(20-09-2014, 02:49 PM)lovely11 Wrote: Pubmed reviews:
http://erc.endocrinology-journals.org/content/6/2/315.long 'Aromatase and gynecomastia'
http://www.princehenrys.org/files/media/2010_Czajka-Oraniec-Endokrynologia-Polska.pdf 'Aromatase research and its clinical significance'
Great find, from the second link you listed I found this related study which is extremely interesting. (Note the family in the study). A healthy approach to express CYP19A1 gene exists, finding it can unlock a huge potential, I have my own theory though lol.
Molecular Bases and Phenotypic Determinants of Aromatase Excess Syndrome
http://www.hindawi.com/journals/ije/2012/584807/
Implication for the Hypothalamus-Pituitary-Gonadal Axis Function
It is notable that a similar degree of FSH-dominant hypogonadotropic hypogonadism is observed in the three types, although E1 and E2 values and E2/T ratios are much higher in the inversion type than in the duplication and deletion types (Table 1). In particular, FSH was severely suppressed even after GnRH priming in the duplication type [4]. This implies that a relatively mild excess of circulatory estrogens can exert a strong negative feedback effect on FSH secretion primarily at the pituitary. This would be consistent with the results of animal studies that show strong inhibitory effect of E2 on transcription of FSH beta-subunit gene in the pituitary cells and almost negligible effect on synthesis of LH beta-subunit and secretion of LH [18, 19]. In this regard, while T responses to hCG stimulation are normal in the duplication and the deletion types and somewhat low in the inversion type, this would be consistent with fairly preserved LH secretion in the three types and markedly increased estrogen values in the inversion type. In addition, whereas fertility and spermatogenesis are normally preserved in the three types, this would be explained by the FSH-dominant hypogonadotropic hypogonadism, because FSH plays only a minor role in male fertility (spermatogenesis) [20].
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Binder et al. studied a family with seven men in three generations affected with gynecomastia that was in- herited in an autosomal dominant pattern [67]. Their testosterone levels were decreased while oestrone and oestradiol were in the high normal range. A strong association of the TTTA repeat polymorphism in the
CYP19A1 gene was observed. In a similar family, the same molecular marker associated with the phenotype was reported by Stratakis et al. [64]. Increased aromatase activity in fibroblasts and strong immunostaining for aromatase in breast tissue samples from family members with gynecomastia were shown. A new promoter was revealed in the non-coding region of the CYP19A1 gene. Its activation could possibly lead to the increased aromatase gene expression.
Other alterations in the promoter region of CYP19A1 were described by Shozu et al. [65]. In three men with severe gynecomastia of prepubertal onset and hypo- gonadotrophic hypogonadism resulting from severe oestrogen excess, two novel gain-of function mutations led to the overexpression of aromatase in many tissues. Heterozygous inversions in the 15q21.2–3 region caused the constitutively active cryptic promoters that normally serve to transcribe two ubiquitously expressed genes — FLJ or TMOD3 — to lie adjacent to the aromatase coding region. Similar regional rearrangements resulting in the formation of cryptic promoters for aromatase gene and its overexpression were described recently by Demura et al. [68].
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When ovarian estrogen synthesis ceases at the menopause, estrogens continue to be synthesized in different tissue compartments from circulating androgens. The key pathway is aromatization of androstenedione into estrone, probably accounting for as much as 90% of the total estrogens synthesized in a postmenopausal woman (Fig. 1). Aromatase, also called estrogen synthetase, is a cytochrome P450-dependent enzyme symbolized as CYP19A1 and catalyzes three consecutive hydroxylation reactions converting C19 androgens to aromatic C18 estrogens. The aromatase enzyme may also use testosterone as a substrate to convert testosterone into estradiol (Fig. 1); however, since the circulating testosterone levels are lower than those of androstenedione, and aromatase has lower activity on testosterone than androstenedione, the contribution of this pathway to estrogen synthesis is only modest. Upon receiving electrons from NADPH-cytochrome P450 reductase, aromatase converts androstenedione and testosterone to estrone and estradiol, respectively (Fig. 1).
CHAPTER 10. The Breast
http://www.sciencedirect.com/science/article/pii/B9781416049074000103
CHAPTER 3. Prolactin in Human Reproduction
http://www.sciencedirect.com/science/article/pii/B9781416049074000036
Pharmacogenetics of anti-estrogen treatment of breast cancer
http://www.sciencedirect.com/science/article/pii/S0305737211001782#f0005
584807.fig.001
Figure 1: Simplified schematic representation indicating the genomic structure of CYP19A1. CYP19A1 is located on 15q21.2 adjacent to DMXL2 and GLDN and consists of at least 11 noncoding exons 1 and nine coding exons 2–10 [9, 10]. Each exon 1 is accompanied by a tissue-specific promoter and is spliced alternatively onto a common splice acceptor site at exon 2 [9–13].
http://www.hindawi.com/journals/ije/2012/584807/