3 December 2019:
a comment on Climacteric Editor’s Choice
“Safety of hormone replacement therapy following risk-reducing salpingo-oophorectomy: systematic review of literature and guidelines” by RFM Vermeulen et al.
Risk-reducing bilateral salpingo-oophorectomy (RRBSO), is the gold standard preventive method to avoid ovarian cancer in women at increased risk. However, by choosing this option, a significant number of women end up with premature iatrogenic surgical menopause with several unwanted health effects. Although hormone (HT) is the only effective strategy to compensate significantly for the hormonal deprivation, there are concerns about the safety of HT in these women with regards to breast cancer (BC) and this is an ongoing challenge for clinicians. Hence, it is important to bridge the gap between risk perception and HT prescription with evidence-based clear advice on HT for women considering RRBSO. The recent publication by Vermeulen et al. is a review of seven articles and 11 National guidelines, which recognized that the short-term use of HT following RRBSO is safe in BRCA1 and BRCA2 mutation carriers . The literature is more reassuring regarding the use of estrogen alone than of combined preparations, however, the use of progestogens cannot be avoided in women with uterus preservation in order to achieve endometrial protection. The evidence for HT safety in premenopausal women without a personal history of BC who undergo RRBSO is scarce. The authors advocate that these subsets of women with prematurely induced menopause need to be counseled for shared decision making on the ideal dose and duration of HT, using the best available information on safety and efficacy.
Women carrying a BRCA mutation have an increased risk of developing breast and ovarian cancer  In the absence of robust screening tools, prophylactic surgical removal of the adnexa is the current key strategy to reduce the burden of ovarian cancer in BRCA1/2 carriers . The bilateral salpingo-oophorectomy, with or without the additional risk-reducing mastectomy, reduces the risk of ovarian cancer by 80- 96% and breast cancer up to 50%. [4,5] Sixty-five percent of women will opt for RRBSO; women carrying a BRCA 1 mutation will undergo the procedure between 35 and 40 years of age, those with a BRCA1 and BRCA2 mutation, between 40 and 45 years and those with a RAD1C/1D mutation, between 40 and 50 years of age. There is growing evidence from observational studies that RRBSO has a detrimental impact on the quality of life, longevity and on all-cause non-survival endpoints in these women, in particular in those carrying a BRCA1 mutation, who are likely to have surgery earlier than those carrying a BRCA2 mutation.
It is well known that HT improves vasomotor symptoms, vulvovaginal atrophy/genitourinary syndrome of menopause, prevents osteoporotic bone loss and reduces cardiovascular mortality, enhances sexual function and has a favorable effect on quality of life [8,9] Therefore, young women without breast cancer are recommended systemic HT after RRBSO. Nora et al compared RRBSO patients with BSO controls and found that only half (16.8% of the RRBSO group and 38.4% of the BSO controls >52 years; p < 0.001) of the eligible women used hormones, indicating that many of these women unnecessarily experience adverse effects . On the other hand, BRCA 2 mutation carriers typically undergo RRBSO at a later age and, given their propensity to develop hormone receptor-positive breast cancers, HT should be adopted with caution in these women.
Recently an interesting editorial by Maria et al. emphasized that data on the use of HT in this subset of patients are less available.  Notably, in a large prospective study Kotsopoulos et al. recorded an 8% reduction in BC risk (HR, 0.92; 95% CI, 0.83–1.01) for every year of estrogen replacement and an 8% increase in breast cancer risk (HR,1.08; 95% CI, 0.92–1.27) for every year of progestin replacement . None of the guidelines are yet based on these results but, in this study, the 10-year actuarial risk of BC was significantly lower for women who used estrogen alone compared with women who used combined estrogen-progestogen therapy (12% vs. 22%; absolute difference 10 %; p=0.04). This effect was stronger in women who underwent RRBSO at a younger age (<45 years: 9% vs. 24%; p=.009). In this subgroup of women who had RRBSO prior to age 45, ERT conferred a protective effect with an 18% risk reduction (95% CI, 0.69–0.97) per year of treatment. In the same subgroup of women, a non-significant increase in BC risk of 14% (95% CI, 0.90–1.46) was calculated for every year of combined HT. However, the risk associated with progestogens may be of little clinical impact in women undergoing both RRBSO and risk-reducing mastectomy. For cases who select not to undergo a mastectomy but have had hysterectomy, previously or in conjunction with the RRBSO, the use of progestogens is avoided. Although prophylactic hysterectomy is not recommended, these women should be made aware, when counseled, that the removal of the uterus would eliminate the need for progestogen use. In women who preserve their uterus, for whom a progestogen is necessary, micronized progesterone is recommended as a safer alternative [12,13].
In women who develop hypoactive sexual desire disorder, testosterone therapy is recommended, with or without concurrent estrogen therapy, at doses that determine physiological blood concentrations of this hormone, as it exerts a beneficial effect on sexual function. Available data suggest that short-term transdermal testosterone therapy does not impact breast cancer risk (Level I, Grade A). However, as per expert opinion, caution is recommended for testosterone use in women with hormone-sensitive breast cancer .
Very little research has been done on the duration of HT use in BRCA1/ BRCA2 mutation carriers who have an acute onset of menopause due to RRBSO.  Thus, it is essential that women receive evidence-based information and advice on appropriate HT with multidisciplinary specialist counseling to deal with adverse health effects following RRBSO. This manuscript is a much-needed contribution to this hot topic of great clinical significance. Very few reviews have evaluated studies and guidelines to give a strong orientation to the obstetrician-gynecologists, gynecologic oncologists, medical oncologists, who are caring for women considering risk-reducing surgery or who have undergone the procedure and are anxious about the potential value of HT. Several guidelines do recommend systemic HT following premenopausal oophorectomy until the expected age of menopause, if not contraindicated [13, 16,17,18].
To conclude, with the increasing adoption of RRBSO for the prevention of ovarian cancer, more women will be exposed to the long-term consequences of premature surgical menopause. The use of estrogen therapy after RRBSO does not increase the risk of breast cancer among women with a BRCA 1 mutation and should reassure BRCA1 mutation carriers considering preventive surgery that HT is safe. Health care professionals should be aware of these findings when counseling BRCA carriers and their families, before RRBSO, and in the follow- up of patients experiencing early menopause. The lack of post-RRBSO health-care guidelines has resulted in inconsistent care until now. It is mandatory to develop International guidelines to standardize care while maintaining an individualized approach, with the goal of optimizing long-term survival in this unique cohort of young cancer previvors. Further research is warranted on the appropriate form, long -term use of HT and the potential adverse effect of progestin-containing HT in women with prior RRBSO in terms of BC risk.
Professor Obstetrics & Gynaecology,
Senior consultant Fortis Escort Hospital, Jaipur, India
Executive Board Member, International Menopause Society
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