Eye differences between women, men need to be considered for diagnosis and treatment

Key takeaways:

• Differences between the eyes of men and women may influence disease susceptibility and symptoms.
• Previous exclusion of women in clinical trials has resulted in a data gap.

There are subtle but significant differences in the morphology and biochemistry of the eye between men and women.

These differences may affect disease susceptibility, symptoms and progression, response to therapy, outcomes of surgical interventions and even the process of visual perception. In all areas of medicine, more awareness of sex and gender differences and more studies are needed to develop increasingly personalized care and targeted treatments, moving away from the old androcentric perspective.

“Until 1993, the policies by the NIH and FDA in the United States either excluded or strongly discouraged the participation of women in clinical trials, especially women of childbearing age,” Sotiria Palioura, MD, MSc, PhD, said. “That means that a lot of the data we have now in medicine is based on only half of the population.”

Even in the laboratory, all studies were performed on male mice for fear that hormonal changes in female mice would affect study results.

The consequences of a data gap

The rationale behind the exclusion of women from clinical trials was to protect them from unknown drug effects, especially during fertile age and pregnancy, but the result of this policy was a massive data gap.

“The guidelines we use in medicine to diagnose certain conditions, the thresholds in our testing and the drug dosages were all developed based on male physiology, the assumption being that the results would be universally applicable,” Palioura said.

This false assumption resulted in important long-lasting consequences.

“In pharmacology, we have learned the hard way that women metabolize some drugs differently due to variations in body composition and liver enzyme activity, and that partly explains why women often experience more side effects from medications that were primarily initially tested for men,” she said.

Another consequence was that the cutoff value for troponin levels indicative of a probable heart attack, originally calibrated using male subjects, led to a lot of missed heart attacks in women.

Differences between women and men are now emerging through studies in various fields of medicine. In cardiology, it has been shown that women often present with symptoms of heart attack that are not so common in men, such as back and jaw pain, fatigue, nausea and shortness of breath. In neurology, Alzheimer’s disease and multiple sclerosis have been found to be more prevalent in women, possibly due to hormonal and immune system differences.

In ophthalmology, there is also a growing body of research addressing the differences between male and female eyes.

“Several studies have shown that women tend to have shorter axial lengths, steeper corneas and shallower anterior chambers, and that, of course, has a lot of implications when we do biometry for IOL calculations,” Palioura said. “The risk of angle-closure glaucoma is different in women than in men. But other than that, we know that dry eye disease is much more common in women, especially around menopause, and research through real-world registries has explored sex-based differences in outcomes for cataract surgery and anti-VEGF therapy.”

Differences in biometric measurements

Looking at Swedish National Cataract Register data from the early 2000s, Anders Behndig, MD, PhD, and colleagues found that the biometry prediction error was larger in women than in men.

“This was between 2004 and 2006, and from 2007, this difference had mysteriously disappeared,” he said. “Looking deeper into these data, in a study that we published in 2014, we realized that the change happened when we switched from the SRK-T formula to the Haigis formula for IOL calculation.”

The SRK-T formula, which was used in nearly all cataract surgeries in those early years, was calibrated for an eye with a rather flat cornea and long axial length. By analyzing the biometry data in the registry, it became clear that, for the same refraction, women have a slightly steeper cornea and a shorter eye while men have a flatter cornea and a longer eye.

“As it is often the case in medicine, the SRK-T formula had been better calibrated for men than for women,” Behndig said. “With the newer Haigis formula, one of the main differences was that we started to measure the anterior chamber depth instead of just estimating it. This led to better results for both women and men, and the difference disappeared.”

After the study was published, there was a rapid switch to the newer formula among cataract surgeons in Sweden.

“It should be added that the differences between women and men are very small, and it wouldn’t have been possible to find them if we hadn’t had the large amount of data available through the registry,” Behndig said. “Even in a small country like Sweden, we do enormous amounts of cataract procedures, and even if from an individual’s perspective the differences are quite small and go unnoticed, they become apparent when you multiply them by very big numbers.”

Even better formulas are in use nowadays, and those differences in outcomes have disappeared. However, those old data reflect the general principle that registries are critically important to look at large numbers, find small errors and adjust them.

“Small errors are hidden for the individual surgeon if you don’t gather data from a lot of other surgeons,” Behndig said. “If you discover that a male patient has a little bit better chance than a woman to be spectacle-free after surgery, then you have to do something about it.”

The correlation between length and volume

Some differences in ocular biometry parameters between male and female patients exist at birth, Marie-José Tassignon, MD, PhD, said.

“Baby boys have longer axial length than baby girls,” she said. “And later in life, the male eye is longer than the female eye for the same refractive error.”

At the University of Antwerp, Belgium, together with her former PhD student Jos Rozema, now head of the Visual Optics Lab Antwerp, Tassignon has been conducting research on ocular biometry within the local population.

Controlling confounding effects was not easy in the diverse population of Belgium, with a significant presence of people of Asian and African origins and a lot of interracial mixing.

“However, we could conclude that there was a difference between female and male eyes,” Tassignon said. “For the same refractive error, they have different parameters, including the axial length, the relationship between axial length and corneal radius curvature, and the lens thickness.”

Those parameters should be taken into account when selecting an IOL rather than relying on just formulas and refractive targets.

A difference in axial length also correlates with a difference in the volume of the eye and therefore the volume of the vitreous, she said.

“Volume is a parameter that is much more significant than length. When we measure the eye, would it not be better to think volumetrically instead of thinking only in millimeters?” Tassignon said.

A lot yet to be discovered

Accurately determining the effective lens position is crucial to the success of cataract surgery. If sizes and volumes of eyes are different in men compared with women, that means that the effective lens position will also be different.

“In all my career, I have never relied on just a formula,” Tassignon said. “I always look at all the parameters: the axial length, the anterior chamber, the curvature and the stiffness of the cornea, and the position of the crystalline lens based on OCT. We are lucky to have IOL formulas to help us, but we are not there yet. We need more information.”

The zonules, for instance, are “a big question mark.” They are made of collagen, and collagen deteriorates with age. The ligament of Wieger will detach with time, leading to detachment of the anterior hyaloid. Therefore, the water surrounding the capsular bag-lens complex will be diluted and provide less support.

“So, age-related changes of the eye, male vs. female variations and changes in the biometrical parameters — all this makes it a little complex for us to satisfy all types of eyes and all our patients. We have to study further,” Tassignon said.

Vitreous liquefaction is also a natural process that occurs with age. There is currently no means to measure the degree of viscosity of the vitreous, which may also differ between men and women.

“We can guess where we are with the liquefaction process by assessing the mobility of the vitreous at the slit lamp or looking at the OCT or even ultrasound. But what we want to achieve is a quantification of viscosity, and we have no instruments to measure that at present,” Tassignon said.

Just the one simple question — Is there a difference between men and women? — can open up the opportunity for many new studies that might play a pivotal role in advancing eye care, she said. “Luckily, it’s not yet finished. There is always something new we can discover.”

Same symptoms, different etiologies

The same symptoms may be indicative of different conditions in women vs. men, according to Anat Galor, MD, MSPH. As a cornea and ocular surface disease specialist, she sees many patients with ocular pain, but the etiology is often different.

“Autoimmune conditions such as Sjögren’s syndrome are much more common in women, while traumatic brain injury is more common in men,” Galor said. “When you take a big category like ocular pain, causes are different, and those causes have different gender predilection.”

There are also differences in the frequency and severity of ocular pain between men and women, which may be due to higher sensitivity to pain in women. In a review article, Galor and co-authors mentioned a study by Li and colleagues in which women showed greater pain sensitivity than men among 287 respondents to a questionnaire.

With respect to the common belief that dry eye disease more frequently affects women than men, Galor took a step back and said that it is true that immune-mediated dry eye is more frequent among women, but meibomian gland dysfunction-related dry eye is equally distributed across women and men.

By looking at the underlying causes of specific symptoms, ophthalmologists can help in the diagnosis of systemic diseases.

“In a woman with an inflammatory eye condition, it is important to ask yourself, ‘Could this be part of a systemic condition?’ In women, it is often an autoimmune process that should not be missed,” Galor said.

Her advice to ophthalmologists is to understand the epidemiology of systemic diseases that present with symptoms or signs in the eye and be aware of which ones are more common in women or men.

“But do not ignore the fact that the other gender can also be affected,” she said. “It’s important to consider gender but not to do that exclusively because there are also other factors that come into play.”

Lifestyles, hormones and response to therapies

There are three areas that have to be considered when diagnosing eye conditions, according to Galor: environmental factors and lifestyle choices, ocular factors, and ocular manifestations of systemic disease.

“Any of those can have male-female disparities,” Galor said.

Women wear makeup, while most men do not, and makeup products often contain chemicals that in the long term can be unhealthy for the eye. Lash extensions also have an impact on the ocular surface, and medical treatment to improve lash length can cause the lashes to turn in and cause significant discomfort, she said.

In both men and women, hormone receptors are present throughout the ocular surface. Hormonal changes in the perimenopausal age might predispose women to developing dry eye, while androgen deficiency can contribute to dry eye in men.

“There are many examples where men who have prostate cancer and go on androgen blockers have meibomian gland dysfunction,” Galor said.

In addition, there might be gender differences in the response to therapies, but studies on dry eye disease drugs give only the data on active treatment vs. placebo and do not segment patients into responders and nonresponders.

“It would be interesting to understand, within the study populations, if men or women were more likely to respond to a particular agent. The data are there but are not presented,” Galor said.

There are still questions that need to be answered and studies that need to be done, but men and women cannot be put in the same exact category because they have different pain perception, different risk rates for different diseases, and different environmental exposure.

“We have to consider those differences when we put together an overall plan for the patient,” she said.

Immune responses

Palioura, who is a cornea, ocular surface and cataract specialist, observed in her practice that women have more severe and more symptomatic dry eye, often with minimal clinical signs.

She also noticed that women have a more robust inflammatory response after surgical procedures such as cataract surgery, corneal transplantation and pterygium removal.

“They will have more redness, discomfort, sometimes even delayed healing, and this is probably because of differences in the immune system activity,” Palioura said. “Women tend to mount stronger immune responses, which protects them from infections, but at the same time, they can be counterproductive for tissue healing.”

In consideration of this, Palioura’s preoperative planning and preoperative approach for cataract surgery are more aggressive in women.

“I optimize the ocular surface more aggressively in order to avoid any errors in IOL calculations, and postoperatively, I am more vigilant about inflammation in female patients,” she said. “I may see them more frequently and adjust my topical steroid regimen to be more aggressive if I see that they have a more robust inflammatory response.”

Earlier in her career, Palioura encountered cases in which women had refractive surprises after cataract surgery because their biometric parameters fell outside what traditional formulas accounted for. She also encountered situations in which women’s dry eye symptoms were dismissed, leading to a lot of frustration and dissatisfaction.

“These gaps in our understanding were frustrating not only for our women patients but also for us physicians. These differences also emphasize the need to include sex as a variable in our future studies,” she said.

AI reveals sex differences in retina

AI can help identify features in the retina that are predictive of biological sex.

“I have more than 30 years of experience in examining retinas, but if you show me a picture of the retina, I cannot say this is male or female,” Christina N. Grupcheva, MD, PhD, said. “Suddenly, artificial intelligence started to distinguish the gender of the retina, and we asked ourselves: Where exactly is the difference?”

Inspired by AI’s performance, several groups of researchers have tried to highlight and map out the areas that AI models use for sex classification, suggesting that the retinal vasculature, the peripapillary area and the macula are possible sources of this information.

“First thing is vasculature. Men have more vessels with a wider vascular branching,” Grupcheva said. “Then we have the peripapillary area, which is usually darker in men. We have no idea what the measures are that AI models use, but we guess that this peripapillary area may be the second important source of sex biomarkers. And when it comes to the macula, interestingly, men have a thicker macula than women of the same age group. Other studies have looked at the structure of the retina and found that men have a thicker retinal nerve fiber layer.”

This information, when used by human observers within studies, improved the ability to detect sex differences above the 50% threshold.

“We are still far from the sensitivity of AI, which is constantly growing and is now close to 100%,” Grupcheva said.

Color vision

These findings could have important implications on epidemiology, the discovery of biomarkers and the development of prediction models of retinal diseases. They may also reveal the reasons why some retinal diseases, like macular degeneration, are more common in women, and others, like diabetic macular edema, are more common in men. This could lead to a deeper understanding of evolutionary traits that distinguish men and women.

“If we go back to the hunter-gatherer era, the man, who was the hunter, needed to have very good contrast sensitivity for catching prey during the night and very good coordination between eye and hand. The woman, who was the gatherer, needed better color sensitivity to pick up small fruits,” Grupcheva said.

Color blindness is far less common in women, and several studies have shown that women have better color discrimination; some female subjects have tetrachromacy, sensitivity for ultraviolet colors, which explains this phenomenon, she said.

Grupcheva shared the anecdote of a rare case of color blindness she found in a female patient. She worked in a strawberry farm in the United Kingdom, and her employer threatened to fire her because she kept picking green strawberries.

“She came to me, I evaluated her color deficiency, and I prescribed for her a contact lens that enhanced color perception that she would wear in the right eye,” she said. “Her performance was immediately better, and to thank me, she brought from the UK a big basket of strawberries.”

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For more information:

Anders Behndig, MD, PhD, of Umeå University Hospital, Sweden, can be reached at anders.behndig@umu.se.
Anat Galor, MD, MSPH, of Bascom Palmer Eye Institute, Miami, can be reached at agalor@med.miami.edu.
Christina N. Grupcheva, MD, PhD, of Medical University of Varna, Bulgaria, can be reached at cgrupcheva@gmail.com.
Sotiria Palioura, MD, MSc, PhD, of Bascom Palmer Eye Institute, Miami, can be reached at sotiria.palioura@gmail.com.
Marie-José Tassignon, MD, PhD, of Antwerp University Hospital, Belgium, can be reached at mj.tassignon@gmail.com.