Influence of gender and the endocrine environment on the distribution of androgen receptors in the lacrimal gland

doi:10.1016/0960-0760(93)90314-M

The Journal of Steroid Biochemistry and Molecular Biology

Volume 46, Issue 6, December 1993, Pages 737-749

https://doi.org/10.1016/0960-0760(93)90314-M Get rights and content

Abstract

Androgens are known to regulate both the structure and function of lacrimal tissue in a variety of species. To explore the endocrine basis for this hormone action, the following study was designed to: (1) determine the cellular distribution of androgen receptors in the lacrimal gland; and (2) examine the influence of gender and the endocrine environment on the glandular content of these binding sites. Lacrimal glands were obtained from intact, castrated, hypophysectomized, diabetic or sham-operated male or female adult rats, mice or hamsters, as well as from orchiectomized rats exposed to placebo compounds or physiological levels of testosterone. The cellular of androgen receptors was evaluated by utilizing an immunoperoxidase protocol, in which a purified rabbit polyclonal antibody to the rat androgen receptor was used as the first antibody. Our findings with lacrimal glands showed that: (1) androgen receptors are located almost exclusively in nuclei of epithelial cells; (2) the cellular distribution or intranuclear density of these binding sites is far more extensive in glands of males, as compared to females; (3) orchiectomy or hypophysectomy, but not sham-surgery or diabetes, lead to a dramatic reduction in the immunocytochemical expression of androgen receptors; and (4) testosterone administration to orchiectomized rats induces a marked increase in androgen receptor content, relative to that in placebo-exposed glands. Our results also reveal that a 10 kb androgen receptor mRNA exists in the rat lacrimal gland. Overall, these findings demonstrate that gender and the endocrine system may significantly influence the distribution of androgen binding sites in rat lacrimal tissue. Moreover, our results show that androgens up-regulate their own lacrimal gland receptors.

References (33)

D.A. Sullivan et al.
Potential therapeutic approach for the hormonal treatment of lacrimal gland dysfunction in Sjögren's syndrome
Clin. Immun. Immunopath.
(1992)
D.A. Sullivan
Influence of the hypothalamic-pituitary axis on the androgen regulation of the ocular secretory immune system
J. Steroid Biochem.
(1988)
D.A. Sullivan et al.
Hormonal influence on the secretory immune system of the eye: endocrine impact on the lacrimal gland accumulation and secretion of IgA and IgG
J. Steroid Biochem.
(1989)
P. Chomczynski et al.
Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction
Analyt. Biochem.
(1987)
J.A. Simental et al.
Transcriptional activation and nuclear targeting signals of the human androgen receptor
J. Biol. Chem.
(1991)
J.A. Kemppainen et al.
Androgen receptor phosphorylation, turnover, nuclear transport and transcriptional activation
J. Biol. Chem.
(1992)
G. de Pergola et al.
Up-regulation of androgen receptor binding in male rat fat pad adipose precursor cells exposed to testosterone: study in a whole cell assay system
J. Steroid. Biochem. Molec. Biol.
(1990)
H. Takeda et al.
Autoregulation of androgen receptor expression in rodent prostate
Biochem. Biophys. Res. Commun.
(1991)
A. Krongrad et al.
Androgen increases androgen receptor protein while decreasing receptor mRNA in LNCaP cells
Molec. Cell. Endocr.
(1991)
J. Trapman et al.
The androgen receptor: functional structure and expression in transplanted human prostate tumors and prostate tumor cell lines
J. Steroid. Biochem. Molec. Biol.
(1990)

S. Ho

Prostatic androgen receptor and plasma testosterone levels in streptozotocin-induced diabetic rats

J. Steroid. Biochem. Molec. Biol.

(1991)

L.J. Blok et al.

Regulation of androgen receptor mRNA and protein in the rat testis by testosterone

J. Steroid Biochem. Molec. Biol.

(1991)

L. Danel et al.

Distribution of androgen and estrogen receptors among lymphoid and haemopoietic cell lines

Leukemia Res.

(1985)

D.A. Sullivan

Hormonal influence on the secretory immune system of the eye

D.A. Sullivan et al.

Immunology of the lacrimal gland

Cited by (56)

Sexual dimorphism of the extraorbital lacrimal glands in SF-1 knockout mice
2021, Acta Histochemica
Citation Excerpt :
This confirms that androgens can induce and up-regulate their receptors as it has been reported before for other tissues. Thus, it seems testosterone has a considerable role in the ocular tissue, although the exact function of this hormone, acting through AR, is not yet understood (Rocha et al., 1993, 1994). As ARs were absent in the cells from mice without testosterone supplementation, it is plausible to speculate that perhaps extended treatment with testosterone would be needed to induce morphological changes in LG, as a certain period after the beginning of the treatment is needed only for the induction of AR expression.
Sexual dimorphism (SD) represents all the differences between males and females of the same species. SD of the murine lacrimal gland and the major effect of testosterone on its formation are well documented. Steroidogenic factor-1 (SF-1, NR5a1) is a nuclear receptor essential for the fetal development of steroid hormones producing organs and SF-1 knockout mice (Sf-1 KO) are therefore born without gonads and adrenal glands. The aim of this study was to investigate whether SD in lacrimal glands is present in the absence of exposure to sex hormones during development. Lacrimal glands from adult Sf-1 KO male and female mice without hormonal exposure, and from males that were treated with testosterone propionate (TP) prior to sacrifice, were examined. After sacrifice, glandular tissue was processed using standard histological procedures. Paraffin sections were analysed by stereology and immunostained against the androgen receptor (AR). Our results showed that there were no statistically significant differences in the mean volumes of acini, connective tissue or ductal system between males, females, and males on TP. The same pertains to the mean length of the ducts in all three groups. In the absence of sex hormones, sex chromosomes proved to be insufficient in inducing sexual dimorphism in LG. However, nuclei of the acinar cells in males on TP were positive for AR, whereas in males without TP no expression of AR was detected. Administration of TP induced the expression of AR in the nuclei of acinar cells of males but did not affect the morphology of LG. We conclude that SD in the lacrimal gland is not present in Sf-1 KO mice and this suggests that sex hormones have a major role in the development of SD in the lacrimal gland.
A Randomized Controlled Double-Masked Study of Transdermal Androgen in Dry Eye Patients Associated With Androgen Deficiency
2019, American Journal of Ophthalmology
Citation Excerpt :
Among studies of androgen treatment for dry eye, animal studies have shown that testosterone treatment of castrated rats likewise stimulated the lacrimal secretory immune system.18 The administration of testosterone to castrated rats restored the number of androgen receptors to the intact male rats, suggesting that androgens autoregulate their own binding sites.21 In humans, Bizzarro and associates showed a therapeutic effect of oral testosterone supplement on autoimmune diseases in 5 patients with hypogonadism and Klinefelter syndrome (3 of whom had Sjögren syndrome and 2 of whom had systemic lupus erythematosus).
To evaluate the efficacy, safety, and quality of life (QOL) of transdermal androgen in treatment of dry eye patients associated with androgen deficiency.
Randomized controlled trial.
Fifty patients with dry eye from a tertiary eye center in northern Thailand were randomized to receive transdermal androgen (AndroGel; Besins Healthcare, Brussels, Belgium) or placebo for 4 weeks. Main outcome measures were symptoms and signs of dry eye. Serum level of sex hormone and QOL questionnaires were also evaluated at the baseline and after treatment.
After 4 weeks, the Ocular Surface Disease Index decreased significantly in the AndroGel group compared to the placebo (−14.36 ± 7.76 vs 0.14 ± 14.60, P < .001). Significant improvements of tear break-up time (7.40 ± 3.37 vs −1.14 ± 1.68 seconds, P < .001), corneal fluorescein staining (−0.62 ± 0.30 vs 0.19 ± 0.37, P < .001), and Schirmer test (6.84 ± 5.10 vs −0.48 ± 2.14 mm, P < .001) were observed in the AndroGel group compared to the placebo. Serum testosterone in female patients significantly increased in the AndroGel group compared to the placebo (P < .001), while no different change was observed in serum testosterone in male subjects and the sex hormone-binding globulin in both groups. In the AndroGel group, 20% of patients had oily skin and 4% had acne. No serious adverse effects were reported. The menopause rating score improved significantly in the AndroGel group compared to the placebo (P < .001), while the aging male symptoms were not different in both groups (P = .589).
Transdermal androgen was effective in relieving symptoms and signs of dry eye as well as improving QOL in aging patients. There were no serious side effects during a short-term treatment.
TFOS DEWS II Sex, Gender, and Hormones Report
2017, Ocular Surface
Citation Excerpt :
In support of this mechanism of action are the observations that: (a) androgen receptor mRNA is expressed in lacrimal glands of mice, rats, hamsters, guinea pigs, rabbits and humans [352,389,414,425,426]; (b) androgen receptor protein is present predominantly within epithelial cell nuclei of lacrimal tissues of mice, rats, hamsters and humans [97,372,385,389,427,428]; (c) lacrimal glands feature a single class of saturable, high-affinity and steroid-specific androgen binding sites, which have a dissociation constant and stereochemical selectivity similar to those found in many cells and tissues throughout the body [425,429]; (d) androgen-androgen receptor complexes in lacrimal tissue associate with DNA [429]; (e) androgen effects in lacrimal glands or in isolated acinar epithelial cells may be curbed by antagonists of, or mutations within, androgen receptors, as well as by inhibitors of transcription and translation [88,102,199,367,414]; (f) androgens, as noted above, exert a significant influence on gene expression and protein synthesis in lacrimal glands [11,13,74,77,79,86–88,91,97,100,102,104,105,352,353,359,363,364,366,371–373,378,381–383,386,388,389]. Androgens also modulate the expression of their own androgen receptors in the lacrimal gland by increasing the content of androgen receptor protein and decreasing the level of androgen receptor mRNA [97,372,389,430]. This form of autoregulation also occurs in other, but not all, androgen target organs [431–435].
One of the most compelling features of dry eye disease (DED) is that it occurs more frequently in women than men. In fact, the female sex is a significant risk factor for the development of DED. This sex-related difference in DED prevalence is attributed in large part to the effects of sex steroids (e.g. androgens, estrogens), hypothalamic-pituitary hormones, glucocorticoids, insulin, insulin-like growth factor 1 and thyroid hormones, as well as to the sex chromosome complement, sex-specific autosomal factors and epigenetics (e.g. microRNAs).
In addition to sex, gender also appears to be a risk factor for DED. “Gender” and “sex” are words that are often used interchangeably, but they have distinct meanings. “Gender” refers to a person’s self-representation as a man or woman, whereas “sex” distinguishes males and females based on their biological characteristics. Both gender and sex affect DED risk, presentation of the disease, immune responses, pain, care-seeking behaviors, service utilization, and myriad other facets of eye health.
Overall, sex, gender and hormones play a major role in the regulation of ocular surface and adnexal tissues, and in the difference in DED prevalence between women and men. The purpose of this Subcommittee report is to review and critique the nature of this role, as well as to recommend areas for future research to advance our understanding of the interrelationships between sex, gender, hormones and DED.
Estrogen and androgen repression of two female specific lacrimal lipocalins in hamster: Pituitary independent and sex hormone receptor mediated action
2007, General and Comparative Endocrinology
Citation Excerpt :
Sex-hormonal induction of gene expression, in reproductive and also non-reproductive tissues, is well known and the molecular mechanism, mostly involving specific nuclear hormone receptors, is being studied in detail. Many inductive effects of androgen on gene expression in LG (a non-reproductive tissue) are well known to be direct effects on LG, mediated by AR in LG and AR-antagonists blocked such inductive effects of androgens (Rocha et al., 1993; Gao et al., 1995; Sullivan et al., 1998; Sullivan, 2004). Regarding estrogens, although their inductive effects on gene expression in many non-reproductive (and reproductive) tissues were known for quite some time, their effects on LG were not appreciated until a very recent micro-array analysis revealed numerous inductive effects of estrogens in mouse LG (Suzuki et al., 2006).
Sexual dimorphism in lacrimal gland (LG) gene expression is believed to be due to direct inductive effects of androgens mediated by androgen receptors (AR) but hypophysectomy dramatically curtails these inductive effects. Since, functional estrogen receptors (ER) could not be detected in LG, estrogen effects on LG are believed to be indirectly mediated by changes in levels of pituitary hormones. We found that two lipocalins expressed in female hamster LG display an unusual and marked repression by both androgens and estrogens, which could be detected both at the level of transcripts and proteins. Here, we investigate whether these repressions, (i) require presence of pituitary and (ii) are mediated by androgen and estrogen receptors. Pituitary-ablation but not gonadectomy reduced LG weights in hamster. However, both pituitary-ablation and gonadectomy induced abundant expression of the LG lipocalins, which were markedly repressed by androgen or estrogen treatment. AR- and ER-antagonists prevented these repressions and only ER-α- but not ER-β-specific agonist could mimic the estrogenic repression. AR transcript and protein and ER-α transcript were also detected in hamster LG. Thus, pituitary factors are neither essential for the expression of these LG lipocalins nor for their estrogenic or androgenic repressions and these repressions are very likely mediated by functional ER and AR present in LG.
Current status of gene delivery and gene therapy in lacrimal gland using viral vectors
2006, Advanced Drug Delivery Reviews
Gene delivery is one of the biggest challenges in the field of gene therapy. It involves the efficient transfer of transgenes into somatic cells for therapeutic purposes. A few major drawbacks in gene delivery include inefficient gene transfer and lack of sustained transgene expression. However, the classical method of using viral vectors for gene transfer has circumvented some of these issues. Several kinds of viruses, including retrovirus, adenovirus, adeno-associated virus, and herpes simplex virus, have been manipulated for use in gene transfer and gene therapy applications. The transfer of genetic material into lacrimal epithelial cells and tissues, both in vitro and in vivo, has been critical for the study of tear secretory mechanisms and autoimmunity of the lacrimal gland. These studies will help in the development of therapeutic interventions for autoimmune disorders such as Sjögren's syndrome and dry eye syndromes which are associated with lacrimal dysfunction. These studies are also critical for future endeavors which utilize the lacrimal gland as a reservoir for the production of therapeutic factors which can be released in tears, providing treatment for diseases of the cornea and posterior segment. This review will discuss the developments related to gene delivery and gene therapy in the lacrimal gland using several viral vector systems.
Marked sexual dimorphism of lacrimal gland peroxidase in hamster: Repression by androgens and estrogens
2006, Biochemical and Biophysical Research Communications
Citation Excerpt :
Immunocytochemical localization of androgen receptors in LG of both sexes of hamster, rat, mouse, rabbit, and human, and specific, high affinity binding sites for androgens in rat LG have been shown earlier [19,20]. However, whether or not estrogens have any direct effect on LG and presence of functional estrogen receptors in these glands is disputed [8,14–20] since no specific, high affinity binding sites for estrogen could be demonstrated when LG of rats were tested [8,19]. Moreover, although transcripts of estrogen receptor-α have been reported in LG of rat, rabbit, and human [35], no immunoreactive estrogen receptor protein has been yet reported in LG of any species.
Peroxidase secreted in tears by the lacrimal glands is a marker of secretory activity of these glands and is believed to have an antimicrobial function. We report for the first time a marked sex difference in lacrimal gland (LG) peroxidase in hamsters (∼3.4-fold higher activity in females), which is due to an unusual repression by physiological levels of androgens in males. LG peroxidase activity was markedly induced in a time-dependent manner after gonadectomy in males and also females (∼8- and 2-fold, respectively) and was strongly repressed by androgen treatment in a dose- and time-dependent manner. Estrogen treatment of gonadectomized hamsters could also repress LG peroxidase but not below female levels. These repressions by androgens and estrogens were significantly prevented upon co-treatment with their respective receptor antagonists. Western blotting showed that differences in LG peroxidase specific activity, in different sex hormonal states and treatments were due to changes in the levels of peroxidase protein in LG. A tear peroxidase with a clear sex difference suggests that it might also have other novel function(s) in hamster tears.

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Influence of gender and the endocrine environment on the distribution of androgen receptors in the lacrimal gland

Abstract

Clin. Immun. Immunopath.

J. Steroid Biochem.

J. Steroid Biochem.

Analyt. Biochem.

J. Biol. Chem.

J. Biol. Chem.

J. Steroid. Biochem. Molec. Biol.

Biochem. Biophys. Res. Commun.

Molec. Cell. Endocr.

J. Steroid. Biochem. Molec. Biol.

J. Steroid. Biochem. Molec. Biol.

J. Steroid Biochem. Molec. Biol.

Leukemia Res.

Hormonal influence on the secretory immune system of the eye

Immunology of the lacrimal gland