The impact of water pollution on the health of older people.

Water pollution exerts a negative impact on the health of both women and men, inducing hormonal changes, accelerating aging, and consequently leading to the premature onset of age-related health problems. Water pollutants can in general be classified as chemical (both organic and inorganic), physical, and biological agents. Certain chemical pollutants have been found to disrupt hormonal balance by blocking, mimicking, or disrupting functions within the intricate homeostasis of the human body. Moreover, certain water pollutants, including specific pesticides and industrial chemicals, have been associated with neurological and psychiatric disorders, such as mood swings, depression, cognitive decline, and anxiety, impacting both women and men. Water pollution is also associated with physical ailments, such as diarrhea, skin diseases, malnutrition, and cancer. Exposure to specific pollutants may promote premature menopause and vasomotor symptoms, elevate the risk of cardiovascular disease, and reduce bone density. In men, exposure to water pollution has been shown to reduce LH, FSH, and testosterone serum levels. The oxidative stress induced by pollutants prompts apoptosis of Sertoli and germ cells, inhibiting spermatogenesis and altering the normal morphology and concentration of sperm. Environmental estrogens further contribute to reduced sperm counts, reproductive system disruptions, and the feminization of male traits. Studies affirm that men generally exhibit a lower susceptibility than women to hormonal changes and health issues attributed to water pollutants. This discrepancy may be attributed to the varied water-related activities which have traditionally been undertaken by women, as well as differences in immune responses between genders. The implementation of effective measures to control water pollution and interventions aimed at safeguarding and enhancing the well-being of the aging population is imperative. The improvement of drinking water quality has emerged as a potential public health effort with the capacity to curtail the onset of cognitive impairment and dementia in an aging population.

Association of Obesity and Bariatric Surgery on Hair Health.

Obesity and obesity-related conditions today constitute a public health problem worldwide. Obesity is an "epidemic" chronic disorder, which is defined by the WHO as normal or excessive fat accumulation that may impair health. It is also defined for adults as a BMI that is greater than or equal to 30. The most common obesity-related diseases are type 2 diabetes mellitus, cardiovascular diseases, metabolic syndrome, chronic kidney disease, hyperlipidemia, hypertension, nonalcoholic fatty liver disease, and certain types of cancer. It has been also proven that obesity can have a negative effect on hair. It can lead to hair thinning. Patients with obesity can undergo bariatric surgery if they meet the inclusion criteria. The four common types of weight loss surgery include a duodenal switch with biliopancreatic diversion, laparoscopic adjustable gastric banding, Roux-en-Y gastric bypass, and sleeve gastrectomy. Bariatric surgery can affect skin and hair and is associated with telogen effluvium due to weight loss, microelement deficiency, anesthesia, low calorie intake, and low protein intake. Patients who undergo bariatric surgery can experience post-bariatric surgery depression. Hair loss can have a major impact on self-esteem, negatively affecting one's self-image. The purpose of this narrative review is to critically review how obesity, obesity-related diseases, and bariatric surgery affect hair health in general and the hair development cycle, and how they influence hair loss.

EMAS position statement: Testosterone replacement therapy in older men.

INTRODUCTION: Late-onset hypogonadism is the clinical entity characterised by low testosterone concentrations associated with clinical symptoms in the absence of organic disease in ageing men. It has been associated with metabolic syndrome, reduced bone mineral density, and increased cardiovascular morbidity and mortality risk. Although testosterone replacement therapy (TRT) reverses most of these conditions in young hypogonadal men, the risk/benefit ratio of TRT in older men is debatable. AIM: To update the 2015 EMAS statement on TRT in older men with new research on late-onset hypogonadism and TRT. MATERIALS AND METHODS: Literature review and consensus of expert opinion. SUMMARY RECOMMENDATIONS: TRT should be offered only to symptomatic older men with confirmed low testosterone concentrations after explaining the uncertainties regarding the long-term safety of this treatment. TRT may be offered to men with severe hypogonadism and erectile dysfunction to improve sexual desire, erectile, and orgasmic function. It should also be considered in hypogonadal men with severe insulin resistance or pre-diabetes mellitus. TRT may also be considered, in combination with proven treatment strategies, for osteoporosis, or for selected patients with persistent mild depressive symptoms and/or low self-perceived quality of life, combined with standard medical care for each condition. TRT is contraindicated in hypogonadal men actively seeking fertility treatment. Due to a lack of data, TRT should not be routinely used in older men to improve exercise capacity/physical function, improve cognitive function, or prevent cognitive decline. TRT must be avoided in older, frail men with known breast cancer or untreated prostate cancer and all men who have had myocardial infarction or stroke within the last four months, and those with severe or decompensated heart failure. The quality of evidence regarding patients with previous prostate cancer or cardiovascular disease is too low to draw definitive conclusions. Any limits on duration of use are arbitrary, and treatment should continue for as long as the man feels the benefits outweigh the risks for him, and decisions must be made on an individual basis. Withdrawal should be considered when hypogonadism is reversed after the resolution of underlying disorder. Short-acting transdermal preparations should be preferred for TRT initiation in older men, but injectable forms may be considered subsequently. Older men on TRT should be monitored at 3, 6, and 12 months after initiation and at least yearly thereafter, or earlier and more frequently if indicated. Evaluation should include assessment of the clinical response, and measurement of total testosterone, haematocrit, and prostate-specific antigen (PSA) concentrations. Bone density and/or quality should also be assessed. Obese and overweight patients should be encouraged to undergo lifestyle modifications, including exercise and weight loss, to increase endogenous testosterone.

Do GLP-1 Analogs Have a Place in the Treatment of PCOS? New Insights and Promising Therapies.

Polycystic ovary syndrome (PCOS) is the most prevalent endocrinopathy in women of reproductive age. This condition is characterized by hyperandrogenism and either oligo- or anovulation. PCOS patients often present comorbidities such as obesity, insulin resistance, impaired glucose metabolism, dyslipidemia, hypertension, metabolic syndrome, and an increased risk of diabetes. Given the profound implications of metabolic impairment in PCOS, the accurate diagnosis and management of these facets are imperative. The first-line approach to treatment involves lifestyle modifications, including dietary adjustments and exercise aimed at achieving weight loss, a strategy consistently emphasized across the literature. Supplementation with probiotics, vitamin D, and L-carnitine have also provided additional benefits to patients. In select cases, pharmacological interventions are needed for optimal therapeutic results. The most common medications used in PCOS include metformin, thiazolidinediones, inositols, and two classes of antidiabetic agents: dipeptidyl peptidase-IV (DPP-IV) inhibitors, and sodium-glucose cotransporter-2 (SGLT-2) inhibitors. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a new addition to the therapeutic arsenal for the metabolic management of PCOS. GLP-1 receptor agonists cause insulin release in a glucose-dependent manner, yielding clinical benefits such as heightened satiety, reduced appetite, and appetite regulation. GLP-1RAs have demonstrated efficacy in reducing glycated hemoglobin levels and promoting weight loss while ameliorating hyperlipidemia. Prior to initiating GLP-1RA therapy, patients should undergo screening for contraindications, including history of pancreatitis, diabetic retinopathy, or thyroid cancer. The effects of treatment should be monitored using laboratory testing and body weight measurements. Effective communication between clinician and patient should be maintained with regular check-in for a period of 6 to 12 months.

Decreased neurokinin B as a risk factor of functional hypothalamic amenorrhea.

BACKGROUND: Neurokinin B (NKB) belongs to the tachykinin family of proteins who's regulation is essential for proper function of the reproductive system. It has been shown that patients with functional hypothalamic amenorrhea (FHA) exhibit decreased levels of serum kisspeptin. As kisspeptin secretion is regulated by NKB signaling, it is reasonable to suspect that patients with FHA will also have abnormal NKB secretion. AIM: To assess NKB levels in patients with FHA and to determine whether NKB signaling is affected in these patients. We hypothesized that decreased NKB signaling is a factor contributing to the development of the FHA. MATERIALS AND METHODS: A total of 147 patients with FHA and 88 healthy age-matched controls were enrolled. Baseline blood samples were drawn from both groups to measure serum concentrations of NKB, luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E2), prolactin (PRL), thyroid-stimulating hormone (TSH), free thyroxine (fT4), cortisol, dehydroepiandrosterone sulfate (DHEA-S), testosterone (T), glucose, and insulin. RESULTS: Mean serum NKB levels were found to be decreased significantly in the FHA group when compared with the control group (628.35 ± 324.92 vs. 721.41 ± 337.57 ng/L, respectively p = 0.002). No statistical difference was observed in NKB-1 levels within the FHA group when selecting for normal and decreased body mass index. CONCLUSIONS: Patients with FHA were found to have decreased serum NKB concentrations when compared to healthy controls. Abnormal NKB secretion is likely a key factor contributing to development of FHA.

Cognitive decline and dementia in women after menopause: Prevention strategies.

Worldwide, cognitive decline and dementia are becoming one of the biggest challenges for public health. The decline in cognition and the development of dementia may be caused by predisposing or trigger factors. There is no consensus over whether the drop in estrogen levels after menopause is a risk factor for cognitive decline and dementia. This article discusses the prevention of cognitive decline and dementia in women after menopause, both primary prevention (essentially pharmacological intervention) and secondary prevention (chiefly diet and weight reduction). Further study is required to clarify whether menopausal hormone therapy (MHT) has a role in dementia.

EMAS position statement: Vitamin D and menopausal health.

INTRODUCTION: There is increasing evidence that vitamin D has widespread tissue effects. In addition to osteoporosis, vitamin D deficiency has been associated with cardiovascular disease, diabetes, cancer, infections and neurodegenerative disease. However, the effect of vitamin D supplementation on non-skeletal outcomes requires clarification, especially in postmenopausal women. AIM: This position statement provides an evidence-based overview of the role of vitamin D in the health of postmenopausal women based on observational and interventional studies. MATERIALS AND METHODS: Literature review and consensus of expert opinion. RESULTS AND CONCLUSIONS: Vitamin D status is determined by measuring serum 25-hydroxyvitamin D levels. Concentrations <20 ng/ml (<50 nmol/l) and <10 ng/ml (<25 nmol/l) are considered to constitute vitamin D deficiency and severe deficiency, respectively. Observational data suggest an association between vitamin D deficiency and adverse health outcomes in postmenopausal women, although they cannot establish causality. The evidence from randomized controlled trials concerning vitamin D supplementation is not robust, since many studies did not consider whether people were deficient at baseline. Moreover, high heterogeneity exists in terms of the population studied, vitamin D dosage, calcium co-administration and duration of intervention. Concerning skeletal health, vitamin D deficiency is associated with low bone mass and an increased risk of fractures. Vitamin D supplementation at maintenance doses of 800-2000 IU/day (20-50 µg/day), after repletion of vitamin D status with higher weekly or daily doses, may be of benefit only when co-administered with calcium (1000-1200 mg/day), especially in the elderly populations and those with severe vitamin D deficiency. Concerning cardiovascular disease, vitamin D deficiency is associated with an increased prevalence of cardiovascular risk factors, mainly metabolic syndrome, type 2 diabetes mellitus and dyslipidemia. Vitamin D deficiency, especially its severe form, is associated with an increased risk of cardiovascular events (coronary heart disease, stroke, mortality), independently of traditional risk factors. Vitamin D supplementation may have a modestly beneficial effect on lipid profile and glucose homeostasis, especially in obese individuals or those ≥60 years old and at doses of ≥2000 IU/day (≥50 µg/day). However, it has no effect on the incidence of cardiovascular events. Concerning cancer, vitamin D deficiency is associated with increased incidence of and mortality from several types of cancer, such as colorectal, lung and breast cancer. However, the data on other types of gynecological cancer are inconsistent. Vitamin D supplementation has no effect on cancer incidence, although a modest reduction in cancer-related mortality has been observed. Concerning infections, vitamin D deficiency has been associated with acute respiratory tract infections, including coronavirus disease 2019 (COVID-19). Vitamin D supplementation may decrease the risk of acute respiratory tract infections and the severity of COVID-19 (not the risk of infection). Concerning menopausal symptomatology, vitamin D deficiency may have a negative impact on some aspects, such as sleep disturbances, depression, sexual function and joint pains. However, vitamin D supplementation has no effect on these, except for vulvovaginal atrophy, at relatively high doses, i.e., 40,000-60,000 IU/week (1000-1500 IU/week) orally or 1000 IU/day (25 µg/day) as a vaginal suppository.

Stress, kisspeptin, and functional hypothalamic amenorrhea.

Functional hypothalamic amenorrhea (FHA) is the most common cause of secondary amenorrhea in women of reproductive age. FHA is predominantly caused by stress, decreased caloric intake, excessive exercise, or a combination thereof. These physical, psychological, and metabolic stressors cause aberration in the pulsatile release of gonadotropin-releasing hormone (GnRH) and subsequently impair function of the hypothalamic-pituitary-ovarian (HPO) axis. Various neurotransmitters acting in the central nervous system are involved in control of the HPO axis and of these, kisspeptin is one of the most important. Corticotropin-releasing hormone (CRH), also inhibits the pulsatile secretion of GnRH and also acts as an intermediary between stress factors and the reproductive system. One of the main ongoing concerns in patients with FHA is chronic hypoestrogenism, a condition, which is associated with sexual dysfunction and infertility. It may also lead to osteoporosis, and predispose to neurodegenerative and cardiovascular diseases. Treatment of FHA requires the elimination of causative factors, however, making the necessary lifestyle changes is not always easy to initiate and maintain. Broadening our knowledge of the complex neural mechanisms regulating reproductive function in which kisspeptin plays a key role can help in the development of new treatment options such as the potential of kisspeptin receptor agonists for patients with FHA.

The influence of estro-progestin therapy on neurohormonal activity in functional hypothalamic amenorrhea.

Background: Functional hypothalamic amenorrhea (FHA) is a chronic endocrine disorder caused by the abnormal pulsatile secretion of neurohormones in the hypothalamus. Secretion of GnRH is regulated by kisspeptin/neurokinin B/dynorphin (KNDy) neurons. These neurons produce, among other neurohormones, neurokinin B (NKB) which regulates the coordinated stimulation or inhibition of GnRH secreting neurons. Aim of the study: Assessment and comparison of serum NKB in patients with FHA at baseline, and following 6 months of estrogen-progestagen therapy. Materials and methods: Fifty-five patients with functional hypothalamic amenorrhea were included in the study group. Serum concentrations of neurokinin B (NKB), follicle stimulating hormone (FSH), luteinizing hormone (LH), 17-ß-estradiol (E2), prolactin (PRL), cortisol, testosterone (T), dehydroepiandrosterone sulfate (DHEA-S), thyroid-stimulating hormone (TSH), free thyroxine (fT4), fasting glucose and insulin, as well as lipid profile were measured at baseline. At the time of diagnosis, patients with FHA were prescribed a course of 2 mg 17-ß-estradiol and 10 mg dydrogesterone for duration of 6 months. Serum NKB was then reassessed following treatment at 6 months. Results: At baseline, the FHA group was found to have a decreased serum NKB concentration when compared to a healthy control group. Following 6 months of sequential estrogen-progestogen hormone therapy, this study did not find any statistically significant difference in serum NKB concentration in the treatment arm compared to baseline. Conclusions: For the first time, NKB secretion has been studied in patients with FHA. A significantly lower level of serum NKB was observed in these patients at baseline, when compared to a control group. After 6 months of combination estrogen-progesterone therapy, no significant changes in NKB levels were observed in these patients. These findings, for the first time in the literature, provide insight into the perceived benefit of HRT, calling into question its benefit in addressing the underlying etiopathogenetic contributors of FHA. These new findings may contribute to more targeted and appropriate treatment of such patients in the future.

Nesfatin-1 as a potential marker for functional hypothalamic amenorrhea.

OBJECTIVE: Nesfatin-1 plays an important role in regulating metabolism, appetite, gut motility, and eating behavior. It is suspected that abnormalities in nesfatin-1 secretion may be involved in the development of anorexia nervosa, and as such, this study aims to investigate the "circumstances of" nesfatin-1 in patients with functional hypothalamic amenorrhea (FHA). MATERIALS AND METHODS: One hundred and forty-seven patients with FHA were enrolled to the present study. A control group consisting of 88 healthy, age-matched subjects was used. Both study and control groups had blood samples drawn to establish baseline serum concentrations of luteinizing hormone, follicle-stimulating hormone, estradiol, prolactin, thyroid-stimulating hormone, fT4, morning cortisol, dehydroepiandrosterone sulfate, testosterone, glucose, and insulin. Nesfatin-1 was also measured with the use of enzyme-linked immunosorbent assay. RESULTS: Patients with FHA were found to have a significantly decreased concentration of serum nesfatin-1 when compared to healthy controls (6.21 ± 4.79 vs. 8.64 ± 6.63 respectively, p = 0.005). No statistically significant difference in nesfatin-1 levels was found between patients with normal and decreased BMI in the FHA group. Significant positive correlation was observed between serum nesfatin-1 concentration and 17-ß-estradiol, while a significant negative correlation was observed between serum nesfatin-1 concentration and patient age, fasting glucose, and HDL levels. CONCLUSIONS: This is the first known study to examine nesfatin-1 concentration in the context of clinical FHA. Patients with FHA were found to have decreased serum nesfatin-1 concentrations. This finding may prove instrumental in our future approach managing patients with FHA.

From diagnosis to treatment of androgen-secreting ovarian tumors: a practical approach.

About 5% of all ovarian tumors develop some form of hormonal activity. Only 1% of ovarian tumors will secrete androgens causing clinical hyperandrogenism. Most androgen-secreting neoplasms (ASN) derive from sex cord or stroma cells of the ovary and may affect both premenopausal and postmenopausal women. Typically, a patient will present reporting symptoms of rapidly increasing hyperandrogenization such as: hirsutism, acne, frontal/male pattern balding, and in severe cases even virilization. Sertoli-Leydig Cell Tumors are the most frequent ASN and constitute about 0.5% of all ovarian neoplasms. Typically affecting women under 30 years of age, these tumors are usually unilateral and benign. They are also the most common tumor in postmenopausal women suffering with hyperandrogenism. Other tumors originating from the sex-cord stroma are also known to develop in this population, but the incidence of these is much lower. Approaching suspected hyperandrogenemia and its related symptoms in a clinical setting can be a significant diagnostic challenge. When evaluating a patient for hyperandrogenism, it is important to assess the severity of symptoms but most of all it is critical to assess the time of onset and dynamics of symptom progression. Diagnostic tools including laboratory tests and imaging studies should also be engaged. When deriving a differential diagnosis for androgen-secreting ovarian tumors, adrenal gland tumors should be considered as well as typical endocrine pathologies including polycystic ovary syndrome, congenital adrenal hyperplasia, Cushing's disease, and acromegaly. Treatment options for an androgen-secreting ovarian tumors is mainly surgical, but in exceptional cases can involve pharmacotherapy alone.

Menopause, wellbeing and health: A care pathway from the European Menopause and Andropause Society.

This care pathway from the European Menopause and Andropause Society (EMAS) provides an updated pathway for monitoring and guidance of women at midlife, focusing on those approaching the end of the reproductive life-cycle, going through the menopausal transition and beyond. The care pathway is written by professionals involved in women's health and provides a stepwise individualized approach, stratified according to needs, symptoms and reproductive stage. Furthermore, the pathway provides details on screening for chronic diseases related to menopause and ageing. Treatment options for climacteric symptoms range from menopausal hormone therapy to non-hormonal alternatives and lifestyle modifications. Therapy should be tailored to personal needs and wishes. The pathway aims to offer a holistic, balanced approach for monitoring middle-aged women, aiming to control health problems effectively and ensure healthy ageing.

Neuroendocrine Determinants of Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women and a major cause of anovulatory infertility. A diagnosis of PCOS is established based the presence of two out of three clinical symptoms, which are criteria accepted by the ESHRE/ASRM (European Society of Human Reproduction and Embryology/American Society for Reproductive Medicine). Gonadotropin-releasing hormone (GnRH) is responsible for the release of luteinizing hormone, and follicle stimulating hormone from the pituitary and contributes a leading role in controlling reproductive function in humans. The goal of this review is to present the current knowledge on neuroendocrine determinations of PCOS. The role of such neurohormones as GnRH, and neuropeptides kisspeptin, neurokinin B, phoenixin-14, and galanin is discussed in this aspect. Additionally, different neurotransmitters (gamma-aminobutyric acid (GABA), glutamate, serotonin, dopamine, and acetylcholine) can also be involved in neuroendocrine etiopathogenesis of PCOS. Studies have shown a persistent rapid GnRH pulse frequency in women with PCOS present during the whole ovulatory cycle. Other studies have proved that patients with PCOS are characterized by higher serum kisspeptin levels. The observations of elevated serum kisspeptin levels in PCOS correspond with the hypothesis that overactivity in the kisspeptin system is responsible for hypothalamic-pituitary-gonadal axis overactivity. In turn, this causes menstrual disorders, hyperandrogenemia and hyperandrogenism. Moreover, abnormal regulation of Neurokinin B (NKB) is also suspected of contributing to PCOS development, while NKB antagonists are used in the treatment of PCOS leading to reduction in Luteinizing hormone (LH) concentration and total testosterone concentration. GnRH secretion is regulated not only by kisspeptin and neurokinin B, but also by other neurohormones, such as phoenixin-14, galanin, and Glucagon-like peptide-1 (GLP-1), that have favorable effects in counteracting the progress of PCOS. A similar process is associated with the neurotransmitters such as GABA, glutamate, serotonin, dopamine, and acetylcholine, as well as the opioid system, which may interfere with secretion of GnRH, and therefore, influence the development and severity of symptoms in PCOS patients. Additional studies are required to explain entire, real mechanisms responsible for PCOS neuroendocrine background.

The Genetic Backdrop of Hypogonadotropic Hypogonadism.

The pituitary is an organ of dual provenance: the anterior lobe is epithelial in origin, whereas the posterior lobe derives from the neural ectoderm. The pituitary gland is a pivotal element of the axis regulating reproductive function in mammals. It collects signals from the hypothalamus, and by secreting gonadotropins (FSH and LH) it stimulates the ovary into cyclic activity resulting in a menstrual cycle and in ovulation. Pituitary organogenesis is comprised of three main stages controlled by different signaling molecules: first, the initiation of pituitary organogenesis and subsequent formation of Rathke's pouch; second, the migration of Rathke's pouch cells and their proliferation; and third, lineage determination and cellular differentiation. Any disruption of this sequence, e.g., gene mutation, can lead to numerous developmental disorders. Gene mutations contributing to disordered pituitary development can themselves be classified: mutations affecting transcriptional determinants of pituitary development, mutations related to gonadotropin deficiency, mutations concerning the beta subunit of FSH and LH, and mutations in the DAX-1 gene as a cause of adrenal hypoplasia and disturbed responsiveness of the pituitary to GnRH. All these mutations lead to disruption in the hypothalamic-pituitary-ovarian axis and contribute to the development of primary amenorrhea.

Hyperthyroidism associated with struma ovarii - a case report and review of literature.

BACKGROUND: Hyperthyroidism is a state characterized by elevated serum level of thyroid hormones: thyroxine (T4) and triiodothyronine (T3). This is mainly related to the condition and functioning of the thyroid gland. In 60-80% of cases elevation of these hormones are caused by Grave's disease. Thyrotoxicosis is an extreme presentation of hyperthyroidism which can, in rare cases, be caused by excessive synthesis of thyroxine by tumor cells. Struma ovarii is a rare ovarian teratoma composed of thyroid tissue in more than 50%. OBJECTIVE AND METHOD: To present a case of a 30-year-old female patient with a past history of Grave's disease treated by strumectomy 7 years prior; now presenting for the assessment of secondary amenorrhea. Pelvic ultrasound revealed bilateral solid tumors on the left and right ovary, respectively measuring 5 cm and 6 cm in diameter. Her clinical presentation was suggestive of overt hyperthyroidism, and she presented with a significantly elevated CA-125 (152.7 U/mL). RESULTS: The patient subsequently underwent a bilateral oophorectomy in which both masses were excised and histopathological examination confirmed teratoma maturum cysticum. Struma ovarii was noted as a component of the left ovary teratoma. CONCLUSION: Establishing a proper diagnosis of hyperthyroidism and elucidating its origin is often challenging. Struma ovarii is a rare cause of hyperthyroidism but should always be considered in case of treatment resistant hyperthyroidism. This case-report lends itself as an example of the value in maintaining gynecological-endocrinological knowledge in the setting if clinical gynecology.

18-Year-old patient with Klinefelter syndrome (47, XXY) and complete androgen insensitivity syndrome (CAIS) - case report.

AIMS: The aims of the presented case report are to emphasize the importance of a proper diagnostics and treatment in the case of the coexistence of Klinefelter syndrome (KS, 47 XXY) and complete androgen insensitivity syndrome (CAIS). Since there is no causal treatment it is necessary to provide the patient with a good quality of life, including psychological and sexological support. MATERIALS AND METHODS: The presented case report is the retrospective analysis of the patient's medical history over the 3 years. RESULTS: At the age of 15, the patient was directed to genetic testing due to primary amenorrhea. The results of the patient showed an incorrect male karyotype with the SRY gene present (47, XXY). A molecular diagnostics revealed a very rare variant of the androgen receptor (AR) mutation responsible for tissue insensitivity to androgens. The detected mutation has not been described in the available databases so far. Following a diagnosis of the presence of Klinefelter syndrome (KS, 47 XXY) together with complete androgen insensitivity syndrome (CAIS), the patient underwent a bilateral gonadectomy. CONCLUSIONS: In women with KS and CAIS physiological reproduction and maintenance of normal sex, hormone levels are not possible. A gonadectomy is performed due to the risk of malignant testicular tumors.

Autoimmune Diseases in Patients with Premature Ovarian Insufficiency-Our Current State of Knowledge.

Premature ovarian insufficiency (POI), previously known as premature ovarian failure or premature menopause, is defined as loss of ovarian function before the age of 40 years. The risk of POI before the age of 40 is 1%. Clinical symptoms develop as a result of estrogen deficiency and may include amenorrhea, oligomenorrhea, vasomotor instability (hot flushes, night sweats), sleep disturbances, vulvovaginal atrophy, altered urinary frequency, dyspareunia, low libido, and lack of energy. Most causes of POI remain undefined, however, it is estimated that anywhere from 4-30% of cases are autoimmune in origin. As the ovaries are a common target for autoimmune attacks, an autoimmune etiology of POI should always be considered, especially in the presence of anti-oocyte antibodies (AOAs), autoimmune diseases, or lymphocytic oophoritis in biopsy. POI can occur in isolation, but is often associated with other autoimmune conditions. Concordant thyroid disorders such as hypothyroidism, Hashimoto thyroiditis, and Grave's disease are most commonly seen. Adrenal autoimmune disorders are the second most common disorders associated with POI. Among women with diabetes mellitus, POI develops in roughly 2.5%. Additionally, autoimmune-related POI can also present as part of autoimmune polyglandular syndrome (APS), a condition in which autoimmune activity causes specific endocrine organ damage. In its most common presentation (type-3), APS is associated with Hashomoto's type thyroid antibodies and has a prevalence of 10-40%. 21OH-Antibodies in Addison's disease (AD) can develop in association to APS-2.

Chronic Low Grade Inflammation in Pathogenesis of PCOS.

Polycystic ovary syndrome (PCOS) is a one of the most common endocrine disorders, with a prevalence rate of 5-10% in reproductive aged women. It's characterized by (1) chronic anovulation, (2) biochemical and/or clinical hyperandrogenism, and (3) polycystic ovarian morphology. PCOS has significant clinical implications and can lead to health problems related to the accumulation of adipose tissue, such as obesity, insulin resistance, metabolic syndrome, and type 2 diabetes. There is also evidence that PCOS patients are at higher risk of cardiovascular diseases, atherosclerosis, and high blood pressure. Several studies have reported the association between polycystic ovary syndrome (PCOS) and low-grade chronic inflammation. According to known data, inflammatory markers or their gene markers are higher in PCOS patients. Correlations have been found between increased levels of C-reactive protein (CRP), interleukin 18 (IL-18), tumor necrosis factor (TNF-α), interleukin 6 (IL-6), white blood cell count (WBC), monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1α (MIP-1α) in the PCOS women compared with age- and BMI-matched controls. Women with PCOS present also elevated levels of AGEs and increased RAGE (receptor for advanced glycation end products) expression. This chronic inflammatory state is aggravating by obesity and hyperinsulinemia. There are studies describing mutual impact of hyperinsulinemia and obesity, hyperandrogenism, and inflammatory state. Endothelial cell dysfunction may be also triggered by inflammatory cytokines. Many factors involved in oxidative stress, inflammation, and thrombosis were proposed as cardiovascular risk markers showing the endothelial cell damage in PCOS. Those markers include asymmetric dimethylarginine (ADMA), C-reactive protein (CRP), homocysteine, plasminogen activator inhibitor-I (PAI-I), PAI-I activity, vascular endothelial growth factor (VEGF) etc. It was also proposed that the uterine hyperinflammatory state in polycystic ovary syndrome may be responsible for significant pregnancy complications ranging from miscarriage to placental insufficiency. In this review, we discuss the most importance evidence concerning the role of the process of chronic inflammation in pathogenesis of PCOS.

Hyperthecosis: an underestimated nontumorous cause of hyperandrogenism.

Hyperthecosis is defined as the presence of nests of luteinized theca cells in the ovarian stroma. Persistent testosterone released by ovarian theca cells is unmasked postmenopausally through the loss of granulosa cell-mediated aromatization of testosterone to estradiol. Ovarian hyperthecosis (OH) usually presents with symptoms of hyperandrogenism and is often described as a severe or extreme form of Polycystic Ovary Syndrome (PCOS). Serum testosterone levels in excess of 150 ng/dl (>5.2 nmol/l) are seen in affected patients and this threshold is used to confirm a diagnosis. Treatment of hyperthecosis is multi-faceted. It addresses the attendant hyperandrogenism (hirsutism and virilization) as well as metabolic complications such as obesity and insulin resistance. Ultimately, laparoscopic bilateral salpingo-oophorectomy is definitive treatment. This remains the treatment of choice in postmenopausal women whereas treatment using GnRH agonists may be used in women of reproductive age, especially younger women. Nevertheless, if serum testosterone remains elevated despite several months of therapy with a GnRH agonist, surgery is often required for biopsy sample collection and further definitive therapy. In order to mitigate the common clinical manifestations of hyperandrogenism, anti-androgen therapy (either cyproterone acetate or spironolactone) may be used to suppress the actions of testosterone on tissues. In patients with impaired glucose metabolism and insulin resistance, Metformin should also be considered as part of treatment. Combined, such a treatment regimen will often lead to decreased ovarian androgen secretion.

Kisspeptin and LH pulsatility in patients with functional hypothalamic amenorrhea.

PURPOSE: Functional hypothalamic amenorrhea (FHA) occurs in response to exaggerated stressors with or without body weight loss. Various hormones, neurotransmitters, and neuromodulators are involved in the control of GnRH and kisspeptin is one of them. Our study aimed to evaluate the putative temporal coupling between kisspeptin and GnRH-induced LH pulsatile secretion. METHODS: In total, 71 patients with FHA were selected for this study. All patients undergo to a pulsatility study for LH and kisspeptin evaluation (120 min, sampling every 10 min), and to an endocrine evaluation for prolactin (PRL), estradiol (E2), androstenedione (A), 17-hydroxy-progesterone (17OHP), TSH, fT3, fT4, insulin, cortisol and testosterone (T), glucose, total cholesterol, triglycerides. RESULTS: Our data demonstrated kisspeptin and LH pulsatile secretions and that both hormones are co-secreted and temporally coupled at time 0 (p < 0.05). When patients were subdivided in hypo-LH (≤3 mIU/ml, n = 58) and normo-LH (>3 mIU/ml, n = 13), more insights were observed on the specific correlations of metabolic and hormone profiles with pulsatility indexes of LH and kisspeptin. CONCLUSIONS: Our study demonstrated the presence of a distinct kisspeptin episodic secretion in patients with FHA, and showed the temporally coupling of kisspeptin with LH secretory episodes thus supporting that though in amenorrhea, the reproductive axis is still relying on kisspeptin to drive GnRH discharge. In addition, correlations among hormonal data sustain the hypothesis that stress-induced compensatory events are the main direct and indirect promoters of the reproductive blockade in patients affected by FHA.