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International Journal of Molecular... Nov 2023Human sexual and reproductive development is regulated by the hypothalamic-pituitary-gonadal (HPG) axis, which is primarily controlled by the gonadotropin-releasing... (Review)
Review
Human sexual and reproductive development is regulated by the hypothalamic-pituitary-gonadal (HPG) axis, which is primarily controlled by the gonadotropin-releasing hormone (GnRH) acting on its receptor (GnRHR). Dysregulation of the axis leads to conditions such as congenital hypogonadotropic hypogonadism (CHH) and delayed puberty. The pathophysiology of GnRHR makes it a potential target for treatments in several reproductive diseases and in congenital adrenal hyperplasia. GnRHR belongs to the G protein-coupled receptor family and its GnRH ligand, when bound, activates several complex and tissue-specific signaling pathways. In the pituitary gonadotrope cells, it triggers the G protein subunit dissociation and initiates a cascade of events that lead to the production and secretion of the luteinizing hormone (LH) and follicle-stimulating hormone (FSH) accompanied with the phospholipase C, inositol phosphate production, and protein kinase C activation. Pharmacologically, GnRHR can be modulated by synthetic analogues. Such analogues include the agonists, antagonists, and the pharmacoperones. The agonists stimulate the gonadotropin release and lead to receptor desensitization with prolonged use while the antagonists directly block the GnRHR and rapidly reduce the sex hormone production. Pharmacoperones include the most recent GnRHR therapeutic approaches that directly correct the misfolded GnRHRs, which are caused by genetic mutations and hold serious promise for CHH treatment. Understanding of the GnRHR's genomic and protein structure is crucial for the most appropriate assessing of the mutation impact. Such mutations in the GNRHR are linked to normosmic hypogonadotropic hypogonadism and lead to various clinical symptoms, including delayed puberty, infertility, and impaired sexual development. These mutations vary regarding their mode of inheritance and can be found in the homozygous, compound heterozygous, or in the digenic state. GnRHR expression extends beyond the pituitary gland, and is found in reproductive tissues such as ovaries, uterus, and prostate and non-reproductive tissues such as heart, muscles, liver and melanoma cells. This comprehensive review explores GnRHR's multifaceted role in human reproduction and its clinical implications for reproductive disorders.
Topics: Female; Male; Humans; Receptors, LHRH; Puberty, Delayed; Hypogonadism; Gonadotropin-Releasing Hormone; Luteinizing Hormone; Follicle Stimulating Hormone; Klinefelter Syndrome
PubMed: 37958948
DOI: 10.3390/ijms242115965 -
Life Sciences Dec 2023Polycystic Ovary Syndrome (PCOS) and osteoporosis, though seemingly unrelated, exhibit intricate connections influenced by genetic and epigenetic factors. PCOS,... (Review)
Review
Polycystic Ovary Syndrome (PCOS) and osteoporosis, though seemingly unrelated, exhibit intricate connections influenced by genetic and epigenetic factors. PCOS, characterized by elevated androgen levels, insulin resistance, and increased body weight, has historically been considered protective against bone fragility disorders. However, emerging research suggests that chronic inflammation, prevalent in PCOS, can adversely affect bone health. Studies have demonstrated variable bone mineral density loss in PCOS, often associated with leptin resistance and hyperinsulinemia. Key genes such as INS, IGF1, CTNNB1, AKT1, and STAT3 play pivotal roles in the complex interplay between PCOS and osteoporosis, influencing insulin signaling, oxidative stress, and inflammatory pathways. Oxidative stress, a prominent element in PCOS, can lead to osteoporosis through hormonal imbalances, chronic inflammation, insulin resistance, and lifestyle factors. The insulin signaling pathway also significantly impacts both conditions by contributing to hormonal imbalances and bone health alterations. This intricate network of genetic and epigenetic factors underscores the need for a deeper understanding of their interrelationships. Thus, this review elucidates the multifaceted genetic, epigenetic, and inflammatory connections between PCOS and osteoporosis, highlighting their implications for bone health management in individuals with PCOS.
Topics: Female; Humans; Polycystic Ovary Syndrome; Insulin Resistance; Hyperandrogenism; Insulin; Osteoporosis; Inflammation
PubMed: 37981226
DOI: 10.1016/j.lfs.2023.122280 -
Drug Discovery Today Dec 2023Polycystic ovary syndrome (PCOS) prevails in approximately 33% of females of reproductive age globally. Although the root cause of the disease is unknown, attempts are... (Review)
Review
Polycystic ovary syndrome (PCOS) prevails in approximately 33% of females of reproductive age globally. Although the root cause of the disease is unknown, attempts are made to clinically manage the disturbed hormone levels and symptoms arising due to hyperandrogenism, a hallmark of PCOS. This review presents detailed insights on the etiology, risk factors, current treatment strategies, and challenges therein. Medicinal agents currently in clinical trials and those in the development pipeline are emphasized. The significance of the inclusion of herbal supplements in PCOS and the benefits of improved lifestyle are also explained. Last, emerging therapeutic targets for treating PCOS are elaborated. The present review will assist the research fraternity working in the concerned domain to access significant knowledge associated with PCOS.
Topics: Female; Humans; Polycystic Ovary Syndrome; Hyperandrogenism; Dietary Supplements; Risk Factors
PubMed: 37935329
DOI: 10.1016/j.drudis.2023.103821 -
Clinical Endocrinology Sep 2023Congenital adrenal hyperplasia (CAH) caused by 21-hydroxylase deficiency accounts for 95% of all CAH cases and is one of the most common inborn metabolic conditions. The... (Review)
Review
Congenital adrenal hyperplasia (CAH) caused by 21-hydroxylase deficiency accounts for 95% of all CAH cases and is one of the most common inborn metabolic conditions. The introduction of life-saving glucocorticoid replacement therapy 70 years ago has changed the perception of CAH from a paediatric disorder into a lifelong, chronic condition affecting patients of all age groups. Alongside health problems that can develop during the time of paediatric care, there is an emerging body of evidence suggesting an increased risk of developing co-morbidities during adult life in patients with CAH. The mechanisms that drive the negative long-term outcomes associated with CAH are complex and involve supraphysiological replacement therapies (glucocorticoids and mineralocorticoids), excess adrenal androgens both in the intrauterine and postnatal life, elevated steroid precursors and adrenocorticotropic hormone levels. Alongside a review of mortality outcome, we discuss issues that need to be addressed when caring for the CAH patient including female and male fertility, cardio-metabolic morbidity, bone health and other important long-term outcomes of CAH.
PubMed: 37680029
DOI: 10.1111/cen.14967 -
Frontiers in Endocrinology 2023
Topics: Humans; Hyperaldosteronism; Adrenal Gland Neoplasms; Endocrinology
PubMed: 37484952
DOI: 10.3389/fendo.2023.1237733 -
Ugeskrift For Laeger Mar 2024Congenital adrenal hyperplasia (CAH) arises from genetic enzyme defects, often in CYP21A2, causing primary adrenal insufficiency. In this case report, a man in his late...
Congenital adrenal hyperplasia (CAH) arises from genetic enzyme defects, often in CYP21A2, causing primary adrenal insufficiency. In this case report, a man in his late 20s with lifelong CAH faced challenges in adhering to medication. Suboptimal treatment led to the development of testicular adrenal rest tumours, diagnosed by ultrasound, and hypogonadism. Enhanced adherence restored hormone levels, promoting eugonadism. Adherence plays a crucial role in diminishing tumour size and preventing complications, potentially necessitating orchiectomy in severe cases.
Topics: Humans; Male; Adrenal Hyperplasia, Congenital; Adrenal Rest Tumor; Hypogonadism; Steroid 21-Hydroxylase; Testicular Neoplasms; Adult
PubMed: 38533865
DOI: 10.61409/V12230794 -
Current Atherosclerosis Reports Dec 2023Characterize the risk of cardiovascular disease (CVD) in individuals with polycystic ovarian syndrome (PCOS). Review the pathophysiological pathways that confers CVD... (Review)
Review
PURPOSE OF REVIEW
Characterize the risk of cardiovascular disease (CVD) in individuals with polycystic ovarian syndrome (PCOS). Review the pathophysiological pathways that confers CVD risk in individuals with PCOS and interventions to reduce CVD risk.
RECENT FINDINGS
PCOS is a complex syndrome characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovaries that has metabolic and cardiovascular implications. Intrinsic hormonal dysregulation and chronic low-grade inflammation play an important role in the progression of atherosclerosis in young premenopausal individuals and development of CVD independently of associated traditional risk factors. Management with metformin reduces CVD risk by reducing atherosclerosis progression. PCOS is an important CVD risk factor among individuals of reproductive age. Early detection and interventions are needed to mitigate development of CVD.
Topics: Female; Humans; Polycystic Ovary Syndrome; Cardiovascular Diseases; Risk Factors; Hyperandrogenism; Inflammation; Atherosclerosis
PubMed: 38048007
DOI: 10.1007/s11883-023-01168-1 -
Clinica Chimica Acta; International... Jan 2024The measurement of steroid hormones in blood and urine, which reflects steroid biosynthesis and metabolism, has been recognized as a valuable tool for identifying and... (Review)
Review
The measurement of steroid hormones in blood and urine, which reflects steroid biosynthesis and metabolism, has been recognized as a valuable tool for identifying and distinguishing steroidogenic disorders. The application of mass spectrometry enables the reliable and simultaneous analysis of large panels of steroids, ushering in a new era for diagnosing adrenal diseases. However, the interpretation of complex hormone results necessitates the expertise and experience of skilled clinicians. In this scenario, machine learning techniques are gaining worldwide attention within healthcare fields. The clinical values of combining mass spectrometry-based steroid profiles analysis with machine learning models, also known as steroid metabolomics, have been investigated for identifying and discriminating adrenal disorders such as adrenocortical carcinomas, adrenocortical adenomas, and congenital adrenal hyperplasia. This promising approach is expected to lead to enhanced clinical decision-making in the field of adrenal diseases. This review will focus on the clinical performances of steroid profiling, which is measured using mass spectrometry and analyzed by machine learning techniques, in the realm of decision-making for adrenal diseases.
Topics: Humans; Adrenal Gland Diseases; Adrenocortical Adenoma; Adrenocortical Carcinoma; Steroids; Adrenal Cortex Neoplasms
PubMed: 38169194
DOI: 10.1016/j.cca.2023.117749 -
Frontiers in Endocrinology 2023Polycystic ovarian syndrome (PCOS) is a metabolic, reproductive, and psychological disorder affecting 6-20% of reproductive women worldwide. However, there is still no... (Review)
Review
Polycystic ovarian syndrome (PCOS) is a metabolic, reproductive, and psychological disorder affecting 6-20% of reproductive women worldwide. However, there is still no cure for PCOS, and current treatments primarily alleviate its symptoms due to a poor understanding of its etiology. Compelling evidence suggests that hyperandrogenism is not just a primary feature of PCOS. Instead, it may be a causative factor for this condition. Thus, figuring out the mechanisms of androgen synthesis, conversion, and metabolism is relatively important. Traditionally, studies of androgen excess have largely focused on classical androgen, but in recent years, adrenal-derived 11-oxygenated androgen has also garnered interest. Herein, this Review aims to investigate the origins of androgen excess, androgen synthesis, how androgen receptor (AR) signaling mediates adverse PCOS traits, and the role of 11-oxygenated androgen in the pathophysiology of PCOS. In addition, it provides therapeutic strategies targeting hyperandrogenism in PCOS.
Topics: Female; Humans; Polycystic Ovary Syndrome; Hyperandrogenism; Androgens; Phenotype
PubMed: 38152131
DOI: 10.3389/fendo.2023.1273542 -
Endocrinology and Metabolism Clinics of... Jun 2024Premature pubarche (PP) is a common and usually benign variant of normal puberty most often seen in 5-year-old to 9-year-old children. Some providers routinely order... (Review)
Review
Premature pubarche (PP) is a common and usually benign variant of normal puberty most often seen in 5-year-old to 9-year-old children. Some providers routinely order laboratory testing and a bone age to try to rule out other diagnoses including nonclassic congenital adrenal hyperplasia and gonadal or adrenal tumors. I review the natural history of PP and studies which suggest that without clinical features such as rapid growth and progression or genital enlargement, it is unlikely that a treatable condition will be found. Therefore it is recommended that patients with PP not undergo testing unless there are red flags at the time of the initial visit.
Topics: Humans; Puberty, Precocious; Child; Female; Child, Preschool
PubMed: 38677863
DOI: 10.1016/j.ecl.2024.02.001