Dana Sawan  MD (gynecologist). 

Henri Mondor Breast Center, Henri Mondor University Hospitals, 51 Avenue Marechal de Lattre de Tassigny, 94010 Créteil, France. dana.s.sawan@gmail.com

Barbara Hersant MD, PhD (plastic surgeon).

Department of Maxillo-facial Surgery, Plastic and Reconstructive, Henri Mondor University Hospitals, 51 Avenue Marechal de Lattre de Tassigny, 94010 Créteil, France. barbara.hersant@gmail.com

Introduction

Breast cancer is the most common cancer and the leading cause of cancer death in women. 

The ¾ of breast cancers express estrogen receptors, including Estrogen Receptor alpha (ERα) (1- 4). 

Tumours that do not express oestrogen receptors often express epidermal growth factor receptor (EGFR). 

The latter has been correlated with larger tumours and metastatic forms (5).

The hormone sensitivity and hormone dependence of breast cancers makes hormone therapy one of the main means of treating these cancers. 

It consists of weaning them from the oestrogenic intake that maintains their growth, either by suppressing endogenous production (chemotherapy or irradiation of the ovaries), or by administering an anti-estrogenic substance systemically.

Advances in breast cancer detection technology now make it possible to detect tumours at an earlier stage than before and, as adjuvant chemotherapy is associated with ovarian failure (6) an increasing proportion of breast cancer survivors are becoming postmenopausal at an earlier age after cancer treatment (7).

In addition, estrogen levels gradually decline as menopause approaches, leading to genital and urinary symptoms in affected women (8).

Hormone replacement therapy (HS) is known to be effective and recommended in the control of menopausal symptoms such as hot flashes, sleep disorders, sexual dysfunction or vaginal atrophy and even the prevention of osteoporosis and cardiovascular disease (9,10).

In general, systemic estrogen therapy is recommended for women with general symptoms, while local estrogen therapy is recommended for those suffering from vulvo-vaginal atrophy (VVA) or genito-urinary menopausal syndrome (GUMS) (11).

However, HS is risky in breast cancer survivors. Indeed, it has been shown that current and former HS users have a higher risk of developing breast cancer because estrogen plays a central role in the development of breast cancer (12).

Thus, women who have received primary treatment for early breast cancer may have a recurrence of the disease after HS (13).

Clinicians must therefore consider the goals of systemic endocrine therapy and the safety of this treatment modality in healthy women and those with a history of breast cancer (11).

Given the safety concerns regarding the use of HS in women with a history of breast cancer, this document examines alternatives to estrogen replacement therapy that may help address specific survivorship issues such as GUMS in this group of women.

Alternatives to Hormone Replacement Therapy

Several alternatives to the use of hormone replacement therapy have been proposed to women who have already been diagnosed with breast cancer. 

1. Medical means

1.1. Platelet-rich autologous plasma and hyaluronic acid (Cellular Matrix)

A multicentre, randomised, controlled, open-label study of 144 women found that hyaluronic acid vaginal gel was effective in improving vaginal dryness in post-menopausal women (14).

A recent phase 2 clinical study suggested that intraperitoneal administration of a combination of autologous platelet-rich plasma and hyaluronic acid appeared to improve MUMS in women with a previous diagnosis of breast cancer (15).

Researchers reported a significant increase in the volume of vaginal secretions after the start of treatment.

The quality of sexual life of the participants was also significantly improved, as evidenced by a decrease in the female sexual distress score one, three and six months after treatment with platelet-rich autologous plasma and hyaluronic acid (15).

Cellular Matrix INTIMACY

The patient’s own platelet-rich plasma combined with hyaluronic acid for the regeneration of the skin and mucous membranes.

TREATMENT OF GENITOURINARY MENOPAUSAL SYNDROME (GUMS):

    1. New vascularisation stimulated by the release of vascular endothelial growth factor (VEGF).

    2.  Increase in elasticity thanks to a new synthesis of collagen and elastin.

    3. Overall reduction in pain and discomfort.

GUMS : Set of symptoms and signs associated with a decrease in oestrogen.

    1. Genital symptoms: – Dryness – Burning – Irritation.

    2. Sexual symptoms: – Lack of lubrication – Discomfort / pain – Impaired functioning.

    3. Urinary symptoms: – Emergency – Dysuria – Recurrent urinary infections.

The cell matrix is also evaluated for sclerosing lichen, bartholinitis, caesarean section scars, episiotomy scars and stretch mark treatments. 

1.2. Vaginal laser therapy 

Laser therapy has recently been proposed as a viable treatment for GUMS.  The use of vaginal carbon dioxide laser for menopausal symptoms is somewhat new and very few studies have explored its effectiveness as recently as 12 weeks after therapy (16-18).  

    • A single-arm pilot study showed that the vaginal carbon dioxide laser improved VVA symptoms and sexual dysfunction (16).   

    • In addition, a systematic review of 6 non-randomized studies suggested that the vaginal carbon dioxide laser may improve vaginal health in women diagnosed with breast cancer. (19) 

The CO2 laser used to redraw the vaginal epithelium activates heat shock proteins which in turn activate growth factors that increase vascularization, collagen, extracellular matrix production and vaginal mucosal thickness (20).

Recently, the VeLVET trial was conducted to compare the safety and efficacy of laser therapy with vaginal estrogen after six months of follow-up (21). 

  • Investigators found that women in the laser-treated group and the vaginal estrogen group had comparable improvements in GUMS symptoms and sexual function at six months follow-up.

  • About 70-80% of women in both groups reported being satisfied or very satisfied with their treatment option. No serious adverse events were reported by the participants.

The erbium YAG laser was also satisfactorily tested in the GUMS, showing greater long-term efficacy than oestriol (22). 

1.3. Intravaginal use of estrogen gels or creams 

  • The use of estrogen gels and creams provides significant relief for patients suffering from GUMS. The main concern is the safety of this treatment, as the systemic passage of estrogen occurs through the vaginal mucosa. Several studies suggest the safety of this treatment (23,24). Indeed, systemic estrogen levels remain very low and the risk of cancer recurrence is not significantly high for estradiol doses of 0.25 mg and estradiol doses between 12.5 and 25 µg.

  • Aspects that some patients are dissatisfied with are the « messy » nature of the administration, the unhygienic reusable applicator and the approximate dosage, as there is often no dosing device, which is problematic in our population (25).

  • Administration is usually daily for the first two weeks and then bi-weekly for the maintenance period.

    • Intra-vaginal estradiol ova dosed at 4µg are also safely used in breast cancer survivors (25). They offer the advantage of accurate dosing and easier application.

    • Similarly, there are vaginal rings that release estradiol at a sustained release rate of 7.5µg per day and can remain in place for up to 90 days (25).

  • This local hormone therapy should only be used when non-hormonal methods do not work, and if possible for a limited period of time. Long-term use can be made in patients on tamoxifen or raloxifene (22,26,27). The latter block the possible oestrogenic effect in case of significant systemic passage.

  • Hormone therapy should be avoided in any patient with unlabeled vaginal bleeding. Similarly, bleeding that appears under intravaginal hormone therapy should be investigated seriously (imaging, endometrial biopsy). 

1.4. Specific oestrogen receptor modulators (SERMs)

These molecules are non-steroidal agents that exert a plethora of estrogen agonist or antagonist effects on target organs.

  1. – Only ospemifene is currently used in the management of GUMS (60 mg/day), particularly in the treatment of moderate to severe dyspareunia. It improves the maturation of the vaginal mucosa and acidifies the pH (25).

  2. Tamoxifen, on the other hand, has a variety of effects on the vagina and can cause dyspareunia, increased white discharge or vaginal dryness28.

  3. Raloxifene and bazedoxifene do not have a direct effect on the vagina.

  4. However, when combined with equine estrogen (20/0.45 mg per day), they have significantly improved the signs and symptoms of GUMS without causing endometrial hyperplasia (29).

1.5. Vaginal dehydroepiandrosterone (DHEA) 

DHEA is a pro-hormone in the biosynthesis of testosterone and estradiol.

Tests have shown its effectiveness on the symptoms of SGUM (dyspareunia, vaginal maturation index, pH).

DHEA exerts its vaginal effects through in situ conversion to testosterone and oestradiol.

Serum levels are not elevated because these products are locally inactivated (30).

It is therefore a safer alternative to local estrogen in breast cancer survivors.

In addition, since aromatase does not exist in the endometrium, DHEA has no proliferative effect on the endometrium (31).

2. Non-medical means

2.1 Education

Women need to be educated about the changes that occur as a result of the decrease in estrogen.

Many patients are unaware of these changes and therefore cannot seek appropriate medical help.

They need to know that the symptoms and signs of GUMS will not regress spontaneously and to be aware of the various treatment options available to them (25). 

2.2 Vaginal lubricants and humidifiers

They offer an immediate solution to the problem of pain at the intromission which is the result of vaginal dryness.

Lubricants are used at the time of intercourse while humidifiers are used remotely (32).

There are water-based and silicone-based lubricants.

The former do not stain and are better tolerated than the latter. However, the effectiveness of lubricants depends on their osmolarity.

An osmolarity higher than 1200 mOsm/kg is associated with irritation, contact dermatitis and cytotoxicity (32).

Humidifiers increase moisture in the vaginal mucosa by adhering to it, mimicking vaginal secretions.

They also contain additives that lower the pH and affect osmolarity (32).

2.3. Use of vibrators and vaginal dilators

They help maintain sexual function by stretching the vaginal and vulvar tissues.

In fact, they stimulate these tissues and increase blood flow to them, whether or not the patient has a sexual partner (25).

Women who have vaginismus can use these devices for conscious relaxation to facilitate the resumption of penetrative sexual activity (33).

2.4. Pelvic floor re-education

Physiotherapy should ideally be guided by a professional specialising in pelvic pathology.

It is indicated for women with pelvic muscle hypertonia caused by painful sexual activity secondary to GUMS (34).

2.5 Topical Lidocaine

4% aqueous lidocaine applied in the vulval vestibule a few minutes before intercourse significantly reduces the pain of penetration.

It can be used as an adjunct to other measures (lubricants, humidifiers, rehabilitation (35).

Conclusion

Genitourinary menopausal syndrome is a consequence of breast cancer treatment that deprives the body of its estrogen supply.

It poses a management problem because all modalities including estrogen must either be ruled out or carefully weighed on the risk/benefit balance.

However, there are many other options available that allow most patients to find the right formula for them

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