Ocular Implications of Medical Fertility and Hormonal Treatment

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Article initiated by:
Avery Zhou, Sabrina Ho, Lena Hummel, Mohammad Pakravan, Andrew Go Lee, MD
All contributors:
Mohammad Pakravan
Assigned editor:
Review:
Assigned status Update Pending
.


Background

Medical fertility managements are aimed to correct reversible etiologies of infertility, largely through the use of ovulation induction agents such as clomiphene citrate, aromatase inhibitors such as letrozole, and gonadotropin therapy.[1] Use of a specific agent is dependent on the patient’s underlying cause of anovulation. Clomiphene citrate, a non-steroidal compound similar in structure to estrogen, is considered first line treatment of anovulatory infertility.[2] Clomiphene citrate is an oral medication that works by blocking the estrogen receptors in the hypothalamus, thus triggering follicle-stimulating hormone (FSH) release and inducing ovulation.[2] Letrozole, a second line oral treatment option, prevents the conversion of androgen to estrogen.[2] The resulting decrease in serum estrogen results in an increase of FSH release.[2] Usually in situations following failure of clomiphene citrate and letrozole therapy, gonadotropin therapy may be considered.[3] Gonadotropin therapy involves directly injecting FSH or a combination of FSH and luteinizing hormone (LH) to stimulate ovulation.[3]

Although these therapies target infertility, the hormonal effects of these interventions have been cited to affect some ocular disorders as well. Table 1 summarizes the ocular disorders that have been reported to be associated with hormone replacement therapy (HRT) or fertility treatments, including in-vitro fertilization (IVF). Worsening of an ocular condition with the agent used signifies a positive association, whereas improvement of the ocular condition with the agent used indicates a negative association.

Agent(s) Studies Supporting a Positive Association Studies Supporting a Negative/No Association
Dry Eye HRT, aromatase inhibitor Cross-sectional studies,[4][5][6] cohort study[7] N/A
Keratoconus IVF, estrogen In vitro model,[8] review article[9] Case series[10]
Central Retinal Vein Occlusion/Cilioretinal Artery Occlusion Clomiphene citrate Case reports[11][12][13][14][15] N/A
Non-Arteritic Anterior Ischemic Optic Neuropathy Clomiphene citrate Case reports[16][17][18] N/A
Retinal Periphlebitis Hormonal treatment (unspecified) Case reports[19] N/A
Maculopathy Clomiphene citrate (overextended period) Case report[20] N/A
Retinal & Choroidal Neovascularization Clomiphene citrate, IVF Case reports,[21][22] cohort study[23] N/A
Meningioma Pregnancy, progesterone, HRT, hormonal contraceptives Case reports,[24] case-control studies[25][26] Case-control studies,[27][28] cohort study[29]
Palinopsia Clomiphene citrate, IVF Case reports[30][31] N/A
Scotoma & Photophobia Clomiphene citrate, IVF Case reports[32][33] N/A

Ocular Disorders Affected By Fertility and Hormonal Treatment

Dry Eye

Prevalence of dry eye syndrome (DES) is significantly higher in women than men (52.6% vs 41.9%),[4] suggesting a possible hormonal component to the syndrome. Women who use hormone replacement therapy were found to have increased risk of developing DES, with prolonged use associated with increased risk.[5] One study demonstrated a significant increase of 15% elevated risk of DES diagnosis with each 3-year increase in duration of hormone replacement therapy.[7] A positive relationship between duration of aromatase inhibitor use and likelihood of experiencing dry eye symptoms has also been identified in the literature.[6]

Keratoconus

Keratoconus causes blurred vision due to thinning and bulging of the cornea. Corneal thickness is greatest during mid-ovulation and at the end of the menstrual period, which correlates with the rise of estrogen and progesterone, respectively.[8] The exact role of hormones is unknown but estrogen supplementation in post-menopausal women has been suggested to increase corneal thickness.[8] Corneal epithelial and conjunctival cells transcribe the genes for enzymes that produce various hormones independently of systemic regulation,[8] such as 3β-hydroxysteroid dehydrogenase which activates estrogens and androgens,[8] indicating that the anterior tissue of the eye may produce hormones to regulate the thickness.[8] Despite previous published reports of estrogen’s effects on increasing corneal thickness,[9] there also exists evidence of patients experiencing keratoconus progression following IVF treatment.[10] Therefore, the role of hormones on keratoconus remains unclear.

Central Retinal Vein Occlusion/Cilioretinal Artery Occlusion

Multiple case reports have reported central retinal vein occlusion (CRVO) in patients who undergo clomiphene citrate therapy. This effect appeared to be dependent on total drug dose and duration of exposure, with symptoms generally improving after termination of therapy.[13][12][11]

There are also cases of concurrent CRVO as well as cilioretinal artery occlusion occurring shortly after starting hormone replacement therapy.[14] Another case report mentions the use of hyperbaric oxygen treatment after onset of vision loss secondary to CRVO and cilioretinal artery occlusion in a patient after hormonal treatment for induction of ovulation.[15]

Non-Arteritic Anterior Ischemic Optic Neuropathy

There are multiple case reports describing non-arteritic anterior ischemic optic neuropathy (NAION) after the initiation of clomiphene citrate.[18][17][16] In these cases, clomiphene citrate was the only drug used and there were no comorbid conditions. The relationship between NAION and clomiphene citrate therapy is hypothesized to be an increase in estradiol, which is potentially thrombogenic and increases blood viscosity.

Retinal Periphlebitis

Retinal periphlebitis has been reported in a male patient following hormonal treatment for infertility. The patient experienced a unilateral severe decrease in visual acuity. Fluorescein angiography demonstrated delayed filling of the veins. Administration of systemic corticosteroids provided rapid improvement in visual acuity.[19]

Maculopathy

One case of vision loss secondary to maculopathy has been reported in the literature following use of clomiphene citrate for an overextended period of three years. Vision did not return following cessation of the hormone therapy.[20]

Retinal & Choroidal Neovascularization

IVF treatment has been identified as a risk factor for retinal detachment, including a case of bilateral retinal detachment following initiation of clomiphene citrate for ovulation induction.[21] The exact mechanism is unknown but the hypothesis is that IVF increases the levels of vascular endothelial growth factor (VEGF).[23] This is further supported by evidence showing a correlation between follicle stimulating hormone (FSH) and VEGF levels.[23] In animal models, overexpression of VEGF led to neovascularization and retinal detachment.[23] Another report described choroidal neovascular membrane after IVF and elevated levels of VEGF may have initiated the development of CNV.[22] Treatment with anti-VEGF through intravitreal injection was effective in reducing CNV and restoring vision.[22]

Meningioma

There is evidence that growth of intracranial meningiomas is influenced by progesterone, as meningioma tumors are twice as common in women than in men, and evaluation of meningioma tumors are found to largely contain (>70%) progesterone receptors.[34] Meningiomas have been reported to grow and regress in concordance with pregnancy and childbirth, respectively.[24] Multiple studies have also demonstrated a significantly increased relative risk of being diagnosed with meningioma in patients undergoing hormone replacement therapy (HRT) compared to those who never used HRT.[25][26] However, other large-scale studies find no association between pregnancy or HRT use with meningioma occurrence, suggesting that hormonal changes are not risk factors for meningiomas.[27][28][29] The relationship between meningiomas and hormones still remains contested.

Palinopsia

Fertility treatment has also been cited to cause palinopsia, an abnormal persistence of an image, and photophobia. There has been one study (n=3) and a case report which documents fertility treatment associated with cases of palinopsia and photophobia that persisted despite years of drug discontinuation.[30][31] The pathophysiology of fertility treatment causing palinopsia is thought to be due to estrogen’s inhibitory effect on the synthesis of gamma-aminobutyric acid, which causes an increased excitatory effect on the visual cortex and produces visual hallucinations.[31]

Other Side Effects

Clomiphene has been reported to cause unexplained scotomas that may persist despite drug cessation. One study reported 3 middle aged women that received IVF developed central and peripheral scotomas that lasted years after stopping clomiphene, though further testing revealed that the visual effects were more likely due to a transient effect on the visual cortex rather than on the retina.[32] Another study demonstrated scotoma development which disappeared after discontinuation of clomiphene citrate, recurred with re-administration of clomiphene citrate, and did not recur with placebo.[33]

Conclusion

Medications used for fertility treatment or hormone replacement therapy have systemic effects that may also impact the eyes. Many of these relationships are known because of published case reports, but a few large-cohort prospective studies have also been performed to determine hormonal correlations with eye disorders. It is important for clinicians to be aware of these associated effects linked to hormone treatment as it may help guide the workup and management for patients with a known history. Awareness of this relationship could lead clinicians to consider working in tandem with the patient’s endocrinologist or obstetrician/gynecologist to personalize a plan that appropriately addresses the patient’s complaints and mitigates ocular side effects.

  1. ↑ Kuohung, W. & Hornstein, M.D. (2021). Treatments for female infertility. In K. Eckler (Eds.), UptoDate. Available from https://www.uptodate.com/contents/treatments-for-female-infertility
  2. ↑ 2.0 2.1 2.2 2.3 Kamath MS, George K. Letrozole or clomiphene citrate as first line for anovulatory infertility: a debate. Reprod Biol Endocrinol. 2011;9:86. Published 2011 Jun 21. doi:10.1186/1477-7827-9-86
  3. ↑ 3.0 3.1 Fauser, B. C. (2021). Patient education: Infertility treatment with gonadotropins (Beyond the Basics). In R.L. Barbieri, K. A. Martin (Eds.), UptoDate. Available from https://www.uptodate.com/contents/infertility-treatment-with-gonadotropins-beyond-the-basics
  4. ↑ 4.0 4.1 Choi HR, Kim NH, Lee JM, et al. Risk Factors Influencing the Occurrence and Severity of Symptomatic Dry Eye Syndrome: A Cross-sectional Study. Ophthalmic Epidemiol. 2021;28(6):488-494. doi:10.1080/09286586.2021.1879172
  5. ↑ 5.0 5.1 AlAwlaqi A, Hammadeh M. Examining the relationship between hormone therapy and dry-eye syndrome in postmenopausal women: a cross-sectional comparison study. Menopause. 2016;23(5):550-555. doi:10.1097/GME.0000000000000570
  6. ↑ 6.0 6.1 Khoo, P., Groeneveld, T., Boyle, F. et al. Dry eye signs and symptoms in patients on aromatase inhibitor therapy. Eye 36, 766–772 (2022). https://doi.org/10.1038/s41433-021-01538-6
  7. ↑ 7.0 7.1 Schaumberg DA, Buring JE, Sullivan DA, Dana MR. Hormone Replacement Therapy and Dry Eye Syndrome. JAMA. 2001;286(17):2114–2119. doi:10.1001/jama.286.17.2114
  8. ↑ 8.0 8.1 8.2 8.3 8.4 8.5 McKay TB, Hjortdal J, Sejersen H, Karamichos D. Differential Effects of Hormones on Cellular Metabolism in Keratoconus In Vitro. Sci Rep. 2017;7:42896. Published 2017 Feb 17. doi:10.1038/srep42896
  9. ↑ 9.0 9.1 McKay TB, Priyadarsini S, Karamichos D. Sex Hormones, Growth Hormone, and the Cornea. Cells. 2022;11(2):224. Published 2022 Jan 11. doi:10.3390/cells11020224
  10. ↑ 10.0 10.1 Yuksel E, Yalinbas D, Aydin B, Bilgihan K. Keratoconus Progression Induced by In Vitro Fertilization Treatment. J Refract Surg. 2016;32(1):60-63. doi:10.3928/1081597X-20151207-10
  11. ↑ 11.0 11.1 Politou, M., Gialeraki, A., Merkouri, E., Travlou, A., & Baltatzis, S. (2009). Central retinal vein occlusion secondary to clomiphene treatment in a male carrier of factor V Leiden. Genetic Testing and Molecular Biomarkers, 13(2), 155-7. https://doi.org/10.1089/gtmb.2008.0104
  12. ↑ 12.0 12.1 Lee VY, Liu DT, Li CL, Hoi-Fan, Lam DS. Central retinal vein occlusion associated with clomiphene-induced ovulation. Fertil Steril. 2008;90(5):. doi:10.1016/j.fertnstert.2008.01.056
  13. ↑ 13.0 13.1 Viola M, I, Meyer D, Kruger T: Association between Clomiphene Citrate and Visual Disturbances with Special Emphasis on Central Retinal Vein Occlusion: A Review. Gynecol Obstet Invest 2011;71:73-76. doi: 10.1159/000319497
  14. ↑ 14.0 14.1 Murray DC, Christopoulou D, Hero M. Combined central retinal vein occlusion and cilioretinal artery occlusion in a patient on hormone replacement therapy. Br J Ophthalmol. 2000;84(5):549-550. doi:10.1136/bjo.84.5.546e
  15. ↑ 15.0 15.1 Khallouli A, Khelifi K, Saidane R, Choura R, Maalej A, Sassi RB. Hyperbaric oxygen treatment of central retinal vein occlusion with cilioretinal artery occlusion secondary to hormonal treatment: Case report and review. Diving Hyperb Med. 2020;50(4):431-436. doi:10.28920/dhm50.4.431-436
  16. ↑ 16.0 16.1 Perin AF, Chacko JG, Goyal S. Nonarteritic ischemic optic neuropathy associated with clomiphene citrate use. J Neuroophthalmol 2017; 37: 106–107.
  17. ↑ 17.0 17.1 Alizadeh Y, Moravvej Z, Khakpour Y, Azaripour E, Akbari M, Soltani-Moghadam R. Presumed clomiphene-induced optic neuropathy: A case report. Int J Reprod Biomed. 2021;19(5):471-476. Published 2021 Jun 23. doi:10.18502/ijrm.v19i5.9257
  18. ↑ 18.0 18.1 Lawton AW. Optic neuropathy associated with clomiphene citrate therapy. Fertil Steril 1994; 61: 390–391.
  19. ↑ 19.0 19.1 Rock T, Dinar Y, Romem M. Retinal periphlebitis after hormonal treatment. Ann Ophthalmol. 1989;21(2):75-76.
  20. ↑ 20.0 20.1 Tunc M. Maculopathy following extended usage of Clomiphene citrate. Eye (Lond). 2014;28(9):1144-1146. doi:10.1038/eye.2014.121
  21. ↑ 21.0 21.1 Lokaj, A. and Rama, B. (2018) Bilateral Retinal Detachment Secondary to Clomiphene Citrate. Open Journal of Ophthalmology, 8, 31-35. doi: 10.4236/ojoph.2018.81005.
  22. ↑ 22.0 22.1 22.2 Ciucci F, Sacchetti M, Gaetano CD, Bardocci A, Lofoco G. Choroidal neovascular membrane following hormonal stimulation for in vitro fertilization. Eur J Ophthalmol. 2015;25(5):e95-e97. Published 2015 Jul 30. doi:10.5301/ejo.5000607
  23. ↑ 23.0 23.1 23.2 23.3 Ratson R, Sheiner E, Davidson E, Sergienko R, Beharier O, Kessous R. Fertility treatments and the risk for ophthalmic complications: a cohort study with 25-year follow-up. J Matern Fetal Neonatal Med. 2016;29(19):3094-3097. doi:10.3109/14767058.2015.1120717
  24. ↑ 24.0 24.1 Bickerstaff ER, Small JM, Guest IVA . The relapsing course of certain meningiomas in relation to pregnancy and menstruation. J Neurol Neurosurg Psychiatry 1958; 21: 89–91.
  25. ↑ 25.0 25.1 Annette Wigertz, Stefan Lönn, Tiit Mathiesen, Anders Ahlbom, Per Hall, Maria Feychting, and the Swedish INTERPHONE Study Group, Risk of Brain Tumors Associated with Exposure to Exogenous Female Sex Hormones, American Journal of Epidemiology, Volume 164, Issue 7, 1 October 2006, Pages 629–636, https://doi.org/10.1093/aje/kwj254
  26. ↑ 26.0 26.1 Benson, V.S., Pirie, K., Green, J., Bull, D., Casabonne, D., Reeves, G.K., Beral, V. and (2010), Hormone replacement therapy and incidence of central nervous system tumours in the Million Women Study. Int. J. Cancer, 127: 1692-1698. https://doi.org/10.1002/ijc.25184
  27. ↑ 27.0 27.1 Korhonen, K., Raitanen, J., Isola, J. et al. Exogenous sex hormone use and risk of meningioma: a population-based case–control study in Finland. Cancer Causes Control 21, 2149–2156 (2010). https://doi.org/10.1007/s10552-010-9634-2
  28. ↑ 28.0 28.1 Claus, E. B., Calvocoressi, L., Bondy, M. L., Wrensch, M., Wiemels, J. L., & Schildkraut, J. M. (2013). Exogenous hormone use, reproductive factors, and risk of intracranial meningioma in females, Journal of Neurosurgery JNS, 118(3), 649-656. Retrieved Apr 10, 2022, from https://thejns.org/view/journals/j-neurosurg/118/3/article-p649.xm
  29. ↑ 29.0 29.1 Pettersson-Segerlind, J., Mathiesen, T., Elmi-Terander, A. et al. The risk of developing a meningioma during and after pregnancy. Sci Rep 11, 9153 (2021). https://doi.org/10.1038/s41598-021-88742-2
  30. ↑ 30.0 30.1 Purvin VA. Visual disturbance secondary to clomiphene citrate. Arch Ophthalmol. 1995;113(4):482-484. doi:10.1001/archopht.1995.01100040102034
  31. ↑ 31.0 31.1 31.2 Venkatesh R, Yadav NK, Sinha S. Illusory palinopsias induced by in vitro fertilization treatment: a case report. J Med Case Rep. 2019;13(1):164. Published 2019 May 30. doi:10.1186/s13256-019-2115-7
  32. ↑ 32.0 32.1 Farzinvash Z. A young woman with sudden visual field shimmering: A case report. Indian J Ophthalmol. 2018;66(10):1504-1505. doi:10.4103/ijo.IJO_515_18
  33. ↑ 33.0 33.1 ROCH LM, GORDON DL, BARR AB, PAULSEN CA. Visual Changes Associated With Clomiphene Citrate Therapy. Arch Ophthalmol. 1967;77(1):14–17. doi:10.1001/archopht.1967.00980020016004
  34. ↑ Rose, Geoffrey. (1993). Orbital meningiomas: Surgery, radiotherapy, or hormones?. The British journal of ophthalmology. 77. 313-4. 10.1136/bjo.77.5.313.
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