Estrogens and progestins are groups of sex hormones that play an important role during the developmental and reproductive phases of women. The different types of sex hormones and the amount produced is dependent on the reproductive status of the women and they peak and wane throughout women's reproductive cycles, from normal menstruation to pregnancy to the cessation of menstruation after menopause. The highest amount is synthesized during reproductive years starting with menarche and declining with increasing age and further during the peri- and postmenopausal time (17, 18).
In our study, the indication for most female patients taking estrogen- and/or progestin-preparations systemically was contraception. Regarding their epistaxis or telangiectasia, most patients reported an improvement or no changes. Very few patients recognized a disease progression with hormonal intake. In HHT, Harrison et al. also observed improvement in epistaxis with oral contraceptive use (19). The rationale behind this effect is still not clear. One hypothesis for the effect of daily intake of stable systemic estrogen concentrations on epistaxis is that estrogen might induce squamous metaplasia of the nasal mucosa resulting in improved coverage and protection of the vascular tissues and thus making them less vulnerable to trauma (20). However, the prothrombotic effect of hormonal drugs such as estrogen or progestin preparations has also been speculated to play a role (21). Additionally, histological studies have shown that estrogen increases the stability of the epithelium and the perivascular connective tissue (6, 22, 23). Based on this, a few small nonrandomized studies using systemic estrogen preparations were published reporting a reduction of epistaxis in HHT patients (24–27). Furthermore, systemic progestin preparation was used in 3 patients with impressive results (28). A male patient was shown to have successfully treated by the oral synthetic androgen, Danazol (29). After that, Vase reported a study where 17 patients (females and males, age range in years [28–83]) were treated with estrogen (estradiol valerate) and 14 with placebo for 3 months. The only statistically significant change was a slight reduction of transferrin in the estrogen group (30). This is the only randomized control trail using systemic estrogen published in the literature showing a limited benefit of estrogens for patients with HHT so far. Since then, the usage of systemic estrogen seems to have been abandoned. This can be attributed to two reasons. The first being the adverse effects noted due to systemic estrogen especially in men and these included breast tenderness and enlargement, anorexia, fluid retention, flushing, loss of libido and weight gain. The second reason being the establishment of a direct link between estrogen and progestin combinations and breast and gynecologic cancers and increased thromboembolic events (31). Additionally, participants of the named studies took different estrogen formulas. Most contraceptives contain ethinylestradiol (EE), whereas hormone replacement therapy or estrogen mono -therapy bases on estadiol or equine estrogens, that bind less strong to estrogen receptors compared to EE. Therefore, different effects of contraceptives and estrogen therapies beyond contraception are expectable.
Regarding local treatment options, application of topical estriol has been claimed to have a positive effect on epistaxis severity in HHT (32). However, the only randomized placebo-controlled study analyzing the topical nasal treatment with estriol in patients with HHT was not able to confirm this (33). Interestingly, local estriol has no systemic effects and local therapy may be not efficacious. Moreover, a lack of estrogen and progestin receptor expression in nasal telangiectasia in HHT was published. (34). In this study, we asked for systemic or vaginal application of different hormone preparations but did not specify the local application in all cases (such as nasal or vaginal cream, that is expected to show no effect on HHT symptoms if estriol was used).
Selective estrogen receptor modulators (SERM) have been used as an alternative being associated with a more favorable risk profile. In a pilot study, Albiana et al. showed that the molecular mechanisms of raloxifene involve counteracting the haploinsufficiency of ENG and ALK1. Thus, they suggested that raloxifene might be a therapeutic option in especially menopausal women with HHT. Moreover, in a double-blind placebo-controlled study followed by a long-term clinical trial Yaniv et al. demonstrated that tamoxifen seemed to be an effective agent for the treatment of recurrent nosebleeds (35–37). In addition, SERM are mentioned as a promising therapeutic option in the second international guidelines for HHT (38). In line with this, men also reported a systemic hormonal intake for bleeding control in this study. It is known that in vitro SERM lead to an increase of endoglin (ENG) and ALK1 (mRNA expression and protein level). This improves the endothelial cell function and might compensate the haploinsufficiency of these genes (35).
One third of the female patients who underwent gynecological surgeries stated an increase of HHT symptoms afterwards. However, there was no significant difference between those who received an ovariectomy and those who had surgeries without hormonal changes following bilateral ovariectomy.