Genitourinary syndrome of menopause in breast cancer survivors:  Treatments are available

VAGINAL ANDROGEN THERAPY: DHEA

After menopause, as the ovaries stop making estrogen from androstenedione, some production continues in other tissues, with DHEA as the primary precursor of androgens that are ultimately converted to estrogen. This has led to the theory that the cause of GSM is not estrogen deficiency but androgen deficiency. Evidence reviewed by Labrie et al¹¹ shows that vulvovaginal atrophy is caused by decreased DHEA availability, which in turn causes sex steroid deficiency-related menopausal symptoms.¹¹ Thus, it is reasonable to conclude that menopausal symptoms can be relieved by giving DHEA.

This theory has been borne out in clinical trials, in which DHEA in a vaginal tablet formulation increased the maturation of vaginal cells and lowered vaginal pH, leading to relief of GSM symptoms.¹²

The only DHEA product FDA-approved for treating GSM-related symptoms is prasterone (Intrarosa), indicated for moderate to severe dyspareunia due to vulvovaginal atrophy. The recommended dosing is a single 6.5-mg intravaginal tablet (0.5% prasterone) inserted nightly at bedtime. Its efficacy for treating hypoactive sexual desire disorder in postmenopausal women is being investigated.

Breast cancer implications

Because DHEA is converted to estrogen by aromatization, healthcare providers might hesitate to use it in women who have a history of hormone-sensitive cancer. Data on the safety of intravaginal DHEA use in breast cancer survivors are limited. However, studies have found that prasterone has highly beneficial effects on dyspareunia, vaginal dryness, and objective signs of vulvovaginal atrophy without significant drug-related adverse effects.^12,13 In these studies, serum estrogen levels in women treated with DHEA were within the values observed in normal postmenopausal women. In addition, there are no aromatase enzymes in the endometrium, so even high doses of vaginal DHEA (in contrast to high doses of vaginal estrogen) will not stimulate the endometrium.

Clinically, this evidence indicates that DHEA exerts both estrogenic and androgenic activity in the vagina without increasing serum estrogen levels, making it a good alternative to topical estrogen therapy.

OSPEMIFENE: AN ESTROGEN RECEPTOR AGONIST/ANTAGONIST

Ospemifene (Osphena) is an estrogen receptor agonist/antagonist, a class of drugs previously called selective estrogen receptor modulators (SERMs). It is FDA-approved to treat moderate to severe dyspareunia secondary to vulvar and vaginal atrophy.

Ospemifene has unique estrogenic effects on the vaginal mucosa, having been shown to increase the number of epithelial cells, lower the vaginal pH, and decrease the percentage of parabasal cells seen on Papanicolaou smears after 12 weeks of use.¹⁴

Unlike tamoxifen, another drug of this class, ospemifene does not change the endometrial lining.¹⁴ Similarly, ospemifene acts as an estrogenic agonist in bone and, thus, has the potential for use in preventing and managing osteoporosis or for use in women at risk of fractures.

Breast cancer impact

In preclinical trials, ospemifene was found to have antiestrogenic effects on breast tissue, similar to those seen with tamoxifen.

In a model using human tumor grafts, ospemifene decreased tumor growth in mice implanted with estrogen receptor-positive breast cancer cells.¹⁵

In a mouse model using breast cancer cells that were biologically and histologically similar to those of humans, ospemifene had strong antiestrogenic effects on the breast tissue.¹⁶ The evidence suggests that ospemifene has a favorable effect on vulvar and vaginal atrophy.¹⁷

Ospemifene is FDA-approved to treat moderate to severe dyspareunia secondary to menopause. Recommended dosing is 60 mg/day orally with food.

Its antiestrogenic effects on breast tissue make it a promising option for women with a history of estrogen-receptor positive breast cancer. However, further study is needed to fully understand its effects on human breast tissue. According to the manufacturer’s package insert (www.osphena.com/files/pdf/osphena_prescribing_information.pdf), because the drug has not been adequately studied in women with breast cancer, it should not be used in women with known or suspected breast cancer or a history of breast cancer.

CONJUGATED ESTROGENS PLUS BAZEDOXIFENE

The combination of conjugated estrogens and bazedoxifene (Duavee) is a progesterone-free alternative for treating various menopausal symptoms. Bazedoxifene is another estrogen receptor agonist/antagonist, and it was added to counteract estrogen’s effects on the endometrium, thus replacing progesterone. This protective effect has been validated in clinical trials, which also found a favorable safety profile in breast tissue.^18,19

SMART trials. The efficacy of this combination was studied in a series of large phase 3 multicenter trials called the SMART (Selective Estrogens, Menopause, and Response to Therapy) trials.^20–23 Treated patients had markedly fewer vasomotor symptoms at 1 year, along with an increase in superficial cells and intermediate cells of the vaginal epithelium and a decrease in parabasal cells. They also had a substantial decrease in the incidence of dyspareunia.

Its effects on breast tissue were evaluated in the SMART-5 trial. Therapy had no net impact on breast density, suggesting that it has an estrogen-neutral effect on the breast.²³

These results suggest that combined conjugated estrogens and bazedoxifene could be a noteworthy treatment option for GSM in women with a history of estrogen receptor-positive breast cancer, particularly in those with vasomotor symptoms and bone loss. However, the combination has not been studied specifically in breast cancer survivors.

Dosage. The FDA-approved dosing is 20 mg/0.45 mg per day orally to treat vasomotor symptoms, GSM, and osteoporosis in postmenopausal women with a uterus.

LASER THERAPY AND RADIOFREQUENCY HEAT: AN OFF-LABEL OPTION

Low-dose radiofrequency thermal therapy, delivered by carbon dioxide laser or by radiofrequency heat, has been used with some success to treat urinary stress incontinence and vaginal laxity in postpartum women. It may be an option for GSM, although it is not FDA-approved for this indication, and the FDA has recently issued a warning about it.²⁴

Marketing literature promotes laser therapy as an effective option that stimulates vaginal connective tissue to produce new collagen, which then promotes improved blood flow and tissue regeneration for vaginal lubrication and elasticity.

A study comparing fractional carbon dioxide vaginal laser treatment and local estrogen therapy in postmenopausal women with vulvovaginal atrophy found that laser therapy was an effective treatment for vulvovaginal atrophy (dyspareunia, dryness, and burning), both alone and with local estrogen.²⁵

Despite the promising effects of laser therapy for treating vulvovaginal atrophy in GSM, studies have not determined its short-term or long-term safety profile. Furthermore, laser therapy does not improve impaired sexual function, ie, decreased libido, arousal, and sexual satisfaction. Another important consideration is that the cost of laser therapy in 2017 was estimated to be $2,000 to $3,000 per treatment, not covered by healthcare insurance.