How is estrogen and androgen synthesis controlled

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The hormones, though, are more plentiful and play a larger role in females than in males. The hormones, though, are more plentiful and play a larger role in females than in males. In women, estrogen levels vary through life, surging at adolescence, seesawing monthly in the reproductive years, and waning to low levels during menopause.

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Estrogens are a group of chemically similar steroid hormones. Steroids are a special kind of fat molecule with a four-ringed, carbon atom backbone, or core, like their cholesterol predecessor. A series of chemical reactions, spurred by proteins called enzymes, remove and add groups to cholesterol's core. These actions transform it first into the steroid pregnenolone and then into androgens. Special aromatase enzymes convert androgens into the estrogens estradiol and estrone.

In humans and other vertebrates, estrogens are made primarily in the female ovaries and in small amounts in the male testes and the adrenal glands, brain, and fat of both sexes. Estrone and estriol are other types. Estrogen-like chemicals play a poorly understood role in the reproductive cycle of some invertebrates, including mollusks and corals Di Cosmo et al.

Birth control, hormone replacement therapies HRT , cancer drugs, and other pharmaceuticals contain synthetic estrogens. Some, like ethinyl estradiol, are used alone or combined with artificial progesterone-like hormones in birth control. In HRT, natural and synthetic estrogens with or without artificial progesterone control menopause symptoms such as hot flashes, skin and vaginal dryness, and bone loss.

However, higher risks of breast cancer, heart attack, blood clots, and other serious threats temper the benefits Women's Health Initiative Steering Committee ; Writing Group for the Women's Health Initiative Investigators Women can tailor treatments by weighing known risks and benefits. Like all steroid hormones, estrogens produce effects by docking with receptors on the cell's membrane surface or inside the cell in the liquid cytoplasm. This suggests that the up-regulated genes between MENT and LH are mostly overlapping while the down-regulated genes are very different.

Red indicates up-regulated genes; green indicates down-regulated genes. Solid arrow indicates androgen synthesis pathway; Dash arrow indicates steroid metabolism; Double arrows indicates transport of cholesterol. These results indicate that both LH and MENT cause cell cycle arrest by inducing similar cell cycle arrest regulators.

When we examined the transcription pathway, we found that MENT and LH regulated quite different sets of transcription factors.

We divided the patterns of gene expression in four categories. This suggests that MENT function through divergent transcriptional regulation. Red indicates that the gene is up-regulated; green indicates that the gene is down-regulated. A Up-regulated expression of genes. Rps16 was used as a house-keeping gene.

We found similar trends in these gene changes in the microarray Figure 6 , which indicates that the microarray analysis is reliable. We found that androgen receptor antagonist flutamide reversed the regulation of these genes by MENT Figure 7.

This suggests that MENT up-regulates these genes though androgen receptors. A Western blot; B Quantitative data. As shown in Figure 9 , the activity of all enzymes paralleled changes in their mRNA levels. However, LH down-regulates the expression of steroid metabolic enzyme genes, Akr1c14 and Sult1a1 , thereby increasing the androgen formation of rat immature Leydig cells. LH is essential for Leydig cell function because it is the principle stimulating hormone of androgen production in adult Leydig cells 1.

Previous studies have shown that LH stimulated the development of rat progenitor Leydig cells into immature Leydig cells 5 , 11 , In this study, we also demonstrated that LH stimulated the function of immature Leydig cells. In the steroidogenic pathway, LH up-regulated the expression of Scarb1 , Cyp11a1 , and Cyp17a1 , and down-regulated the expression of Sult1a1 and Akr1c14 Fig. Our previous studies have demonstrated that immature Leydig cells matured into adult Leydig cells by increase in the expression of Scarb1 , Cyp11a1 , and Cyp17a1 and down-regulation of Akr1c14 7 , Therefore, LH is an important factor for function and differentiation of immature Leydig cells.

The up-regulation of other biomarker of mature Leydig cells such as Insl3 also suggests that LH is a factor for inducing the differentiation of immature Leydig cells.

Knocking out Lhcgr in mice led to defects in the function of Leydig cells with no adult Leydig cells in the adult testis 13 , Figure 5. The expression levels of Leydig cell maturation markers Insl3 and Cyp17a1 in mice lacking functional NR3C4 were significantly reduced 16 , Although the role of NR3C4 in other cell types in Tfm cannot be ruled out, Leydig cell condition knockout mice for Nr3c4 also resulted in a significant reduction in mature Leydig cell biomarkers Cyp17a1 , Hsd17b3 , and Insl3 Obviously, NR3C4 acts through the androgen response element of the target gene.

In this regard, in the Insl3 gene, the region that mediates androgen action has been mapped to the sequence of to in the promoter According to reports 16 , 18 , 31 , in Tfm or Leydig cell conditionally knocked out NR3C4 mice, Cyp17a1 expression levels were significantly down-regulated. However, there is little information about the NR3C4 stimulation site in Cyp17a1.

In contrast, in mature Leydig cells, androgens actually inhibit the expression level of Cyp17a1 through the binding sequence in the cAMP response region of the Cyp17a1 promoter This difference in the androgen effect on the expression of Cyp17a1 may depend on the maturity of Leydig cells.

Our data also points to androgen stimulation of immature Leydig cell maturation, as indicated by increased expression of Cyp17a1 , Cdkn1a , Svs5 , and Ptgds.

Cyp17a1 7 , Cdkn1a 34 , Svs5 35 , and Ptgds 36 have been identified as biomarkers for Leydig cell maturation. Although some effects of LH on the gene expression may be mediated by testosterone, immature Leydig cells secrete a very low amount of testosterone and the major androgen is androstanediol, which almost has no binding to the androgen receptor.

Furthermore, we found that LH and androgen regulate different sets of transcriptional factors related to Leydig cell differentiation. LH significantly up-regulated the expression of Crem1 , Atf3 , Egr1 , and Runx1 Figure 5 , and down-regulated transcription factor Aes. It has been reported that LH up-regulated Egr1 in gonadal cells 40 , which is critical for steroidogenesis in Leydig cells There are also reports that Runx1 is up-regulated by LH and is involved in steroidogenesis in gonadal cells In conclusion, this study shows that androgen and MENT can induce immature Leydig cells to differentiate into adult Leydig cells.

Androgen and androgen act on their respective receptors and activated different sets of transcriptional factors to regulate the function of immature cells into adult Leydig cells Supplementary Figure S2. The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

KY performed microarray analysis. XL drafted the manuscript. R-SG edited the manuscript. All authors contributed to the article and approved the submitted version. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Supplementary Figure 2 Illustration of androgen MENT and luteinizing hormone LH regulating steroid synthesis and metabolism in Leydig cells through different pathways and targets.

Endocr Rev — Haider SG. Cell biology of Leydig cells in the testis.