 41/8,102 (0.18%) in the placebo group [hazard ratio 1.98 (1.36–2.87), P<0.001].

By contrast, transdermal oestrogens are absorbed directly into the systemic circulation, bypassing significant hepatic metabolism. This route minimises their impact on coagulation pathways, resulting in a lower associated risk of VTE (15,18-20).

A meta-analysis compared the risk of VTE associated with oral versus transdermal oestrogen therapy (21). The analysis included seven population-based observational studies, comprising four case-control studies and three cohort studies, and a total of 26,471 VTE cases. Among these cases, 735 (19.2%) involved users of transdermal oestradiol, 3,103 (80.8%) involved users of oral oestrogen, and 22,633 (85.5%) were women not using HRT. The findings demonstrated that women using transdermal oestradiol preparations did not experience an increased risk of VTE compared to non-users of HRT, with a relative risk (RR) of 0.97 (95% confidence interval: 0.87–1.09). Similarly, a nested case-control study confirmed that transdermal oestrogen preparations were not associated with an increased risk of VTE across different regimens, further supporting their favourable safety profile (22). This contrasts with the higher VTE risk consistently observed in users of oral oestrogens.

Type and route of progestogens

The progestogen component of HRT is also a significant factor influencing the risk of VTE. Synthetic progestins and micronised progesterone differ substantially in how they interact with various steroid receptors, including progesterone, glucocorticoid, androgen, and mineralocorticoid receptors, leading to distinct pharmacokinetic profiles and differences in safety and efficacy outcomes (23).

Certain synthetic progestins, such as MPA and norpregnane derivatives, have been linked to adverse effects on lipid metabolism, glucose tolerance, and an elevated risk of VTE in postmenopausal women (21,24). These progestins may exacerbate the procoagulant effects of oestrogen by enhancing the production of clotting factors. Observational studies have consistently demonstrated an increased risk of VTE in users of synthetic progestins compared to those using natural micronised progesterone (15,25).

In contrast, micronised progesterone, a bioidentical body-identical progestogen, appears to have a neutral or potentially protective effect on the haemostatic system. This lower risk has been supported by findings from the PEPI trial (26). Micronised progesterone’s pharmacodynamic properties closely resemble the body’s natural hormone profile, contributing to a lower risk of vascular complications than oral progestogens, especially when used in combination with transdermal oestradiol.

The Mirena^®, levonorgestrel-releasing intrauterine system (LNG-IUS), is used for contraception, heavy menstrual bleeding, and HRT in menopause. It releases a small amount of levonorgestrel locally in the uterus, minimising systemic hormone exposure. The LNG-IUS does not appear to increase risk of VTE, likely because the dose of progesterone that is delivered is small, primarily acting locally with minimal systemic absorption (27). The combination of transdermal oestradiol with micronised progesterone or an LNG-IUS may offer a safer vascular risk profile compared to regimens containing synthetic progestins.

Testosterone and VTE risk

Although there is limited research on the use of testosterone in women, transdermal testosterone therapy is generally considered safe with respect to cardiovascular risk in general and VTE risk in particular. A recent meta-analysis focusing on testosterone use in men, who typically receive much higher doses than women undergoing HRT, found no increased VTE risk associated with transdermal testosterone preparations (28).

Moreover, a study examining transdermal testosterone as gender-affirming hormone therapy for masculinisation—administered at higher doses—reported no cases of thrombosis among 428 transgender men, with a median treatment duration of 577 days (29). These findings suggest that transdermal testosterone therapy is unlikely to pose a significant thrombotic risk, even at higher doses.

Rationale and knowledge gap

Despite accumulating evidence of its benefits, many clinicians remain hesitant to prescribe transdermal HRT due to perceived safety concerns, including the perception of an increased risk of VTE. However, the risk of VTE is influenced by several factors related to oestrogen use, including the type (synthetic vs. body-identical 17β-oestradiol), route of administration (oral vs. transdermal), and possible dose (licensed vs. off-label). For women with a uterus, the choice of progestogen for endometrial protection also likely plays a critical role in modulating VTE risk.

Outdated research on older HRT formulations continues to perpetuate confusion among healthcare professionals and anxiety among patients, influencing clinical decisions and contributing to widespread undertreatment of potentially severe menopausal symptoms (30). Additionally, there remains a lack of robust data regarding the VTE risk associated with modern transdermal preparations of both oestradiol and testosterone. This data gap has led to hesitation among general practitioners (GPs), many of whom have ceased prescribing HRT altogether.

Objective

No prior study has examined the VTE risk in women receiving body-identical HRT, specifically with transdermal oestradiol and micronised progesterone/LNG-IUS combined with transdermal testosterone. This study addresses this gap by examining a large cohort of peri- and postmenopausal women receiving transdermal HRT. We present this article in accordance with the PROCESS reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-662/rc).

Methods

Study design and population

This consecutive case series examines the incidence VTE in patients receiving standard HRT with the majority also receiving transdermal testosterone. Data was collected at the Newson Health Menopause and Wellbeing Clinic in Stratford-upon-Avon, the largest specialist menopause clinic in the UK. The study included women who attended the clinic between January 1 and December 31, 2023.

Patients were eligible for inclusion in the study if they were peri- or postmenopausal women attending the clinic with at least two appointments during the study period (initial consultations and follow-up). Eligible patients were prescribed HRT during this time, either initiated at the clinic or optimised from pre-existing regimens. Patients were excluded if they were unable to complete at least one follow-up appointment or were not treated with transdermal oestradiol.

Current clinical practice

Most women with perimenopausal or menopausal symptoms sought care through self-referral, often experiencing symptoms such as vasomotor disturbances or low mood. Approximately two-thirds of patients were receiving some portion of their HRT from GPs or other healthcare providers, while the remainder were entirely managed within the clinic. Patients initiated on HRT were typically followed up after three months and subsequently on an annual basis, although those with severe symptoms required more frequent reviews.

Treatment at the clinic was personalised, accounting for each woman’s symptoms, medical history, and preferences. In accordance with National Institute for Health and Care Excellence (NICE) guidelines, HRT was the standard first-line treatment for vasomotor symptoms and low mood, with testosterone added for those experiencing low sexual desire (1). Care was delivered using a shared decision-making model to ensure that patients were actively involved in their treatment plans.

HRT doses were carefully individualised in keeping with menopause guidelines, which recommend tailoring therapy to account for variations in absorption, metabolism, clearance, and tissue sensitivity. Prescription data, extracted from electronic medical records (Semble Ltd., London, UK), revealed that most patients were treated with body-identical oestradiol, micronised progesterone, and testosterone. This approach reflects the clinic’s commitment to optimising HRT regimens to align with each patient’s unique needs and physiological responses.

For a significant proportion of women, testosterone therapy was prescribed based on their menopause symptom score. All women receiving testosterone were treated with transdermal preparations, either as a cream or gel. Women initiating testosterone therapy for the first time (testosterone naïve) were started on a standard female dose, which consisted of 0.5 mL of 10 mg/mL (1%) testosterone cream or 1/8 of a sachet containing 40.5 mg testosterone in 2.5 mL gel, administered daily. Women already using testosterone (‘testosterone non-naïve’) who continued to experience symptoms and had subtherapeutic levels, defined as a free androgen index (FAI) below 2%, were prescribed higher, individualised doses aimed at restoring physiological levels (FAI 2–5%).

Regarding oestradiol dosing, the British Menopause Society (BMS) guidelines (HRT Preparations and Equivalent Alternatives) were used to standardise and compare doses across different oestradiol formulations. The oestradiol dose was categorised using a ‘pump equivalents’ (PE). For instance, women using four pumps of Oestrogel daily or a 100 µg patch applied twice weekly were classified within the “4 PE” dose category.

All patient data was securely recorded and managed using a web-based clinic management system (Semble Ltd, UK). Key characteristics of the study population, such as age, menopausal status, and HRT regimen (including type, dose, and formulation), were extracted from these medical records for analysis.

VTE incidence

The primary outcome, VTE incidence, was based on patient-reported events during routine consultations. Patients were specifically asked about any event of DVT or PE since their previous appointment. For reported events, clinicians reviewed available hospital discharge summaries, imaging reports, or specialist letters, where accessible, to confirm the diagnosis. Where no external documentation was available, events were classified as patient-reported and included in the analysis to ensure comprehensive data collection. Patient-reported outcomes (PROs) are increasingly recognised as valuable tools for capturing patient-centred data, particularly in settings where diagnostic confirmation may be unavailable (31).

Primary outcome

The primary outcome was the incidence of VTE in the entire study cohort, with an optional comparison to the background incidence of VTE in the general population.

Secondary outcomes

Secondary outcomes included the incidence of VTE stratified by the following variables:

Age and menopausal status

VTE incidence was analysed based on patients’ age and menopausal status, exploring potential differences between perimenopausal and postmenopausal women.

Transdermal oestradiol (TD E2) dose

The relationship between VTE incidence and oestradiol dose was evaluated. This included comparing mean doses or categorising doses as “on-label” versus “off-label,” based on regulatory guidelines.

Testosterone use

The impact of testosterone use on VTE incidence was assessed, with patients categorised into users and non-users.

Statistical analysis

Categorical variables were summarised as counts (percentages) and compared using Fisher’s exact test due to sparse cell counts in the VTE group. Continuous variables were summarised as mean (standard deviation) and compared using an unpaired t-test. All tests were two-sided, and P<0.05 was considered statistically significant. Analyses were performed using GraphPad Prism version 10.3.1 [464].

Research ethics and consent

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by institutional ethics board of University College London (No. 9093.008). Written informed consent was obtained from all patients for their data to be used for the purpose of research and audit.

Results

13,026 patients attended NH between 1 January 2023 – 31 December 2023 and were eligible for inclusion in the study (see Table 1). The average age was 53.6±6.4 years, with 4,653/13,026 (35.7%) being perimenopausal and 8373/13,026 (64.3%) being postmenopausal. A small cohort of postmenopausal women had more complex diagnoses including polycystic ovarian insufficiency (POI) or surgical menopause.

Table 1. Primary outcomes in the study cohort.

Primary variables	Category	Whole cohort (n=13,026)			VTE (n=7)			No VTE (n=13,019)
		n	%		n	%		n	%
Age	<40 years	160	1.2		0	0		160	1.2
	41–50 years	3,832	29.4		1	14.3		3,831	29.4
	51–60 years	7,457	57.2		6	85.7		7,451	57.2
	61–70 years	1,400	10.7		0	0		1,400	10.8
	>70 years	177	1.4		0	0		177	1.4
Diagnosis	Perimenopause	4,653	35.7		4	57.1		4,649	35.7
	Menopause	7,498	57.6		3	42.9		7,495	57.6
	POI/early menopause	327	2.5		0	0		327	2.5
	Surgical menopause	487	3.7		0	0		487	3.7
	Late menopause (over 55 years)	61	0.5		0	0		61	0.5
Oestradiol dose equivalent (PE)	1	379	2.9		0	0		379	2.9
	2	2,015	15.5		0	0		2,015	15.5
	3	2,641	20.3		1	14.3		2,640	20.3
	4	4,080	31.3		2	28.6		4,078	31.3
	5	1,199	9.2		0	0		1,199	9.2
	6	1,360	10.4		3	42.9		1,357	10.4
	7	251	1.9		0	0		251	1.9
	8	603	4.6		0	0		603	4.6
	>8	498	3.8		1	14.3		497	3.8
Oestradiol formulation	Gel	4,429	34		4	57.1		4,425	34
	Patch	4,899	37.6		3	42.9		4,896	37.6
	Spray	165	1.3		0	0		165	1.3
	Prescription by GP	3,533	27.1		0	0		3,533	27.1
Testosterone	Yes	11,071	85		7	100		11,064	85
	No	1,955	15		0	0		1,955	15
Progesterone formulation	Utrogestan/LNG-IUS	7,233	55.5		7	100		7,226	55.5
	Prescribed by GP	5,793	44.5		0	0		5,793	44.5

GP, general practitioner; LNG-IUS, levonorgestrel-releasing intrauterine system; PE, pulmonary embolism; POI, premature ovarian insufficiency; VTE, venous thromboembolism.

Nine thousand one hundred and fifteen/13,026 (70%) of the patients were prescribed licensed doses of oestradiol (1–4 PE dose), with 3,911/13,026 (30%) using off-label doses (≥5 PE). The average oestradiol dose overall was 4.0 PE, equivalent to 100 µg. Eleven thousand and seventy-one/13,026 women (85%) were also prescribed transdermal testosterone during the study period.

Oestrogen type (patch, gel or spray) differed between patients. Newson Health fulfilled prescriptions for 9,493/13,026 women (72.9%), with 4,899/9,493 (51.6%) using a patch, 4,429/9,493 (46.7%) using gel, and 165/9,493 (1.7%) using spray. HRT formulation was not available for 3,533/13,026 (27.1%) women, in the vast majority of cases because they received their HRT from their GP (likely transdermal preparations as per national guidance, NICE, 2015).

Seven thousand two hundred and thirty-three/13,026 women (55.5%) were prescribed a progestogen with Newson Health, whereas the remainder (5,793/13,026, 44.5%) received their progestogen from their GP. Among women prescribed a progestogen at Newson Health, all received body-identical progesterone in the form of utrogestan or the Mirena^® intrauterine system.

VTE incidence

The incidence of VTE in the cohort was 7/13,026 (0.054%). Of these, four cases were classified as hospital-associated thrombosis (HAT), defined as a blood clot occurring during hospitalisation or within 90 days of discharge (32). Recognised risk factors for HAT included surgery, critical illness, or prolonged immobility. The remaining three cases were classified as unprovoked VTE (see Table 2). Due to the small number of VTE events (n=7), confidence intervals and standard error measures were not calculated, as they would not provide meaningful variability estimates.

Table 2. The data summarise 7 patients who experienced an event of VTE during the study period.

ID	Age (years)	Medical history	VTE details	BMI (kg/m2)	Alcohol (units/week)	Exercise habit	Prescription	VTE risk factors
1	59	Hypertension	DVT following an orthopaedic surgical procedure, resulting in prolonged immobility	28.4	18	Currently unable to exercise due to a foot condition	3 pumps (gel), testosterone and micronised progesterone	Surgery, immobility, overweight
2	51	Hypothyroidism	Patient reported bilateral PE in October 2022. Possibly related to a history of previous hip and pelvic surgeries	26	0	Currently undergoing rehabilitation following surgical complications	150 μg (patch), testosterone and micronised progesterone	Surgery, immobility, overweight
3	52	PCOS	Patient experienced a DVT while wearing an orthopaedic boot for immobilisation, after discontinuing anticoagulation therapy	23.9	6	N/A	4 pumps (gel), testosterone and micronised progesterone	Immobility
4	52	Partial thyroidectomy February 2020 due to goitre	Patient reported bilateral PE in February 2023 following major surgery (hysterectomy)	32.2	0	N/A	150 μg (patch), testosterone and micronised progesterone	Surgery, obesity
5	49	Chronic migraine	Patient experienced a PE and DVT following knee surgery, with postoperative immobility	36.9	4	The patient reported being significantly limited in physical function	4 pumps (gel), testosterone and micronised progesterone	Surgery, immobility, obesity
6	54	Depression, bilateral mastectomy, asthma	Patient developed a PE in early July following a COVID-19 infection	37.7	0	N/A	6 pumps per day (gel), testosterone and Mirena coil	Infection (COVID-19), obesity
7	53	Factor V Leiden deficiency, IVF	Patient was diagnosed with a PE and subsequently found to have a hereditary factor V Leiden deficiency	39.5	30	The patient also uses fentanyl patches to manage chronic back pain	200 μg (patches) + 4 pumps (gel), testosterone and Mirena coil	Factor V Leiden deficiency, immobility, obesity

Information includes medical history, family history, and consultation records detailing the circumstances surrounding the thrombotic event, such as potential triggers, predisposing conditions, and relevant clinical factors. BMI classification is based on the NICE guideline (NG246): underweight (<18.5 kg/m²), normal weight (18.5–24.9 kg/m²), overweight (25.0–29.9 kg/m²), and obese (≥30.0 kg/m²). BMI, body mass index; COVID-19, coronavirus disease 2019; DVT, deep vein thrombosis; IVF, in vitro fertilization; N/A, not available; PCOS, polycystic ovary syndrome; PE, pulmonary embolism; VTE, venous thromboembolism.

The mean age of women who experienced VTE was 52.9 years (±3.1 years), compared to 53.6 years (±6.43 years) for women who did not experience a thrombotic event. An unpaired t-test comparing age between the two groups yielded a non-significant P value of 0.757, indicating there was no statistically significant difference in age between women with and without VTE.

Transdermal oestradiol and testosterone therapy

The mean oestradiol dose in patients with VTE was 5.4 PE (±1.8 PE), compared to 4.1 PE (±1.9 PE) in patients with no history of VTE the study period. Contingency analysis showed this difference was not significant when comparing the two groups (P=0.22).

Seven/7 (100%) of the women with a history of VTE in the cohort were prescribed testosterone, compared to 11,071/13,026 (85%) of women without a thrombotic event. Contingency analysis showed this difference was not statistically significant (P=0.60). These findings align with population demographics for this age group, showing no significant difference in VTE risk between women treated with testosterone and those not receiving testosterone.

Discussion

This consecutive retrospective cohort study aimed to assess the incidence of VTE in peri- and postmenopausal women treated with transdermal oestradiol and micronised progesterone in a real-world clinical setting. The VTE incidence rate of 0.054% in this cohort aligns with general population demographics for this age group and is lower than the 0.1–0.2% reported in earlier studies (11). These findings reinforce the safety profile of transdermal HRT, addressing concerns about thrombotic risks linked to older formulations, such as those highlighted in the WHI trial (33).

Consistent with previous research, transdermal oestradiol was not associated with an increased risk of VTE, regardless of dose, emphasizing that the route of administration is critical in mitigating thrombotic risk (22,24). The lack of significant association between testosterone use and VTE further supports its safety when used in physiological doses, providing reassurance in its use alongside transdermal oestradiol. This study is the first to address VTE risk in a large cohort of women treated with transdermal testosterone, contributing valuable data to the limited evidence in this area.

Strengths and limitations

A key strength of this study is its large sample size. The real-world clinical setting enhances the relevance of the findings to current prescribing practices, with transdermal oestradiol and micronised progesterone being the first-line treatments in a variety of clinical settings.

The study also had several limitations. The reliance on patient-reported VTE events introduces potential recall bias and incomplete reporting. To mitigate this, efforts were made to verify diagnoses using available hospital or clinical documentation Additionally, another study suggested that patients reliably report significant diagnoses (31). This approach reflects real-world secondary care settings where direct access to diagnostic records is often unavailable. However, despite these measures there remains a possibility that VTE incidence may be understated in this study design. While secondary variables such as BMI and lifestyle factors were collected during the study, missing data across these parameters lead to exclusion of these variables from final analysis to maintain data integrity. This limitation highlights the challenges of retrospective data collection in real-world clinical settings.

Another limitation was the homogenous ethnic make-up of the participants. However, while the study population predominantly consisted of White British women, this to a large extent mirrors disparities in HRT prescribing observed in primary care (34). The geographic diversity of the cohort and the clinic’s focus on treating high-risk patients with complex menopausal needs strengthen the generalisability of the findings. Nonetheless, further research is needed to assess VTE risk in more diverse ethnic and socioeconomic groups.

A final limitation of this study is the small number of VTE events, which precludes the calculation of meaningful confidence intervals or variability measures, including regression analysis of VTE risk factors. However, this finding supports the safety profile of modern HRT formulations and future studies with larger numbers of events are required to provide more precise statistical estimates.

Conclusions

This study seeks to address a critical gap in the literature by evaluating VTE risk in a large cohort of peri- and postmenopausal women treated with body-identical HRT and transdermal testosterone. The low VTE incidence observed supports the safety profile of these transdermal formulations, even at higher doses. Additionally, the absence of significant associations between VTE and transdermal testosterone use reinforces its safety in physiological doses. These results provide clinicians with additional evidence to confidently prescribe transdermal HRT, alleviating concerns and enabling better care for women with perimenopausal and menopausal symptoms. Further work may focus on optimization of dosing and targeting specific postmenopausal symptoms.

Supplementary

The article’s supplementary files as

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by institutional ethics board of University College London (No. 9093.008). Written informed consent was obtained from all patients for their data to be used for the purpose of research and audit.

Data Sharing Statement

Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-662/dss

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DOI: 10.21037/tau-2025-662