Hormone replacement therapy is a common treatment for menopause-related symptoms, and new research from the University of Pittsburgh Graduate School of Public Health reinforces the importance of tailoring hormone therapy to each patient, based on her individual risk factors for cardiovascular disease.
In a study published today in the Journal of the American Heart Association, Pitt researchers showed for the first time that hormone replacement therapy affects the accumulation of heart fat – a new risk factor for cardiovascular disease in midlife women.
Importantly, they found that the formulation and delivery route of hormones – whether as a pill taken orally or a patch placed on the skin – mattered when it came to the types of fat deposits women developed and whether those fat deposits translated to hardening of the arteries.
“We cannot treat all menopause hormone therapy types the same,” said study lead author Samar El Khoudary, Ph.D., M.P.H., associate professor of epidemiology at Pitt Public Health.
“We’re adding to the recognized list of cardiovascular-related effects of menopause hormone therapy by showing a novel cardiovascular risk factor that’s specific to menopausal women also is affected by hormone therapy.”
Menopause commonly comes with a host of challenges – including hot flashes, night sweats, vaginal dryness and increased risk of osteoporosis – and hormone therapy is the primary treatment.
The researchers used data from 474 healthy women ages 42 through 58 enrolled in the Kronos Early Estrogen Prevention Study (KEEPS), which was a multi-center, randomized, placebo-controlled clinical trial of the effects of oral conjugated equine estrogens and transdermal 17-beta estradiol on atherosclerosis progression.
Participants enrolled between 2005 and 2008 and were followed for four years.
“The KEEPS trial is unique because it focuses on younger women close to the onset of menopause, and tested both a pill and patch formulation of menopausal hormone therapy,” said study coauthor JoAnn Manson, M.D., Dr.P.H., physician at Brigham and Women’s Hospital and Harvard Medical School.
“This allowed us to see the effects of different types of hormone therapy and whether the route of delivery – oral or through the skin – affected heart health in otherwise healthy women.”
An earlier study from El Khoudary’s group showed that postmenopausal women with lower serum estrogen levels had a greater volume of paracardial fat – meaning fat that accumulates outside the pericardium – and also higher rates of coronary artery calcification, compared to premenopausal women.
El Khoudary and her team hypothesized that menopause hormone therapy would be protective against heart fat accumulation, but what they found was not so simple.
The type of hormone therapy and route of administration mattered.
The transdermal estradiol patch – generally considered to be safer – compounded the harmful effects of paracardial fat deposition on coronary artery calcification (CAC) progression.
In contrast, women on the estrogen pill were less likely to see increases in heart fat in the epicardial space immediately surrounding the heart or worsening CAC.
“That was surprising,” El Khoudary said.
“The patch is thought to be safer because it’s not systemic, just topical, and it doesn’t have an impact on inflammation or triglyceride levels like oral hormones.”
El Khoudary cautions against making generalizations about oral versus transdermal hormone delivery or extending these findings to other treatments or patient groups.
Still, she hopes clinicians will take these findings into account when treating healthy menopausal women with the drugs used in the study.
“Many clinical guidelines recommend consideration of transdermal estradiol as a first line treatment for hormone therapy because it is associated with less risk for blood clot events compared to oral conjugated estrogen,” said study coauthor Nanette Santoro, M.D., professor of obstetrics and gynecology at the University of Colorado.
“This study makes us think twice about that recommendation and reminds us that there is more complexity to the story of how or whether menopausal hormones protect women against heart disease later in life or increase their risk.”
Menopause hormone therapy
Estrogens can be administered orally, transdermally, percutaneously, intramuscularly, intranasally, subcutaneously, or locally (vaginally) with doses and timing tailored to each patient.
The transdermal administration is preferred in case of oral treatment intolerance, alteration of liver function, hypertriglyceridemia, diabetes mellitus, and in case of a risk of thromboembolic disease. This administration route bypasses the first-pass effect seen with the oral route of administration and the resulting load of the liver cell, provides better bioavailability, and facilitates a long-term balance of estrogen levels and the physiological ratio of the levels of estradiol and estrone.
The newest application method is the metered-dose transdermal spray (EMDTS). In one recent study, the serum levels of estradiol, estrone, and estrone sulfate increased with the number of EMDTS 1.53 mg doses in symptomatic menopausal women.3 Maximum levels were 36 pg/mL estradiol and 50 pg/mL estrone after one puff, and 54 pg/mL and 71 pg/mL after three puffs. The maximum estradiol concentration was achieved 18–20 hours after application. A stable level was reached on the 7th–8th day of application. Transdermal estrogen spray combines the advantages of safety of transdermal application with the possibility of precise dosing.3
ET is for women without a uterus. For women with intact uterus, estrogen–progestogen blends are administered, and their application regimen consists of continual administration or cyclic administration for 21 days with a 7-day pause. Standard and low doses of estrogens have mitogenic activity for endometrium cells; therefore, they must be administered in combination with progestins to women with an intact uterus. Progestins administered continuously or sequentially for 10–14 days in the second half of the cycle cause endometrium growth and thus also pseudomenstrual bleeding. The progestin used affects clinical and metabolic effects of the preparation. In practice, micronized progesterone and dydrogesterone appear to have the most favorable safety profile from all progestogens. IUS-LNG has a local effect on the endometrium with minimal systemic effects.4
Benefits of menopause hormone therapy
Vasomotor symptoms
Vasomotor symptoms (VMS) in menopause are associated with sleeping disorders, concentration disorders, and lowered quality of life and overall health condition (cardiovascular risk, cognitive functions, bone loss). They last on average for 7.4 years. Estrogens reduce the frequency of symptoms by 75% and their intensity by 87%. Low doses (conjugated equine estrogen [CEE] 0.3 mg, estradiol 0.5 mg, estradiol patch 0.025 mg) need 6–8 weeks to reach their maximum effect.5Gestagen therapy (medroxyprogesterone acetate 10 mg per day, megestrol acetate 20 mg per day, micronized progesterone 300 mg) is effective, but it does not have long-term safety data. After discontinuing treatment, the problems return in about 50% of women. It has not been proved whether it is better to quit ‘cold turkey’ or step by step.6
Sleeping disorders
MHT improves chronic insomnia in menopausal women. Some progestogens (especially oral micronized progesterone) have a slight sedative effect probably due to their agonistic action on gamma-aminobutyric acid (GABA) receptors.7
Sexuality
The positive effect of estrogens on sexuality is caused by resolving vulvovaginal atrophy (VVA) and reducing VMS. Other mechanisms have not been proved. Transdermal estrogens are preferred to oral estrogens in women with lowered libido because they do not increase the level of sex hormone-binding globulin (SHBG) and thus do not reduce bioavailability of testosterone.8 Continuous testosterone therapy has benefits for women diagnosed with hypoactive sexual desire disorders.9
Premature ovarian insufficiency
Premature ovarian insufficiency (POI), or premature ovarian failure or premature menopause, is defined as a primary hypogonadism before the age of 40 years. Premature onset of estrogen deficiency is associated with a risk of persistent VMS, bone loss, VVA, mood swings, ischemic cardiac disease, dementia, cerebrovascular accidents, Parkinsonism, eye disorders, and increased overall mortality. POI management includes, besides suitable MHT, calcium supplements, vitamin D, and exercise. Hormonal contraception without a hormone-free interval is also suitable.10 POI is a mandatory indication for hormone therapy.
Quality of life
MHT increases quality of life by eliminating VMS symptoms.11 Estrogens modify the course of inflammation and regeneration of the epithelium. They improve the quality of skin.12 MHT increases the risk of dry eye syndrome but reduces the risk of cataract and glaucoma.13
Musculoskeletal system
A standard dose of estrogen prevents bone loss by inhibition of osteoclast activity and reducing bone turnover, and reduces the number of osteoporosis fractures in all locations – even in women without osteoporosis. However, MHT is not first-line therapy position for osteoporosis, but is best for prevention of osteoporosis. Studies about the effect on joints have inconsistent results but the positive effect prevails. The effect of MHT on frailty syndrome and sarcopenia is positive especially in combination with exercise.14
Diabetes mellitus
MHT users have a significantly lower risk of the onset of type 2 diabetes mellitus. Its protective effect disappears when discontinued.15 Estrogens may help to prevent fat accumulation by stimulating estrogen receptor alpha.16
Depression and memory
MHT improves mood and has a positive effect on menopause-associated depression.17Cognitive functions are improved by MHT only in case of an early start (critical window hypothesis, healthy cell bias hypothesis).18 On the contrary, at the age over 65, it increases the risk of dementia. The same dependence applies to Alzheimer’s disease.19
Cardiovascular diseases
The positive effect of MHT on ischemic cardiac disease prevails in healthy women within 10 years of their menopause or, more precisely, until the age of 60 years the number of cerebrovascular accidents does not increase.20 According to the Cochrane database, the risk ratio (RR) of ischemic cardiac disease is 0.52 and RR for overall mortality is 0.7 when MHT is started within 10 years from the menopause.21,22
Risks of menopause hormone therapy
As with every therapeutic agent, MHT brings certain risks and undesirable side effects that should be taken into account.
Mastodynia, fluid retention, nausea, lower extremities cramps, and headache may occur during usage of estrogens. Depression, anxiety, flatulence, and increased appetite are associated with the gestagen components. When using MHT, unwanted bleeding caused by a decrease in hormone levels, may be detected.23–25
Relative contraindications of MHT such as hypertension, ischemic cardiac disease, diabetes mellitus, migraine, benign breast disease, uterus myomatosus, and endometriosis have nowadays been abandoned as unjustified. There are only several instances where MHT is contraindicated (Box 1).26
Box 1
Contraindications of MHT
- ➢ Breast carcinoma – current, in personal anamnesis, suspected
- ○ invasive breast carcinoma, premalignant changes of breast (atypical ductal hyperplasia, lobular neoplasia) and a ductal carcinoma in situ (intraductal carcinoma)
- ➢ Estrogen-dependent malignant carcinoma – known or suspected
- ○ e.g. unfounded bleeding from genitals as a sign of endometrial carcinoma
- ➢ Untreated estrogen-dependent carcinomas
- ○ endometrial carcinoma, breast carcinoma, endometrial stromal sarcoma
- ➢ Active hepatopathy
- ➢ Anamnestic or current idiopathic thromboembolic disease
- ○ pulmonary embolism, phlebothrombosis
- ➢ Active or recent arterial thromboembolism
- ○ e.g. coronary thrombosis, angina pectoris
- ➢ Known intolerance to a certain constituent of the preparation.
MHT, menopause hormone therapy.
Long-term use of MHT (more than 10 years) increases the risk of breast cancer by 10–30%. Estrogens do not induce breast cancer as oncogenes but may become a promoter of its growth. In 1997, the Collaborative Group on Hormonal Factors in Breast Cancer published a reanalysis of 51 epidemiologic studies (52,705 women with carcinoma, 108,411 healthy women) and found a relative risk (RR) when used for less than 5 years of 1.023 per year of use, and an RR of 1.35 when used for more than 5 years.27 At 5 years after discontinuing MHT, the RR was 1.0 independent on the length of use. The influence of MHT decreases with increasing body mass index (BMI).
Beral and colleagues summarized the results of the following studies: HERS, WHI, WEST, and EVTET.28 These were placebo-controlled, prospective studies with more than 20,000 women observed for 4–9 years. In summary, they stated that MHT significantly increases the risk of thromboembolic disease (TEN) with an RR of 2.16.
The ESTHER study comprised 155 TEN cases and 381 controls. The results showed, not only a significant RR of thromboembolic disease for users of oral estrogen replacement therapy (RR 3.5 [CI: 1.8–6.8]) compared with women without treatment, but also with women undergoing transdermal treatment (RR 4 [CI: 1.9–8.3]).29
There is an RR of 2.3–9.5 that endometrial carcinoma may arise in women with intact uterus when using unopposed estrogens. Adding progestin reduces the risk to a value lower than the value in nonusers. That has been proved even by the EPT arm of the WHI study (RR 0.81 [0.46–1.36]).30
Tibolone
Tibolone is a progestogen with selective tissue estrogenic activity. It exhibits weak estrogenic, progestogenic, and androgenic activity. It suppresses vasomotor problems and improves mood and libido at the recommended dose of 2.5 mg/day. It improves vaginal atrophy but it does not affect the endometrium. It has a protective effect on bone mass, even in a dose of 1.25 mg/day. It reduces proliferation of breast epithelial cells, does not increase mammographic density, and reduces cyst diameter of fibrocystic mastopathy.31,32
Tibolone is a therapy of choice for women with a history of endometriosis and unwanted side effects with conventional MHT (Box 2).33 However, prolonged use of tibolone in older women has been associated with an increased risk of stroke.34 There is also evidence that tibolone could slightly increase the risk of recurrence in breast cancer patients.35
Box 2
Guidelines on tibolone administration: when to prefer tibolone to MHT
| Postmenopausal women with acute climacteric syndrome |
| Lower sexual appetite or sexual dysfunctionMood swingsAccelerated bone loss (osteoporosis prevention during the early postmenopausal periodAnamnesis of premenopausal mastalgia and breast tensionHigh breast densityMyomasUrogenital problems |
| Transfer from MHT to tibolone |
| Mastalgia or breast tensionIncreased breast density with need to repeat mammography or when the mammogram is unreadableMood swingsSexual appetence disordersIrregular bleeding without a histopathological finding |
| Women without acute climacteric syndrome |
| Lowered sexual appetenceMood swingsOsteopenia |
| Younger women – possible use |
| Premature ovarian failure – with sexual dysfunction and mood swingsLong-term add-back therapy of agonists GnRH |
GnRH, gonadotropin-releasing hormone; MHT, menopause hormone therapy.
Estetrol
In the 1960s, estetrol E4 joined the hitherto known natural estrogens – estrone E1, estradiol E2, and estriol E3. It is a steroid with an estrogen structure and four hydroxyl groups: estra-1, 3, 5(10)-trien-3, 15α,16α,17β-tetrol. It can be also called 15α-hydroxyestriol. It is produced exclusively by cell microsomes of fetal liver.36
Esterol has a very good oral bioavailability: 70% in comparison with subcutaneous application. It binds to estrogen receptor (ER) alpha 4–5 times stronger than to ER beta. Unlike the other estrogens, it does not induce production of SHBG and does not bind to it. Initial studies showed efficacy at tested doses of 2 and 10 mg E4 per day.37
The potential of E4 when used as hormone replacement in women after breast cancer surgery, in women treated by aromatase inhibitors or tamoxifen, has been indicated by initial observation within a clinical study.38
Selective estrogen receptor modulators
The clinically oldest selective estrogen receptor modulator (SERM), tamoxifen, acts in breast tissue as an estrogen antagonist and therefore it is used in treatment and chemoprevention of breast carcinoma while its agonistic effect causes endometrial hyperplasia.39
Bazedoxifene (BZA) is a new SERM that verifiably reduces bone mass loss in postmenopausal women and reduces the risk of vertebral and nonvertebral (in the high-risk group) fractures without stimulating breast tissue or endometrium.40
It can be used for treatment or prevention of osteoporosis in postmenopausal women. It does not stimulate the mammary gland or the endometrium. When used at a dose of 20 or 40 mg per day, it protects the endometrium during systematic estrogen treatment (tissue selective estrogen complexes [TSECs]).41
More information: Samar R. El Khoudary et al. Effects of Hormone Therapy on Heart Fat and Coronary Artery Calcification Progression: Secondary Analysis From the KEEPS Trial, Journal of the American Heart Association (2019). DOI: 10.1161/JAHA.119.012763
Journal information: Journal of the American Heart Association
Provided by University of Pittsburgh
