Tag: Estrogen

Early onset of menstruation and menopause associated with increased risk of COPD

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In a recent study published in Thorax, a group of researchers evaluated the association between female reproductive factors such as age at menarche, stillbirth, number of children, infertility, miscarriage, and age at natural menopause—and the risk of developing chronic obstructive pulmonary disease (COPD).

Study: Female reproductive histories and the risk of chronic obstructive pulmonary disease. Image Credit: Image Point Fr/Shutterstock.com

Background

COPD is a significant global health issue, with a prevalence of approximately 3.9% in 2017, showing slight gender differences in rates between men and women. Notably, women are more susceptible to developing severe COPD at younger ages than men, and the majority of non-smokers with COPD are women.

This suggests that female sex hormones, such as estrogen and progesterone, play crucial roles in lung development and the pathogenesis of COPD. These hormones influence bronchodilation, inflammation, and cellular proliferation, key factors in COPD development.

The variability in the female hormonal environment throughout different reproductive stages- menarche, pregnancy, menopause, and conditions like infertility or pregnancy loss- highlights the complex relationship between female reproductive health and COPD risk.

However, research specifically exploring this connection remains limited, indicating a need for further research into how reproductive history impacts COPD risk.

About the study

The present study conducted by the International Collaboration for a Life Course Approach to Reproductive Health and Chronic Disease Events (InterLACE) consortium utilized data from over 850,000 women across 12 countries.

It focused on three cohorts with information on reproductive factors and COPD: the Australian Longitudinal Study on Women’s Health, the United Kingdom (UK) Biobank, and the Swedish Women’s Lifestyle and Health Study.

To ensure accuracy, the study excluded women who had developed COPD by age 40 from analyses involving infertility, miscarriage, stillbirths, and parity due to the absence of specific ages for these events.

Only women who had experienced natural menopause were considered for analysis regarding menopause age, and those with COPD before natural menopause were omitted.

The researchers carefully handled missing data, ensuring participants had complete records on critical factors such as race, education, smoking history, body mass index, and asthma.

To address potential biases, including the impacts of coronavirus disease 2019 (COVID-19), follow-up adjustments were made across cohorts, and reproductive histories were detailed, including menarche to menopause.

COPD was identified through diverse data, ensuring accuracy. Statistical analysis, including Cox regression and sensitivity tests, explored reproductive factors’ influence on COPD risk, highlighting their importance in women’s health research.

Study results

In the present comprehensive study encompassing 283,070 women with a median age of 54 years, researchers embarked on an 11-year journey to unravel the intricate relationship between women’s reproductive history and the development of COPD.

Throughout this period, 3.8% of the participants, equivalent to 10,737 women, were diagnosed with COPD at a median age of 63 years.

The identification of COPD cases varied, with 7,983 cases recognized through a singular data source—ranging from survey data to hospital records—and 2,754 through multiple sources.

The initial characteristics of these women highlighted certain risk factors, including advanced age at cohort entry, lower educational attainment, higher body mass indices, significant smoking histories, and pre-existing asthma conditions.

The researchers excluded 53,205 women due to incomplete data, particularly regarding smoking habits and body mass index, ensuring the robustness of their findings.

A nuanced pattern emerged, linking the age of menarche with COPD risk; notably, women who experienced menarche at age 11 or younger, as well as those who began menstruating after 13, saw an increased risk, with a particularly sharp rise observed in those who started menstruating at age 14 or beyond.

Furthermore, the study revealed that motherhood also influenced COPD risk, with women having one or more children facing higher risks compared to childless counterparts. This risk escalated with the number of children borne.

Additionally, experiences of infertility and miscarriages further intensified COPD risks, painting a complex picture of how reproductive history shapes respiratory health.

Women who had undergone natural menopause presented an inverse risk relationship with COPD, dependent on the age at menopause. Those entering menopause before age 40 faced the highest risk, whereas the risk diminished for women experiencing menopause at or beyond age 54.

The study also used rigorous sensitivity analyses, including random effects modeling and competing risk analysis, to validate these findings.

Notably, the association between infertility and COPD risk diminished in some analyses, yet the overarching trends remained consistent across various subgroups, including smokers and non-smokers, as well as women with and without a history of asthma.

The analysis extended to explore the impact of bilateral oophorectomy age on COPD risk, finding a heightened risk among women who underwent the procedure at younger ages.

Further, the study delved into the specific effects of reproductive history facets such as age at menarche, miscarriages, stillbirths, and menopause timing on COPD risk, with findings echoing across individual cohort studies and meta-analyses.

Despite some variability, especially concerning the age at menarche, most evidence pointed towards a consistent relationship between reproductive factors and the development of COPD.

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February 14, 2024
Androgen receptor signaling found to upregulate gene driving melanoma severity in men

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In a recent study published by Nature Communications, researchers uncovered a previously unknown method by which androgen-activated androgen receptors (ARs) increase fucosyltransferase 4 (FUT4) expression, which promotes melanoma invasiveness by interfering with adherens junctions (AJs).

Study: Androgen drives melanoma invasiveness and metastatic spread by inducing tumorigenic fucosylation. Image Credit: Image Point Fr/Shutterstock.com

Background

Melanoma incidence and death rates are higher in males than in females, and sex hormones play a crucial role in the disease’s biology and progression. Studies have demonstrated that androgen and its receptor have tumorigenic functions in melanoma, although the underlying processes are poorly understood.

Men with advanced melanoma typically have lower clinical outcomes. Sex hormones, such as G protein-coupled estrogen receptor (GPER) signaling, inhibit tumor development and boost anti-programmed death cell death 1 (anti-PD-1) immune checkpoint blockade effectiveness in a female mouse model.

Global fucosylation disrupts as melanoma progresses, affecting cell motility and ribonucleic acid (RNA) processing.

About the study

In the present study, researchers investigated ways in which sex-hormone-regulated fucosylation leads to disparately poor outcomes in male melanoma patients.

The researchers investigated the effects of androgen-induced and transcriptionally active androgen receptors on melanoma biology and tumorigenicity. They concentrated on the AR-FUT4 signaling pathway and its role in male sex-related biological consequences in melanoma.

They confirmed the presence of a putative androgen response element (ARE) in the FUT4 5′-promoter region and created mutant promoter constructs.

The researchers further confirmed the androgen receptor-fucosyltransferase-4 axis modulation of cell signaling pathways in melanoma by creating empty vector (EV) controls or fucosyltransferase 4-overexpressing (FUT4-OE) melanoma cells.

They conducted phosphoproteomic profiling of empty vectors and Ari-treated or untreated FUT4-overexpressing cells, followed by multiple-stage comparative analysis. The study sought to understand how ARs regulate fucosylation machinery genes and their significance in melanoma biology.

The team discovered 368 distinct proteins (denoted by 484 phosphopeptide proteins) that were decreased by ≥2.0-fold in ARi-treated empty vector-WM793 cells (ARi-reduced phosphopeptide proteins).

They then classified the phosphopeptides as those that FUT4 overexpression could restore (AR-FUT4-based effector molecules, n=95) and those unrestored by fucosyltransferase-4 overexpression (“AR-based, FUT4-independent effector molecules, n=241).

The researchers performed further ingenuity pathway analysis (IPA) on 141 androgen receptor-fucosyltransferase-4 axis down- or upregulated signatures in WM1366 and WM793 cells.

They measured the contacts between β-catenin, N-cadherin, and δ1-catenin, primary cytoplasmic adherens junction interactors. They performed proliferation and motility experiments to confirm the phosphoproteomic results and determine the effect of AR-FUT4-AJ signaling on melanoma biology.

The team also investigated whether FUT8 contributes to the motility effects caused by FUT4. They also assessed AR expression and its relationships with downstream effectors in human melanoma samples.

Results

Researchers uncovered a method by which androgen-activated androgen receptors increase FUT4 expression, which promotes melanoma invasiveness by interacting with AJs. FUT4 is a critical transcriptional target of AR, disrupting cell-cell adhesion complexes in melanoma.

AR-FUT4-mediated melanoma metastasis requires L1CAM, a downstream effector fucosylated by FUT4. Tumor microarray and gene expression analysis revealed that AR-FUT4-L1CAM-AJs signaling is associated with clinical staging in melanoma patients.

The researchers found that sex hormone-regulated fucosylation leads to the poor outcomes seen in male melanoma patients.

The mechanism shows that androgen or its receptor signaling influences melanoma malignancy by increasing invasive and metastatic potential through tumorigenic fucosylation.

Androgen/AR regulates cellular fucosylation in melanoma, with AR binding sites found in four genes (FUT4, FUT1, SLC35C2, and FUK). Androgen stimulation causes FUK to downregulate while FUT4 upregulates, indicating that AR modulates FUK and FUT4 expression in melanoma cells.

The researchers discovered that 2FF and FUT4-OE reduce and promote melanoma cell motility, but ectopic FUT4 expression restores ARi-suppressed invasive potential. FUT4 levels are higher in metastatic lesions than in original melanoma tissues.

They identified L1CAM as an essential target for the AR-FUT4 axis-induced melanoma invasiveness. FUT4-overexpressing cell lines produced more fucosylated proteins than FUT4-knockdown cell lines.

DHT stimulation significantly elevated the fucosylation of L1CAM, and knockdown or overexpression of FUT4 resulted in lower or higher cellular levels of fucosylated L1CAM. L1CAM deletion inhibited DHT- or FUT4-induced melanoma motility.

AR levels were higher in metastatic tumors from male patients, as was activated AR. Single-cell segmentation analysis revealed that metastatic lesions included fewer activated AR-high cells than initial tumors, demonstrating AR’s tumor-promoting involvement, particularly in male melanoma patients.

Conclusion

The study findings showed that androgen-triggered signaling is critical in melanoma, specifically targeting AR/FUT4 and its effectors.

It supports the use of AR antagonists to treat melanomas and advises employing androgen- and fucosylation-based indicators to stratify therapy.

AR activation enhances tumorigenic FUT4, resulting in worse clinical outcomes in male patients. The work also relates the AR transcriptional repertoire to oncogenic protein fucosylation, which promotes melanoma invasiveness in androgen-responsive melanomas.

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February 12, 2024
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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February 12, 2024
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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February 9, 2024
Are younger women experiencing a higher incidence of breast cancer?
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In a recent study published in the journal JAMA Network Open, researchers evaluated the incidence of breast cancer among young women between the ages of 20 and 49 years. They assessed the incidence according to age at diagnosis, tumor stage, estrogen and progesterone hormone receptor status, and race and ethnicity.

Study: Breast Cancer Incidence Among US Women Aged 20 to 49 Years by Race, Stage, and Hormone Receptor Status. Image Credit: Thinnapob Proongsak/Shutterstock.com

Background

In the United States (U.S.), breast cancer is not only the most common form of cancer diagnosed among women, but it is also associated with the highest rate of cancer-related mortality. Furthermore, breast cancer in younger women tends to be more aggressive, with advanced tumor stage and larger tumor size at diagnosis, as compared to that in older women.

Younger women with breast cancer also tend to have negative estrogen and progesterone receptor status and human epidermal growth factor receptor 2 (ERBB2) overexpression, which indicates poor prognosis.

Although recent research indicates that the incidence of breast cancer is increasing among younger women, women under the age of 40 are not eligible for breast cancer screening programs unless they are at high risk of the disease. Furthermore, there is a paucity of data on breast cancer incidence patterns according to race, cancer stages, and hormone receptor status. The influence of ecological and social environments on the incidence of breast cancer among younger women has also not been examined in the context of cohort or period effects.

About the study

In the present study, the researchers calculated the incidence of breast cancer among women between the ages of 20 and 49 over the last 20 years, with the analyses stratified according to age at diagnosis, tumor stage, estrogen, and progesterone receptor status, and race and ethnicity using data obtained from Surveillance, Epidemiology, and End Results Program.

Additionally, the researchers examined how unique ecological and social environments impact a population of individuals born in the same year, also known as cohort effects. The study also investigated the role of period effects, or the role of the environmental or social context of a specific calendar time in modifying the risk of breast cancer in young women.

The study population included women aged 20 to 49 years with a diagnosis of primary invasive breast cancer, unstaged or between I to IV stages, for whom information on race and ethnicity was available. The information about age at diagnosis was grouped into five-year age groups, which were then used to calculate the age-standardized breast cancer incidence rates. Additionally, data on hormone receptor status was used to classify the participants into four groups based on the combined receptor status for estrogen and progesterone receptors.

The data was also categorized for the various race and ethnic groups and the tumor stages. The primary outcome investigated in the study was the age-standardized incidence rates of breast cancer. Subgroup analyses were conducted to understand any heterogeneity in the incidence rates based on race and ethnicity. Incidence rate ratios were also computed to understand the differences in incidence between different racial or ethnic groups.

Results

The results showed an increase in the incidence of breast cancer among young women in the U.S., especially after 2016. The incidence rates were the highest among non-Hispanic Black women between the ages of 20 and 29 and 30 and 39 years. The findings also indicated that the incidence of tumors positive for estrogen receptors was on the rise while that of tumors negative for estrogen receptors was decreasing. Similarly, the incidence of tumors in stages I and IV was seen to be increasing, while that of tumors in stages II and III was decreasing.

The trends indicated that women from the non-Hispanic Black group also had a high incidence of advanced-stage breast cancer, potentially contributing to the high mortality rates among women of that racial and ethnic group. These results highlight the need for early assessment of breast cancer risk and targeted screening for breast cancer being recommended earlier for young non-Hispanic Black women.

Additionally, while the cohort effect explained a large portion of the increase in breast cancer incidence rates, period effects were also significant in most of the racial and ethnic groups. These findings indicated that intrinsic biological differences between races or ethnicities alone do not account for disparities in breast cancer incidence rates. Social environments could potentially play a significant role in determining the risk of breast cancer, and identification of these social factors could provide modifiable risk factors that can be addressed to prevent the disease.

Conclusions

Overall, the findings suggested that the incidence of breast cancer was increasing among women between the ages of 20 and 49, with young non-Hispanic Black women having the highest incidence rates. Cohort and period effects were observed to play a significant role, indicating the potential role of modifiable social or environmental risk factors.
Journal reference:

Xu, S., Murtagh, S., Han, Y., Wan, F., & Toriola, Adetunji T. (2024). Breast Cancer Incidence Among U.S. Women Aged 20 to 49 Years by Race, Stage, and Hormone Receptor Status. JAMA Network Open, 7(1), e2353331–e2353331. https://doi.org/10.1001/jamanetworkopen.2023.53331 https://doi.org/10.1001/jamanetworkopen.2023.53331
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January 31, 2024