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Breast Cancer Research : BCR Oct 2022Breast cancer (BC) has the highest cancer incidence and mortality in women worldwide. Observational epidemiological studies suggest a positive association between...
BACKGROUND
Breast cancer (BC) has the highest cancer incidence and mortality in women worldwide. Observational epidemiological studies suggest a positive association between testosterone, estradiol, dehydroepiandrosterone sulphate (DHEAS) and other sex steroid hormones with postmenopausal BC. We used a two-sample Mendelian randomization analysis to investigate this association.
METHODS
Genetic instruments for nine sex steroid hormones and sex hormone-binding globulin (SHBG) were obtained from genome-wide association studies (GWAS) of UK Biobank (total testosterone (TT) N: 230,454, bioavailable testosterone (BT) N: 188,507 and SHBG N: 189,473), The United Kingdom Household Longitudinal Study (DHEAS N: 9722), the LIFE-Adult and LIFE-Heart cohorts (estradiol N: 2607, androstenedione N: 711, aldosterone N: 685, progesterone N: 1259 and 17-hydroxyprogesterone N: 711) and the CORtisol NETwork (CORNET) consortium (cortisol N: 25,314). Outcome GWAS summary statistics were obtained from the Breast Cancer Association Consortium (BCAC) for overall BC risk (N: 122,977 cases and 105,974 controls) and subtype-specific analyses.
RESULTS
We found that a standard deviation (SD) increase in TT, BT and estradiol increased the risk of overall BC (OR 1.14, 95% CI 1.09-1.21, OR 1.19, 95% CI 1.07-1.33 and OR 1.03, 95% CI 1.01-1.06, respectively) and ER + BC (OR 1.19, 95% CI 1.12-1.27, OR 1.25, 95% CI 1.11-1.40 and OR 1.06, 95% CI 1.03-1.09, respectively). An SD increase in DHEAS also increased ER + BC risk (OR 1.09, 95% CI 1.03-1.16). Subtype-specific analyses showed similar associations with ER+ expressing subtypes: luminal A-like BC, luminal B-like BC and luminal B/HER2-negative-like BC.
CONCLUSIONS
TT, BT, DHEAS and estradiol increase the risk of ER+ type BCs similar to observational studies. Understanding the role of sex steroid hormones in BC risk, particularly subtype-specific risks, highlights the potential importance of attempts to modify and/or monitor hormone levels in order to prevent BC.
Topics: 17-alpha-Hydroxyprogesterone; Adult; Aldosterone; Androstenedione; Breast Neoplasms; Dehydroepiandrosterone Sulfate; Estradiol; Female; Genome-Wide Association Study; Gonadal Steroid Hormones; Humans; Hydrocortisone; Longitudinal Studies; Mendelian Randomization Analysis; Progesterone; Sex Hormone-Binding Globulin; Testosterone
PubMed: 36209141
DOI: 10.1186/s13058-022-01553-9 -
Clinical Endocrinology Aug 2022Androgen excess in women typically presents clinically with hirsutism, acne or androgenic alopecia. In the vast majority of cases, the underlying aetiology is polycystic... (Review)
Review
Androgen excess in women typically presents clinically with hirsutism, acne or androgenic alopecia. In the vast majority of cases, the underlying aetiology is polycystic ovary syndrome (PCOS), a common chronic condition that affects up to 10% of all women. Identification of women with non-PCOS pathology within large cohorts of patients presenting with androgen excess represents a diagnostic challenge for the endocrinologist, and rare pathology including nonclassic congenital adrenal hyperplasia, severe insulin resistance syndromes, Cushing's disease or androgen-secreting tumours of the ovary or adrenal gland may be missed in the absence of a pragmatic screening approach. Detailed clinical history, physical examination and biochemical phenotyping are critical in risk-stratifying women who are at the highest risk of non-PCOS disorders. Red flag features such as rapid onset symptoms, overt virilization, postmenopausal onset or severe biochemical disturbances should prompt investigations for underlying neoplastic pathology, including dynamic testing and imaging where appropriate. This review will outline a proposed diagnostic approach to androgen excess in women, including an introduction to androgen metabolism and provision of a suggested algorithmic strategy to identify non-PCOS pathology according to clinical and biochemical phenotype.
Topics: Adrenal Hyperplasia, Congenital; Androgens; Female; Hirsutism; Humans; Hyperandrogenism; Polycystic Ovary Syndrome; Virilism
PubMed: 35349173
DOI: 10.1111/cen.14710 -
The Journal of Clinical Endocrinology... May 2022Androgen prohormones such as dehydroepiandrosterone (DHEA) increase in early puberty, peak in the second and third decade, and thereafter decline, independent of... (Review)
Review
CONTEXT
Androgen prohormones such as dehydroepiandrosterone (DHEA) increase in early puberty, peak in the second and third decade, and thereafter decline, independent of menopausal status. Investigators have examined their potential beneficial effects in normal women and those with DHEA-deficient states.
EVIDENCE ACQUISITION
A review of the literature from 1985 to 2021 on the potential benefits and risks of androgen prohormones in women.
EVIDENCE SYNTHESIS
Studies have examined the potential benefit of DHEA therapy for anti-aging, sexual dysfunction, infertility, metabolic bone health, cognition, and wellbeing in hormone-deficient states such as primary adrenal insufficiency, hypopituitarism, and anorexia as well as administration to normal women across the lifespan.
CONCLUSIONS
Data support small benefits in quality of life and mood but not for anxiety or sexual function in women with primary or secondary adrenal insufficiency or anorexia. No consistent beneficial effects of DHEA administration have been observed for menopausal symptoms, sexual function, cognition, or overall wellbeing in normal women. Local administration of DHEA shows benefit in vulvovaginal atrophy. Use of DHEA to improve induction of ovulation response in women with diminished ovarian reserve is not recommended. Risks of high physiologic or pharmacologic use of DHEA include androgenic and estrogenic side effects which are of concern for long-term administration.
CLINICAL CASE
A 49-year-old woman with Addison's disease who is on low dose estrogen with cyclic progesterone therapy for menopausal symptoms returns for follow-up. She is on a stable glucocorticoid replacement strategy of hydrocortisone 10 mg in the morning and 5 mg in the early afternoon and fludrocortisone 0.05 mg each morning. She has read on the internet that additional therapy with DHEA may help her overall quality of life and libido. She asks whether she should add this therapy to her regimen and at what dose.
Topics: Androgens; Anorexia; Dehydroepiandrosterone; Estrogens; Female; Hormone Replacement Therapy; Humans; Middle Aged; Quality of Life
PubMed: 35254428
DOI: 10.1210/clinem/dgac130 -
American Journal of Men's Health Nov 2016An increasing number of men are being diagnosed with hypogonadism. While many benefit from testosterone supplementation therapy, others who do not meet the criteria for... (Review)
Review
An increasing number of men are being diagnosed with hypogonadism. While many benefit from testosterone supplementation therapy, others who do not meet the criteria for hormone supplementation have turned to dietary adjuncts as a way or gaining improvements in libido, energy, and physical performance. These oral adjunct medications include controlled substances such as androstenedione, androstenediol as well as other "over-the-counter" options like DHEA (dehydroepiandrosterone) and herbal remedies like Tribulus terrestris This review will focus on the use of these adjunct medications in isolation, or in combination with testosterone supplementation therapy as well as the biochemical nature of the supplements, the results of scientific trials as well as the side effects that limit their use. At the end of this review, physicians will have an improved understanding of the popular testosterone adjuncts being used currently as well as the availability of these substances and how they are used.
Topics: Androstenediol; Androstenedione; Dehydroepiandrosterone; Dietary Supplements; Hormone Replacement Therapy; Humans; Hypogonadism; Male; Quality of Life; Testosterone; Time Factors
PubMed: 26272885
DOI: 10.1177/1557988315598554 -
The Journal of Clinical Endocrinology... Feb 2022Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD) is characterized by impaired cortisol synthesis and excess androgen production....
CONTEXT
Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD) is characterized by impaired cortisol synthesis and excess androgen production. Corticotropin-releasing factor type 1 receptor (CRF1R) antagonism may decrease adrenal androgen production.
OBJECTIVE
This work aimed to evaluate the safety, tolerability, and efficacy of crinecerfont (NBI-74788), a selective CRF1R antagonist, in 21OHD.
METHODS
This open-label, phase 2 study, with sequential cohort design (NCT03525886), took place in 6 centers in the United States. Participants included men and women, aged 18 to 50 years, with 21OHD. Interventions included 4 crinecerfont regimens, each administered orally for 14 consecutive days: 50 or 100 mg once daily at bedtime (cohorts 1 and 2, respectively); 100 mg once daily in the evening (cohort 3); and 100 mg twice daily (cohort 4). Participants could enroll in more than 1 cohort. Main outcomes included changes from baseline to day 14 in adrenocorticotropin (ACTH), 17-hydroxyprogesterone (17OHP), androstenedione, and testosterone.
RESULTS
Eighteen participants (11 women, 7 men) were enrolled: cohort 1 (n = 8), cohort 2 (n = 7), cohort 3 (n = 8), cohort 4 (n = 8). Mean age was 31 years; 94% were White. Median percent reductions were more than 60% for ACTH (-66%), 17OHP (-64%), and androstenedione (-64%) with crinecerfont 100 mg twice a day. In female participants, 73% (8/11) had a 50% or greater reduction in testosterone levels; male participants had median 26% to 65% decreases in androstenedione/testosterone ratios.
CONCLUSION
Crinecerfont treatment for 14 days lowered ACTH and afforded clinically meaningful reductions of elevated 17OHP, androstenedione, testosterone (women), or androstenedione/testosterone ratio (men) in adults with 21OHD. Longer-term studies are required to evaluate the effects of crinecerfont on clinical end points of disordered steroidogenesis and glucocorticoid exposure in patients with 21OHD.
Topics: Adolescent; Adult; Female; Humans; Male; Middle Aged; Young Adult; 17-alpha-Hydroxyprogesterone; Administration, Oral; Adrenal Hyperplasia, Congenital; Adrenocorticotropic Hormone; Androstenedione; Azabicyclo Compounds; Biomarkers; Dose-Response Relationship, Drug; Oxadiazoles; Receptors, Corticotropin-Releasing Hormone; Testosterone; Treatment Outcome
PubMed: 34653252
DOI: 10.1210/clinem/dgab749 -
Life (Basel, Switzerland) Jan 2023Exposure to endocrine disrupting chemicals (EDCs) can result in alterations of the female reproductive system, including polycystic ovary syndrome (PCOS). The aim of... (Review)
Review
Exposure to endocrine disrupting chemicals (EDCs) can result in alterations of the female reproductive system, including polycystic ovary syndrome (PCOS). The aim of this review was to summarize the knowledge about the association of EDCs (bisphenols, parabens, and triclosan) with PCOS. We conducted an electronic literature search using PubMed for studies published between January 2007 and October 2022 on EDCs related to PCOS, and evaluated the association of PCOS with bisphenols, parabens and triclosan in 15 articles. Most studies revealed significantly higher plasma, urinary or follicular fluid levels of bisphenol A (BPA) in women with PCOS, and some showed a positive correlation of BPA with insulin resistance, polycystic morphology on ultrasound, hepatic steatosis, bilirubin levels, as well as free androgen index, androstenedione and testosterone serum levels, and markers of low-grade chronic inflammation. There was a negative correlation of BPA with markers of ovarian reserve, sex hormone binding globulin and vitamin D-binding protein. Parabens and triclosan have been studied in only one study each, with no significant associations with PCOS observed. Our review revealed an association of BPA with PCOS and negative effects of BPA on human ovaries; more research is needed to assess the potential associations of parabens and triclosan with PCOS.
PubMed: 36676087
DOI: 10.3390/life13010138 -
The Journal of Clinical Endocrinology... Oct 2023Crinecerfont, a corticotropin-releasing factor type 1 receptor antagonist, has been shown to reduce elevated adrenal androgens and precursors in adults with congenital...
CONTEXT
Crinecerfont, a corticotropin-releasing factor type 1 receptor antagonist, has been shown to reduce elevated adrenal androgens and precursors in adults with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD), a rare autosomal recessive disorder characterized by cortisol deficiency and androgen excess due to elevated adrenocorticotropin.
OBJECTIVE
To evaluate the safety, tolerability, and efficacy of crinecerfont in adolescents with 21OHD CAH.
METHODS
This was an open-label, phase 2 study (NCT04045145) at 4 centers in the United States. Participants were males and females, 14 to 17 years of age, with classic 21OHD CAH. Crinecerfont was administered orally (50 mg twice daily) for 14 consecutive days with morning and evening meals. The main outcomes were change from baseline to day 14 in circulating concentrations of ACTH, 17-hydroxyprogesterone (17OHP), androstenedione, and testosterone.
RESULTS
8 participants (3 males, 5 females) were enrolled; median age was 15 years and 88% were Caucasian/White. After 14 days of crinecerfont, median percent reductions from baseline to day 14 were as follows: ACTH, -57%; 17OHP, -69%; and androstenedione, -58%. In female participants, 60% (3/5) had ≥50% reduction from baseline in testosterone.
CONCLUSION
Adolescents with classic 21OHD CAH had substantial reductions in adrenal androgens and androgen precursors after 14 days of oral crinecerfont administration. These results are consistent with a study of crinecerfont in adults with classic 21OHD CAH.
Topics: Male; Adult; Humans; Female; Adolescent; Androgens; Adrenal Hyperplasia, Congenital; Androstenedione; 17-alpha-Hydroxyprogesterone; Testosterone; Adrenocorticotropic Hormone
PubMed: 37216921
DOI: 10.1210/clinem/dgad270 -
Clinical Endocrinology Aug 2023Monitoring of hormone replacement therapy represents a major challenge in the management of congenital adrenal hyperplasia (CAH). In the absence of clear guidance and... (Review)
Review
Monitoring of hormone replacement therapy represents a major challenge in the management of congenital adrenal hyperplasia (CAH). In the absence of clear guidance and standardised monitoring strategies, there is no consensus among clinicians regarding the relevance of various biochemical markers used in practice, leading to wide variability in their application and interpretation. In this review, we summarise the published evidence on biochemical monitoring of CAH. We discuss temporal variations of the most commonly measured biomarkers throughout the day, the interrelationship between different biomarkers, as well as their relationship with different glucocorticoid and mineralocorticoid treatment regimens and clinical outcomes. Our review highlights significant heterogeneity across studies in both aims and methodology. However, we identified key messages for the management of patients with CAH. The approach to hormone replacement therapy should be individualised, based on the individual hormonal profile throughout the day in relation to medication. There are limitations to using 17-hydroxyprogesterone, androstenedione and testosterone, and the role of additional biomarkers such 11-oxygenated androgens which are more disease specific should be further established. Noninvasive monitoring via salivary and urinary steroid measurements is becoming increasingly available and should be considered, especially in the management of children with CAH. Additionally, this review indicates the need for large scale longitudinal studies analysing the interrelation between different monitoring strategies used in clinical practice and health outcomes in children and adults with CAH.
PubMed: 37608608
DOI: 10.1111/cen.14960 -
Journal of Endocrinological... Aug 2022The aim of this study was to examine the hormonal profile in early-pubertal girls with obesity. We hypothesized that these patients might already present hormonal...
PURPOSE
The aim of this study was to examine the hormonal profile in early-pubertal girls with obesity. We hypothesized that these patients might already present hormonal alterations with POCS-like features.
METHODS
Cross-sectional study in a sample of 283 peri-pubertal girls (prepubertal and early-puberty subgroups), aged 6.1-12.0 years, diagnosed with obesity (BMI-SDS > 2.0, 97th percentile), so-called obesity group. They all underwent clinical examination and blood testing for hormonal measurements (leptin, TSH, FT4, IGF-1, IGFBP3, prolactin, insulin, FSH, LH, estradiol, ACTH, cortisol, 17-OH-P, DHE-S, androstenedione, testosterone and free testosterone). A control group was recruited: 243 healthy girls, aged 6.3-12.1 years, with normal BMI status.
RESULTS
Prepubertal girls with obesity had significantly higher values (p < 0.05) for BMI-SDS, leptin, insulin and HOMA-IR levels than control group. Early-pubertal girls with obesity also had significantly higher values (p < 0.05) for BMI-SDS, leptin, IGF-1, IGFBP3, insulin and HOMA-IR, LH, ratio LH/FSH, ACTH, DHE-S, androstenedione, testosterone and free testosterone levels than control group. In early-pubertal girls with obesity (not prepubertal girls), there was a positive correlation (p < 0.01) between leptin levels with LH, androstenedione and testosterone, and HOMA-IR with LH and testosterone levels. There was also a positive correlation (p < 0.01) between IGF-1 levels with LH, androstenedione, DHE-S and testosterone; and LH levels with testosterone.
CONCLUSION
The results obtained support our hypothesis that an abnormal hormonal profile with POCS-like features can already be detected (insulin resistance and hyperinsulinemia, increased secretion of LH and ACTH, and overproduction of ovarian and adrenal androgens) in early-pubertal girls with obesity.
Topics: Adrenocorticotropic Hormone; Androgens; Androstenedione; Cross-Sectional Studies; Female; Follicle Stimulating Hormone; Humans; Insulin; Insulin-Like Growth Factor I; Leptin; Obesity; Puberty; Puberty, Precocious; Testosterone
PubMed: 35412268
DOI: 10.1007/s40618-022-01797-4 -
Journal of Obstetrics and Gynaecology... Oct 2020To determine whether androgens [androstenedione (A4), 17-hydroxy progesterone (17OHP) and dehydroepiandrosterone (DHEA)] were elevated in women with classically defined...
OBJECTIVE
To determine whether androgens [androstenedione (A4), 17-hydroxy progesterone (17OHP) and dehydroepiandrosterone (DHEA)] were elevated in women with classically defined idiopathic hirsutism (IH)/patient-important hirsutism (PIH).
STUDY DESIGN
Retrospective analysis.
SETTING
Outpatient endocrine department of a tertiary care hospital.
PATIENTS
In total, 30 consecutive women with IH/PIH were included. IH/PIH was defined as presentation with hirsutism with normal menstrual cycles (25-35 days), normal total (< 45 ng/dL) and free T (fT) (< 0.6 ng/dL) and normal ovaries sonologically (transabdominal ultrasonogram ovarian volume < 10 cm) without any other signs of virilization. Clinical and biochemical details were collected and analyzed. Androgens were measured by LC-MS/MS. A4 ≥ 2.5 ng/mL, DHEA ≥ 15 (age < 18) or ≥ 11.8 (age ≥ 18) ng/mL, DHEAS ≥ 2847 ng/mL or 17OHP ≥ 2 ng/mL were considered high.
RESULTS
With the mean age of 22 years and mean BMI of 25 kg/m, 12/30 (40%) had IH and remaining PIH. DHEA alone was elevated in 60% and A4 alone in 33%. Overall, 23/30 (73%) had any one elevated androgen with normal total and free testosterone. There was no correlation with modified Ferriman-Gallwey score, and there was no significant difference in androgens between IH and PIH.
CONCLUSION
A high proportion of women with classically defined IH/PIH have elevated DHEA and/or A4. Though on pharmacotherapy basis, there would be no change in management, the role of hyperandrogenemia detected by sensitive assays on metabolic functions and cardiovascular risk has to be studied.
PubMed: 33041554
DOI: 10.1007/s13224-020-01324-6