Systemic hormones influence all cells and tissues within the body during embryonic development, puberty, and into adulthood, including ocular tissues. They regulate everything from hunger to sleep to reproduction as they travel through the bloodstream and other fluids to various body organs and tissues.
Consequently, the ocular surface is constantly exposed to circulating hormones.1
Disclaimer: This article is focused on the concept of biological sex and not gender. Sex is a biological classification based on chromosomes and reproductive organs, while gender is a socially constructed concept related to an individual's self-representation and cultural roles associated with masculinity or femininity.
In the context of this article, terms like "female," "male," "woman," and "man" refer to biological sex characteristics that are directly impacted by sex hormones rather than gender identity.
Brief overview of sex hormones
Sex hormones, in particular, play a critical role in corneal development and function due to the presence of sex hormone receptors in the corneal epithelium, stroma, and endothelium. Sex-hormone-specific receptors are also found in the conjunctiva, lacrimal glands, and meibomian glands, and have been shown to have a major impact on the ocular surface and ocular surface disease (OSD).2,3
Sex hormones are produced by the gonads and adrenal glands, and they determine primary and secondary sexual characteristics, as well as impact the functioning of multiple body systems. Some anterior segment tissues, including the cornea, meibomian glands, and conjunctiva, can also express enzymes that can produce endogenous sex hormones.1
The main classes of sex hormones are:3
- Androgens (including testosterone)
- Estrogens
- Progesterones
The relationship between hormones and OSD
Numerous studies have shown that many ocular conditions, including ocular surface disease, differ significantly in prevalence between women and men.4 OSD is thought to impact women two to four times more than men of the same age.
This worsens after menopause, suggesting a role of sex hormones in the pathogenesis of dry eye disease.5 Endocrine abnormalities are now well known to be an inciting factor as one aspect of the multifactorial nature of dry eye disease.
Conditions related to hormone abnormalities and fluctuations can all contribute to dry eye disease, such as:1
- Pregnancy
- Menopause
- Menstrual cycle variations
- Polycystic ovarian syndrome (POS)
- Endometriosis
- Androgen resistance
- Treatments involving hormones, including antiandrogens and the use of oral contraceptives
Steroid sex hormones contribute to maintaining the function of the ocular surface; however, their exact mechanisms are not yet clear. It is likely that they impact tissues both directly, by binding to receptors, and indirectly, through vascular, immune, and neuro-endocrine regulation. Production and secretion of meibum by the meibomian glands are critical for the protection of the ocular surface and the prevention of desiccation.
Meibocytes within meibomian glands produce meibum through holocrine secretion; meibum is then deposited on the ocular surface with each blink. The composition of lipids in meibum is complex and unique, and alterations in composition or secretion can contribute to tear film instability and symptoms of dry eye.6
Historically, reduced estrogen levels were thought to be the primary contributor to age-related dry eye, but androgens are now understood to play a protective function on the ocular surface, and reduced levels may play a larger role than initially thought.7
Studies by Cavdar et al. indicated that while statistically significant differences in tear breakup time had not been noted throughout the menstrual cycle or during pregnancy, Ocular Surface Disease Index (OSDI) scores worsened during times of peak estrogen levels.8 Patients may feel particularly symptomatic during this time.
Estrogens
Estrogen promotes inflammation of the ocular surface, decreases secretion of sebaceous glands, and inhibits lipogenesis.4
While not fully understood, two potential mechanisms are:
- Estrogen downregulates the cyclic AMP signaling pathway, which causes meibomian gland cell proliferation.9
- The competitive link estrogens exert on androgen receptors.10
The clinical data surrounding the nature of estrogen in dry eye symptoms appears to conflict. Some studies show a worsening of dry eye symptoms during periods of high estrogen levels, such as in the follicular phase of the menstrual cycle, indicating the pro-inflammatory role of estrogen.
Contrarily, other studies show an increase in symptoms during times of low levels of estrogen, such as during menopause.1 Additionally, other studies have indicated that the use of hormone replacement therapy also increases the risk of dry eye disease.11
Androgens
Androgens, on the other hand, stimulate lipogenesis and maturation of acinar cells in meibomian glands.12 By inhibiting the synthesis of interleukin-1β and TNF-α and stimulating the synthesis of TGF-β, androgens have an anti-inflammatory role.13
Studies have shown that treatment with anti-androgen drugs for conditions like prostate cancer has led to dry eye disease, in particular evaporative dry eye disease, further indicating the importance of adequate androgen levels for proper function of the meibomian glands.14
The impact of hormones on the cornea
The structural shape of the cornea has also been shown to change during pregnancy and throughout the normal menstrual cycle. Corneal thickness, curvature, and sensitivity vary over the course of each menstrual cycle. Corneal thickness increases during peak estrogen and progesterone levels during the ovulatory and luteal phases.15
Estrogens specifically stimulate the activation of collagenolytic enzymes, proteinases of the corneal stromal matrix, and deposition of hyaluronic acid leading to an increase in central corneal thickness, changes in corneal curvature, and an increase in intraocular pressure. These changes have also been noted during pregnancy, particularly in the third trimester.16
Estrogen is also thought to play a part in corneal wound healing. In vitro studies have shown stimulation of proliferation and migration of corneal epithelial cells and production of epidermal growth factor by 17β-estradiol, which is a critical mediator in corneal wound healing.17
Recent studies have also shown a possible role of sex hormones in the pathogenesis of keratoconus, as a few studies noted a significant worsening of the progression of keratoconus during pregnancy, which is a time of increased hormones. However, the mechanisms are not yet understood.18
Three stages of hormonal change
There are three major stages of hormonal changes in women:
- Maturity
- Pregnancy
- Menopause
In men and premenopausal women, differing levels of estrogen and testosterone can greatly impact the ocular surface. Testosterone, an androgen, is secreted in higher levels in men, while premenopausal women produce much higher levels of estrogen.
Testosterone increases the quantity and quality of tear secretions by altering gene activity in meibomian, lacrimal, and goblet cells. It also suppresses inflammation in the meibomian and lacrimal glands in addition to down-regulating hyperkeratinization of epithelial cells.12
As we mature, so do our eyes
Estrogen promotes epithelial cell maturation, stimulates goblet cell secretion, blocks the binding of androgens, decreases meibomian and lacrimal gland secretion, and decreases corneal sensitivity. The use of oral contraceptives can contribute to ocular surface symptoms as contraceptives suppress ovulation by decreasing serum estrogen levels. Progesterone also decreases meibomian gland secretions.19
The menstrual cycle begins with the follicular phase, which occurs from day 1 until ovulation; during this phase, ovarian follicles are activated by higher levels of luteinizing hormone and follicle-stimulating hormone to produce estrogen, and once estrogen reaches a certain level, there is a surge of luteinizing hormone which causes ovulation typically around day 14, which is followed by the luteal phase.
If fertilization does not occur, levels of estrogen and progesterone decrease which stimulates follicle-stimulating hormone to recruit follicles for the next follicular phase, and the cycle continues month after month. Estrogen levels are highest at ovulation, while progesterone is highest during the luteal phase, and both are lowest during the follicular phase.2
Pregnancy’s effect on ocular health
There are massive hormone changes during pregnancy. The ovaries, placental tissues, and pituitary glands release increased estrogen, progesterone, and prolactin. Ocular surface changes occur during the entirety of pregnancy, but are most common during the third trimester when hormone levels are at their peak.20
During pregnancy, there is increased volume, thickness, and curvature of the cornea, along with reduced sensitivity. There is also reduced secretion of the lacrimal and meibomian glands, and destruction of acinar tissue of the lacrimal gland.21 Post pregnancy, as hormones return to normal, most ocular surface symptoms will improve.
Patients trying to achieve pregnancy may be on hormone-related therapies such as in vitro fertilization (IVF). During IVF circulating estrogen increases significantly—up to 10 to 50 times higher than normal levels. A study by Boga et al. showed an increase in symptoms of ocular pain and dryness and changes in tear film parameters during peak estrogen levels.22
Menopause and the eye
The final hormonal milestone for women is menopause, a 2- to 8-year process typically occurring between the ages of 40 to 55, caused by aging of the ovaries and marked by no menstrual cycle for 12 or more months.19 There is a decline in estrogen and testosterone as the ovaries stop their secretion.
At the same time, there is a corresponding age-related decrease in progesterone.23 A common treatment for non-ocular menopausal symptoms (mood changes, hot flashes, sleep disturbance, etc.) is hormone replacement therapy (HRT).
There is no consensus on the impact of HRT on ocular surface dryness, and more research is needed. HRT can also be prescribed for hormone imbalance, prostate cancer, and gender-affirming care.
Hormone considerations in disease management
Changes to the ocular surface should be expected during times of great hormonal fluctuation or change, such as during pregnancy, menopause, and in patients receiving hormone replacement therapies. Even the use of anti-nausea medication for morning sickness during pregnancy can contribute to worsening ocular surface dryness.20
The biomechanical changes to the cornea, including increased thickness during times of high estrogen and progesterone levels, are important to consider during surgical treatments such as refractive surgery.23 Avoiding these procedures during pregnancy or discontinuing any hormone-based treatments or contraceptive medications may need to be considered.
In addition, warning pregnant patients of possible refractive changes during pregnancy may be necessary, as these changes are typically not permanent. Those treating OSD should be well versed in the impacts of hormones on ocular surface disease, and take into account the variations and changes to expect while treating patients.
Conclusion
It is important to consider fluctuations and changes over time in sex hormones when managing our patients for any conditions related to the anterior segment and ocular surface.
It is critical to ask in intake forms if patients are pregnant, menopausal, or on any hormone therapies, and discuss with patients their potential impacts on their ocular surface.
