Secondary Logo

Journal Logo

SEX STEROIDS AND MACULAR TELANGIECTASIA TYPE 2

Müller, Simone, MD*; Allam, Jean-Pierre, MD; Bunzek, Christopher, G., MD; Clemons, Traci, E., PhD; Holz, Frank, G., MD*; Issa, Peter, CHARBEL, MD, DPhil*,§

doi: 10.1097/IAE.0000000000001789
Original Study
Free

Purpose: To investigate the relationship between macular telangiectasia Type 2 and systemic levels of sex steroids or their antagonization.

Methods: In a prospective single-center study, 90 patients with macular telangiectasia Type 2 were investigated. Female patients were evaluated for previous surgical (e.g., ovariectomy) and/or pharmacological (e.g., aromatase inhibitors, tamoxifen) therapy resulting in reduced action of sex steroids. In males, free serum testosterone levels were assessed in patients and controls.

Results: Fourteen of 49 (29%) female patients had a history of pharmacological suppression of sex steroids and/or ovariectomy. These patients were younger at disease onset when compared with those without such medical history (mean ± SD: 47.1 ± 7.8, range: 38–59, versus 60.1 ± 7.6, range: 45–76; P < 0.0001). Male patients showed significantly lower free serum testosterone levels compared with controls at younger age (P < 0.0001 and 0.04 in the first and second age quartiles, respectively), as opposed to nonsignificant differences in older patients. In men ≤ 60 years of age, a biochemical hypogonadism (free serum testosterone < 0.05 ng/mL) was present in 53% (8/15) and 4% (2/49) of patients and controls, respectively (P < 0.0001).

Conclusion: The results indicate that steroidal sex hormones might be involved in the presumably multifactorial pathophysiology of macular telangiectasia Type 2.

Female patients with macular telangiectasia (MacTel) Type 2—especially those with a young age of onset—frequently have a history of therapy antagonizing sex steroids or decreasing their systemic levels. Young male patients may have reduced systemic testosterone levels. Thus, sex steroids might modify the disease course of MacTel type 2.

*Department of Ophthalmology, University of Bonn, Bonn, Germany;

Department of Dermatology/Andrology Unit, University of Bonn, Bonn, Germany;

The EMMES Corporation, Rockville, Maryland; and

§Oxford Eye Hospital, OUH NHS Foundation Trust and the Nuffield Laboratory of Ophthalmology, Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.

Reprint requests: Peter Charbel Issa, MD, DPhil, Oxford Eye Hospital, John Radcliffe Hospital, Headley Way, Oxford OX3 9DU, United Kingdom; e-mail: study-enquiry@outlook.com

Supported by the Lowy Medical Research Institute, La Jolla; ProRetina, Aachen, Germany; Oxford NIHR Biomedical Research Centre, Oxford, United Kingdom; Jenapharm, Jena, Germany.

None of the authors has any conflicting interests to disclose.

Macular telangiectasia (MacTel) Type 2 may affect an oval area of a relatively uniform size centered on the fovea, with a temporal epicenter of structural and functional alterations.1 Although its pathophysiology is not yet well understood, recent detailed phenotypic observations have led to the hypothesis of a neurodegenerative disease with additional vascular alterations. Characteristic funduscopic findings include loss of retinal transparency, crystalline deposits, widening of macular capillaries, and focal hyperpigmentations. However, funduscopic signs may be very mild. Cross-sectional optical coherence tomography scans commonly show hyporeflective spaces and atrophy of the photoreceptor layer.1

The affected retinal region and the findings on funduscopy and various imaging modalities seem to distinguish MacTel Type 2 from most other macular diseases. However, similar morphologic changes including foveal hyporeflective spaces on optical coherence tomography scans and crystalline retinal deposits affecting a comparable retinal region have been observed in cancer patients treated with tamoxifen,2–6 which is a selective estrogen receptor modulator.7

The phenotypic similarity with tamoxifen retinopathy and the observation that first symptoms in patients with MacTel Type 2 usually occur around the menopause8 have led us to the hypothesis that sex steroids could be involved in the pathophysiology of MacTel Type 2. We thus prospectively investigated the medical history of female patients to determine the proportion of individuals with previous or current pharmacotherapy (e.g., tamoxifen) or past surgery (e.g., ovariectomy) resulting in modified effects or low levels of sex steroids. A similar investigation in male patients seemed inappropriate as pharmacological suppression of the sex steroids in men at similar age is uncommon. However, we took advantage of the less variable levels of sex steroids in men compared with women and prospectively assessed serum testosterone levels in male patients with MacTel Type 2 compared with age-matched controls.

Back to Top | Article Outline

Methods

In this single-center cross-sectional study, the diagnosis of MacTel Type 2 was based on characteristic findings on funduscopy, spectral-domain optical coherence tomography, macular pigment distribution, and fluorescein angiography.1 Patients of the MacTel natural history and observation study were recruited from a single-center cohort at the Department of Ophthalmology, University of Bonn, Germany. The study was approved by the Ethics Committee of the University of Bonn; it was in adherence to the tenets of the Declaration of Helsinki, and patients provided informed consent.

Disease onset was determined through an interview about the patients' first disease-related visual disturbances as described previously.8 Moreover, a detailed medical history was obtained with special attention to previous surgical or systemic therapies resulting in reduced systemic availability of sex steroids or suppression of their effects.

Blood samples for assessing serum levels of total testosterone, sex hormone–binding globulin (SHBG), and albumin in male patients (n = 41) were obtained at 9 AM (±30 minutes), as sex steroid levels underlie a circadian rhythm.9 Sex hormone–binding globulin was not stratified regarding the body mass index because none of our patients was morbidly obese. Free testosterone was calculated according to the formula of Vermeulen et al,10 and results were compared with a male control cohort (n = 156, of which 115 were in the age range of the patients). The control cohort was recruited at a general practitioner from individuals presenting for routine medical checkup who gave written informed consent. In this study, free serum testosterone levels below 0.05 ng/mL were defined as biochemical testosterone deficiency/hypogonadism.11 Free serum testosterone levels were not measured in women because of assumed lower effect sizes.

Analysis of variance models were used to compare testosterone levels by case/control group. Quantile regression stratified by case/control was used to determine whether there was a trend in testosterone levels by age. Analysis of covariance models were also used to assess potential confounders and interaction effects. Statistical analyses were conducted using SAS Version 9.2 (SAS Institute, Inc, Cary, NC). The significance level for all comparisons was chosen as 0.05.

Back to Top | Article Outline

Results

Medical Interventions Resulting in Reduced Effects or Low Levels of Sex Steroids

Of 49 consecutive female patients with MacTel Type 2 with a mean age of 68.6 years (±SD: 8.6; range: 47–83), 14 (29%) had a history of pharmacological suppression of sex steroids and/or ovariectomy (Table 1). These 14 patients were, on average, younger at disease onset when compared with those without previous therapy affecting sex steroids (mean ± SD: 47.1 ± 7.8; range: 38–59, versus 60.1 ± 7.6; range: 45–76; P < 0.0001; Figure 1A and Table 1). Hence, the frequency of such medical history was much higher in patients with an early disease onset (≤50 years) compared with those with a later disease onset (8/13, 61.5% versus 6/36, 16.7%; Figure 1B). The mean interval (±SD) between initiation of therapy/surgery and first symptoms was 3.4 ± 5.0 years. Only 1 patient was diagnosed with MacTel Type 2 before the onset of an antiestrogenic therapy (patient 1). Anecdotally, she reported deterioration of her visual disturbances after starting the therapy.

Table 1

Table 1

Fig. 1

Fig. 1

Back to Top | Article Outline

Serum Testosterone Levels in Male Patients

The physiologic decrease of free testosterone serum level with age12 was seen in controls. By contrast, the 41 patients with MacTel Type 2 exhibited relatively low free testosterone serum levels throughout all age groups tested (Figure 2A). In a quantile regression model assessing the effect of age on testosterone levels stratified by case/control, the trend for controls was significantly larger than the trend for cases (P < 0.0001). Hence, the relationship between testosterone serum levels and cases/controls should be interpreted referring to age. When comparing cases versus controls at the quartiles for age, differences were significant for the first and second age quartiles (P < 0.0001 and 0.04, respectively; Figure 2B).

Fig. 2

Fig. 2

Figure 2C illustrates the proportion of patients with a free testosterone level in serum < 0.05 μg/L (biochemical hypogonadism). In those ≤ 60 years of age, such biochemical hypogonadism was much more frequent in patients with MacTel Type 2 (53%, 8/15) compared with controls of the same age range (4%, 2/49) (Fisher's exact test, P < 0.0001). Because of the age-related physiologic decline in sex steroid blood levels in normal controls, this difference was less pronounced in those > 60 years of age (patients: 54%, 14/26; controls: 36%, 24/66) (Fisher's exact test, P = 0.16).

Back to Top | Article Outline

Discussion

The data presented herein suggest a role of sex steroids in the pathogenesis of MacTel Type 2. In this cohort, 29% of the female patients had a history of either pharmacological therapy or a previous ovariectomy, resulting in a modified effect or reduced systemic availability of sex steroids, respectively. Although this seems to be a large proportion, we cannot comment with certainty whether the rate of patients with tamoxifen treatment, for example, or previous ovariectomy would be higher than expected because of the lack of comparable control data. Nevertheless, these health conditions preceded the onset of first visual symptoms in 93% and were associated with a significantly younger age of onset when compared with patients without such medical history. Serum sex steroid levels were not measured in the female cohort because of the highly variable levels of female sex steroids.

Men younger than 70 years rarely have a medical condition that would require comparable pharmacological or surgical treatment resulting in reduced action of sex steroids. However, serum levels of sex steroids in men fluctuate much less than in women, allowing for representative measures at random time points (provided circadian variation is considered). In line with the observation in women, the youngest male patients showed overall lower serum levels of free testosterone compared with controls. Of note, one of the youngest male patients had the lowest serum testosterone level because of pharmacological suppression (GnRH-analogon) after surgery for prostate cancer diagnosed at an unusually early age.

Although the etiology of MacTel Type 2 currently remains unknown, a genetic disease cause has been discussed based on occurrence in families.13–17 However, inconsistent heritability and a large variability of the disease severity may be suggestive of a multifactorial/complex disease, where a genetic predisposition is modified by other genetic and/or environmental factors. Possibly, sex steroids influence metabolic, apoptotic, and/or neuroprotective pathways in the retina that—genetically determined— play a role in the pathophysiology of MacTel Type 2. Such relationship might also, at least in part, explain the age-related increase of the disease frequency with a peak age of onset around the menopause.8

Previous laboratory-based observations indicate neuroprotective properties of sex steroids in various models of brain injury, neurodegeneration, and neuronal dysfunction,18–20 and a similar situation may be assumed for the retina. Indeed, neuronal and glial cells of the retina express neurosteroids/sex steroids as well as appropriate steroid receptors.21–23 Moreover, the lipophilic sex steroids from the systemic circulation may pass the blood retina barrier, and testosterone may be converted to estradiol in the retina.23,24

Estradiol was shown to protect retinal cells from oxidative stress, excitotoxicity, and apoptosis.25,26 In vivo studies provided evidence for a neuroprotective potential of estradiol in retinal degenerative disorders, including glaucoma, diabetic retinopathy, and age-related macular degeneration.24,27–29 In vitro studies also suggested such neuroprotective effects on Müller cells which have been implicated to play an important role in the pathophysiology of MacTel Type 2.27

Local estradiol levels in the retina may depend on both the local enzymatic activities and the amount of systemically available sex steroids (primarily estradiol and progesterone in women, testosterone in males).23,30 Low systemic levels of testosterone as found in our male patients might therefore contribute to low local estradiol levels in the retina. However, the exact regulation of retinal sex steroid synthesis and potential effects of retinal disease currently seem incompletely understood.

This study may also implicate reconsideration of the relation between MacTel Type 2 and tamoxifen retinopathy. Initial reports on tamoxifen retinopathy indicated that patients who received very high cumulative doses of tamoxifen may show cystoid macular edema and retinal changes exceeding the macular area usually affected by MacTel Type 2.31–33 Later, more subtle phenotypes were described in up to 6% of patients continuously taking low-dose tamoxifen.34–36 Recent studies which included high resolution retinal imaging in patients who received low-dose tamoxifen therapy suggested retinal alterations similar to those observed in patients with MacTel Type 2.2–6 Many of these reports showed findings indistinguishable from MacTel Type 2, which suggests one of the following explanations:

  1. The macular phenotype has erroneously been interpreted as a side effect of tamoxifen in patients also affected by MacTel Type 2. However, such coincidence seems unlikely, considering the substantial rate of current or previous tamoxifen intake in our rather young female patient cohort (16.3%, 8/49).
  2. Related pathophysiological pathways are involved in two phenotypically similar but separate disease entities. This possibility cannot be excluded and would imply that improved understanding of tamoxifen retinopathy would also shed light on the as yet unknown pathophysiology of MacTel Type 2.
  3. The most intriguing explanation would be a trigger effect of estrogen receptor modulation by tamoxifen in patients (genetically) susceptible for developing MacTel Type 2. Such interpretation would imply a multifactorial pathophysiology, which would account for the observed phenotypic variability. Although the exact mechanism would currently remain obscure, possible explanations may include antagonization of estrogen's neuroprotective properties, or retinal excitatory toxicity and Müller cell stress through tamoxifen-dependent reduced glutamate clearance by the retinal pigment epithelium.37

As a selective estrogen receptor modulator, tamoxifen is known to exert variable tissue and context-dependent agonist and antagonist effects on estrogen receptor expressing cells.38 However, its effect on retinal cells is not fully understood, and mechanisms independent from estrogen receptor and estrogen receptor-related effects have recently been discussed.2,32,39

In summary, our data indicate that reduced action of sex steroids might be involved in the pathophysiology of MacTel Type 2. Such an effect may be due to independent medical conditions, surgical and pharmacological interventions, or due to an age-related decline of sex steroid levels. Independent investigations to either confirm or reject this hypothesis may include a larger repeat study in an independent patient cohort, pathway analysis in omics studies or high-quality phenotyping of a larger patient cohort with long-term tamoxifen intake. If sex steroids indeed influence the disease, they might be considered as a neuroprotective treatment strategy in patients with MacTel Type 2.

Back to Top | Article Outline

References

1. Charbel Issa P, Gillies MC, Chew EY, et al. Macular telangiectasia type 2. Prog Retin Eye Res 2013;34:49–77.
2. Gualino V, Cohen SY, Delyfer MN, et al. Optical coherence tomography findings in tamoxifen retinopathy. Am J Ophthalmol 2005;140:757–758.
3. Mauget-Faysse M, Gambrelle J, Quaranta-El Maftouhi M. Optical coherence tomography in tamoxifen retinopathy. Breast Cancer Res Treat 2006;99:117–118.
4. Ritter C, Renner AB, Wachtlin J, et al. Tamoxifen retinopathy: a case series of clinical and functional data [in German]. Ophthalmologe 2008;105:544–549.
5. Hager T, Hoffmann S, Seitz B. Unusual symptoms for tamoxifen-associated maculopathy [in German]. Ophthalmologe 2010;107:750–752.
6. Doshi RR, Fortun JA, Kim BT, et al. Pseudocystic foveal cavitation in tamoxifen retinopathy. Am J Ophthalmol 2014;157:1291–1298.e1293.
7. Riggs BL, Hartmann LC. Selective estrogen-receptor modulators—mechanisms of action and application to clinical practice. N Engl J Med 2003;348:618–629.
8. Heeren TF, Holz FG, Charbel Issa P. First symptoms and their age of onset in macular telangiectasia type 2. Retina 2014;34:916–919.
9. Diver MJ, Imtiaz KE, Ahmad AM, et al. Diurnal rhythms of serum total, free and bioavailable testosterone and of SHBG in middle-aged men compared with those in young men. Clin Endocrinol (Oxf) 2003;58:710–717.
10. Heinemann LAJ ZT, Vermeulen A, Thiel C, Hummel W. A new “aging males” symptoms' rating scale. Aging Male 1999;2:105–114.
11. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2010;95:2536–2559.
12. Feldman HA, Longcope C, Derby CA, et al. Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study. J Clin Endocrinol Metab 2002;87:589–598.
13. Gillies MC, Zhu M, Chew E, et al. Familial asymptomatic macular telangiectasia type 2. Ophthalmology 2009;116:2422–2429.
14. Hannan SR, Madhusudhana KC, Rennie C, Lotery AJ. Idiopathic juxtafoveolar retinal telangiectasis in monozygotic twins. Br J Ophthalmol 2007;91:1729–1730.
15. Menchini U, Virgili G, Bandello F, et al. Bilateral juxtafoveolar telangiectasis in monozygotic twins. Am J Ophthalmol 2000;129:401–403.
16. Siddiqui N, Fekrat S. Group 2A idiopathic juxtafoveolar retinal telangiectasia in monozygotic twins. Am J Ophthalmol 2005;139:568–570.
17. Scerri TS, Quaglieri A, Cai C, et al. Genome-wide analyses identify common variants associated with macular telangiectasia type 2. Nat Genet 2017;49:559–567.
18. Reddy DS. Neurosteroids: endogenous role in the human brain and therapeutic potentials. Prog Brain Res 2010;186:113–137.
19. Siddiqui AN, Siddiqui N, Khan RA, et al. Neuroprotective role of steroidal sex hormones: an overview. CNS Neurosci Ther 2016;22:342–350.
20. Engler-Chiurazzi EB, Singh M, Simpkins JW. From the 90's to now: a brief historical perspective on more than two decades of estrogen neuroprotection. Brain Res 2016;1633:96–100.
21. Kobayashi K, Kobayashi H, Ueda M, Honda Y. Estrogen receptor expression in bovine and rat retinas. Invest Ophthalmol Vis Sci 1998;39:2105–2110.
22. Wickham LA, Gao J, Toda I, et al. Identification of androgen, estrogen and progesterone receptor mRNAs in the eye. Acta Ophthalmol Scand 2000;78:146–153.
23. Cascio C, Russo D, Drago G, et al. 17beta-estradiol synthesis in the adult male rat retina. Exp Eye Res 2007;85:166–172.
24. Cascio C, Deidda I, Russo D, Guarneri P. The estrogenic retina: the potential contribution to healthy aging and age-related neurodegenerative diseases of the retina. Steroids 2015;103:31–41.
25. Neumann F, Wurm A, Linnertz R, et al. Sex steroids inhibit osmotic swelling of retinal glial cells. Neurochem Res 2010;35:522–530.
26. Arevalo MA, Azcoitia I, Garcia-Segura LM. The neuroprotective actions of oestradiol and oestrogen receptors. Nat Rev Neurosci 2015;16:17–29.
27. Kaarniranta K, Machalinska A, Vereb Z, et al. Estrogen signalling in the pathogenesis of age-related macular degeneration. Curr Eye Res 2015;40:226–233.
28. Bucolo C, Drago F. Effects of neurosteroids on ischemia-reperfusion injury in the rat retina: role of sigma 1 recognition sites. Eur J Pharmacol 2004;498:111–114.
29. Russo R, Cavaliere F, Watanabe C, et al. 17Beta-estradiol prevents retinal ganglion cell loss induced by acute rise of intraocular pressure in rat. Prog Brain Res 2008;173:583–590.
30. Wang S, Wang B, Feng Y, et al. 17beta-estradiol ameliorates light-induced retinal damage in Sprague-Dawley rats by reducing oxidative stress. J Mol Neurosci 2015;55:141–151.
31. McKeown CA, Swartz M, Blom J, Maggiano JM. Tamoxifen retinopathy. Br J Ophthalmol 1981;65:177–179.
32. Bourla DH, Sarraf D, Schwartz SD. Peripheral retinopathy and maculopathy in high-dose tamoxifen therapy. Am J Ophthalmol 2007;144:126–128.
33. Kaiser-Kupfer MI, Lippman ME. Tamoxifen retinopathy. Cancer Treat Rep 1978;62:315–320.
34. Pavlidis NA, Petris C, Briassoulis E, et al. Clear evidence that long-term, low-dose tamoxifen treatment can induce ocular toxicity. A prospective study of 63 patients. Cancer 1992;69:2961–2964.
35. Gorin MB, Day R, Costantino JP, et al. Long-term tamoxifen citrate use and potential ocular toxicity. Am J Ophthalmol 1998;125:493–501.
36. Heier JS, Dragoo RA, Enzenauer RW, Waterhouse WJ. Screening for ocular toxicity in asymptomatic patients treated with tamoxifen. Am J Ophthalmol 1994;117:772–775.
37. Maenpaa H, Mannerstrom M, Toimela T, et al. Glutamate uptake is inhibited by tamoxifen and toremifene in cultured retinal pigment epithelial cells. Pharmacol Toxicol 2002;91:116–122.
38. Lonard DM, Smith CL. Molecular perspectives on selective estrogen receptor modulators (SERMs): progress in understanding their tissue-specific agonist and antagonist actions. Steroids 2002;67:15–24.
39. Nayfield SG, Gorin MB. Tamoxifen-associated eye disease. A review. J Clin Oncol 1996;14:1018–1026.
Keywords:

macular telangiectasia Type 2; MacTel Type 2; sex steroids; estradiol; testosterone; neuroprotection; tamoxifen; aromatase inhibitors; biochemical hypogonadism

© 2018 by Ophthalmic Communications Society, Inc.