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Association between estradiol and idiopathic macular hole in postmenopausal women

Background Estradiol, a predominant female sex hormone, is not only related to reproductive function but also to the ocular disorders. The purpose of this study was to investigate the association between estradiol and idiopathic macular hole (IMH) in postmenopausal women. Method This study included 30 postmenopausal patients with IMH for the study group and 32 postmenopausal patients with uncomplicated primary retinal detachment for the control group. The two groups were compared of serum and vitreous estradiol levels, and clinical variables. Results There was no statistically significant difference in age between the two groups ( P = 0.071). Estradiol in the serum was lower in subjects with idiopathic macular hole than that in control participants (18.9 ± 4.5 vs. 43.7 ± 6.1 pg/mL, P < 0.001). Estradiol in the vitreous body was higher in the study group than in the controls (121.2 ± 41.6 vs. 79.8 ± 10.1 pg/mL, P < 0.001). There was a significant correlation between serum estradiol and vitreous estradiol (r = - 0.440, P < 0.001). Conclusion Lower estradiol levels in the serum and higher estradiol levels in the vitreous body after menopause are associated with the occurrence of idiopathic macular hole in postmenopausal women.


Background
Idiopathic macular hole (IMH), which is widely thought caused by the vitreoretinal contraction (1,2), is a major cause of diminished vision in the elderly. Previous studies have reported that IMH has strong correlations with female sex (the female-to-male ratio is 3.3:1) (3,4) and predominantly occur in postmenopausal women (5).
However, the precise reason for the higher risk of IMH development in postmenopausal women is not yet clear.
Estradiol (E2), synthesized mainly in the ovaries and placent, and acting on various tissues in the body such as bone and cardiovascular system (6), is recognized as a predominant female sex hormone. And also, it can be synthesized in the retina through cholesterol-based pathway and testosterone aromatization (7). E2 is reported to exert a neuroprotective role and influence tissue perfusion by modulating retinal and choroid blood flow in the eyes (8). Evidence exists about the presence of estradiol receptors (ERs) in the retina, which mediates immediate responses to E2 (9).
Although some studies have been carried out on the relationship between E2 and certain retinal disorders such as age-related macular degeneration, diabetic retinopathy or glaucoma (10)(11)(12)(13), further studies are still essential owing to limited research on E2 and IMH.
The aim of this paper was to elucidate the association between E2 and IMH in postmenopausal women, and to help with designing potential new strategies for preventing and treating IMH.

Study design
This study included 30

Inclusion and Exclusion Criteria
The study group were female patients diagnosed of full-thickness

The general characteristics of IMH patients
The general characteristics of IMH patients are shown in Table 1.
The mean age of the study group and the control group was 63.0 ± 4.6 years and 60.7 ± 5.2 years, respectively. There was no statistically significant difference in age between the two groups (P = 0.071). Plasma fibrinogen in IMH group was 2.9 ± 0.3 g/L, which was lower than that in controls (P = 0.034). The analysis of the logMAR BCVA showed a significant difference between the IMH patients and the controls (1.0 ± 0.3 vs. 1.3 ± 0.5, P = 0.030).
However, there was no significant difference in hypertension, coronary artery disease, hyperlipidemia, pseudophakia between the two groups (P ＞ 0.05).

E2 levels in the postmenopausal IMH patients and the control group
The mean E2 in the serum samples obtained from the postmenopausal IMH patients was 18.9 ± 4.5 pg/mL, which was significantly lower than that in the controls (43.7 ± 6.1 pg/mL, P < 0.001) (Figure 1). The mean E2 in the vitreous samples obtained from the postmenopausal IMH patients was 121.2 ± 41.6 pg/mL, which was significantly higher than that in the controls (79.8 ± 10.1 pg/mL, P < 0.001). In the two groups, E2 in the vitreous body was significantly higher than that in the serum (P < 0.001, respectively) ( Figure 1).

Discussion
To  (17,18), which is related to PVD, and then progress to IMH (19). It is also reported that E2 has an effect on hyaluronic acid metabolism from the influences of E2 on the production of hyaluronic acid in skin (20) and differences of the hyaluronic acid in the rabbit vitreous body after hormonal treatment (21). The biological activities of E2 are mainly mediated by their interaction with ERs. The expression of ER-α founded in the retina and RPE of young women, is undetected within the eyes of postmenopausal women, which indicates that age affects the expression of ERs (9).
In our study, E2 in the vitreous body is higher than that in the serum of IMH patients. Higher intraocular E2 levels in IMH patients supports the previous observation that E2 could be locally synthesized in retina (7). The formation of E2 in retina reportedly depends on the process of cholesterol synthesis and testosterone aromatization by the enzymatic activity regulations of cytochrome P450 side-chain cleavage enzyme (P450scc) and aromatase (7). The synthesis of E2 begins with the process of cholesterol synthesis that is converted into pregnenolone after the catalytic action of the cytochrome P450scc (7,22). And then, pregnenolone is converted into progestin and androgen metabolites, and eventually into E2 with the action of aromatase (7,23). Reactive astrocytes are found conducive to the production of E2 by manifesting aromatase when injuries occur in the brain (28).
Evidence also shows that expression of aromatase in embryonic rat RPE (29) and the capillary of choroid of rats (30). Assuming that the glial cells in brain and retina are of the same characteristics, reactive astrocytes that migrate from the retina to the vitreous surface may express aromatase to promote E2 synthesis through testosterone aromatization procedure. However, the vitreous E2 in the control group was similarly higher than that in the serum, which may be due to the presence of a certain degree of vitreoretinal disorder, as we can not obtain the normal human vitreous. However, the reason for the difference in E2 levels between vitreous and serum has yet to be identified, and further investigation is required.
There are some limitations to this study that must be addressed.
First, our subjects were selected from the Chinese population, so the findings may not be entirely used to determine IMH in other ethnic individuals. Second, we chose the patients undergoing a vitrectomy for uncomplicated primary RD as the control group due to the limited collection of the normal human vitreous. Therefore, it was unable to compare the E2 levels of IMH with normal people.

Conclusion
In conclusion, the findings of this study suggest that lower E2 levels in the serum and higher E2 levels in the vitreous body after menopause are associated with the occurence of IMH. While further research should be undertaken to explore the reason for the difference in E2 between the eyes and blood circulation, and the role of E2 in the prevention and treatment of IMH.