HT update: spotlight on estradiol/norethindrone acetate combination therapy

Figures & data

Table 1 Benefits/risks of hormone therapy: 2004 Executive Summary (ACOG)

Benefits	Comment	Relative risk: based on conjugated estrogen (CEE)/medroxyprogesterone (MPA) vs placebo of WHI
Vasomotor symptoms	Estrogens most effective treatment	N/A
Sexual dysfunction	Estrogens effective in relieving atrophy and dyspareunia	N/A
Skin	Increased collagen content and wrinkle reduction (non-sun-exposed areas	N/A
Genitourinary tract	Reduces atrophic vaginitis	N/A
Depression	Estrogen may have antidepressant effects	N/A
Colorectal cancer		0.56 (0.38–0.81)
Osteoporosis	Estrogens are effective antiresorptive agents and improves bone density	0.76 (0.69–0.83)a
Risks
Breast cancer	20 per 10,000 risk over 5 years if use combined estrogen/progestin therapy, no increased risk with estrogen therapy alone	1.24 (1.01–1.54)
Coronary heart disease	Age:
	50–59	1.27 (0.75–2.20)
	60–69	1.05 (0.70–1.80)
	70–79	1.44 (0.90–2.00)
	Years since menopause:
	<10	0.89 (0.50–1.50)
	10–19	1.22 (0.80–1.80)
	20+	1.71 (1.20–2.50)
Thromboembolic disease	2-fold greater risk with increased risk of PE, highest risk during first year of use	DVT: 1.95 (1.43–2.67) PE: 2.13 (1.45–3.11)
Stroke	Randomized controlled trials show increased risk	1.31 (1.02–1.68)
Cognition	Women’s Health Initiative Memory Study (WHIMS) – sbset of WHI, found increased risk of probable dementia	2.05 (1.21–3.48)
Neutral
Weight changes/insulin resistance	No changes, glycemic control in type 2 diabetes unchanged by hormonal therapy	N/A
Osteoarthritis		N/A
Ovarian and endometrial cancer		Ovarian: 1.58 (0.77–3.24) Endometrial: 0.81 (0.48–1.36)

a number of total fractures, including hip, vertebral and lower arm/wrist.

Abbreviations: PE, pulmonary embolism; DVT, deep vein thrombosis.

Table 2 Intensity of hot flushes after 12 months of hormone therapy

Intensity of hot flushes	E2 50 μg	E2 50 μg/NETA 140 μg	E2 50 μg/NETA 200 μg	E2 50 μg/NETA 400 μg
Baseline	1.32	1.32	1.42	1.54
Endpoint	0.18	0.35	0.19	0.14

Table 3 Changes in bone mineral density after 2 years of E2/NETA therapy

	Total body	Lumbar spine	Total femur	Femoral neck
Percentage change	+2.9 (±2.4)	+6.9 (±4.2)	+3.4 (±3.6)	+4.0 (±3.4)

Table 4 Changes in bone mineral density with E2/NETA vs alendronate

	Spine	Hip	Forearm	Total body
2 mg E2/1 mg	+5.14%	+3.21%	+0.54%	+2.59%
NETA	p < 0.01	p < 0.001		p < 0.001
Alendronate	+3.34%	+1.60%	−1.14%	0.64%

Table 5 Incidence of endometrial hyperplasia with unopposed estrogen or combination norethindrone acetate/estradiol therapy

	E2 1 mg	E2 1 mg/NETA 0.5 mg	E2 1 mg/NETA 0.25 mg	E2 1 mg/NETA 0.1 mg
Patients undergoing endometrial biopsy	247	241	251	249
Patients with endometrial hyperplasia	36 (14.6%)	1 (0.4%)*	1 (0.4%)*	2 (0.8%)*

* p < 0.01

Table 6 Incidence of endometrial hyperplasia after treatment of unopposed E2 vs E2/NETA after one year of therapy

Medication	E2 50 μg	E2 50 μg/NETA 140 μg	E2 50 μg/NETA 200 μg	E2 50 μg/NETA 400 μg
Endometrial hyperplasia	37.9%	0.8%*	1%*	1.1%* *p < 0.01

* p < 0.01

Table 7 Side effects of E2/NETA based on three randomized controlled trials

Study	Endometrial: hyperplasia 12 months duration		Vasomotor symptom study: 3 months		Osteoporosis study: 24 months
Medication	1.0 mg E2/0.5 mg NETA		1.0 mg E2/0.5 mg NETA		1.0 mg E2/0.5 mg NETA
Duration of medication	12 months		3 months		24 months
Control group	Estradiol 1 mg		Placebo		Placebo
Side effect	E2/NETA	Estradiol	E2/NETA	Placebo	E2/NETA	Placebo
Headache	16%	5%	3%	3%	6%	4%
Gastroenteritis	2%	2%	0%	0%	6%	4%
Nausea	3%	5%	10%	0%	11%	0%
Breast pain	24%	10%	21%	0%	17%	8%

Table 8 Contraindications to combination estradiol/progestin therapy

Undiagnosed vaginal bleeding

Personal history of breast cancer

Known history of estrogen-dependent neoplasia

Active or history of deep venous thrombosis or pulmonary embolism

Active or history of arterial thrombotic event, including myocardial infarction or cerebral vascular accident

Liver disease

Hypersensitivity to medication

Pregnancy

Executive SummaryObstet Gynecol2004104Suppl1S4S15458927

 PubMedGoogle Scholar