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Clinica Chimica Acta; International... Jun 2022A polycystic ovarian syndrome (PCOS) is the most common endocrine disorder affecting females. Furthermore, it is a heterogeneous disease with a variety of etiologies and... (Review)
Review
A polycystic ovarian syndrome (PCOS) is the most common endocrine disorder affecting females. Furthermore, it is a heterogeneous disease with a variety of etiologies and outcomes. Patients frequently complain about infertility, irregular menstruation, acne, seborrheic dermatitis, hirsutism, and obesity. PCOS can be caused by hypothalamic-pituitary-ovarian axis dysfunction, heredity, or metabolic abnormalities. PCOS is characterized by chronic low-level inflammation, which includes an imbalance in pro-inflammatory factor secretion, endothelial cell dysfunction, and leukocytosis. PCOS is also distinguished by hormonal and immune dysregulation. During PCOS, immune cells and immune regulatory molecules play critical roles in maintaining metabolic homeostasis and regulating immune responses. Because of oligo/anovulation, patients with PCOS have low progesterone levels. Therefore, low progesterone levels in PCOS overstimulate the immune system, causing it to produce more estrogen, which leads to a variety of autoantibodies. This review aims to summarize the immune regulation involved in the pathogenesis of PCOS and pave the way for the development of better PCOS treatment options in the near future.
Topics: Anovulation; Female; Hirsutism; Humans; Hyperandrogenism; Polycystic Ovary Syndrome; Progesterone
PubMed: 35447143
DOI: 10.1016/j.cca.2022.04.234 -
The Medical Clinics of North America Nov 2021The approach to hyperandrogenism in women varies depending on the woman's age and severity of symptoms. Once tumorous hyperandrogenism is excluded, the most common cause... (Review)
Review
The approach to hyperandrogenism in women varies depending on the woman's age and severity of symptoms. Once tumorous hyperandrogenism is excluded, the most common cause is PCOS. Hirsutism is the most common presenting symptom. The woman's concern about her symptoms plays an important role in the management of disease. Although measurement of testosterone is useful in identifying an underlying cause, care must be taken when interpreting the less accurate assays that are available commercially. Surgical resection is curative in tumorous etiologies, whereas medical management is the mainstay for non-tumorous causes.
Topics: Age Factors; Androgen Antagonists; Female; Humans; Hyperandrogenism; Polycystic Ovary Syndrome; Racial Groups; Testosterone; Women's Health
PubMed: 34688417
DOI: 10.1016/j.mcna.2021.06.008 -
The Journal of Clinical Endocrinology... Apr 2023Postmenopausal hyperandrogenism is a condition caused by relative or absolute androgen excess originating from the ovaries and/or the adrenal glands. Hirsutism, in other... (Review)
Review
Postmenopausal hyperandrogenism is a condition caused by relative or absolute androgen excess originating from the ovaries and/or the adrenal glands. Hirsutism, in other words, increased terminal hair growth in androgen-dependent areas of the body, is considered the most effective measure of hyperandrogenism in women. Other symptoms can be acne and androgenic alopecia or the development of virilization, including clitoromegaly. Postmenopausal hyperandrogenism may also be associated with metabolic disorders such as abdominal obesity, insulin resistance, and type 2 diabetes. Mild hyperandrogenic symptoms can be due to relative androgen excess associated with menopausal transition or polycystic ovary syndrome, which is likely the most common cause of postmenopausal hyperandrogenism. Virilizing symptoms, on the other hand, can be caused by ovarian hyperthecosis or an androgen-producing ovarian or adrenal tumor that could be malignant. Determination of serum testosterone, preferably by tandem mass spectrometry, is the first step in the endocrine evaluation, providing important information on the degree of androgen excess. Testosterone >5 nmol/L is associated with virilization and requires prompt investigation to rule out an androgen-producing tumor in the first instance. To localize the source of androgen excess, imaging techniques are used, such as transvaginal ultrasound or magnetic resonance imaging (MRI) for the ovaries and computed tomography and MRI for the adrenals. Bilateral oophorectomy or surgical removal of an adrenal tumor is the main curative treatment and will ultimately lead to a histopathological diagnosis. Mild to moderate symptoms of androgen excess are treated with antiandrogen therapy or specific endocrine therapy depending on diagnosis. This review summarizes the most relevant causes of hyperandrogenism in postmenopausal women and suggests principles for clinical investigation and treatment.
Topics: Female; Humans; Hyperandrogenism; Androgens; Diabetes Mellitus, Type 2; Postmenopause; Polycystic Ovary Syndrome; Virilism; Testosterone; Adrenal Gland Neoplasms
PubMed: 36409990
DOI: 10.1210/clinem/dgac673 -
Endocrinology and Metabolism Clinics of... Mar 2021Congenital adrenal hyperplasia encompasses a group of autosomal recessive defects in cortisol biosynthesis, and 21-hydroxylase deficiency accounts for 95% of such cases.... (Review)
Review
Congenital adrenal hyperplasia encompasses a group of autosomal recessive defects in cortisol biosynthesis, and 21-hydroxylase deficiency accounts for 95% of such cases. Non-classic 21-hydroxylase deficiency is due to partial enzymatic defects, which present with normal cortisol synthesis, but excessive production of adrenal androgens, including 11-oxygenated androgens. Non-classic 21-hydroxylase deficiency is relatively common, and its phenotype resembles closely that of polycystic ovary syndrome. This review focuses primarily on non-classic 21-hydroxylase deficiency, its clinical features, diagnosis, and management.
Topics: Adrenal Hyperplasia, Congenital; Androgens; Endocrinologists; Female; Humans; Polycystic Ovary Syndrome
PubMed: 33518183
DOI: 10.1016/j.ecl.2020.10.008 -
The Journal of Neuroscience : the... Jan 2020Phoenix et al. (1959) reported that treating pregnant guinea pigs with testosterone had enduring effects on the sex-related behavior of their female offspring. Since... (Review)
Review
Phoenix et al. (1959) reported that treating pregnant guinea pigs with testosterone had enduring effects on the sex-related behavior of their female offspring. Since then, similar enduring effects of early testosterone exposure have been found in other species, including humans, and for other behaviors that show average sex differences. In humans, the affected outcomes include gender identity, sexual orientation, and children's sex-typical play behavior. The evidence linking early testosterone exposure to sex-typed play is particularly robust, and sex-typed play is also influenced by many other factors, including socialization by parents and peers and self-socialization, based on cognitive understanding of gender. In addition to influencing behavior, testosterone and hormones produced from testosterone affect mammalian brain structure. Studies using human autopsy material have found some sex differences in the human brain similar to those seen in other species, and have reported that some brain sex differences correlate with sexual orientation or gender identity, although the causes of these brain/behavior relationships are unclear. Studies that have imaged the living human brain have found only a small number of sex differences, and these differences are generally small in magnitude. In addition, they have not been linked to robust psychological or behavioral sex differences. Future research might benefit from improved imaging technology, and attention to other brain characteristics. In addition, it might usefully explore how different types of factors, such as early testosterone exposure and parental socialization, work together in the developmental system that produces sex/gender differences in human brain and behavior.
Topics: Adrenal Hyperplasia, Congenital; Adult; Aggression; Animals; Brain; Child; Child Rearing; Empathy; Environment; Female; Forecasting; Gender Identity; Humans; Male; Neurosciences; Organ Size; Parent-Child Relations; Peer Group; Play and Playthings; Pregnancy; Prenatal Exposure Delayed Effects; Puberty; Sex; Sex Characteristics; Sexual Behavior; Spatial Navigation; Species Specificity; Testosterone
PubMed: 31488609
DOI: 10.1523/JNEUROSCI.0750-19.2019 -
Nature Reviews. Endocrinology Jun 2022Treatment for congenital adrenal hyperplasia (CAH) was introduced in the 1950s following the discovery of the structure and function of adrenocortical hormones. Although... (Review)
Review
Treatment for congenital adrenal hyperplasia (CAH) was introduced in the 1950s following the discovery of the structure and function of adrenocortical hormones. Although major advances in molecular biology have delineated steroidogenic mechanisms and the genetics of CAH, management and treatment of this condition continue to present challenges. Management is complicated by a combination of comorbidities that arise from disease-related hormonal derangements and treatment-related adverse effects. The clinical outcomes of CAH can include life-threatening adrenal crises, altered growth and early puberty, and adverse effects on metabolic, cardiovascular, bone and reproductive health. Standard-of-care glucocorticoid formulations fall short of replicating the circadian rhythm of cortisol and controlling efficient adrenocorticotrophic hormone-driven adrenal androgen production. Adrenal-derived 11-oxygenated androgens have emerged as potential new biomarkers for CAH, as traditional biomarkers are subject to variability and are not adrenal-specific, contributing to management challenges. Multiple alternative treatment approaches are being developed with the aim of tailoring therapy for improved patient outcomes. This Review focuses on challenges and advances in the management and treatment of CAH due to 21-hydroxylase deficiency, the most common type of CAH. Furthermore, we examine new therapeutic developments, including treatments designed to replace cortisol in a physiological manner and adjunct agents intended to control excess androgens and thereby enable reductions in glucocorticoid doses.
Topics: Adrenal Hyperplasia, Congenital; Androgens; Biomarkers; Glucocorticoids; Humans; Hydrocortisone
PubMed: 35411073
DOI: 10.1038/s41574-022-00655-w -
The Journal of Clinical Endocrinology... Apr 2021Standard glucocorticoid therapy in congenital adrenal hyperplasia (CAH) regularly fails to control androgen excess, causing glucocorticoid overexposure and poor health... (Randomized Controlled Trial)
Randomized Controlled Trial
CONTEXT
Standard glucocorticoid therapy in congenital adrenal hyperplasia (CAH) regularly fails to control androgen excess, causing glucocorticoid overexposure and poor health outcomes.
OBJECTIVE
We investigated whether modified-release hydrocortisone (MR-HC), which mimics physiologic cortisol secretion, could improve disease control.
METHODS
A 6-month, randomized, phase 3 study was conducted of MR-HC vs standard glucocorticoid, followed by a single-arm MR-HC extension study. Primary outcomes were change in 24-hour SD score (SDS) of androgen precursor 17-hydroxyprogesterone (17OHP) for phase 3, and efficacy, safety and tolerability of MR-HC for the extension study.
RESULTS
The phase 3 study recruited 122 adult CAH patients. Although the study failed its primary outcome at 6 months, there was evidence of better biochemical control on MR-HC, with lower 17OHP SDS at 4 (P = .007) and 12 (P = .019) weeks, and between 07:00h to 15:00h (P = .044) at 6 months. The percentage of patients with controlled 09:00h serum 17OHP (< 1200 ng/dL) was 52% at baseline, at 6 months 91% for MR-HC and 71% for standard therapy (P = .002), and 80% for MR-HC at 18 months' extension. The median daily hydrocortisone dose was 25 mg at baseline, at 6 months 31 mg for standard therapy, and 30 mg for MR-HC, and after 18 months 20 mg MR-HC. Three adrenal crises occurred in phase 3, none on MR-HC and 4 in the extension study. MR-HC resulted in patient-reported benefit including menses restoration in 8 patients (1 on standard therapy), and 3 patient and 4 partner pregnancies (none on standard therapy).
CONCLUSION
MR-HC improved biochemical disease control in adults with reduction in steroid dose over time and patient-reported benefit.
Topics: Adrenal Hyperplasia, Congenital; Adult; Aged; Anti-Inflammatory Agents; Female; Follow-Up Studies; Humans; Hydrocortisone; Male; Middle Aged; Prognosis; Young Adult
PubMed: 33527139
DOI: 10.1210/clinem/dgab051 -
European Journal of Endocrinology Nov 2021Patients with 21-hydroxylase deficiency congenital adrenal hyperplasia (21OHD-CAH) have poor health outcomes with increased mortality, short stature, impaired fertility,... (Review)
Review
BACKGROUND
Patients with 21-hydroxylase deficiency congenital adrenal hyperplasia (21OHD-CAH) have poor health outcomes with increased mortality, short stature, impaired fertility, and increased cardiovascular risk factors such as obesity. To address this, there are therapies in development that target the clinical goal of treatment, which is to control excess androgens with an adrenal replacement dose of glucocorticoid.
METHODS
Narrative review of publications on recent clinical developments in the pharmacotherapy of congenital adrenal hyperplasia.
SUMMARY
Therapies in clinical development target different levels of the hypothalamo-pituitary-adrenal axis. Two corticotrophin-releasing factor type 1 (CRF1) receptor antagonists, Crinecerfont and Tildacerfont, have been trialled in poorly controlled 21OHD-CAH patients, and both reduced ACTH and androgen biomarkers while patients were on stable glucocorticoid replacement. Improvements in glucocorticoid replacement include replacing the circadian rhythm of cortisol that has been trialled with continuous s.c. infusion of hydrocortisone and Chronocort, a delayed-release hydrocortisone formulation. Chronocort optimally controlled 21OHD-CAH in 80% of patients on an adrenal replacement dose of hydrocortisone, which was associated with patient-reported benefits including restoration of menses and pregnancies. Adrenal-targeted therapies include the steroidogenesis-blocking drug Abiraterone acetate, which reduced adrenal androgen biomarkers in poorly controlled patients.
CONCLUSIONS
CRF1 receptor antagonists hold promise to avoid excess glucocorticoid replacement in patients not controlled on standard or circadian glucocorticoid replacement such as Chronocort. Gene and cell therapies are the only therapeutic approaches that could potentially correct both cortisol deficiency and androgen excess.
Topics: Adrenal Hyperplasia, Congenital; Androgens; Circadian Rhythm; Endocrinology; Glucocorticoids; Hormone Replacement Therapy; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System
PubMed: 34735372
DOI: 10.1530/EJE-21-0794 -
Revista Brasileira de Ginecologia E... Apr 2022Diagnosing polycystic ovary syndrome (PCOS) during adolescence is challenging since normal pubertal development overlap typical features of this syndrome. The authors...
Diagnosing polycystic ovary syndrome (PCOS) during adolescence is challenging since normal pubertal development overlap typical features of this syndrome. The authors aim to summarize the existing evidence concerning PCOS in adolescence, particularly its diagnostic criteria and therapeutic options. A search throughout medical databases such as PubMed and MedScape was performed. Diagnostic criteria include irregular menstrual cycles according to time postmenarche and evidence of clinical hyperandrogenism and/or biochemical hyperandrogenism, provided other causes have been excluded. Polycystic ovarian morphology ought not to be used as a diagnostic criterion. Treatment should target manifestations and/or comorbidities, even in the absence of a definite diagnosis. Lifestyle interventions are the first-line treatment. Combined oral contraceptives, metformin or antiandrogens may also be considered as adjuvants. Screening for PCOS in adolescence is crucial as it allows an early intervention on the symptoms and comorbidities presented leading to better long-term reproductive and metabolic outcomes.
Topics: Adolescent; Female; Humans; Hyperandrogenism; Life Style; Menstruation Disturbances; Metformin; Polycystic Ovary Syndrome
PubMed: 35623621
DOI: 10.1055/s-0042-1742292 -
Reviews in Endocrine & Metabolic... Feb 2023Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders of steroidogenesis of the adrenal cortex, most commonly due to 21-hydroxylase deficiency... (Review)
Review
Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders of steroidogenesis of the adrenal cortex, most commonly due to 21-hydroxylase deficiency caused by mutations in the CYP21A2 gene. Although women with CAH have decreased fecundity, they are able to conceive; thus, if pregnancy is not desired, contraception options should be offered. If fertility is desired, women with classic CAH should first optimize glucocorticoid treatment, followed by ovulation induction medications and gonadotropins if needed. Due to the possible pregnancy complications and implications on the offspring, preconception genetic testing and counseling with a high-risk obstetrics specialist is recommended. For couples trying to avoid having a child with CAH, care with a reproductive endocrinology and infertility specialist to utilize in vitro fertilization can be offered, with or without preimplantation genetic testing for monogenic disorders. Prenatal screening and diagnosis options during pregnancy include maternal serum cell free-DNA for sex of the baby, and chorionic villus sampling and amniocentesis for diagnosis of CAH. Pregnant women with classic CAH need glucocorticoids to be adjusted during the pregnancy, at the time of delivery, and postpartum, and should be monitored for adrenal crisis. Maternal and fetal risks may include chorioamnionitis, maternal hypertension, gestational diabetes, cesarean section, and small for gestational age infants. This review on CAH due to 21-hydroxylase deficiency highlights reproductive health including genetic transmission, contraception options, glucocorticoid management, fertility treatments, as well as testing, antenatal monitoring, and management during pregnancy, delivery, and postpartum.
Topics: Child; Pregnancy; Female; Humans; Adrenal Hyperplasia, Congenital; Glucocorticoids; Cesarean Section; Postpartum Period; Steroid 21-Hydroxylase
PubMed: 36399318
DOI: 10.1007/s11154-022-09770-5