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Endocrinology Nov 2019The increasing occurrence of obesity has become a significant public health concern. Individuals with obesity have higher prevalence of heart disease, stroke,... (Review)
Review
The increasing occurrence of obesity has become a significant public health concern. Individuals with obesity have higher prevalence of heart disease, stroke, osteoarthritis, diabetes, and reproductive disorders. Reproductive problems include menstrual irregularities, pregnancy complications, and infertility due to anovulation, in women, and lower testosterone and diminished sperm count, in men. In particular, women with obesity have reduced levels of both gonadotropin hormones, and, in obese men, lower testosterone is accompanied by diminished LH. Taken together, these findings indicate central dysregulation of the hypothalamic-pituitary-gonadal axis, specifically at the level of the GnRH neuron function, which is the final brain output for the regulation of reproduction. Obesity is a state of hyperinsulinemia, hyperlipidemia, hyperleptinemia, and chronic inflammation. Herein, we review recent advances in our understanding of how these metabolic and immune changes affect hypothalamic function and regulation of GnRH neurons. In the latter part, we focus on neuroinflammation as a major consequence of obesity and discuss findings that reveal that GnRH neurons are uniquely positioned to respond to inflammatory changes.
Topics: Animals; Female; Humans; Hypothalamus; Infertility, Female; Infertility, Male; Inflammation; Male; Neurosecretory Systems; Obesity; Reproduction
PubMed: 31513269
DOI: 10.1210/en.2019-00487 -
Endocrine Reviews Nov 2022Polycystic ovary syndrome (PCOS) is among the most common disorders in women of reproductive age, affecting up to 15% worldwide, depending on the diagnostic criteria....
Polycystic ovary syndrome (PCOS) is among the most common disorders in women of reproductive age, affecting up to 15% worldwide, depending on the diagnostic criteria. PCOS is characterized by a constellation of interrelated reproductive abnormalities, including disordered gonadotropin secretion, increased androgen production, chronic anovulation, and polycystic ovarian morphology. It is frequently associated with insulin resistance and obesity. These reproductive and metabolic derangements cause major morbidities across the lifespan, including anovulatory infertility and type 2 diabetes (T2D). Despite decades of investigative effort, the etiology of PCOS remains unknown. Familial clustering of PCOS cases has indicated a genetic contribution to PCOS. There are rare Mendelian forms of PCOS associated with extreme phenotypes, but PCOS typically follows a non-Mendelian pattern of inheritance consistent with a complex genetic architecture, analogous to T2D and obesity, that reflects the interaction of susceptibility genes and environmental factors. Genomic studies of PCOS have provided important insights into disease pathways and have indicated that current diagnostic criteria do not capture underlying differences in biology associated with different forms of PCOS. We provide a state-of-the-science review of genetic analyses of PCOS, including an overview of genomic methodologies aimed at a general audience of non-geneticists and clinicians. Applications in PCOS will be discussed, including strengths and limitations of each study. The contributions of environmental factors, including developmental origins, will be reviewed. Insights into the pathogenesis and genetic architecture of PCOS will be summarized. Future directions for PCOS genetic studies will be outlined.
Topics: Female; Humans; Polycystic Ovary Syndrome; Hyperandrogenism; Diabetes Mellitus, Type 2; Obesity; Genomics
PubMed: 35026001
DOI: 10.1210/endrev/bnac001 -
Journal of Circadian Rhythms Mar 2020The reproductive function of humans is regulated by several sex hormones which are secreted in synergy with the circadian timing of the body. Sleep patterns produce... (Review)
Review
The reproductive function of humans is regulated by several sex hormones which are secreted in synergy with the circadian timing of the body. Sleep patterns produce generic signatures that physiologically drive the synthesis, secretion, and metabolism of hormones necessary for reproduction. Sleep deprivation among men and women is increasingly reported as one of the causes of infertility. In animal models, sleep disturbances impair the secretion of sexual hormones thereby leading to a decrease in testosterone level, reduced sperm motility and apoptosis of the Leydig cells in male rats. Sleep deprivation generates stressful stimuli intrinsically, due to circadian desynchrony and thereby increases the activation of the Hypothalamus-Pituitary Adrenal (HPA) axis, which, consequently, increases the production of corticosterone. The elevated level of corticosteroids results in a reduction in testosterone production. Sleep deprivation produces a commensurate effect on women by reducing the chances of fertility. Sleeplessness among female shift workers suppresses melatonin production as well as excessive HPA activation which results in early pregnancy loss, failed embryo implantation, anovulation and amenorrhea. Sleep deprivation in women has also be found to be associated with altered gonadotropin and sex steroid secretion which all together lead to female infertility. Poor quality of sleep is observed in middle-aged and older men and this also contributes to reduced testosterone concentrations. The influence of sleep disturbances post-menopausal is associated with irregular synthesis and secretion of female sex steroid hormones.
PubMed: 32256630
DOI: 10.5334/jcr.190 -
Autophagy Oct 2021Polycystic ovary syndrome (PCOS) is a unification of endocrine and metabolic disorders and has become immensely prevalent among women of fertile age. The prime organ... (Review)
Review
Polycystic ovary syndrome (PCOS) is a unification of endocrine and metabolic disorders and has become immensely prevalent among women of fertile age. The prime organ affected in PCOS is the ovary and its distressed functioning elicits disturbed reproductive outcomes. In the ovary, macroautophagy/autophagy performs a pivotal role in directing the chain of events starting from oocytes origin until its fertilization. Recent discoveries demonstrate a significant role of autophagy in the pathogenesis of PCOS. Defective autophagy in the follicular cells during different stages of follicles is observed in the PCOS ovary. Exploring different autophagy pathways provides a platform for predicting the possible cause of altered ovarian physiology in PCOS. In this review, we have emphasized autophagy's role in governing follicular development under normal circumstances and in PCOS, including significant abnormalities associated with PCOS such as anovulation, hyperandrogenemia, metabolic disturbances, and related abnormality. So far, few studies have linked autophagy and PCOS and propose its essential role in PCOS progression. However, detailed knowledge in this area is lacking. Here we have summarized the latest knowledge related to autophagy associated with PCOS. This review's main objective is to provide a background of autophagy in the ovary, its possible connection with PCOS and suggested a novel proposal for future studies to aid a better understanding of PCOS pathogenesis.: AE: androgen excess; AF: antral follicle; AKT/PKB: AKT serine/threonine kinase; AMH: anti-Mullerian hormone; AMPK: AMP-activated protein kinase; ATG: autophagy-related; BCL2: BCL2 apoptosis regulator; BECN1: beclin 1; BMP: bone morphogenetic protein; CASP3: caspase 3; CL: corpus luteum; CYP17A1/P450C17: cytochrome P450 family 17 subfamily A member 1; CYP19A1: cytochrome P450 family 19 subfamily A member 1; DHEA: dehydroepiandrosterone; EH: endometrial hyperplasia; FF: follicular fluid; FOXO: forkhead box O; FSH: follicle stimulating hormone; GC: granulosa cell; GDF: growth differentiation factor; HA: hyperandrogenemia; HMGB1: high mobility group box 1; IGF1: insulin like growth factor 1; INS: insulin; IR: insulin resistance; LHCGR/LHR: luteinizing hormone/choriogonadotropin receptor; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MAPK/ERK: mitogen-activated protein kinase; MAPK8/JNK: mitogen-activated protein kinase 8; MTOR: mechanistic target of rapamycin kinase; MTORC: mechanistic target of rapamycin complex; NAFLD: nonalcoholic fatty liver disease; NFKB: nuclear factor kappa B; OLR1/LOX-1: oxidized low density lipoprotein receptor 1; oxLDL: oxidized low-density lipoproteins; PA: palmitic acid; PCOS: polycystic ovary syndrome; PF: primary follicle; PGC: primordial germ cell; PI3K: phosphoinositide 3-kinase; PMF: primordial follicle; ROS: reactive oxygen species; RP: resting pool; SIRT1: sirtuin 1; SQSTM1/p62: sequestosome 1; T2DM: type 2 diabetes mellitus; TC: theca cell; TUG1: taurine up-regulated 1.
Topics: Autophagy; Diabetes Mellitus, Type 2; Dissent and Disputes; Female; Humans; Phosphatidylinositol 3-Kinases; Polycystic Ovary Syndrome
PubMed: 34161185
DOI: 10.1080/15548627.2021.1938914 -
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 -
Journal of Clinical Pathology Sep 2019Subfertility affects one in seven couples and is defined as the inability to conceive after 1 year of regular unprotected intercourse. This article describes the... (Review)
Review
Subfertility affects one in seven couples and is defined as the inability to conceive after 1 year of regular unprotected intercourse. This article describes the initial clinical evaluation and investigation to guide diagnosis and management. The primary assessment of subfertility is to establish the presence of ovulation, normal uterine cavity and patent fallopian tubes in women, and normal semen parameters in men. Ovulation is supported by a history of regular menstrual cycles (21-35 days) and confirmed by a serum progesterone >30 nmol/L during the luteal phase of the menstrual cycle. Common causes of anovulation include polycystic ovary syndrome (PCOS), hypothalamic amenorrhoea (HA) and premature ovarian insufficiency (POI). Tubal patency is assessed by hysterosalpingography, hystero-contrast sonography, or more invasively by laparoscopy and dye test. The presence of clinical or biochemical hyperandrogenism, serum gonadotrophins (luteinising hormone/follicle stimulating hormone) / oestradiol, pelvic ultrasound to assess ovarian morphology / antral follicle count, can help establish the cause of anovulation. Ovulation can be restored in women with PCOS using letrozole (an aromatase inhibitor), clomifene citrate (an oestrogen antagonist) or exogenous gonadotrophin administration. If available, pulsatile gonadotrophin releasing hormone therapy is the preferred option for restoring ovulation in HA. Spermatogenesis can be induced in men with hypogonadotrophic hypogonadism with exogenous gonadotrophins. Unexplained subfertility can be treated with in vitro fertilisation after 2 years of trying to conceive. Involuntary childlessness is associated with significant psychological morbidity; hence, expert assessment and prompt treatment are necessary to support such couples.
Topics: Female; Fertility; Humans; Infertility, Female; Infertility, Male; Male; Ovulation; Predictive Value of Tests; Pregnancy; Reproductive Techniques, Assisted; Risk Factors; Spermatogenesis; Time-to-Pregnancy; Treatment Outcome
PubMed: 31296604
DOI: 10.1136/jclinpath-2018-205579 -
Indian Journal of Pediatrics Oct 2023Hyperandrogenism is a common condition encountered by pediatric and adolescent physicians. Most girls with hyperandrogenism represent physiological pubertal variation;... (Review)
Review
Hyperandrogenism is a common condition encountered by pediatric and adolescent physicians. Most girls with hyperandrogenism represent physiological pubertal variation; pathology may be present in a substantial minority. Systematic evaluation is essential to avoid unnecessary work-up in physiological causes while not missing pathological causes. Polycystic ovarian syndrome (PCOS), unexplained, persistent hyperandrogenism of ovarian origin, is the most common form in adolescent girls. The high prevalence of physiological peripubertal hirsutism, anovulation, and polycystic ovarian morphology results in mislabeling many girls as having the polycystic ovarian syndrome, a disorder with lifelong implications. The use of strict criteria of age-specific anovulation, hyperandrogenism, and duration is essential to reduce their stigmatization. The exclusion of secondary causes by screening tests (cortisol, thyroid profile, prolactin, and 17OHP) is essential before undertaking treatment for PCOS. Lifestyle measures, estrogen-progesterone preparations, antiandrogens, and metformin are the cornerstone of managing the disorder.
Topics: Female; Adolescent; Humans; Child; Hyperandrogenism; Polycystic Ovary Syndrome; Anovulation; Hirsutism
PubMed: 37402107
DOI: 10.1007/s12098-023-04678-7 -
International Journal of Molecular... Nov 2021Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among reproductive-aged women. It is characterized by chronic anovulation, hyperandrogenism, and... (Review)
Review
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among reproductive-aged women. It is characterized by chronic anovulation, hyperandrogenism, and the presence of polycystic ovary in ultrasound examination. PCOS is specified by an increased number of follicles at all growing stages, mainly seen in the preantral and small antral follicles and an increased serum level of Anti-Müllerian Hormone (AMH). Because of the strong correlation between circulating AMH levels and antral follicle count on ultrasound, Anti-Müllerian Hormone has been proposed as an alternative marker of ovulatory dysfunction in PCOS. However, the results from the current literature are not homogeneous, and the specific threshold of AMH in PCOS and PCOM is, therefore, very challenging. This review aims to update the current knowledge about AMH, the pathophysiology of AMH in the pathogenesis of PCOS, and the role of Anti-Müllerian Hormone in the treatment of this syndrome.
Topics: Anovulation; Anti-Mullerian Hormone; Female; Humans; Hyperandrogenism; Ovarian Follicle; Polycystic Ovary Syndrome; Ultrasonography
PubMed: 34830389
DOI: 10.3390/ijms222212507 -
European Review For Medical and... Jan 2021D-chiro-Inositol has been widely used in clinical practice to induce ovulation in women with polycystic ovary syndrome. Only recent evidence established that this... (Review)
Review
OBJECTIVE
D-chiro-Inositol has been widely used in clinical practice to induce ovulation in women with polycystic ovary syndrome. Only recent evidence established that this molecule acts through two different mechanisms, with potentially different outcomes. On the one hand, under a metabolic perspective, D-chiro-Inositol improves insulin signaling, thus restoring physiological insulin levels in resistant subjects. On the other hand, at a cellular level, it downregulates the expression of steroidogenic enzyme aromatase, which is responsible for the conversion of androgens to estrogens.
MATERIALS AND METHODS
We reviewed current literature in different databases, searching for D-chiro-Inositol in relation with one of the following keywords: myo-inositol, PCOS, infertility, insulin resistance, aromatase, androgen and inositol, testosterone, estrogen and inositol, estradiol, hypogonadotropic hypogonadism, fat tissue, estrogens and cancer, anovulation, uterine myoma, endometriosis, endometrial hyperplasia.
RESULTS
D-Chiro-Inositol treatment may be helpful in restoring physiological hormonal levels in various clinical disorders. However, D-Chiro-Inositol intervention should be carefully designed to avoid possible undesired side effects stemming from its multiple mechanisms of action.
CONCLUSIONS
We evaluated the optimal D Chiro-Inositol administration for different pathologies, defining dosages and timing. Even though further studies are required to validate our preliminary results, this paper is primarily intended to guide researchers through some of the pathways of D-Chiro-Inositol.
Topics: Aromatase; Down-Regulation; Female; Humans; Inositol; Insulin; Insulin Resistance; Male; Polycystic Ovary Syndrome
PubMed: 33506934
DOI: 10.26355/eurrev_202101_24412