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====Impact of hormones==== Other studies suggest that [[hormones]] play also an important role in vocal fold maturation. Hormones are molecules secreted into the blood stream to be delivered at different targeted sites. They usually promote growth, differentiation and functionality in different organs or tissues. Their effect is due to their ability to bind to intracellular receptors, modulating the gene expression, and subsequently regulating protein synthesis.<ref name=Rios08>{{cite journal |vauthors=Rios OA, Duprat Ade C, Santos AR |title=Immunohistochemical searching for estrogen and progesterone receptors in women vocal fold epithelia |journal=Braz J Otorhinolaryngol |volume=74 |issue=4 |pages=487β93 |year=2008 |pmid=18852972 |doi=10.1016/S1808-8694(15)30593-0 |pmc=9442059 |doi-access=free }}</ref> The interaction between the endocrine system and tissues such as breast, brain, testicles, heart, bones, etc., is being extensively studied. It has clearly been seen that the larynx is somewhat affected by hormonal changes, but, very few studies are working on elucidating this relationship. The effect of hormonal changes in voice is clearly seen when hearing male and female voices, or when listening to a teenage voice changing during puberty. Actually, it is believed that the number of hormonal receptors in the pre-pubertal phase is higher than in any other age.<ref name=Rios08/> Menstruation has also been seen to influence the voice. In fact, singers are encouraged by their instructors not to perform during their pre-menstrual period, because of a drop in their voice quality.<ref name=Rios08/> Vocal fold phonatory functions are known to change from birth to old age. The most significant changes occur in development between birth and puberty, and in old age.<ref name="Hirano, M. 1981"/><ref name=Newman00>{{cite journal |vauthors=Newman SR, Butler J, Hammond EH, Gray SD |title=Preliminary report on hormone receptors in the human vocal fold |journal=J Voice |volume=14 |issue=1 |pages=72β81 |date=March 2000 |pmid=10764118 |doi=10.1016/s0892-1997(00)80096-x}}</ref> Hirano et al. previously described several structural changes associated with aging, in the vocal fold tissue.<ref>{{cite journal |vauthors=Hirano M, Kurita S, Sakaguchi S |title=Ageing of the vibratory tissue of human vocal folds |journal=Acta Otolaryngol. |volume=107 |issue=5β6 |pages=428β33 |year=1989 |pmid=2756834 |doi=10.3109/00016488909127535}}</ref> Some of those changes are: a shortening of the membranous vocal fold in males, a thickening of the vocal fold mucosa and cover in females, and a development of edema in the superficial lamina propria layer in both sexes. Hammond et al. observed that the hyaluronic acid content in the vocal fold lamina propria was significantly higher in males than in females.<ref name=Hammond97/> Although all those studies did show that there are clear structural and functional changes seen in the human vocal cords which are associated with gender and age, none really fully elucidated the underlying cause of those changes. In fact, only a few recent studies started to look at the presence and role of hormone receptors in the vocal cords. Newman et al. found that hormone receptors are indeed present in the vocal cords, and show a statistical distribution difference with respect to age and gender.<ref name=Newman00/> They have identified the presence of [[androgen]], [[estrogen]], and [[progesterone]] receptors in [[epithelial cell]]s, [[granular cell]]s and [[fibroblast]]s of the vocal cords, suggesting that some of the structural changes seen in the vocal cords could be due to hormonal influences.<ref name=Newman00/> In this specific study, androgen and progesterone receptors were found more commonly in males than in females. In others studies, it has been suggested that the estrogen/androgen ratio be partly responsible for the voice changes observed at menopause.<ref>{{cite journal |last=Nelson |first=J.F. |title=The potential role of selected endocrine systems in aging processes |year=1995 |journal=Comprehensive Physiology |pages=377β394 |publisher=Wiley Online Library |url=http://www.comprehensivephysiology.com/WileyCDA/CompPhysArticle/refId-cp110115.html |doi=10.1002/cphy.cp110115 |url-status=live |archive-url=https://web.archive.org/web/20140809215612/http://www.comprehensivephysiology.com/WileyCDA/CompPhysArticle/refId-cp110115.html |archive-date=2014-08-09 |isbn=9780470650714 }}</ref> As previously said, Hammond et al. showed than the hyaluronic acid content was higher in male than in female vocal cords. Bentley et al. demonstrated that sex skin swelling seen in monkey was due to an increase in hyaluronic acid content, which was in fact mediated by estrogen receptors in dermal fibroblasts.<ref>{{cite journal |vauthors=Bentley JP, Brenner RM, Linstedt AD, etal |title=Increased hyaluronate and collagen biosynthesis and fibroblast estrogen receptors in macaque sex skin |journal=J. Invest. Dermatol. |volume=87 |issue=5 |pages=668β73 |date=November 1986 |pmid=3772161 |doi=10.1111/1523-1747.ep12456427|doi-access= }}</ref> An increase in collagen biosynthesis mediated by the estrogen receptors of dermal fibroblasts was also observed. A connection between hormone levels, and [[extracellular matrix]] distribution in the vocal cords depending on age and gender could be made. More particularly a connection between higher hormone levels and higher hyaluronic acid content in males could exist in the human vocal fold tissue. Although a relationship between hormone levels and extracellular matrix biosynthesis in vocal fold can be established, the details of this relationship, and the mechanisms of the influence has not been elucidated yet.
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