Unscheduled Bleeding with HRT

TOG Article: Unscheduled bleeding with HRT

Volume 21, Issue 2 April 2019

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Introduction

• Menopause is diagnosed retrospectively AFTER 1 Year of amenorrhea in absence of hormonal contraception & any pathological disorder
• Average age: between 50-51 years (UK Median age 51 yrs)

Pathophysiology

• Biological ageing process has some changes in hormone levels

FSH: first to increase

Estradiaol: last hormone to decrease

Inhibin A & B: fall 2-3 years before menopause

• Cessation of ovarian function: FSH >50 mU/ml plus Estradiol < 20 pg/ml

• Perimenopause: Transitional period until menopause with irregular menstrual cycles

• PMB: any bleeding occurring after 1 year of menopause regardless of cause

• Perimenopause & postmenopause are associated with certain symptoms

Psychological: 

mood swings, irritability, nervousness, dysphoria & decreased libido, depression, loss of cognitive function & insomnia

Vasomotor:

hot flushes (70-80% women experience it which gradually decreases, with only 25-30% after 5years), night sweats, headaches & palpitations.

Urogenital:

urogenital atrophy including a burning or itching discomfort in vagina, dysparunea & UTIs

Postmenopausal osteoporosis :  

• 1:3 women affected 
• Mainly type 1 which involves trabecular bone
• Reason for fracture in 50% of postmenopausal women

HRT

• Prescribed after thorough risk assessment of VTE, CHD & breast CA
• Absolute contraindications:
• undiagnosed vaginal bleeding
• hepatic disorders
• acute vascular thrombosis
• HRT justified when QoL is adversely affected
• NICE: lowest effective dose to be used for shortest possible time, annually reviewed, continued as long as woman perceives benefit
• Options are
• estrogen only in hysterectomized or 
• combined (estrogen+progesterone) with intact uterus
• Sequential Combined: continuous estrogen & cyclical progesterone for 12-14 days in a 28-day cycle. Regular monthly bleeds.
• Continuous Combined: daily estrogen & progesterone. Usually induces amenorrhea in 6 Months. Could be used in severe endometriosis.
• Routes: Oral, transdermal, subcutaneous, vaginal or intrauterine

Unscheduled bleeding with HRT

• Up to 80% experience unscheduled bleeding on combined HRT in first six months 
• Evaluation must be after 6 months of HRT or after amenorrhea is established (which could be earlier than 6 months)

Prevalence (Important to remember)

• Combined Continuous (oral or transdermal) : 
• 0-77% (in first few months) 
• 3-10% in 9 months
• Transdermal: 10-20% after 1 year of use
• Sequential: 8-40%
• 25-50% women discontinue HRT due to unscheduled bleeding. More in White

Aetiology

• Presence of pathology: atrophic vaginitis, uterine polyps, fibroids, ovarian cysts or cancer, endometrial hyperplasia or cancer & de novo endometrial cancers
• Other causes: Poor/non-compliance; drug interactions e.g anti-epileptics; GI problems; obesity
• Many women have unscheduled bleeding without prevailing pathology
• Fast-tracked referral only if high-risk factors 

Investigations

• Detailed history
• Menstrual diaries
• Most important reason to investigate is to rule out endometrial hyperplasia/ malignancy

Initial Assessment plan:

Ref: TOG

Hysteroscopy:

Gold standard for uterine cavity evaluation but not without risks

Criteria for Hysteroscopy

• Multiple bleeding episodes  
• Focal lesions on transvaginal ultrasound 
• Endometrial thickness (ET) >5 mm on continuous combined HRT and ET >7 mm on sequential combined HRT  
• Incomplete visualization of endometrial echo or fragmentation of endometrial echo on ultrasound scan  
• High-risk group with risk factors for endometrial disease or cancer (e.g. raised body mass index, family history of hereditary nonpolyposis colorectal cancer)

TVS

• Used as in initial tool in evaluation & safe + cost effective
• Sensitivity is not effected by hormonal use
• Allows to detect other pelvic pathologies as well e.g ovarian cysts
• <5mm endometrial thickness in PMB decreases the risk of endometrial cancer by 90% regardless of hormone use
• PMB + No HRT: pretest probability 10% & post test probability 1% (if test negative)
• PMB + Sequential HRT: endometrial thickness is greater than those who are not on sequential HRT

Referral Criteria for USG to check endometrial thickness

• Any bleeding after 6 months of continuous combined HRT even in low-risk women  
• Bleeding after amenorrhoea has been established  
• Any bleeding in first 6 months if any significant risk factors present

Pipelle endometrial sampling

• Histology gives definite diagnosis in PMB
• It can miss 20% of focal lesions if used alone
• Can be used as first -line investigation as detection rate is 99.6%

Further imaging

CT and MRI

Management 

• Appropriate counselling 
• Recommended HRT: Start with sequential therapy, then convert to continuous method 1 year past menopause
• 80% women will be menopausal at 54 years of age

Sequential HRT

• First rule out possible causes like poor compliance, drug interactions etc
• Check endometrial thickness with TVS within a week of last progesterone pill
• Heavy/prolonged withdrawal bleeding: Increase dose of progesterone / Change type of progesterone / Reduce dose of estrogen 
• Bleeding in early progesterone phase: increase dose/change type of progesterone
• Spotting before withdrawal bleeding: Increase dose of estrogen 
• Irregular bleeding: change regime / increase progesterone dose
• Painful bleeding: change type of progesterone

Continuous Combined HRT

• Investigate after 6 months or if bleeding starts after a period of amenorrhea 
• Exclude endometrial pathology
• Lower estrogen dose
• Increase dose of progesterone /change type of progesterone
• If all fails, then to switch to sequential HRT

Other options

Intrauterine System

• Used for endometrial protection in women with estrogen only preparations
• Avoids systemic effects of progesterone, induces endometrial atrophy, causes regression of existing small polyps & reduces formation of new polyps

Topical vaginal estrogen

• Viable alternative in women with significant urogenital symptoms
• Not much risks associated

Surgery

• Endometrial ablation offered to women with poor response to other options
• After that endometrial protection must be offered
• Other options are hysteroscopic myomectomy/polyp resection

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