ERAAs for menopause treatment: Welcome the ‘designer estrogens’

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Estrogen receptor agonist-antagonists (ERAAs) selectively inhibit or stimulate estrogen-like action in targeted tissues. This review summarizes how ERAAs can be used in combination with an estrogen or alone to treat menopausal symptoms (vasomotor symptoms, genitourinary syndrome of menopause), breast cancer or the risk of breast cancer, osteopenia, osteoporosis, and other female midlife concerns.


  • Tamoxifen is approved to prevent and treat breast cancer. It may also have beneficial effects on bone and on cardiovascular risk factors, but these are not approved uses.
  • Raloxifene, a second-generation ERAA, was initially approved for preventing and treating osteoporosis and later received approval to reduce the risk of invasive estrogen receptor-positive breast cancer in postmenopausal women.
  • Ospemifene is approved for treatment of genitourinary syndrome of menopause.
  • The combination of conjugated estrogen and bazedoxifene is approved for treating moderate to severe vasomotor symptoms associated with menopause and also for preventing postmenopausal osteoporosis in women with an intact uterus.



Estrogen receptor agonist-antagonists (ERAAs), previously called selective estrogen receptor modulators (SERMs), have extended the options for treating the various conditions that menopausal women suffer from. These drugs act differently on estrogen receptors in different tissues, stimulating receptors in some tissues but inhibiting them in others. This allows selective inhibition or stimulation of estrogen-like action in various target tissues.1

This article highlights the use of ERAAs to treat menopausal vasomotor symptoms (eg, hot flashes, night sweats), genitourinary syndrome of menopause, osteoporosis, breast cancer (and the risk of breast cancer), and other health concerns unique to women at midlife.


Vasomotor symptoms such as hot flashes and night sweats are common during perimenopause—most women experience them. They are most frequent during the menopause transition but can persist for 10 years or more afterward.2

Genitourinary syndrome of menopause is also common and often worsens with years after menopause.3 It can lead to dyspareunia and vaginal dryness, which may in turn result in lower libido, vaginismus, and hypoactive sexual desire disorder, problems that often arise at the same time as vaginal dryness and atrophy.4

Osteopenia and osteoporosis. A drop in systemic estrogen leads to a decline in bone mineral density, increasing the risk of fractures.5


The current gold standard for treating moderate to severe hot flashes is estrogen, available in oral, transdermal, and vaginal formulations.6 Estrogen also has antiresorptive effects on bone and is approved for preventing osteoporosis. Systemic estrogen may also be prescribed for genitourinary syndrome of menopause if local vaginal treatment alone is insufficient.

If women who have an intact uterus receive estrogen, they should also receive a progestin to protect against endometrial hyperplasia and reduce the risk of endometrial cancer.

Despite its status as the gold standard, estrogen-progestin therapy presents challenges. In some women, progestins cause side effects such as breast tenderness, bloating, fatigue, and depression.7 Estrogen-progestin therapy often causes vaginal bleeding, which for some women is troublesome or distressing; bleeding may be the reason for repeated evaluations, can increase anxiety, and can lead to poor adherence with hormonal treatment. Women who carry a higher-than-normal risk of developing breast cancer or fear that taking hormones will lead to breast cancer may show decreased adherence to therapy. Women who have estrogen receptor-positive breast cancer cannot take estrogen.

Individualized options are needed for women who have progestin-related side effects, unwanted vaginal bleeding, or a higher risk of breast cancer.


An ideal treatment for menopause would relieve vasomotor symptoms and genitourinary syndrome of menopause and increase bone mineral density without causing breast tenderness, vaginal bleeding, or endometrial proliferation.

The “designer estrogens,” or ERAAs, have specific positive effects on the bone, heart, and brain with neutral or antagonist effects on estrogen receptors in other tissues such as the breasts and endometrium.8 While not entirely free of adverse effects, these agents have been developed with the aim of minimizing the most common ones related to estrogen and progestin.

Several ERAAs are currently approved by the US Food and Drug Administration (FDA)for various indications, each having a unique profile. Clomifene was the first agent of this class, and it is still used clinically to induce ovulation. This article highlights subsequently approved agents, ie, tamoxifen, raloxifene, ospemifene, and the combination of conjugated estrogens and bazedoxifene (Table 1).

All ERAAs increase the risk of venous thromboembolism, and therefore none of them should be used in women with known venous thromboembolism or at high risk of it.


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