Carbon Chemist

Tag: Estradiol

  • Genetics of estrogen production linked to endometrial cancer risk in postmenopausal women

    Genetics of estrogen production linked to endometrial cancer risk in postmenopausal women

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    In a recent study published in eBioMedicine, researchers determine the genetic regulation of blood estrone levels in postmenopausal women to explore associations between their genetic loci and endometrial cancer.

    Study: Genome-wide association study identifies genetic regulation of oestrone concentrations and association with endometrial cancer risk in postmenopausal women. Image Credit: Peakstock / Shutterstock.com

    The role of estrogens in endometrial cancer

    Once a woman has gone through menopause, her ovaries no longer produce estrogens, thereby causing her serum estradiol concentrations to be extremely low or undetectable. In Type 1 estrogen-sensitive endometrial cancer, which accounts for over 80% of all endometrial cancers and predominantly affects menopausal women, estrone, the contributing estrogen, is synthesized in non-ovarian tissues like fat. Following the production of estrone in these tissues, this hormone is converted into estradiol, a more potent form of estrogen.

    Previous studies have shown that obesity is a significant risk factor for Type 1 endometrial cancer. This association may be attributed to the greater amount of total fat mass that facilitates more estrone production.

    Alternatively, various genetic factors may lead to increased estrone production after menopause, thereby contributing to an increased risk of endometrial cancer in these women. In fact, one variant in the CYP19A1 gene, which is involved in the aromatization of testosterone to estradiol, has been positively associated with estradiol concentrations and postmenopausal endometrial cancer.

    Importantly, studies investigating the relationship between CYP19A1 variants and endometrial cancer risk have been limited due to their small sample size and lack of sensitive analytical methods.

    About the study

    In the present genome-wide association study (GWAS), researchers quantified blood estrone, testosterone, and dehydroepiandrosterone (DHEA) levels with high precision using liquid chromatography-tandem mass spectrometry (LCMS) to identify single nucleotide polymorphisms (SNPs) associated with sex hormone concentrations. The association between hormone-associated SNPs and endometrial cancer was determined from 205,427 white British females between 39 and 71 years of age, 0.9% of whom were diagnosed with endometrial cancer.

    The study also included women 70 and older from the Sex Hormones in Older Women (SHOW) and ASPirin in Reducing Events in the Elderly (ASPREE) studies. Non-fasting blood samples were obtained from these study participants to measure sex hormone concentrations through LCMS.

    Study findings

    The final analysis cohort comprised 4,951 postmenopausal women of European descent, with a median age of 73.9. No genome-wide signals were observed for testosterone or DHEA, the latter of which is the precursor for both estrone and testosterone. However, the GWAS identified four independent SNPs for estrone concentrations below the genome-wide significance threshold after adjusting for age and BMI.

    These SNPs included rs34670419, which may be involved in transcriptional regulation; rs56400819, which contributes to the DNA damage response; rs2846729, which is mapped to a ribonucleic acid (RNA) gene; and rs2414098, which is mapped to CYP19A1. The SNP with the highest prevalence within this study cohort was rs56400819 at 45% as compared to rs34670419, which had the lowest prevalence in this cohort at 4%.  

    Lower estrone levels were observed for rs34670419, rs2846729, and rs2414098 carriers compared to rs56400819 carriers, who exhibited higher estrone concentrations. Furthermore, rs2414098 carriers had a significantly lower risk of endometrial cancer after adjusting for age at recruitment, BMI, parity, and history of diabetes.

    Conclusions

    Previous GWAS on endometrial cancer have primarily focused on estradiol concentrations; however, this hormone often cannot be accurately quantified, particularly among postmenopausal women. Comparatively, the current study examined estrone concentrations, in which a dose-response relationship was observed between the identified SNPs and estrone concentrations.

    Importantly, the researchers of the current study limited one of their analyses on rs2414098 to women over 58 years of age in an effort to ensure postmenopausal status. These findings confirm that the impact of this SNP on cancer risk can be attributed to estrone and is independent of the effects of circulating estrogens and progesterone.

    The current study highlights the importance of measuring estrone levels, in addition to other sex hormones, in postmenopausal women to determine cancer risk. Some important strengths of this study include the confirmation of postmenopausal women in the study cohort, the large sample size, and the use of LCMS, a highly sensitive and precise analytical instrument.

    Journal reference:

    • Yu, C., Andrew Bakshi, A., Bell, R. J., et al. (2024). Genome-wide association study identifies genetic regulation of oestrone concentrations and association with endometrial cancer risk in postmenopausal women. eBioMedicine. doi:10.1016/j.ebiom.2024.104997

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  • Hormonal steroids could make gonorrhea untreatable

    Hormonal steroids could make gonorrhea untreatable

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    You know that package warning that oral birth control won’t prevent STIs? Well in the case of gonorrhea, the sexually transmitted bacterium that causes the disease can use those hormones to help it resist antibiotic attacks.

    Like many bacteria, this bug, Neisseria gonorrhoeae, is equipped with pumps to push the killing chemicals out of its cells. But what’s unique, according to a Duke and Emory study online this week in Nature Communications, is that the hormones of the human urogenital tract actually allow gonorrhea to make and use more of these pumps to fight intrinsic antimicrobials and prescribed antibiotics.

    The researchers uncovered the trick while examining a transcription factor – a protein that binds to specific sites on the bacterium’s DNA and slows production of the efflux pumps that protect it.

    Led by Duke graduate student Grace Hooks and her mentor, Biochemistry chair Richard Brennan, Ph.D., the study used a variety of approaches to characterize the shape and function of the transcription factor.

    What they found is that, unfortunately, this transcription factor, called MtrR, has an affinity for binding to the hormonal steroids progesterone, estrogen and testosterone and the synthetic hormone ethinyl estradiol. When it binds to a hormone, the transcription factor becomes less effective at suppressing the production of bacterial pumps.

    Hooks said the bacterium appears to be able to sense its hormonal environment and waits for the opportune time in the female’s menstrual cycle to ramp up its colonization.

    Estrogen rises dramatically in the week before ovulation, and progesterone peaks in the two weeks between ovulation and menstruation. These fluctuations are thought to suppress the immune system, giving sperm and eggs a window of opportunity to survive in the urogenital tract, but that same window also creates a vulnerability to this infection.

    It’s kind of utilizing this sensory system to gauge where it is in this cycle and when it can best colonize. It can only survive in the human host, it can’t survive outside. So, it has to really be good at sensing where it is and when’s the best time for colonizing.”


    Grace Hooks, Duke graduate student 

    The transcription factor MtrR also helps signal the bacterium to protect itself against reactive oxygen species. “What this one protein does is a dual system to protect Neisseria gonorrhea,” Brennan said.

    Gonorrhea has been with humans far longer than there have been antibiotics, appearing in texts as ancient as 2600 BC and making famous appearances in Julius Caesar’s Roman legions and the Crimean war.

    Ancient or not, the Centers for Disease Control considers gonorrhea an urgent public health threat, because it is now resistant to every antibiotic except for one, ceftriaxone. But strains resistant to this antibiotic have been identified recently in Europe and Asia.

    Known historically and colloquially as ‘the clap,’ untreated gonorrhea in women can lead to pelvic inflammatory disease and infertility. It may also be passed from mother to infant during childbirth.

    While the infection is more obvious in men, it is less dramatic, as men don’t experience the wider hormonal shifts, nor is their urogenital tract as complicated or deep as a woman’s, Hooks said. But men still carry all the same hormones that the transcription factor latches onto, she added.

    And, of course, the bacteria must thrive in both men and women to be a successful STI. “Neisseria gonorrhoeae is an obligate human pathogen,” Brennan said. “We don’t know where it is the rest of the time.”

    When Hooks presented some of her data in a laboratory meeting, fellow graduate student Emily Cannistraci from the next-door Schumacher laboratory asked if the synthetic hormone ethinyl estradiol, which is found in many oral contraceptives for women, would have a similar effect. Hooks checked, and it certainly did.

    The takeaway is not only the package warning that oral birth control won’t prevent STIs, but in this case, it might even make them worse.

    This research was supported by the National Institutes of Health (R35GM130290, R05 AI048593, R01 AI021150), the US Department of Veterans Affairs and the U.S. Department of Energy.

    Source:

    Journal reference:

    Hooks, G. M., et al. (2024). Hormonal steroids induce multidrug resistance and stress response genes in Neisseria gonorrhoeae by binding to MtrR. Nature Communications. doi.org/10.1038/s41467-024-45195-1

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