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The American Journal of Pathology Dec 2023Pregnancy-related problems have been linked to impairments in maternal uterine spiral artery (SpA) remodeling. The mechanisms underlying this association are still...
Pregnancy-related problems have been linked to impairments in maternal uterine spiral artery (SpA) remodeling. The mechanisms underlying this association are still unclear. It is also unclear whether hyperandrogenism and insulin resistance, the two common manifestations of polycystic ovary syndrome, affect uterine SpA remodeling. We verified previous work in which exposure to 5-dihydrotestosterone (DHT) and insulin (INS) in rats during pregnancy resulted in hyperandrogenism, insulin intolerance, and higher fetal mortality. Exposure to DHT and INS dysregulated the expression of angiogenesis-related genes in the uterus and placenta and also decreased expression of endothelial nitric oxide synthase and matrix metallopeptidases 2 and 9, increased fibrotic collagen deposits in the uterus, and reduced expression of marker genes for SpA-associated trophoblast giant cells. These changes were related to a greater proportion of unremodeled uterine SpAs and a smaller proportion of highly remodeled arteries in DHT + INS-exposed rats. Placentas from DHT + INS-exposed rats exhibited decreased basal and labyrinth zone regions, reduced maternal blood spaces, diminished labyrinth vascularity, and an imbalance in the abundance of vascular and smooth muscle proteins. Furthermore, placentas from DHT + INS-exposed rats showed expression of placental insufficiency markers and a significant increase in cell senescence-associated protein levels. Altogether, this work demonstrates that increased pregnancy complications in polycystic ovary syndrome may be mediated by problems with uterine SpA remodeling, placental functionality, and placental senescence.
Topics: Humans; Rats; Pregnancy; Female; Animals; Placenta; Polycystic Ovary Syndrome; Hyperandrogenism; Uterus; Arteries; Dihydrotestosterone; Insulin; Uterine Artery
PubMed: 37689383
DOI: 10.1016/j.ajpath.2023.08.008 -
Mayo Clinic Proceedings Apr 2023To determine differences in plasma sex hormone levels in male and female coronavirus disease 2019 (COVID-19) patients and healthy volunteers (HVs) because cell entry of...
OBJECTIVE
To determine differences in plasma sex hormone levels in male and female coronavirus disease 2019 (COVID-19) patients and healthy volunteers (HVs) because cell entry of severe acute respiratory syndrome coronavirus 2 occurs via the angiotensin-converting enzyme 2 receptor which is downregulated by 17β-estradiol.
PATIENTS AND METHODS
Citrated plasma samples were collected from 101 patients with COVID-19 upon presentation to the emergency department and from 40 HVs between November 1, 2020, and May 30, 2021. Plasma 17β-estradiol and 5α-dihydrotestosterone (DHT) levels were measured using enzyme-linked immunosorbent assay (pg/mL). Data are presented as median and quartiles (IQR). Wilcoxon rank sum test with a P value less than .05 was considered significant.
RESULTS
Patients with COVID-19 (median age, 49 years) included 51 males and 50 females (25 postmenopausal). Hospital admission was required for 58.8% of male patients (n = 30) and 48.0% of female patients (n = 24) (66.7% postmenopausal, n = 16) Healthy volunteers (median age, 41 years) included 20 males and 20 females (9 postmenopausal). Female patients with COVID-19 were found to have decreased 17β-estradiol levels (18.5 [IQR, 10.5-32.3] pg/mL; 41.4 [IQR, 15.5-111.0] pg/mL, P=.025), and lower 17β-estradiol to DHT ratios (0.073 [IQR, 0.052-0.159] pg/mL; 0.207 [IQR, 0.104-0.538] pg/mL, P=.015) than female HVs. Male patients with COVID-19 were found to have decreased DHT levels (302.8 [IQR, 249.9-470.8] pg/mL; 457.2 [IQR, 368.7-844.3] pg/mL, P=.005), compared with male HVs. Levels of DHT did not differ between female patients with COVID-19 and female HVs, whereas 17β-estradiol levels did not differ between male patients with COVID-19 and male HVs.
CONCLUSION
Sex hormone levels differ between patients with COVID-19 and HVs, with sex-specific patterns of hypogonadism in males and females. These alterations may be associated with disease development and severity.
Topics: Humans; Male; Female; Middle Aged; Adult; Estradiol; Dihydrotestosterone; COVID-19; Testosterone
PubMed: 36872195
DOI: 10.1016/j.mayocp.2022.12.018 -
Fertility and Sterility Dec 2022To characterize the circulating androgen levels across the menstrual cycle in healthy women using highly sensitive and accurate methods and report sex differences in the...
OBJECTIVE
To characterize the circulating androgen levels across the menstrual cycle in healthy women using highly sensitive and accurate methods and report sex differences in the relative levels of dihydrotestosterone (DHT) to testosterone (T) levels.
DESIGN
Prospective cohort study.
SETTING
Research clinic, academic teaching hospital.
PATIENT(S)
Twenty-one healthy premenopausal women, aged 19-40 years, with regular menstrual cycles.
INTERVENTION(S)
Not applicable.
MAIN OUTCOME MEASURE(S)
Serum total T and DHT levels measured using liquid chromatography-tandem mass spectrometry, free T levels measured using a standardized equilibrium dialysis method coupled with measurement of the T levels in the dialysate using liquid chromatography-tandem mass spectrometry, and comparison of the DHT-to-T ratio between healthy women and age-matched healthy men.
RESULT(S)
The serum total and free T levels increased across the follicular phase and peaked at midcycle (total T, 43.6 ± 16.2 ng/dL; free T, 15.6 ± 11.9 pg/mL) and gradually declined in the luteal phase. The DHT level did not significantly change across the menstrual cycle. The DHT-to-T ratios were 1:4 and 1:13 in women and men, respectively.
CONCLUSION(S)
In healthy premenopausal women, the total and free T levels varied significantly across the menstrual cycle, whereas the DHT levels did not change; the peak total and free T levels in the midcycle period were higher than previously reported, underscoring the importance of establishing menstrual phase-specific reference ranges to avoid misdiagnosis of hyperandrogenism. Women have significantly higher DHT levels relative to total T than men; the significance of this sex difference in the DHT-to-T ratio needs further investigation.
Topics: Female; Humans; Male; Testosterone; Prospective Studies; Dihydrotestosterone; Chromatography, Liquid; Menstrual Cycle
PubMed: 36371319
DOI: 10.1016/j.fertnstert.2022.09.011 -
Asian Journal of Andrology 2018Epidemiological studies hint at a beneficial influence of endogenous circulating testosterone (T), or its metabolite dihydrotestosterone (DHT), such that men with lower...
Epidemiological studies hint at a beneficial influence of endogenous circulating testosterone (T), or its metabolite dihydrotestosterone (DHT), such that men with lower concentrations of T or DHT appear to have poorer health outcomes including frailty, diabetes, cardiovascular disease, and mortality. Small interventional studies of T have shown favorable effects on surrogate outcome measures, but a large randomized controlled trial (RCT) with the prespecified outcome of cardiovascular events has not been performed and would be logistically demanding. In the absence of such a definitive RCT, there is a controversy about the cardiovascular risks of T-therapy fuelled by contradictory findings from retrospective analyses of insurance databases of men prescribed T. The US Testosterone Trials (T-Trials) are the largest published RCTs of T-therapy in older men with symptoms or signs of hypogonadism and circulating T <9.54 nmol l at baseline. The T-Trials showed a modest benefit of T-therapy over a 12-month period on sexual function, a significant benefit in bone density and for anemia and neutral effect on cognition. The T-Trials cardiovascular sub-study was designed to determine the effects of T in these older men, and there was a statistically significant difference in the increase in noncalcified plaque volume in the T-treated group compared to placebo, but it is difficult to interpret these results due to differences in baseline coronary plaque burden (>50% difference) between the treatment and placebo arms of the subset involved. Therefore, there continues to be ongoing uncertainty over the effect of T-therapy on the cardiovascular system in men.
Topics: Age Factors; Androgens; Cardiovascular Diseases; Dihydrotestosterone; Hormone Replacement Therapy; Humans; Hypogonadism; Male; Protective Factors; Risk Factors; Testosterone
PubMed: 29405170
DOI: 10.4103/aja.aja_71_17 -
Clinica Chimica Acta; International... Jun 2022Hirsutism is the excessive growth of terminal hair in a male pattern in a female. In most hirsute women, hirsutism is caused by increased androgens. However, not all... (Review)
Review
BACKGROUND
Hirsutism is the excessive growth of terminal hair in a male pattern in a female. In most hirsute women, hirsutism is caused by increased androgens. However, not all women with hirsutism actually show elevated levels of circulating androgens with standard laboratory tests, in which case we speak of idiopathic hirsutism (IH).
OBJECTIVES
The aim of this paper is to investigate whether there are biochemical markers that can be used to unravel the cause in IH.
METHODS
An electronic search through the PubMed database was conducted to find studies describing potential biomarkers for IH.
RESULTS
The majority of included studies claimed an increased 5α-reductase (5α-RD) activity in women with IH by means of increased DHT metabolite levels. Studies investigating abnormalities of the androgen receptor (AR) and serum levels of indirect markers showed no significant differences.
CONCLUSIONS
Our literature search showed that polymorphisms of the AR as well as indirect markers seem to be nonspecific, but that the dihydrotestosterone-reduced metabolite 5α-androstane-3α,17β-diol glucuronide is markedly enhanced in women with IH, suggesting an increased 5α-RD activity in these women. Further studies need to be performed to determine the clinical usefulness of 3α-diol G as a biomarker for IH.
Topics: Androgens; Androstane-3,17-diol; Dihydrotestosterone; Female; Hirsutism; Humans; Testosterone
PubMed: 35292252
DOI: 10.1016/j.cca.2022.03.011 -
Reproductive Sciences (Thousand Oaks,... Dec 2016Atherosclerosis is the main cause of death in men and women. This so-called "hardening of the arteries" results from advanced atherogenesis, the accumulation and death... (Review)
Review
Atherosclerosis is the main cause of death in men and women. This so-called "hardening of the arteries" results from advanced atherogenesis, the accumulation and death of subendothelial fat-laden macrophages (vascular plaque). The macrophages are attracted as the result of signals from injured vessels recruiting and activating cells to quell the injury by inflammation. Among the recruited cells are circulating monocytes that may be captured by the formation of neural cell adhesion molecule (nCAM) tethers between the monocytes and vascular endothelium; the tethers are dependent on electrostatic binding between distal segments of apposed nCAM molecules. The capture of monocytes is followed by their entry into the subendothelial area as macrophages, many of which will remain and become the fat-laden foam cells in vascular plaque. Neural cell adhesion molecules are subject to sialylation that blocks their electrostatic binding. We showed that estradiol-induced nCAM sialylases are present in vascular endothelial cells and tested whether sex steroid pretreatment of human vascular endothelium could inhibit the capture of monocytes. Using in vitro techniques, pretreatment of human arterial endothelial cells with estradiol, testosterone, dehydroepiandrosterone and dihydrotestosterone all induced sialylation of endothelial cells and, in a dose-response manner, reduced the capture of monocytes. Steroid hormones are protective against atherogenesis and its sequellae. Sex steroid depletion is associated with atherosclerosis. Based on this knowledge plus our results using sex steroid pretreatment of endothelial cells, we propose that the blockade of the initial step in atherogenesis by sex steroid-induced nCAM sialylation may be crucial to hormonal prevention of atherosclerosis.
Topics: Animals; Atherosclerosis; Cell Adhesion Molecules; Dehydroepiandrosterone; Dihydrotestosterone; Endothelium, Vascular; Estradiol; Gonadal Steroid Hormones; Humans; Monocytes; Rats; Testosterone
PubMed: 27821559
DOI: 10.1177/1933719116674078 -
Clinics in Dermatology 2017The skin is an endocrine organ with the expression of metabolizing enzymes and hormone receptors for diverse hormones. The sebaceous gland is the main site of hormone...
The skin is an endocrine organ with the expression of metabolizing enzymes and hormone receptors for diverse hormones. The sebaceous gland is the main site of hormone biosynthesis, especially for androgens, and acne is the classical androgen-mediated dermatosis. In sebocytes, conversion of 17-hydroxyprogesterone directly to dihydrotestosterone bypassing testosterone has been demonstrated, while type II 17β-hydroxysteroid dehydrogenase can inactivate the action of testosterone and dihydrotestosterone. The androgen receptor-dependent genomic effect of dihydrotestosterone on sebocytes is confirmed. Further evidence supports the PI3 K/Akt/FoxO1/mTOR signaling in the involvement of the interplay between androgens, insulin, insulin-like growth factor, and hyperglycemic diet in acne. Androgens not only regulate embryology and lipogenesis/sebum synthesis in sebocytes but also influence inflammation in acne. Genetic studies indicate that regulation of the androgen receptor is an important factor in severe acne. Further studies are required to understand the effect of estrogen and progesterone on sebaceous gland and comedogenesis, considering the change of acne in pregnancy and postmenopausal acne. Special attention should be paid to nonobese patients with polycystic ovarian syndrome and hyperandrogenism-insulin resistance-acanthosis nigricans syndrome. In spite of extensive gynecologic experience in the use of combined oral contraceptives for acne, evidence based on dermatologic observation should be intensified.
Topics: 17-Hydroxysteroid Dehydrogenases; Acne Vulgaris; Androgens; Dihydrotestosterone; Female; Gonadal Steroid Hormones; Humans; Insulin; Polycystic Ovary Syndrome; Receptors, Somatomedin; Sebaceous Glands
PubMed: 28274349
DOI: 10.1016/j.clindermatol.2016.10.004 -
Endocrine Reviews Jun 2017
Topics: Dihydrotestosterone; Follicle Stimulating Hormone; Humans; Testosterone
PubMed: 28582536
DOI: 10.1210/er.2017-00091 -
Aging May 2018The cardiovascular effects of testosterone and dihydrotestosterone are generally attributed to their modulatory action on lipid and glucose metabolism. However, no...
The cardiovascular effects of testosterone and dihydrotestosterone are generally attributed to their modulatory action on lipid and glucose metabolism. However, no studies suggest that circulating androgen levels influence the activation and reactivity of blood platelets - one of the main components of the haemostasis system directly involved in atherosclerosis. The levels of testosterone, dihydrotestosterone and oestradiol in plasma from men and women aged from 60 to 65 years were measured by LC-MS; the aim was to identify any potential relationships between sex steroid levels and the markers of platelet activation (surface membrane expression of GPII/IIIa complex and P-selectin) and platelet reactivity in response to arachidonate, collagen or ADP, monitored with whole blood aggregometry and flow cytometry. The results of the part of the study indicate that the concentrations of testosterone and its reduced form, dihydrotestosterone are significantly negatively associated with platelet activation and reactivity. These observations were confirmed in an model: testosterone and dihydrotestosterone significantly inhibited platelet aggregation triggered by arachidonate or collagen. Our findings indicate that testosterone and dihydrotestosterone are significant haemostatic steroids with inhibitory action on blood platelets in older people.
Topics: Aged; Blood Platelets; Dihydrotestosterone; Estradiol; Female; Humans; Male; Middle Aged; Platelet Activation; Platelet Aggregation; Testosterone
PubMed: 29723157
DOI: 10.18632/aging.101438 -
Advances in Experimental Medicine and... 2017The 5ARIs, finasteride and dutasteride, are used to treat benign prostate hyperplasia and lower urinary tract symptoms. At much lower doses, 5ARI treatment reduces male... (Review)
Review
The 5ARIs, finasteride and dutasteride, are used to treat benign prostate hyperplasia and lower urinary tract symptoms. At much lower doses, 5ARI treatment reduces male hair loss. These drugs inhibit the conversion of testosterone to the more active dihydrotestosterone (DHT). In men taking these medications, DHT levels are reduced by some 90% while testosterone levels remain relatively stable. Well known for their negative effects on libido and erectile function, 5ARIs also cause ejaculatory dysfunction in some men, having the potential to decrease semen quality. In fact, some studies of men treated with these drugs have reported lower total sperm count, along with lower sperm motility, although the changes are probably insufficient to reduce fertility in men with normal semen before treatment. There is a population of men with more severely decreased sperm numbers; as low as 10% of pretreatment values. Fewer studies have looked at the lower doses used for male alopecia, indicating little affect in men with normal semen quality, but a negative effect on sperm numbers in men with oligozoospermia. There have been no studies looking at fertility endpoints for these medications.
Topics: 3-Oxo-5-alpha-Steroid 4-Dehydrogenase; 5-alpha Reductase Inhibitors; Dihydrotestosterone; Humans; Libido; Male; Penile Erection; Prostatic Hyperplasia; Sperm Count; Sperm Motility
PubMed: 29256127
DOI: 10.1007/978-3-319-69535-8_7