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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 12 4866-4873
Copyright © 2000 by The Endocrine Society

Original Studies

Impact of Antiandrogen Treatment on the Fatty Acid Profile of Neutral Lipids in Human Meibomian Gland Secretions1

Benjamin D. Sullivan, James E. Evans, Kathleen L. Krenzer, M. Reza Dana and David A. Sullivan

Schepens Eye Research Institute (B.D.S., K.L.K., M.R.D., D.A.S.), Brigham and Women’s Hospital (M.R.D.), Department of Ophthalmology, Harvard Medical School (B.D.S., M.R.D., D.A.S.), and New England College of Optometry (K.L.K.), Boston, Massachusetts 02114; and Eunice Kennedy Shriver Center for Mental Retardation (J.E.E.), Waltham, Massachusetts 02452

Address correspondence and requests for reprints to: David A. Sullivan, Ph.D., Schepens Eye Research Institute, 20 Staniford Street, Boston, Massachusetts 02114. E-mail: sullivan{at}vision.eri.harvard.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The purpose of this study was to determine whether the use of antiandrogen medications is associated with significant alterations in the fatty acid (FA) profiles of neutral lipids in human meibomian gland secretions. Meibomian gland secretions were obtained from both eyes of patients receiving antiandrogen therapy and from age-related controls. Samples were processed for high-performance liquid chromatography/mass spectrometry and an evaluation of the mass/charge ratios of neutral lipid FA. Our results demonstrate that antiandrogen therapy is associated with significant and consistent alterations in the mass/charge ratios of neutral lipid fractions of meibomian gland secretions. Patients taking antiandrogen medications had significant changes in the occurrence of numerous diglyceride, triglyceride, and wax/cholesterol ester FA products, compared with age-matched controls. Statistical analyses of data within groups demonstrated very high correlation coefficients, and cross-correlation analyses revealed characteristic shifts in FA patterns between groups. Our findings show that antiandrogen use is paralleled by significant changes in the FA profiles of neutral lipid fractions in meibomian gland secretions.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
RECENTLY, WE HAVE hypothesized that the meibomian gland is an androgen target organ and that androgens control meibomian gland function, regulate the quality and/or quantity of lipids produced by this tissue, and promote the formation of the tear film’s lipid layer (1). We have also hypothesized that androgen deficiency, such as occurs during the use of antiandrogen medications, menopause, aging in both sexes, certain autoimmune diseases (e.g. Sjögren’s syndrome), and complete androgen insensitivity syndrome will lead to meibomian gland dysfunction, altered lipid profiles in meibomian gland secretions, decreased tear film stability and evaporative dry eye (1).

In support of these hypotheses, we and others have discovered that meibomian glands contain androgen receptor messenger RNA (mRNA) and protein within acinar epithelial cells (2, 3), express mRNAs for both Types 1 and 2 5{alpha}-reductase (3), and respond to an androgen precursor with an increased production and release of lipids (4). We have also found that orchiectomy alters the lipid profile in the rabbit meibomian gland, whereas topical androgen administration begins to restore the lipid pattern to that found in intact animals (5). In addition, we have observed that androgen deficiency seems to be associated with meibomian gland dysfunction and an increase in the signs and symptoms of dry eye.2 Thus, our data suggest that patients taking antiandrogen therapy, compared with controls, have: 1) significant changes in their meibomian glands, including orifice metaplasia, a poorer quality of secretions, and a morphology consistent with severe disease; 2) a significant alteration in the overall neutral lipid pattern of their meibomian gland secretions, including an attenuation in the amounts of cholesterol esters, wax esters, diglycerides, and triglycerides, relative to those of cholesterol; 3) tear film instability; and 4) a higher frequency of ocular surface symptoms (i.e. light sensitivity, painful eyes, blurred vision).

Collectively, these results indicate that androgens play an important role in meibomian gland function. To extend these findings, and to further test our hypotheses, we sought in the present study to determine whether androgen deficiency, as caused by antiandrogen treatment, elicits significant alterations in the expression of specific molecular species in the neutral lipid fractions (i.e. diglycerides, triglycerides, wax and cholesterol esters) of human meibomian gland secretions. These lipid fractions are extremely important for maintaining the stability and preventing the evaporation of the preocular tear film (6, 7, 8), and their disruption may help account for the tear film instability and dry eye observed in androgen-deficient states.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Human subjects

Male subjects receiving antiandrogen treatment for prostatic indications were recruited from the Departments of Urology at the Brigham and Women’s Hospital and Boston University Medical Center (Boston, MA). These patients (n = 15), whose average age was 70.9 ± 1.9 yr, had been treated with antiandrogen medications (i.e. leuprolide acetate, goserelin acetate, bicalutamide, flutamide, and/or finasteride) for intervals ranging from 3–96 months (median, 36 months). Age-related male controls (64.8 ± 1.0 yr old; n = 6), who were not receiving antiandrogen therapy, were recruited from the Boston area. The ages of the patients taking antiandrogen medications and their age-related controls were not significantly different. After providing informed consent, meibomian gland secretions were obtained, as described (see Footnote 1). In brief, secretions were collected from each eye by gently applying pressure against the lower eyelid with a cotton-tipped applicator and collecting the expelled fluid with a chalazion curette (surgical stainless steel). Samples were then placed in glass tubes containing a 2:1 mixture of chloroform-methanol, and these tubes were then capped and stored at -70 C until experimental use. These studies were approved by the Human Studies Committee of the Schepens Eye Research Institute (Boston, MA) and were conducted in accordance with guidelines established by the Declaration of Helsinki.

Additional clinical information about these patient and control groups has been reported in a recent article that describes the results of the subjects’ anterior segment examinations, as well as the percentages of overall lipid categories (i.e. diglycerides, triglycerides, wax and cholesterol esters) in meibomian gland secretions (see Footnote 1).

Biochemical and analytical methods

Meibomian gland secretions were analyzed by high-performance liquid chromatography (HPLC) and mass spectrometry (MS), and predominant peaks in HPLC/MS elution plots were identified, as reported previously (see Footnote 1). MS was performed in positive ion, chemical ionization mode with ammonia reagent gas, and data were acquired with a Teknivent Vector/Two data system (Teknivent Corporation, Maryland Heights, MO). Samples were examined at two separate times (i.e. 6 months apart): the first column run was used for the meibomian gland secretions (both left and right) of 10 patients, whereas the second column run was used for the secretions (both left and right) of 5 patients and the 6 age-related controls.

To permit evaluation of the HPLC/MS data, and to examine whether significant differences exist between the mass spectra of the neutral lipid peaks of patients vs. controls, a discrete, integer-valued distribution of mass/charge (m/z) ratios from m/z 100 to m/z 900 was gathered for each subject in each lipid family. Each distribution represented the time average of a gaussian HPLC peak defined by characteristic ions falling within specific time points of elution [(cholesterol esters: m/z 369 over 1.84–1.87 min), (wax esters: m/z 636, 650, 664, 678 over 1.84–1.87 min), (triglycerides: m/z 551, 577, 579, 603, 605 over 2.24–2.53 min), (diglycerides: m/z 551, 577, 579, 603, 605 over 8.24–8.40 min)]. These profiles were normalized by their individual sums to represent each m/z ratio as a percent composition of the sample.

Treating each m/z as a separate variable and each individual in a group as an observation, a Student’s unpaired t test was performed between patients and controls. For those m/z units with a significant (P < 0.05) alteration between groups, differences in sum normalized mean values above 0.01% were tabulated. Significant differences in random noise appeared at levels on the order of 0.001%.

Correlation coefficients of the m/z distributions were calculated within groups (e.g. controls vs. controls) and between groups (e.g. controls vs. patients) for each lipid family. Iterative calculations within groups produced (n(n-1)/2)-1 values for each internal comparison (n being the number of samples per group) and n1m values for comparisons between groups (n in first group, m in second group). Average correlation coefficients (ACCs) were reported for each comparison. Furthermore, trends with respect to age and treatment time vs. correlation were calculated for each individual and fit to a first order regression line.

In an effort to identify side chain elongation, saturation, and/or epoxidation shifts between patients and controls, integer multiples of methylene or epoxide groups were located within a third order low pass filtered cross-correlation (Eq IGo: X = control, Y = patient matricies) of the sample means of each group. Trends were confirmed with power spectral densities (Eq II). Additionally, cross-correlations were applied to a subset of peaks composed of all m/z less than 2% of the total lipid fraction. The 2% parameter was chosen to keep large ions from dominating the correlation curve, thereby expressing only those trends indicative of the majority of lipids in the sample.



   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
To determine whether the use of antiandrogen medications alters the fatty acid (FA) profiles of neutral lipids in human meibomian gland secretions, secretions were obtained from both eyes of patients receiving antiandrogen therapy (n = 15), as well as from age-related controls (n = 6). Samples were then processed for HPLC/MS and an evaluation of the mass spectra of the neutral lipid FA fragment ions.

Our results demonstrate that antiandrogen treatment is associated with significant and consistent alterations in the expression of specific molecular species in the neutral lipid fractions of meibomian gland secretions. As shown in Figs. 1–3GoGoGo, secretions of patients taking antiandrogen medications, compared with those of age-related controls, had: 1) a decrease (e.g. ions at m/z 168, 255, 257, 338) and an increase (e.g. ions at m/z 122, 369, 383, 386) of numerous FA products in the diglyceride fraction (Fig. 1Go); 2) a decline (e.g. ions at m/z 136, 168, 169, 204, 285) and an enhancement (e.g. ions at m/z 349, 363, 383, 384) of various FA products in the triglyceride fraction (Fig. 2Go); and 3) a drop (e.g. ions at m/z 131, 168, 231, 233) and a rise (e.g. ions at m/z 370, 386) of certain FA products in the wax and cholesterol ester fraction (Fig. 3Go). Many of these changes seemed to be "all" or "none," and almost all samples showed the same group-related FA profile. Moreover, FA profiles in meibomian gland secretions from the left lid of a given individual were identical to those from the right lid. The data in Figs. 1–3GoGoGo were obtained from 8 patient and 10 control samples that had been analyzed on the same HPLC column. Analysis of 20 additional samples from 10 other patients at a different time demonstrated diglyceride, triglyceride, and wax and cholesterol FA patterns that were almost identical to those of the first patient group.



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  		Figure 1. Influence of antiandrogen treatment on the diglyceride mass spectrum of meibomian gland secretions. Secretions were obtained from the left and right eyes of patients taking antiandrogen medications (yellow, n = 8 samples from four individuals) and age-related controls (blue, n = 10 samples from five individuals). Top, The m/z ratio is on the x-axis, and the significant difference in the percentage of total FA fragmentation products is on the y-axis. Positive and negative peaks represent where (and to what extent) the patient or control group is larger, respectively. The negative values are for demonstration purposes. The asterisks denote FA products that were consistently evident in one group of samples and absent in the other. Bottom, The small inset graphs show the patterns of individual samples for a given m/z. Analysis of 20 additional samples from 10 other patients demonstrated a FA profile similar to the patient group of this figure.

 


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  		Figure 2. Effect of antiandrogen therapy on the triglyceride mass spectrum of meibomian gland secretions. Samples were collected, evaluated, and compared, as described in the legend to Fig. 1Go. Analysis of 20 additional samples from 10 other patients showed a FA pattern analogous to the patient group of this figure.

 


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  		Figure 3. Impact of antiandrogen treatment on the wax and cholesterol ester mass spectrum of meibomian gland secretions. Secretions were obtained, analyzed, and compared, as described in the legend to Fig. 1Go. Analysis of 20 additional samples from 10 other patients demonstrated a profile similar to the patient group of this figure.

 
Statistical analysis of the data demonstrated high correlation coefficients within patient and control groups (Fig. 4Go and Table 1Go). Two exceptions to this finding, however, were noted. First, an individual who had been recruited as a control was identified as having hypercholesterolemia. His neutral lipid FA mass spectra were very different than that of other control subjects (e.g. diglyceride FA product correlation coefficient, 0.2515). In addition, the lipid pattern of one patient did not correlate well (e.g. diglyceride correlation coefficient, 0.4945) with that of other patients. This individual had been taking antiandrogen medication for only 3 months, compared with a median treatment interval of 3 yr for the other patients. The data presented in the figures and tables do not include the results from the hypercholesterolemic subject, or from the patient taking antiandrogen treatment for 3 months. There were no consistent, significant trends evident between ACC and subject age or ACC and treatment time, across lipid families.



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  		Figure 4. Correlations within and between the diglyceride FA mass spectra of meibomian gland secretions from patients taking antiandrogen therapy and controls. Samples from patients and controls were obtained and evaluated, as described in the legend to Table 1Go and Materials and Methods.

 

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  		Table 1. ACCs within and between column-matched control and patient mass spectra

 
Statistical evaluation of the data also showed consistently lower correlation coefficients between groups (Fig. 4Go and Table 1Go). This difference was particularly evident when comparing the ACC of diglycerides between patients and controls.

Cross-correlation analyses revealed characteristic shifts in FA patterns between patient and control groups (Fig. 5Go and Table 2Go). These shifts involved apparent changes in saturation or epoxidation, both in terms of elongation (from controls to patients, positive lag) and truncation (from controls to patients, negative lag), with peaks falling on integer multiples of m/z 14. Similar periodicities were evident in the cross-correlation of sample means including only those peaks below 2% of the total lipid fraction (i.e. characteristic shifts between patients and controls were present within the majority of peaks and were not due to large peak overlap).



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  		Figure 5. Saturation/epoxidation shifts in the cross-correlation of diglyceride FA m/z sample means from patients taking antiandrogen therapy and controls. Meibomian gland secretions from patients and controls were collected and analyzed, as described in the legend to Table 2Go and Materials and Methods. Cross-correlations were applied to a subset of peaks comprised of all m/z less than 2% of the total lipid fraction.

 

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  		Table 2. Trends in cross-correlation of sample control mean vs. sample patient mean

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The present study demonstrates that antiandrogen therapy is associated with significant and consistent alterations in the mass spectra of neutral lipid fractions of meibomian gland secretions. Patients taking antiandrogen medications had significant alterations in the occurrence of numerous diglyceride, triglyceride, and wax/cholesterol ester FA products, compared with the patterns of age-related controls. Statistical analyses of data within groups demonstrated very high correlation coefficients, and cross-correlation analyses revealed characteristic shifts in FA patterns between groups. Overall, these findings support our hypothesis that androgen deficiency, such as caused by antiandrogen treatment, leads to altered lipid profiles in meibomian gland secretions.

The mechanism(s) underlying the influence of antiandrogen therapy on human meibomian gland lipids may well be due to a reduction in the androgen control of gene expression, protein elaboration, and ultimately lipid formation in this tissue. This hypothesis is supported by several observations. First, androgens seem to modulate both mRNA species and neutral lipid components in the rabbit meibomian gland (5, 9). Second, androgens are known to regulate multiple lipid metabolic pathways. This hormone action includes control of genes involved in FA synthesis, as well as modulation of the activity of lipogenic enzymes, the incorporation of FAs into neutral lipids, and the level of neutral lipids (10, 11, 12, 13, 14, 15). Third, the meibomian gland is a large sebaceous gland, and androgens have been shown to regulate gene activity, protein synthesis, and lipid production in these glands (16, 17). Conversely, antiandrogen exposure and/or androgen insufficiency causes a significant decrease in sebaceous gland function and lipid output (16, 18). However, whether antiandrogen treatment elicits a similar sequence of events in the human meibomian gland remains to be determined.

A truly remarkable finding in this study was that many of the lipid changes in meibomian gland secretions seemed to be "all" or "none" and that the majority of samples showed the same group-related FA pattern. Indeed, the ACC of the diglyceride FA products were such that they permitted "blind" categorization of people. Thus, if given a sample mean representative of a patient on antiandrogen therapy (for >3 months) or a control, the correlation coefficient would be able to place an individual into one of the two groups without knowing their a priori designation. This high correlation within, and the difference between, the patient and control groups were also underscored by the crosscorrelation analysis. Cross-correlation curves demonstrate how two groups differ from each other in a mean-square sense, and the strong harmonics evident in the power spectral density of the patient vs. control curves provides a unique description as to how sample mean behavior was altered between these groups. Of particular importance, ergodicity in sample mean behavior implies that it might be possible to create a standard curve for normal lipids, which could then be used clinically to diagnose lipid disorders within meibomian gland secretions.

The effect of antiandrogen treatment on the lipid profile of meibomian gland secretions may contribute to the tear film instability and dry eye symptoms observed in patients taking these medications (see Footnote 1). Tear film stability, as well as the maintenance of ocular surface integrity and the preservation of visual acuity, are critically dependent on the release of an optimal mixture of lipids by the meibomian gland (6, 7, 8, 19). A significant alteration in the quality of these lipids, such as induced by antiandrogen therapy, may promote tear film evaporation and consequent dry eye. If so, this finding may help to explain the etiology of the evaporative dry eye observed in other androgen-deficient states (20, 21, 22, 23), such as menopause, aging, Sjögren’s syndrome, and complete androgen insensitivity syndrome (24, 25, 26, 27, 28, 29, 30).


   Acknowledgments
 
We express our appreciation to Barbara Butler, R.N.; Nancy Moran, R.N.; and Jerome P. Richie, M.D. (Boston, MA); Barbara Evans (Waltham, MA); and M. David Ullman, Ph.D. (Bedford, MA) for their help in the performance of this research.


   Footnotes
 
1 Supported by grants from Allergan, Inc. and the National Institutes of Health (EY05612). Back

2 Krenzer, K. L., M. R. Dana, M. D. Ullman, J. M. Cermak, D. B. Tolls, J. E. Evans, and D. A. Sullivan, submitted for publication. Back

Received May 26, 2000.

Revised August 2, 2000.

Accepted September 6, 2000.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Sullivan DA, Wickham LA, Rocha EM, et al. 1999 Androgen and dry eye in Sjögren’s syndrome. Ann NY Acad Sci. 876:312–324.[CrossRef][Medline]
  2. Wickham LA, Gao J, Toda I, Rocha EM, Ono M, Sullivan DA. 2000 Identification of androgen, estrogen and progesterone receptor mRNAs in the eye. Acta Ophthalmol Scand. 78:146–153.[CrossRef][Medline]
  3. Rocha EM, Wickham LA, Silveira LA, et al. 2000 Identification of androgen receptor protein and 5{alpha}-reductase mRNA in human ocular tissues. Br J Ophthalmol. 84:76–84.[Abstract/Free Full Text]
  4. Zeligs MA, Gordon K. 1994 Dehydroepiandrosterone therapy for the treatment of dry eye disorders. Int Patent Application WO 94/04155.
  5. Sullivan DA, Sullivan BD, Ullman MD, et al. 2000 Androgen influence on the meibomian gland. Invest Ophthalmol Vis Sci. In press.
  6. Tiffany JM. 1995 Physiological functions of the meibomian glands. Prog Retinal Eye Res. 14:47–74.
  7. McCulley JP, Shine W. 1997 A compositional based model for the tear film lipid layer. Trans Am Ophthalmol Soc. 95:79–88.[Medline]
  8. Craig JP, Tomlinson A. 1997 Importance of the lipid layer in human tear film stability and evaporation. Optom Vis Sci. 74:8–13.[CrossRef][Medline]
  9. Steagall RJ, Cermak JM, Wickham LA, Sullivan BD, Sullivan DA. 1999 Androgen control of gene expression in the rabbit meibomian gland. Invest Ophthalmol Vis Sci. 40:S537.
  10. Cinci G, Pagani R, Pandolfi ML, Porcelli B, Pizzichini M, Marinello E. 1993 Effects of testosterone on cholesterol levels and fatty acid composition in the rat. Life Sci. 53:91–97.[CrossRef][Medline]
  11. Marra CA, de Alaniz MJ. 1995 Regulatory effect of various steroid hormones on the incorporation and metabolism of [14C]stearate in rat hepatoma cells in culture. Mol Cell Biochem. 145:1–9.[CrossRef][Medline]
  12. Swinnen JV, van Veldhoven PP, Esquenet M, Heyns W, Verhoeven G. 1996 Androgens markedly stimulate the accumulation of neutral lipids in the human prostatic adenocarcinoma cell line LNCaP. Endocrinology. 137:4468–4474.[Abstract]
  13. Ojeda MS, Gomez N, Gimenez MS. 1997 Androgen regulation of lung lipids in the male rat. Lipids. 32:57–62.[Medline]
  14. Swinnen JV, Ulrix W, Heyns W, Verhoeven G. 1997 Coordinate regulation of lipogenic gene expression by androgens: evidence for a cascade mechanism involving sterol regulatory element binding proteins. Proc Natl Acad Sci USA. 94:12975–12980.[Abstract/Free Full Text]
  15. Swinnen JV, Verhoeven G. 1998 Androgens and the control of lipid metabolism in human prostate cancer cells. J Steroid Biochem Mol Biol. 65:191–198.[CrossRef][Medline]
  16. Thody AJ, Shuster S. 1989 Control and function of sebaceous glands. Physiol Rev. 69:383–416.[Abstract/Free Full Text]
  17. Miyake K, Ciletti N, Liao S, Rosenfield RL. 1994 Androgen receptor expression in the preputial gland and its sebocytes. J Invest Dermatol. 103:721–725.[CrossRef][Medline]
  18. Chen C, Puy LA, Simard J, Li X, Singh SM, Labrie F. 1995 Local and systemic reduction by topical finasteride or flutamide of hamster flank organ size and enzyme activity. J Invest Dermatol. 105:678–682.[CrossRef][Medline]
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  20. Labrie F, Belanger A, Cusan L, Gomez JL, Candas B. 1997 Marked decline in serum concentrations of adrenal C19 sex steroid precursors and conjugated androgen metabolites during aging. J Clin Endocrinol Metab. 82:2396–2402.[Abstract/Free Full Text]
  21. Sullivan DA, Bélanger A, Cermak JM, et al. 2000 Are women with Sjögren’s syndrome androgen deficient? Invest Ophthalmol Vis Sci Suppl. 41:S276.
  22. Sullivan DA. 1997 Sex hormones and Sjögren’s syndrome. J Rheumatol. 24(Suppl 50):17–32.
  23. Zhu YS, Cai LQ, Cordero JJ, Canovatchel WJ, Katz MD, Imperato-McGinley J. 1999 A novel mutation in the CAG triplet region of exon 1 of androgen receptor gene causes complete androgen insensitivity syndrome in a large kindred. J Clin Endocrinol Metab. 84:1590–1594.[Abstract/Free Full Text]
  24. Nabata H, Horiuchi H, Miyata K, Tsuru T, Machinami R. 1994 Histopathological study of the human meibomian glands. Invest Ophthalmol Vis Sci Suppl. 35:1789.
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  26. Schaumberg DA, Buring JE, Sullivan DA, Dana MR. Prevalence of dry eye syndrome in U.S. men and women, and its relationship with hormone replacement therapy in women. Proc of the 21st Biennial Cornea Conference, 1999.
  27. Shimazaki J, Goto E, Ono M, Shimmura S, Tsubota K. 1998 Meibomian gland dysfunction in patients with Sjögren’s syndrome. Ophthalmology. 105:1485–1488.[CrossRef][Medline]
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  30. Cermak JM, Krenzer KL, Dana MR, Sullivan DA. 1999 Do individuals with complete androgen insensitivity display the signs and symptoms of dry eye? Invest Ophthalmol Vis Sci. 40:S543.



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