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The Journal of Clinical Endocrinology... Mar 2020Polycystic ovary syndrome (PCOS) is a prevalent disorder in reproductive aged women associated with a number of endocrine and metabolic complications, including...
CONTEXT
Polycystic ovary syndrome (PCOS) is a prevalent disorder in reproductive aged women associated with a number of endocrine and metabolic complications, including increased risk of endometrial cancer.
OBJECTIVE
To study the effect of the characteristic increased androgen levels in PCOS on the endometrium, a novel scaffold-free multicellular endometrial organoid was established.
DESIGN
Human endometrial organoids were constructed using primary endometrial epithelial and stromal cells from endometrial tissues. Organoids were treated for 14 days with physiologic levels of estradiol and testosterone to mimic a normal follicular phase or PCOS hormone profiles. Organoids were harvested for immunostaining and ribonucleic acid sequencing.
SETTING
Academic institution.
PATIENTS
Endometrial tissues from 10 premenopausal women undergoing hysterectomy for benign pathologies were obtained following written consent.
MAIN OUTCOME MEASURES
Organoid architecture, cell specific markers, functional markers, proliferation, and gene expression were measured.
RESULTS
A method to generate scaffold-free endometrial organoids containing epithelial and stromal cells was established. These organoids exhibited distinct organization with epithelial cells lining the outer surface and stromal cells in the center of the organoids. Epithelial cells were polarized, organoids expressed cell type specific and functional markers, as well as androgen, estrogen, and progesterone receptors. Treatment with PCOS hormones increased cell proliferation and dysregulated genes in endometrial organoids.
CONCLUSIONS
A new multicellular, scaffold-free endometrial organoid system was established that resembled physiology of the native endometrium. Excess androgens in PCOS promoted cell proliferation in endometrial organoids, revealing new mechanisms of PCOS-associated with risk of endometrial neoplasia.
Topics: Adult; Androgens; Case-Control Studies; Cell Proliferation; Endometrial Neoplasms; Endometrium; Female; Follow-Up Studies; Humans; Hyperandrogenism; Middle Aged; Organoids; Polycystic Ovary Syndrome; Prognosis; Prospective Studies; Stromal Cells
PubMed: 31614364
DOI: 10.1210/clinem/dgz100 -
Clinical Chemistry Dec 2023Androgens are synthesized from cholesterol through sequential conversions by enzymes in the adrenal glands and gonads. Serum levels of androgens change during the... (Review)
Review
BACKGROUND
Androgens are synthesized from cholesterol through sequential conversions by enzymes in the adrenal glands and gonads. Serum levels of androgens change during the different phases of life and regulate important developmental and maturational processes. Androgen excess or deficiency can therefore present at various ages in various ways.
CONTENT
The diagnostic approach for atypical genitalia, premature pubarche, delayed pubertal onset or progression, and hirsutism or virilization, including measurement of androgens (testosterone, androstenedione, 17-OHprogesterone, dehydroepiandrosterone, and dihydrotestosterone) is discussed in the current review. Androgens can be measured in serum, saliva, urine, or dried blood spots. Techniques to measure androgens, including immunoassays and LC-MS, have their own advantages and pitfalls. In addition, pre- and postanalytical issues are important when measuring androgens.
SUMMARY
During clinical interpretation of androgen measurements, it is important to take preanalytical circumstances, such as time of blood withdrawal, into account. As immunoassays have major drawbacks, especially in samples from women and neonates, concentrations measured using these assays should be interpreted with care. Reference intervals can only be used in relation to the measurement technique and the standardization of the assay. In the near future, new androgens will probably be added to the current repertoire to further improve the diagnosis and follow-up of androgen excess or deficiency.
Topics: Infant, Newborn; Female; Humans; Androgens; Testosterone; Androstenedione; Virilism; Hirsutism; Dehydroepiandrosterone
PubMed: 37794651
DOI: 10.1093/clinchem/hvad146 -
Nature Reviews. Endocrinology May 2020The adrenal gland is a source of sex steroid precursors, and its activity is particularly relevant during fetal development and adrenarche. Following puberty, the... (Review)
Review
The adrenal gland is a source of sex steroid precursors, and its activity is particularly relevant during fetal development and adrenarche. Following puberty, the synthesis of androgens by the adrenal gland has been considered of little physiologic importance. Dehydroepiandrosterone (DHEA) and its sulfate, DHEAS, are the major adrenal androgen precursors, but they are biologically inactive. The second most abundant unconjugated androgen produced by the human adrenals is 11β-hydroxyandrostenedione (11OHA4). 11-Ketotestosterone, a downstream metabolite of 11OHA4 (which is mostly produced in peripheral tissues), and its 5α-reduced product, 11-ketodihydrotestosterone, are bioactive androgens, with potencies equivalent to those of testosterone and dihydrotestosterone. These adrenal-derived androgens all share an oxygen atom on carbon 11, so we have collectively termed them 11-oxyandrogens. Over the past decade, these androgens have emerged as major components of several disorders of androgen excess, such as congenital adrenal hyperplasia, premature adrenarche and polycystic ovary syndrome, as well as in androgen-dependent tumours, such as castration-resistant prostate cancer. Moreover, in contrast to the more extensively studied, traditional androgens, circulating concentrations of 11-oxyandrogens do not demonstrate an age-dependent decline. This Review focuses on the rapidly expanding knowledge regarding the implications of 11-oxyandrogens in human physiology and disease.
Topics: Adrenal Glands; Adrenal Hyperplasia, Congenital; Androgens; Endocrine System Diseases; Female; Humans; Male; Oxygen; Polycystic Ovary Syndrome; Prostatic Neoplasms; Puberty, Precocious
PubMed: 32203405
DOI: 10.1038/s41574-020-0336-x -
FP Essentials Dec 2016Hirsutism is defined as excessive terminal hair growth, such as coarse sexual or secondary hair, that typically appears in a male growth pattern in androgen-dependent... (Review)
Review
Hirsutism is defined as excessive terminal hair growth, such as coarse sexual or secondary hair, that typically appears in a male growth pattern in androgen-dependent areas of the female body. It can occur in men and women. Common etiologies include polycystic ovary syndrome, idiopathic hyperandrogenemia, idiopathic hirsutism, adrenal hyperplasia due to 21-hydroxylase deficiency, androgen-secreting tumors, iatrogenic hirsutism, acromegaly, Cushing syndrome, hyperprolactinemia, and hypo- or hyperthyroidism. Diagnostic guidelines are predominantly aimed at premenopausal women but an appropriate evaluation for underlying endocrinopathies in postmenopausal women and men may be required. Management is aimed at eliminating drugs that cause hirsutism when possible, evaluation of underlying hypothalamic-pituitary-gonadal axis dysregulation, and detection of androgen-secreting tumors. Pharmacotherapy options include combination estrogens-progestins, antiandrogens, 5-alpha reductase inhibitors, biguanides, gonadotropin-releasing hormone agonists, and topical ornithine decarboxylase inhibitors. Surgical excision may be needed for pituitary, adrenal, or ovarian adenomas.
Topics: Androgen Antagonists; Contraceptives, Oral; Endocrine System Diseases; Family Practice; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Hair Removal; Hirsutism; Humans; Luteinizing Hormone; Prolactin; Sex Hormone-Binding Globulin; Thyroid Function Tests
PubMed: 27936531
DOI: No ID Found -
Ceska Gynekologie 2017Overview of excessive hair growth in women, hirsutism. Although women with hirsutism typically present because of cosmetic concerns, the majority also have an underlying... (Review)
Review
OBJECTIVE
Overview of excessive hair growth in women, hirsutism. Although women with hirsutism typically present because of cosmetic concerns, the majority also have an underlying endocrine disorder.
DESIGN
Review article.
SETTING
Department of Gynecology and Obstetrics, General Faculty Hospital and 1st Faculty of Medicine of Charles Universtity, Prague.
MATERIAL AND METHODS
Hirsutism is a clinical diagnosis defined by the presence of excess terminal hair growth (dark, coarse hairs) in androgen-sensitive areas. It affects between five and ten percent of women of reproductive age. It may be the initial, and possibly only, sign of an underlying androgen disorder.
CONCLUSIONS
The most common cause of hirsutism is polycystic ovary syndrome (PCOS). In some cases, hirsutism is mild and requires only reassurance and local (nonsystemic) therapy, while in others it causes significant psychological distress and requires more extensive therapy. In case of rapid progressive hair growth should be first exclude androgen-secerning tumour (ovarian, adrenal) as the most serious condition.
Topics: Female; Hirsutism; Humans; Polycystic Ovary Syndrome
PubMed: 28593779
DOI: No ID Found -
Best Practice & Research. Clinical... Nov 2016Androgen excess (AE) is a key feature of polycystic ovary syndrome (PCOS) and results in, or contributes to, the clinical phenotype of these patients. Although AE will... (Review)
Review
Androgen excess (AE) is a key feature of polycystic ovary syndrome (PCOS) and results in, or contributes to, the clinical phenotype of these patients. Although AE will contribute to the ovulatory and menstrual dysfunction of these patients, the most recognizable sign of AE includes hirsutism, acne, and androgenic alopecia or female pattern hair loss (FPHL). Evaluation includes not only scoring facial and body terminal hair growth using the modified Ferriman-Gallwey method but also recording and possibly scoring acne and alopecia. Moreover, assessment of biochemical hyperandrogenism is necessary, particularly in patients with unclear or absent hirsutism, and will include assessing total and free testosterone (T), and possibly dehydroepiandrosterone sulfate (DHEAS) and androstenedione, although these latter contribute limitedly to the diagnosis. Assessment of T requires use of the highest quality assays available, generally radioimmunoassays with extraction and chromatography or mass spectrometry preceded by liquid or gas chromatography. Management of clinical hyperandrogenism involves primarily either androgen suppression, with a hormonal combination contraceptive, or androgen blockade, as with an androgen receptor blocker or a 5α-reductase inhibitor, or a combination of the two. Medical treatment should be combined with cosmetic treatment including topical eflornithine hydrochloride and short-term (shaving, chemical depilation, plucking, threading, waxing, and bleaching) and long-term (electrolysis, laser therapy, and intense pulse light therapy) cosmetic treatments. Generally, acne responds to therapy relatively rapidly, whereas hirsutism is slower to respond, with improvements observed as early as 3 months, but routinely only after 6 or 8 months of therapy. Finally, FPHL is the slowest to respond to therapy, if it will at all, and it may take 12 to 18 months of therapy for an observable response.
Topics: 5-alpha Reductase Inhibitors; Acne Vulgaris; Alopecia; Androgen Antagonists; Androstenedione; Contraceptives, Oral, Combined; Contraceptives, Oral, Hormonal; Dehydroepiandrosterone Sulfate; Eflornithine; Female; Hair Removal; Hirsutism; Humans; Hyperandrogenism; Ornithine Decarboxylase Inhibitors; Polycystic Ovary Syndrome; Testosterone
PubMed: 27387253
DOI: 10.1016/j.bpobgyn.2016.05.003 -
Frontiers of Hormone Research 2019Androgen excess is often associated with obesity states, at any age of life, because of changes in the pattern of secretion or metabolism of androgens and in their... (Review)
Review
Androgen excess is often associated with obesity states, at any age of life, because of changes in the pattern of secretion or metabolism of androgens and in their actions at the level of target tissues, particularly the adipose tissue. Androgen excess plays an important role in favouring the expansion of visceral fat, which characterize so-called visceral obesity. Moreover, there is evidence that the combination of androgen excess and obesity may favour the development of metabolic disorders, such as the metabolic syndrome and type 2 diabetes. In obese adolescent girls, androgen excess may also suggest the potential development of the polycystic ovary syndrome (PCOS). A new hypothesis, based on long-term lifestyle intervention programs or bariatric surgery, supports the concept that a "PCOS secondary to obesity" may exist, as confirmed by the complete resolution of all features defining PCOS after considerable weight loss. Obesity can also develop after long-term exposure to chronic stress, which is characterized by increased activity of the hypothalamic-pituitary-adrenal axis and the sympathetic system combined with higher than normal androgen production rates in women. This increasingly observed condition, often underestimated, should be considered more carefully, not only in mature women but also in girls during adolescence. The presence of a hyperandrogenic state can also be detected in menopausal women, as a consequence of the rearrangement of the sex hormone balance which, in turn, may play some role in determining the development of both visceral adiposity and even obesity and, consequently, metabolic disorders. Undoubtedly, the recognition of the potential negative effects of androgen excess in obese women may open new therapeutic perspectives aimed at achieving a sustained weight loss and its maintenance for as long as possible.
Topics: Adolescent; Adult; Androgens; Female; Humans; Intra-Abdominal Fat; Obesity; Polycystic Ovary Syndrome; Stress, Psychological
PubMed: 31499497
DOI: 10.1159/000494908 -
Current Opinion in Pharmacology Feb 2023Polycystic ovary syndrome is a prevalent endocrinopathy involving androgen excess, and anovulatory infertility. The disorder is also associated with many comorbidities... (Review)
Review
Polycystic ovary syndrome is a prevalent endocrinopathy involving androgen excess, and anovulatory infertility. The disorder is also associated with many comorbidities such as obesity and hyperinsulinemia, and an increased risk of cardiovascular complications. Reproductive, endocrine, and metabolic symptoms are highly variable, with heterogenous phenotypes adding complexity to clinical management of symptoms. This review highlights recent findings regarding emerging therapies for treating polycystic ovary syndrome, including i) pharmacological agents to target androgen excess, ii) modulation of kisspeptin signalling to target central neuroendocrine dysregulation, and iii) novel insulin sensitisers to combat peripheral metabolic dysfunction.
Topics: Female; Humans; Polycystic Ovary Syndrome; Androgens; Insulin Resistance; Comorbidity; Obesity
PubMed: 36621270
DOI: 10.1016/j.coph.2022.102345 -
Frontiers of Hormone Research 2019Although polycystic ovary syndrome (PCOS) is the most common androgen excess disorder, screening for Cushing's Syndrome (CS) should be considered in women with PCOS... (Review)
Review
Although polycystic ovary syndrome (PCOS) is the most common androgen excess disorder, screening for Cushing's Syndrome (CS) should be considered in women with PCOS phenotype, particularly if they are also affected by other disturbances that increase their pretest probability (e.g., osteoporosis/bone fractures). Approximately 70-80% of women with CS present menstrual abnormalities, and PCOS findings are found in 46% of these patients. Diagnostic efforts should strengthen if the clinical picture is severe or of rapid onset in order to ensure the earliest and most appropriate treatment. If the diagnosis of CS is challenging, its differentiation from PCOS is not outdone: isolated PCOS may be associated to hypothalamic-pituitary-adrenal axis disruption, leading to false-positive results in screening tests. Because of this overlap, the diagnosis of CS is initially missed or delayed. Diagnostic utility of serum androgen assessment is controversial, but the widespread use of high-performance liquid chromatography and gas chromatography-mass spectrometry for urinary steroid profiling is showing promising results. According to the role of adrenocorticotropic hormone (ACTH) in adrenal androgen secretion, it is not surprising that the levels of dehydroepiandrosterone, dehydroepiandrosterone-sulfate, and androstenedione (A4) are generally elevated or in the upper normal range in patients with ACTH-dependent CS. Conversely, adrenal androgens are generally low in patients with cortisol-secreting adrenocortical adenoma. However, androgen-secreting adrenal tumors (adenoma and carcinoma) can be also associated with severe hyperandrogenism. Regression of hypercortisolism after treatment causes disappearance of hyperandrogenism. However, signs of androgen excess may be detectable in well-controlled CS as a result of ACTH compensatory response to certain adrenal steroidogenesis inhibitors.
Topics: Adrenocorticotropic Hormone; Androgens; Comorbidity; Cushing Syndrome; Female; Humans; Hyperandrogenism; Polycystic Ovary Syndrome
PubMed: 31499501
DOI: 10.1159/000494904 -
International Journal of Molecular... Jul 2023Endometrial receptivity is a state of the endometrium defined by its readiness for embryo implantation. When the receptivity of the endometrium is impaired due to... (Review)
Review
Endometrial receptivity is a state of the endometrium defined by its readiness for embryo implantation. When the receptivity of the endometrium is impaired due to hyperandrogenism or androgen excess, this condition can lead to pregnancy loss or infertility. Hyperandrogenism encompasses a wide range of clinical manifestations, including polycystic ovary syndrome (PCOS), idiopathic hirsutism, hirsutism and hyperandrogaenemia, non-classical congenital adrenal hyperplasia, hyperandrogenism, insulin resistance, acanthosis nigricans (HAIR-AN), ovarian or adrenal androgen-secreting neoplasms, Cushing's syndrome, and hyperprolactinaemia. Recurrent miscarriages have been shown to be closely related to elevated testosterone levels, which alter the endometrial milieu so that it is less favourable for embryo implantation. There are mechanisms for endometrial receptivity that are affected by excess androgen. The HOXA gene, aVβ3 integrin, CDK signalling pathway, MECA-79, and MAGEA-11 were the genes and proteins affect endometrial receptivity in the presence of a hyperandrogenic state. In this review, we would like to explore the other manifestations of androgen excess focusing on causes other than PCOS and learn possible mechanisms of endometrial receptivity behind androgen excess leading to pregnancy loss or infertility.
Topics: Female; Pregnancy; Humans; Hyperandrogenism; Polycystic Ovary Syndrome; Hirsutism; Androgens; Endometrium; Infertility
PubMed: 37569402
DOI: 10.3390/ijms241512026