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Immunohistochemical Localization of Gonadotropin and Gonadal Steroid Receptors in Human Pineal Glands—Author’s Response^e

Haemek Medical Center Afula, Israel Peretz Lavie Technion, Israel Institute of Technology Haifa, Israel

We appreciate the comments (in the Letter to the Editor) of Dr. Rao about our recent study (1). In this study, we used immunohistochemistry and demonstrated the presence of gonadal steroid (AR, ER) and go-nadotropin (LH-R, FSH-R) receptors in human pineal glands obtained at autopsy in prepubertal children and adult males (1). We do not dispute the comments by Dr. Rao, although we believe that the design of the study is correct and does not invalidate the results for a number of reasons. Because immunolocalization of receptor proteins does not directly imply that the entire receptor is present or functioning (2), the implications of our findings are merely speculative. This idea was cautiously mentioned in the conclusion of our manuscript (1). We used the term Positivity Index (PI) to describe the percentage of positively stained cells rather than receptor density. Because this method is a semiquantitative evaluation of positivily stained cells, it may result in a slight underestimation of the number of receptors (ligand free and bound) present in the tissue (3). Although circulating levels of androgens, estrogens, and gonadotropins are very low in prepubertal children, we observed a very high percentage of positively stained cells in two children, and in the other three children the PI’s were similar to the values observed in adults. Since the pineal gland in humans and mammals does not contain gonadal steroids or gonadotropins (4, 5), this may suggest that the receptors were ligand free and were associated in a complex with HSP 90 in the cytoplasm (6). In addition, our findings are further supported by the nuclear location of FSH-R and by the observation that positive staining for gonadal steroid and gonadotropin receptors was absent in brain tissue adjacent to the pineal gland. The findings of a significant day/night difference in FSH-R PI’s (LH-R and AR also demonstrated higher levels at night, albeit statistically not significant) in the present study (1) and the novel demonstration of significant seasonal variation in gonadotropin receptors in human pineal glands (7) strongly suggest that gonadal steroid hormones and gonadotropin receptors are present in human pinealocytes. This is further supported by the fact that circulating gonadotropin and gonadal steroid hormones do not exhibit an annual or daily cycle (8).

Our recent findings support the idea that in humans gonadal steroid hormones and gonadotropin receptors are present in the pinealocytes from infancy to old age. Gonadotropin receptors exhibited seasonal variation with higher values in the winter. Further studies are needed to more directly test the hypothesis that the presence of these receptors and their ligands is crucial in pineal melatonin secretion.

Footnotes

^e Received May 13, 1997. Address correspondence to: Dr. R. Luboshitzky, Endocrine Institute, Haemek Medical Center, Afula, 18101, Israel.

References

1. Luboshitzky R, Dharan M, Goldman D, Hiss Y, Herer P, Lavie P. 1997 Immunohistochemical localization of gonadotropin and gonadal steroid receptors in human pineal glands. J Clin Endocrinol Metab. 82:977–981.[Abstract/Free Full Text]
2. MacLusky NJ. Sex steroid receptors. 1995 In: Adashi EY, Rock JA, Rosenwaks Z, eds. Reproductive endocrinology, surgery, and technology. Philadelphia: Lippincott-Raven; pp 627–663.
3. Murdoch FE, Gorski J. 1991. The role of ligand in estrogen receptor regulation of gene expression. Mol Cell Endocrinol. 78:C103–C108.
4. Arendt J. 1995 Biochemistry of the pineal. In: Arendt J, ed. Melatonin and the mammalian pineal gland. London: Chapman & Hall; pp 46–49.
5. Erlich SS, Apuzzo MLJ. 1985 The pineal gland: anatomy, physiology, and clinical significance. J Neurosurg. 63:321–341.[Medline]
6. Koshigama M, Konishi I, Nanbu K, et al. 1995 Immunohistochemical localization of heat shock proteins HSP 70 and HSP 90 in the human endometrium: correlation with sex steroid receptors and Ki-67 antigen expression. J Clin Endocrinol Metab. 80:1106–1112.[Abstract]
7. Luboshitzky R, Dharan M, Goldman D, Herer P, Hiss Y, Lavie P. Seasonal variation of gonadotropins and gonadal steroids receptors in the human pineal gland. Brain Res Bull. In press.
8. Turek FW, Van Cauter E. 1994 Rhythms in reproduction. In: Knobil E, Neil JD, eds. The physiology of reproduction. 2nd ed. New York: Raven Press; pp 487–540.

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