What are the concerns of using sublingual Hormone Replacement Therapy (HRT) over time?

Concerns of Using Sublingual HRT Over Time

The primary concerns with long-term sublingual HRT use mirror those of all systemic HRT formulations: increased risks of breast cancer (particularly after 5+ years), cardiovascular events including stroke and venous thromboembolism (especially in the first year), and gallbladder disease, with risks accumulating over time and persisting years after discontinuation. 1, 2, 3, 4

Critical Time-Dependent Risks

Early Risks (First 1-2 Years)

• Venous thromboembolism risk increases 2-fold overall, with the highest risk (3.5-fold increase) occurring within the first year of use 1, 4
• Deep venous thrombosis increases from 13 to 26 per 10,000 women-years 1, 4
• Pulmonary embolism increases from 8 to 18 per 10,000 women-years 1, 4
• Coronary heart disease events show an increased relative risk in year 1, though this trend decreases in subsequent years 5

Intermediate Risks (2-5 Years)

• Stroke risk increases by approximately 30%, with 33 versus 25 events per 10,000 women-years 3
• Gallbladder disease risk increases 1.8-fold for current users, rising to 2.5-fold for those using HRT longer than 5 years 1, 2
• Risk for cholecystitis remains elevated even among past users 1

Long-Term Risks (5+ Years)

• Breast cancer risk becomes apparent after several years of use, with the greatest concern emerging after 5-10 years of continuous therapy 1, 3, 4, 5
• For estrogen plus progestin, invasive breast cancer increases from 33 to 41 cases per 10,000 women-years 4, 5
• The breast cancer risk persists for more than 10 years after HRT discontinuation 3, 4, 5
• Long-term estrogen-alone use (≥20 years) shows a relative risk of 1.42 for breast cancer 1

Route-Specific Considerations for Sublingual Administration

While the evidence provided does not specifically isolate sublingual HRT from other systemic routes, sublingual administration results in systemic absorption and therefore carries the same risks as oral formulations 2. The key distinction is:

• Transdermal routes are preferred over oral/sublingual routes because they avoid hepatic first-pass metabolism and minimize thrombotic risk 2, 6
• Sublingual absorption, like oral administration, undergoes hepatic metabolism and may have greater impact on coagulation factors compared to transdermal delivery 2

Endometrial Cancer Risk (Unopposed Estrogen)

• Unopposed estrogen increases endometrial cancer risk 2.3-fold compared to nonusers, escalating to 9.5-fold with 10 years of use 1, 4, 5
• This risk remains elevated 5-15 years after discontinuation of unopposed estrogen 1, 4, 5
• Combined estrogen-progestin regimens do not increase endometrial cancer risk and may actually decrease it 1

Ovarian Cancer Uncertainty

• Evidence regarding ovarian cancer risk is inconsistent, though two high-quality cohort studies reported 1.8-2.2 fold increased risks with 10+ years of HRT use 1
• The data are insufficient to determine differential effects between unopposed estrogen and estrogen-progestin combinations 1

Cognitive Decline Concerns

• In women aged 65-79 years, estrogen-alone therapy showed a relative risk of 1.49 for probable dementia 4
• This finding emphasizes the importance of age at initiation, as HRT started more than 10 years after menopause or after age 60 carries higher risks 2, 3

Critical Clinical Pitfalls to Avoid

Duration Mismanagement

• Continuing HRT for extended periods without reassessing the risk-benefit ratio increases cumulative risks, particularly for breast cancer and cardiovascular disease 2, 3
• The absolute risk in any single year is small, but risks accumulate over time with long-term use 7

Inappropriate Indications

• HRT should never be used for primary or secondary prevention of cardiovascular disease, as it does not reduce and may increase CHD risk 1, 2, 3
• Using HRT solely for osteoporosis prevention is not recommended when alternative therapies (bisphosphonates, weight-bearing exercise) are available 2, 3

Formulation Errors

• Unopposed estrogen in women with an intact uterus dramatically increases endometrial cancer risk and must be avoided 2, 4, 5
• All women with a uterus require progestin addition to estrogen therapy 2, 4, 5

Evidence-Based Management Algorithm

For women considering or currently using sublingual HRT:

1. Limit use to moderate-to-severe vasomotor or genitourinary symptoms only 2, 3
2. Initiate only if within 10 years of menopause or under age 60 2, 3
3. Use the lowest effective dose for the shortest duration necessary 2, 3
4. Consider switching to transdermal formulations to reduce thrombotic risk 2, 6
5. Reassess risk-benefit ratio every 3-6 months initially, then annually once stable 6
6. Monitor for warning signs: unilateral leg swelling (DVT), chest pain/dyspnea (PE), sudden neurological changes (stroke), breast lumps, or abnormal vaginal bleeding 1, 4, 5

Absolute Contraindications

Do not use sublingual or any systemic HRT in women with: 6, 3

• History of estrogen-sensitive malignancy
• Active or recent venous thromboembolism
• Active liver disease
• Uncontrolled cardiovascular disease
• History of stroke