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Biomed Grid | Arab Society for Pediatric Endocrinology and Diabetes (ASPED) Masterclass in Pediatric Bone Disease 2nd November 2018, Dubai, United Arab Emirates

The Arab society of Pediatric Endocrinology and diabetes held a masterclass for pediatric bone diseases in Dubai, United Arab Emirates (UAE) in collaboration of Kyowa Kirin. This 1-day event was run within the framework of the ASPED School and was attended by 76 delegates and 14 faculty. Plenary lectures and. patient case reports were presented. The talks covered all aspects related to rickets and highlighted that nutritional vitamin D deficiencies are relatively common. This is the case despite the availability of proper nutrition and the adequate level of sun light. It was emphasized that is it vital to establish a diagnosis considering potential underlying genetic abnormalities or comorbidities which may mask initial laboratory assessments and potentially lead to an unsuitable treatment choice. Considering a less common genetic form of rickets is important in the region owing to the high frequency of consanguinity. It has been pointed out that even when a correct diagnosis and initial management is selected, it is essential to follow up patients regularly and adjust their treatment to match their needs during different growth phases.

Overall, the 14 regional and international speakers discussed nutritional and hereditary rickets, disorders of phosphate homeostasis, management of hypophosphataemic rickets and skeletal disorders beyond rickets. Lively discussions around all presented topics dominated the day, with an interest in new treatments, including burosumab as a novel fully human anti-FGF23 monoclonal antibody therapy. Burosumab has demonstrated effective inhibition of the FGF23-mediated pathway and has received approval by the US Food and Drug Administration (FDA) for the treatment of adults and children with X-linked hypophosphataemia (XLH). Preliminary experience in the region of its use has been presented.

The Arab Society for Pediatric Endocrinology and Diabetes (ASPED) www.asped.orgmmary

ASPED was launched in Abu Dhabi, UAE in September 2012, upon the initiative of a group of pediatric endocrinologists from the Middle East and North Africa. The society is a non-profit scientific organization and is registered under the Dubai Association Center (DAC) under license number DAC-0001. Its aim is to ensure a high standard of care and development in the field of pediatric endocrinology and diabetes in the Arab region extending from the Gulf through the Northern African countries.

Kyowa Kirin

Founded in 1949 in Japan, Kyowa Hakko Kirin Co., Ltd (KHK) has a track record in Japan and is now expanding globally. Its daughter company, Kyowa Kirin International (KKI) showed a rapid growth in pharmaceutical industry in various therapeutic areas including oncology, nephrology and central nervous system disorder. Many of KKI’s therapies are based on antibody technology with enhanced antibody efficacy and safety.

Acknowledgement

ASPED is grateful to all the speakers and moderators (regional and international) who contributed to the course and made it a meeting appreciated for its high educational level. We also thank Kyowa Kirin, Gulf for its collaboration and support of pediatric bone disease education in our region.

Kyowa Kirin-ASPED Pediatric Bone Disease

Masterclass

The Kyowa Kirin-ASPED masterclass in pediatric bone disease was a 1-day meeting as part of a 3-day ASPED School at the Holiday Inn, Festival City, Dubai, 31 October-3 November 2018. The masterclass aimed to educate, empower and update physicians practicing in Arab countries and involved in the care of young people with bone disorders. The masterclass was planned to be a platform to share expertise and the latest developments in clinical approaches to treatment of diseases linked to metabolic and genetic bone diseases. Including prominent international and regional speakers, the masterclass attracted 76 attendees from the Middle East and African countries.

Presentation Summaries

Nutritional and Hereditary Rickets

Aetiology and Treatment of Rickets: an overview

Abdelhadi Habeb, Kingdom of Saudi Arabia (KSA): Maternity and Children Hospital & Prince Mohammed bin Abdulaziz Hospital, KSA. Rickets occurs relatively commonly in the Middle East, Africa, and Asia. It is a gender-independent condition that starts typically between the ages of 3 and 18 months resulting in weak or soft bones in children. Although first described in 1650, the treatment of rickets remained a medical challenge well into the 20th century Early treatments were based on cod liver oil trials, and experimentation with sunlight exposure. Four subtypes of rickets are commonly distinguished and include vitamin D-related, hypocalcemia-related, hypophosphatemia-related and secondary rickets with alternative causes, such as cancer.

Hypophosphatasemia is fundamental in the development of rickets, and it was recognized early on that vitamin D deficiency, hereditary or nutritional, is the leading cause of reduced intestinal calcium absorption, resulting in increased renal phosphate excretion via activation of the parathyroid hormone pathway. Hypophosphatasemia results in accumulation or impaired apoptosis of the hypertrophic chondrocytes in the growth plate of long bone joints without enough calcification; this leads to symptoms such as bowed legs, stunted growth, bone pain and swollen joint areas. Complications may include bone fractures, muscle spasms, an abnormally curved spine or intellectual disability. Diagnosis is generally based on X-rays together with blood test findings of low calcium, low phosphorus, and high alkaline phosphatase (ALP) levels. Radiological assessment has been reported as not very successful in the diagnosis.

Treatment depends on the underlying cause or subtype of rickets. Enough vitamin D levels can be achieved through dietary supplementation and/or exposure to sunlight. Various vitamin D supplements are available, with vitamin D3 being a preferred treatment option as it is more readily absorbed than vitamin D2. However, vitamin D treatment for other forms of rickets may require calcium or phosphate supplementation to ensure appropriate metabolism of vitamin D.

Nutritional Rickets Revisited: Zulf Mughal, UK: Royal Manchester Children’s Hospital Manchester, UK. Nutritional rickets is a preventable disease and a result of insufficient vitamin D intake or absorption. A diagnosis of nutritional rickets is unlikely if there is a strong family history of rickets, associated features such as alopecia or hepatomegaly are displayed, severe skeletal deformities at a very young age or poor response to vitamin D therapy. In young children, manifestations of vitamin D deficiency include wide gait, swollen long bone joints, rachitic rosary, dental problems and osteomalacia in adolescents. In rare instances, cases of dilated cardiomyopathy have been reported.

While in early vitamin D deficiency, calcium levels are still normal and phosphate levels are decreased, patients with severe vitamin D deficiency display reductions in both calcium and phosphate. In rare cases of parathyroid hormone resistance, where calcium levels are reduced, and phosphate levels increased, calcium supplementation was seen to rescue the biochemical pattern of this phenotype. Calcium supplementation has shown to reverse symptoms of rickets in terms of radiological, histological and biochemical features. For infants 0-6 and 6-12 months of age, adequate calcium intake is 200 and 260 mg/day, respectively.

For children over 12 months of age, dietary calcium intake of <300 mg/day increases the risk of rickets independent of serum vitamin D levels. For children over 12 months of age, dietary calcium intake was classified as enough (>500 mg/day), insufficient (300- 500 mg/day) and deficient (<300 mg/day). Therefore, guidelines recommend treatment doses for 12 weeks based on age and level of deficiency with a follow-up maintenance dose as regular reassessment of the patient’s mineral status. In prevention studies, a dose of 400 IU daily has been shown as adequate to prevent rickets.

Rickets Case Reports

Case 1: Asmahan T Abdalla, Sudan: Gaafar Ibn Auf Pediatric Tertiary Hospital, Sudan Medical Specializations Board, Sudan. A case of rickets was reported in a female Sudanese child of consanguineous parents, despite high exposure to sunlight. The patient presented with recurring rickets on treatment discontinuation from the ages of 18 months to 20 years with clinical, laboratory and radiological features. First symptoms at 18 months old included floppy infant syndrome, open anterior fontanel, broad wrists, bowing of the legs and rosaries without organomegaly, skin, nail or hair abnormalities.

Following 6 months of conventional therapy of vitamin D3 and calcium, her walking abilities and laboratory parameters started to improve. Over the years she started having dental abnormalities and bone pain coupled with severe genu varum deformity. Repeat therapy alleviated the symptoms. The patient’s sisters presented at the ages of 2 and 12 years with similar symptoms, most prominently a very low vitamin D level at <7.5 ng/mL. Therefore, treatment with various doses of calcium and calcitriol was initiated and genetic testing was performed after investigations ruled out liver or renal disease and malabsorption.

Molecular analysis identified a previously unknown mutation (homozygosity at position 85 [C>T]), which resulted in a truncated and non-functional CYP2R1 gene. As a result of this analysis, 25-hydroxylase deficiency and, ultimately, vitamin D-dependent rickets type 1B was diagnosed. In general, even if genetic testing is not available, genetic rickets should be suspected in an environment with high levels of sunlight in a child who presents with history of rickets that is dependent on therapy or resistant to it, with history of consanguinity and a similar history in the family.

Case 2: Abdulla Al-Harbi, KSA: Madinah Maternity and Children Hospital, Madinah, KSA. A case of rickets was reported in the second child of consanguineous parents at 3 months of age following a fullterm pregnancy. The couple’s first child died at 3 months showing signs of hypocalcemia and skeletal deformities. The patient was bottle fed and received vitamin D3 supplement. However, supplementation was ineffective and lower limb deformities, wrist widening, and frontal bossing were observed at 14 months of age. Laboratory analyses demonstrated highly elevated ALP and parathyroid hormone (PTH) levels. Following a 1-week vitamin D3 washout, biochemical analysis was repeated showing even more increased ALP and PTH levels and calcium and phosphate levels below the normal range, while both 25-hydroxyvitamin D (25[OH] D) and 1,25-dihydroxycholecalciferol (1,25 [OH]2D) were normal.

To ascertain the type of rickets, renal phosphate regulation was assessed. Results showed low phosphate levels, low tubular reabsorption of phosphate (TRP) at 80% and normal vitamin D levels, and the patient was diagnosed with XLH-linked rickets. Treatment with phosphate 40 mg/kg/day and 1-alpha vitamin D was initiated. At 3 months follow-up, all values had normalized; however, phosphate levels were higher than normal. After a further 3 months, the child was referred to an endocrinologist as no improvements were seen in phosphate biochemistry or lower limb deformities.

Endocrinological assessment highlighted short stature and low weight, generalized hypotonia, sitting with support, wide wrists and fontanels, rachitic rosaries, and angulation of tibias and ankles without organomegaly or components of the cardiovascular system (CVS)/chest abnormalities. Repeated laboratory analysis showed low calcium levels, high phosphate and PTH levels with normal ALP. The patient was re-diagnosed with vitamin D deficient rickets type 1 (1-alpha hydroxylase deficiency) as a result of a frame-shift mutation in the CYP27B1 gene. Phosphate treatment was discontinued while the patient continued 1-alpha calcidiol only, which normalized all laboratory values and over time induced improvements of bone deformities. The patient has been stable for the past 2.5 years, highlighting that continued monitoring and re-evaluation of the underlying disease is required to adequately manage patients with mineral and bone abnormalities. When diagnosing a patient, it is vital to bear in mind that empirical use of 1-alpha calcitriol can mask 1-alpha hydroxylase deficiency and that in XLH-related rickets, very high ALP and PTH are unusual, although it can be difficult to normalize phosphate levels.

Case 3: Ahmed Yousef, UAE: Sheikh Khalifa Medical City, Abu Dhabi, UAE. A 16-month old boy presented to the clinic after unsuccessful treatment in various hospitals with systemic pain, especially under movement or when touched, leading to irritability, crying and failure to thrive. His symptoms started to become apparent at 10 months old and included arrested gross motor development, deformity in all extremities, respiratory distress and recurrent chest infections.

Initial biochemical analysis showed low levels of phosphate, calcium, and 25(OH)D, whereas ALP and PTH were at high levels. The patient was treated with 15 μg/day calcitriol and oral calcium carbonate up to 6400 mg/day.

A slight clinical improvement could be observed with stabilization of calcium levels; however, PTH and ALP remained high. Repeat analysis for 1,25 (OH)2D in another laboratory revealed a much higher level than previously reported. Genetic testing confirmed a pathological novel mutation in the VDR gene, which led to a diagnosis of vitamin D-dependent rickets type 2 (VDDR2) or hereditary vitamin D-resistant rickets.

Subsequently, the patient was treated with long-term continuous infusion of calcium to which he responded well. Radiological features improved, pain subsided, and the child achieved growth expected for his age. After a few years, the patient returned to the clinic with pain in his limbs, worsening gait and leg deformities. Home treatment with calcium carbonate 324 mg/ kg/day and cholecalciferol 10,000 IU daily was not effective, and laboratory values indicated a worsening of the condition with calcium, phosphorus and magnesium well below the normal range and ALP and PTH above normal levels. Vitamin D levels had improved to within the normal range and urine creatinine analysis did not show any abnormalities.

A repeat continuous infusion with calcium gluconate 570 mg/kg/24 hour, cholecalciferol 600,000 IU injection, hydrochlorothiazide 35 mg once daily (OD), magnesium oxide 200 mg twice daily (BID) and phosphate 250 mg BID was administered, which brought calcium, phosphate and PTH levels close to or within the normal range. This case highlights that, despite a correct diagnosis and correct initial management, it is essential to follow up with patients regularly and adjust their treatment to match the body’s needs during different growth phases.

Disorders of phosphate homeostasis

Physiology of phosphate homeostasis: Dieter Haffner, Germany: Medizinische Hochschule Hannover, Germany. Phosphates are pivotal for the regulation of metabolic processes and cellular functions. Phosphate is a constituent of DNA, membrane lipids, high-energy phosphates, and second messengers such as inositol trisphosphate, cyclic adenosine monophosphate and cyclic guanosine monophosphate and is used in protein phosphorylation. It is essential for the regulation of enzyme and receptor activities, energy metabolism, cell signaling, nucleic acid synthesis and membrane function, as well as skeletal health and integrity and growth. Physiology has evolved to conserve this rare mineral through efficient use of phosphate transport systems. Phosphate homeostasis is tightly regulated via feedback loops by hormones including the PTH and fibroblast growth factor 23 (FGF-23) and phosphorus is mainly contained within the intestine, kidney and bone.

The regulation of phosphorus is complex and involves both acute and chronic processes. Recent evidence showed that FGF23 regulates serum phosphate concentration and calcitriol metabolism. FGF23 is secreted in response to hyperphosphatemia and vitamin D decreasing renal phosphate reabsorption by lowering NPT2a and NPT2c expression and diminishing calcitriol (Vitamin D) synthesis by inhibiting 1α hydroxylase and stimulating its catabolizing enzyme 24, 25 hydroxylases. To achieve this, FGF23 binds to and activates a composite receptor formed by the conjunction of FGF receptor 1 (FGFR1), FGFR3 and or FGFR4 with klotho. Overexpression of FGF23 results in marked increase in urinary phosphate excretion and severe hypophosphatemia leading to many bone disorders.

Klotho is a transmembrane protein expressed on the surface of tissues like kidneys, parathyroid glands, brain and skeletal muscle, and acts as a co-factor that is mandatory for FGF23 activity. In the kidney, Klotho is mainly expressed in the distal tubule, whereas FGF23 exerts its action on the proximal tubule. The mechanism by which FGF23 modifies proximal tubule functions is unknown. Furthermore, a soluble form of Klotho provides a non-enzymatic molecular scaffold for FGF23 hormone signaling.

High dietary or serum phosphorus is reduced by stimulation of PTH or increased secretion of FGF23 and a feedback loop between both systems, which in turn reduce phosphorus reabsorption in the kidney. An additional mechanism acts via decreased vitamin D synthesis in the kidney as a result of high FGF23 secretion and a resulting reduction in intestinal phosphorus absorption. However, in XLH, an excess of FGF23 impairs renal phosphate and vitamin D metabolism. In patients with advanced or chronic kidney disease (CKD), elevated PTH levels are required to eliminate excess phosphate (a known cardiovascular toxin) and counterbalance vitamin D deficiency. At later stages of CKD, PTH levels progressively increase with declining glomerular filtration rate due to hyperphosphatemia, hypocalcemia and vitamin D deficiency, in order to increase phosphaturia, calcitriol synthesis and serum calcium.

Hypophosphatemic rickets: clinical features, genetics and differential diagnosis: Zulf Mughal, UK: Royal Manchester Children’s Hospital, UK. The clinical features of hypophosphataemic rickets often include impaired skeletal mineralization, impaired linear growth, impaired muscle function, propensity to dental abscess development, premature fusion of cranial sutures, fractures and pseudo-fractures, hearing impairment and calcification of spinal and paraspinal ligaments in adults, which results in stiffness.

A biochemical work-up including serum calcium, phosphate and ALP, as well as serum sodium, potassium, creatinine, 25OHD and 1,25(OH)2D should be performed. Plasma analysis should include PTH and intact FGF23. Urine testing should always be performed and analyzed for TRP, renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/ GFR), calcium/creatinine ratio, urine amino acids, urine potassium and bicarbonate, as well as urine protein/creatinine ratio and low-molecular-weight protein. A schematic developed to diagnose patients with low serum phosphate demonstrates the sequence of assessments necessary to identify the cause of hypophosphatemia (Figure 1).

Figure 1:Decision chart for identification of the underlying cause of hypophosphatemia rickets. P, phosphate.

This schematic allows to identify whether rickets due to low serum P-value is caused by dietary deficiency or malabsorption of phosphate, isolated urinary phosphate loss or Fanconi syndrome. Rickets due to urinary phosphate loss may be FGF23-mediated or due to FGF23-independent renal tubular disorders. Family history and genetic studies will help in distinguishing between XLH, autosomal dominant hypophosphataemic rickets (ADHR), AHRH-1 & AHRH-2 without prior history of generalized arterial calcification of infancy. It is also important to consider tumorinduced osteomalacia, especially in patients with isolated urinary phosphate loss and profound myopathy. However, urinary testing for hypercalciuria, and proteinuria by dipstick is vital as it may make downstream diagnostic testing obsolete.

Unusual Cause of Hypophosphataemic Rickets: Najlla Al- Jassas, KSA: King Fahd Specialist Hospital and Research Centre, Dammam (please check), KSA. The case of a 10-year-old Saudi boy with polyostotic fibrous dysplasia (FD) and hypophosphataemic rickets was reported. FD consists of rare and benign osseous lesions of unknown aetiology and represents 2.5% of all bone and 7% of benign bone tumors in young, predominantly male patients. Although hypophosphatasemia and hypophosphataemic rickets in patients with FD is infrequent, a renal tubulopathy including some degree of phosphate wasting is one of the most commonly associated extra-skeletal manifestations. It is now understood that FD-associated phosphate wasting arises from overproduction of FGF23 by abnormal osteogenic precursors. Treatment with bisphosphonate has been promising.

The patient presented at the age of 6 years with right thigh pain and limping for the past year. X-ray of the right femur revealed a lytic lesion and active rickets. In addition to a history of fractures, on physical examination, the boy appeared well, but showed symptoms of wide wrists and ankles, antalgic gait and heterogeneous increased density of the frontal skull region with extensive craniofacial involvement. The patient did not display signs of skin hyperpigmentation or endocrine hyperfunction. Bone biopsy confirmed the diagnosis of FD with a bone mineral density (BMD) Z-score of –3.6 SD below the mean.

Biochemical investigation revealed low phosphate, phosphaturia, normokalaemia, normal PTH and elevated FGF23 and ALP levels. Therefore, the diagnosis was extended to polyostotic FD with hypophosphataemic rickets due to vitamin D insufficiency. Genetic testing did not reveal mutations in the GNAS1 gene, the product of which is responsible for G-protein function and involved in hormonal signaling. The patient was treated for rickets with 1-alpha calcidol, oral calcium and oral phosphate and zoledronic acid infusion every 6 months for FD. Bisphosphonate was used due to its ability to reduce pain and fracture rate. Bisphosphonate has also been implicated in FD lesion size reduction and filling in of bony defects in adults and children; however, the effect is not consistent across patients. On follow-up, while progression of FD has been positively impacted with zoledronic acid in terms of lack of new lesions and improvement of BMD, the main challenge identified with this patient was persistent elevation of FGF23 and phosphaturia, which may be the result of non-adherence to rickets treatment. This case highlights the challenges of treating XLH in the presence of active FD lesions and the benefit of zoledronic acid in the management of pain and disease progression.

XLH with Mild Renal Phenotype: Bashir Elnaem, KSA: Madinah Maternity and Children Hospital, Madinah, KSA. Identifying the type of hypophosphataemic rickets requires detailed analysis. A boy of just under 6 years presented to gain a second opinion for his bowed legs. He showed symptoms of severe skeletal deformity including short stature, frontal posing and palpable sagittal suture, craniosynostosis, small dental abscess, bilateral genu, coxa Varus and mild renal phenotype without rickets rosary or organomegaly.

He has been treated with different vitamin D preparations for rickets by three individual hospitals for the past 2 years but has not received medication for the past 2 months. His medical history was unremarkable without neonatal or systemic problems and he showed no signs of developmental abnormalities. Initial investigations identified low phosphate levels (0.9 mmol/L), low TRP (80%) and low TmP/GFR (0.81 mmol), as well as radiological signs of rickets. All other laboratory values were within normal range. Both parents tested within the normal range for calcium, phosphate and ALP.

The child was treated initially with phosphate 40 mg/kg/day and 1 μg/day of one-alpha, which was subsequently increased to 125 mg/kg/day and was seen by an orthopedic surgeon for epiphysiodesis, a neurosurgeon and dentist. Over time (2 years) his phosphate levels normalized but remained close to the lower limit, while his PTH levels increased above normal. Calcium, ALP and TRP% remained stable and his bone deformities improved markedly without any signs of nephrocalcinosis. This patient case demonstrates the need for adequate assessment of potentially underlying comorbidities which may mask initial laboratory measurements and potentially result in inadequate treatment.

Challenges in Hypophosphataemic Rickets Management

Traditional and new management of XLH: Dieter Haffner, Germany: Medizinische Hochschule Hannover, Germany. XLH requires life-long management from a range of specialists owing to the multitude of symptoms and organ systems affected by this inherited disorder. Early diagnosis and management is vital to address symptoms early before they impact development and result in functional limitations and poor quality of life. Combination therapy with multiple doses of oral phosphorus and active vitamin D analogues to counter calcitriol deficiency, prevent secondary hyperparathyroidism and increase phosphorus reabsorption from the gut are the conventional treatment regimens. The overall treatment goals include healing rickets for clinical and radiological signs, control pain, encourage growth within the normal range and prevention of rickets in infants with a positive family history.

Despite the wide-spread use of these therapies, patient response is variable and the disease itself is not cured. Furthermore, there is an increased risk to develop side effects such as nephrocalcinosis and hyperparathyroidism, as well as stimulation of FGF23 secretion, which in turn promotes increased phosphate leakage. Strict monitoring every 3 months for biochemical values and every 12 months for ultrasound and radiological features is recommended. Before burosumab was available, conventional treatment was tailored to address specific clinical features and individualize patient management. However, especially in children and adolescents, inconsistent adherence to therapy might negate positive treatment outcomes. In addition to medicine-based therapy, collaboration with experienced orthopedic surgeons and physiotherapists are recommended to correct complex misalignments, reinforce muscles, improve joint stability and provide a good physical framework in which children can grow to their adult stature.

A novel fully human anti-FGF23 monoclonal antibody therapy, burosumab, has demonstrated effective inhibition of the FGF23- mediated pathway and phosphate excretion. It has been trialled as 2-weekly and 4-weekly injectable formulation in children and adults with XLH in Phase 2 and 3 studies, where it demonstrated significant improvements in the rickets severity score, radiographic features, walking test, growth velocity, standing height and markers of bone turnover to support fracture healing. Furthermore, normalisation of ALP, vitamin D and serum phosphate levels have been reported. In terms of patient-reported outcomes, burosumab significantly improved stiffness and physical functions, and provided alleviation from pain compared with placebo. These results led to burosumab approval by both the EMA and the FDA.

Genotype and Phenotype of XLH in Riyadh: A Case Series: Fahd Al-Juraibah, KSA: King Abdullah Specialized Children’s Hospital, Riyadh, KSA.Normal bone growth and mineralization require adequate calcium and phosphate. Hypophosphatemic rickets are a result of renal phosphate wasting due to primary renal tubular defects in phosphate reabsorption or the generation of excessive amounts of phophatonins (FGF23, MEPE, FRP4 and FGF7), which inhibit renal tubular reabsorption of phosphate. Causes of phosphopenia include non-hyperphosphaturic causes such as low body weight, vitamin D deficiency, total parenteral nutrition, short bowel syndrome, chronic diarrhea, and aluminum/ calcium-containing antacids, as well as hyperphosphaturic pathways including non-FGF23-mediated, FGF23-mediated and those governed by high PTH.

A case series of six patients with XLH in Riyadh was discussed highlighting the different symptoms patients can present with and the importance of assessing their laboratory values considering these symptoms. All patients, evenly mixed by gender, presented very early on in life between the ages of 5 months and 1 year often with tell-tale deformities. In all but one of the patients, the family history of rickets was known, supporting diagnosis by genetic testing. Heterozygous mutations in the PHEX gene, the product is thought to be involved in bone and dentin mineralization and renal phosphate reabsorption, were the most prominent causes of XLH, albeit different mutations within the same gene were causing the disease (c.2070+5G>A and c.1682G>A). A homozygous mutation in the DMP1 gene exon 2, a protein critical for correct mineralization of bone and dentin, as well as a novel frameshift mutation of the PHEX gene (c.1077del) have been identified as contributing to a hypophosphataemic rickets phenotype.

New Management of XLH: KSA Experience: Mohamed Al- Dubayee, KSA: King Abdullah Specialized Children’s Hospital, Riyadh, KSA. In addition to conventional treatment of XLH, a novel fully human anti-FGF23 monoclonal antibody therapy, burosumab, has demonstrated effective inhibition of the FGF23-mediated pathway, thus stimulating renal phosphate reabsorption and increasing serum phosphorus and active vitamin D levels.

Monoclonal antibodies are an effective therapy characterized by high target specificity. The FDA and EMA have recently approved burosumab for the treatment of XLH in adult and pediatric patients 1 year of age and older for the treatment of XLH with radiographic evidence of bone disease in children 1 year of age and older and adolescents with growing skeletons, respectively.

In children, burosumab demonstrated improvements in serum phosphorus levels, renal tubular phosphate reabsorption, serum 1,25(OH)2D and ALP into the normal range with both 2-weekly and 4-weekly administrations and a rapid onset of action within the first 2–4 weeks. When compared with conventional therapy of oral phosphate and active vitamin D, burosumab showed superiority leading to the adoption of this treatment by the Saudi Food and Drug Authority.

The recommended starting dose is 0.8 mg/kg, rounded to the nearest 10 mg administered every 2 weeks in children and 1 mg/ kg rounded to the nearest 10 mg up to a maximum dose of 90 mg every 4 weeks in adults. The first dose of burosumab should be given in an inpatient setting to allow observation of any side effects. Oral phosphate and vitamin D analogues must be stopped 1 week prior to burosumab initiation to allow fasting serum phosphate to drop below the reference range for age prior to initiation of treatment. Furthermore, burosumab should not be initiated if serum phosphorus is within or above the normal range for age or in patients with renal impairment or end-stage renal disease.

Prior to initiation of subcutaneous burosumab injection, fasting baseline tests should be performed to assess standard biochemistry of the patient. Testing should include serum complete blood count, urea and electrolytes, bone profile, liver profile, ALP, PTH, 25(OH)D, 1,25(OH)2D, urine phosphate, calcium and creatinine to calculate TmP/GFR, as well left-hand X-ray for a rickets survey. After starting burosumab, fasting serum phosphate should be monitored every 2 weeks for the first month of treatment, every 4 weeks for the following 2 months and thereafter every 3 months or as appropriate. Serum phosphorus should be maintained between 1–1.6 mmol/L. The burosumab dose may be increased stepwise up to approximately 2 mg/kg if serum phosphorus is below the reference for age; however, dosing should not be adjusted more frequently than every 4 weeks and adequate monitoring should be provided.

Burosumab is the first treatment to target regulatory pathways instead of achieving clinically normal levels of minerals by dietary supplementation.

Skeletal Disorders Beyond Rickets

An approach to a child with multiple fracture: Rasha Hamza, Egypt: Ain Shams University, Cairo, Egypt. Recurrent fractures in children are not coincidental and the underlying disease may present at differing severity across a wide spectrum, creating a challenge for diagnosis. Patients may present with several numbers of fractures, stature abnormalities, hearing problems, dental or eye abnormalities, deformities, osteopenia, bone formation abnormalities and random calcifications.

Bone strength is affected when there is an imbalance of bone formation and bone resorption, a finely tuned system that is regulated via the receptor activator of nuclear factorkappa B-receptor activator of nuclear factor-kappa B ligandosteoprotegerin (RANK-RANKL-OPG) pathway. RANKL/RANK signaling regulates osteoclast formation, activation and survival in normal bone modelling and remodeling and in a variety of pathologic conditions characterized by increased bone turnover. OPG protects bone from excessive resorption by binding to RANKL and preventing it from binding to RANK. Thus, the relative concentration of RANKL and OPG in bone is a major determinant of bone mass and strength. Bone strength is further determined by bone mineral density and material as well as structural properties such as geometry, microarchitecture, mineralization, collagen and non-collagen proteins. Bone mass, however, can be governed by hormonal factors such as growth hormone and nutritional factors including vitamin D and calcium among others. There are currently no guidelines for the management of fractures in healthy children, and general measures to improve bone health include weightbearing physical activities, diet adequate in calcium and correction of vitamin D deficiency.

In a child with a history of fractures (vertebral or long bones), bone health as well as dietary calcium intake need to be assessed. Furthermore, clinical/social and laboratory assessments of serum calcium, serum phosphorus, serum ALP, serum 25OHD and serum PTH together with radiological imaging and genetic testing should be performed prior to a bone biopsy for ultimate confirmation for disease. Various antibody-based therapies have been developed to regulate imbalanced bone development pathways.

Challenges in the Management of Hypocalcemia: Amir Babiker, KSA: King Abdullah Specialized Children’s Hospital, King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh, KSA. Calcium is a physiologically important element governing many functions throughout the body. Calcium plays a part in neuromuscular excitability, blood coagulation, hormonal secretion and enzymatic regulation, as well as providing structural integrity to the skeleton. Calcium homeostasis is regulated by the hormones PTH and 1,25(OH)2D (the active form of vitamin D). Hypocalcemia stimulates PTH secretion, which acts via three mechanisms to increase calcium levels: firstly, PTH stimulates the release of Ca from the bone, in part by stimulating bone resorption, secondly PTH decreases urinary loss of Ca by stimulating Ca reabsorption and lastly, PTH indirectly stimulates Ca absorption in the small intestine by stimulating synthesis of 1,25(OH)2D in the kidney.

Causes of hypocalcemia tend to fall within three categories: hypo parathyroid, non-Para hypothyroid or PTH resistance with each category containing multiple diseases itself. Clinical features include neuromuscular irritability, neurological signs and symptoms, abnormal mental status, ectodermal changes, smooth-muscle involvement, ophthalmological manifestations and cardiac features. Extensive laboratory investigations should be performed to identify the exact cause of calcium deficiency and treatment should be based on the underlying cause. If the patient has a vitamin D imbalance, vitamin D and calcium supplementation should be prescribed, whereas acid citrate dextrose and calcium or PTH replacement therapy should be employed if PTH imbalance is diagnosed.

An Approach to the Child with Hypercalcemia: Sarah Ehtisham, UAE: Mediclinic City Hospital, Dubai Healthcare City, Dubai, UAE. Hypercalcemia is a disorder which is specified by excessive calcium levels in the blood serum. Clinical symptoms include insidious onset, a general feeling of discomfort, behavioral change, constipation, anorexia, weight loss, dehydration, polyuria and polydipsia, bone pain, hypertension and short QTc.

Hypercalcemia can have many underlying causes that are stratified based on PTH level. Low PTH can have genetic causes or secondary causes such as malignancy, vitamin D excess, adrenal insufficiency or thyrotoxicosis. Normal PTH levels in hypercalcemia can be associated with familial hypocalciuric hypercalcemia’s and elevated PTH can be attributed to hyperparathyroidism or parathyroid carcinoma. Key investigations that should be performed to identify the underlying cause of hypercalcemia include bone profiling (calcium, phosphate, ALP and AIb), renal function assessment (electrolytes and creatinine), PTH, 25(OH) D, urine calcium/creatinine ratio or 24 hour urine calcium, store serum (may require 1,25(OH)2D, PTH-related peptide or genetic analysis) and potentially renal ultrasound, parental bloods, skeletal survey and parathyroid imaging.

The treatment of hypercalcemia includes the lowering of calcium at first, but also correcting the underlying disease. Calcium-intake reduction, promotion of mobility, as well as an increase in urinary calcium excretion through hydration and diuretic use support the reduction of overall systemic calcium. In addition, a reduction in PTH secretion, intestinal calcium absorption and bone resorption and treatment with cinacalcet, glucocorticoids, bisphosphonates, calcitonin, dialysis or parathyroidectomy contribute to a calciumlowering effect.

Genetic Backgrounds of Bone Diseases in the UAE: Asma Deeb, UAE: Mafraq Hospital, Abu Dhabi, UAE. Bone diseases are often associated with dysregulation of complex metabolic or hormonal systems and constitute an interesting spectrum in pediatrics. Genetic testing may be required to confirm diagnosis of bone disease if initial treatment is ineffective or no clear diagnosis can be drawn from physical, biochemical and radiological assessments, especially in a region with a high rate of consanguinity. As genetic testing is not widely available in the Middle East, regional and international collaborations are crucial to support this line of investigation. A series of cases in whom genetic diagnosis was made was presented highlighting the complexity and multiple pathways involved in bone disease.

In a family with consanguineous parents, seven of their 11 children presented with symptoms of hematuria, loin pain or recurrent urinary tract infection. Although symptoms were relatively consistent between the siblings, calcium, magnesium, hypercalciuria and nephrocalcinosis status were relatively varied. Genetic analysis identified a novel mutation in the CLDN16 gene as responsible for this phenotype. In another case, heterozygous mutation in the CaSR gene (Ser113Cys) led to the diagnosis of autosomal dominant hypocalcemia and familial hypocalcemia hypocalciuria. Two partial gene deletions have also been associated with syndromes of abnormal calcaemia, namely William syndrome and DiGeorge syndrome.

A novel FOXI1 homozygous missense mutation, p.L146F, located within evolutionary highly conserved residues of the FOXI1 protein, was the underlying cause of patients presenting with earlyonset sensorineural deafness and distal renal tubular acidosis based on dysfunction of electrolyte regulation. Fanconi syndrome has been identified in a patient with mutations in the SLC34A1 gene on chromosome 5q35 resulting in poor growth, subtle dysmorphic features and low phosphate. In another case, a 5-year-old child presented with increasing deformity, hypophosphatemia, high 1,25(OH)2D and normal FGF23 levels. Genetic analysis did not identify abnormalities in the PHEX or SLC34A3 genes, excluding XLH and hereditary hypophosphataemic rickets with hypercalciuria from the diagnosis, respectively. Potential mutations in the FGF23 gene could be responsible for this phenotype.

Mutations leading to abnormal bone growth and abnormal growth plates include COL1A gene mutation type 3, LIFR (5p13.1) gene mutation leading to Stuve-Weidemann syndrome/Schwartz- Jampel type 2 syndrome, MMP2 gene mutation (TPOp.R665Q, c.1994G>A) leading to multicentric osteolysis and nodulus arthropathy, homozygous ADAMTSL2 gene mutation (c.938T˃C, p.M313T, exon 10), homozygous mutation of the EVC gene (c.1405delC) leading to Ellis-van Creveld syndrome, GALNS gene mutation, FGFR3 gene mutation, deletions in the CHRNA1 gene associated with congenital myasthenia, heterozygous mutations in the NPR2 gene causing short stature, COL2A1 gene mutation leading to sporadic Spondyloepiphysia congenita, homozygous RAB33B gene mutation causing Smith McCort dysplasia and a novel homozygous mutation in the PAPSS2 gene (c.826_828delGAG(p. E276del)) leading to brachyolmia type 4 with mild epiphysial and metaphyseal changes.

Meeting discussions

Lively discussions around all presented topics dominated the day. Table 1 captures the most discussed topics by theme Figure 2.

Figure 2: ASPED steering committee with regional and international speakers.

Table 1: Discussion themes throughout the meeting.

EMA, European Medicines Agency; FDA, Food and Drug Administration; FGF23, fibroblast growth factor 23; GCC, Gulf Cooperation Council; GFR, glomerular filtration rate; IGF-1, insulinlike growth factor-1; KSA, Kingdom of Saudi Arabia; MRI, magnetic resonance imaging; PTH, parathyroid hormone; RAAS, reninangiotensin- aldosterone system; RSS, rickets severity scoring; XLH, X-linked hypophosphataemia

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Juniper Publishers-The Altered Hormonal Homeostasis with Aging, Neuronal Dysfunction and Cognitive Decline

Abstract

Overview-Neurohormonal Aging: The human aging brings about various changes in hormonal homeostasis which include alterations in hormonal secretion, feedback loops and sensitivity of receptors and tissues. These changes have fallouts on cognitive functions through the receptors in brain areas, hormonal effects on neurotransmitters (NTM) and increased oxidative stress, and neuronal degeneration. The hormonal alterations occur across lifespan and play a role in cognitive dysfunction in form of mild cognitive impairment (MCI) and Alzheimer's disease (AD), and affect the health and activity of daily living (ADL) and quality of life (QOL) during later years.

The Endocrinological Alterations: Most of the hormones decrease with aging, like estrogen (in women), testosterone (in men), growth hormone and melatonin. The thyroid hormones may also decrease and subclinical hypothyroidism is common in older adults. Some hormones tend to remain at physiological levels as in younger adults, like cortisol and insulin except in disease conditions. But, the endocrine function may suffer with age because the hormonal receptors may become less sensitive. Whereas, some hormones increase in absolute or a relative ratio and include FSH, LH, norepinephrine, epinephrine, leptin and parathormone.

Pathophysiology of Neuronal Impact: Among the hormones, estrogen, progesterone and testosterone act directly on neurones in the brain, facilitate neurotransmission, enhance cerebral vasodilatation and blood flow, and protect neurones from neurotoxins and free radicals. Progesterone stimulates the GABA receptors and has an overall calming effect on the brain. The thyroid hormones (TH) regulate brain glucose utilization, neuronal metabolic activity and cerebral blood flow. The alterations in TH manifest as cognitive decline and increased risk for AD. With insulin deficiency, in the type 1 diabetes (T1DM) there occurs a slower information processing and cognitive decline. Whereas, in type 2 diabetes (T2DM), the associated deranged metabolic function and insulin resistance, leads to memory and cognitive dysfunctions, and neurodegenerative disorders. The decline in the overall GH level with age is called somatopause, and manifests as sleep disturbance and cognitive dysfunction. Adrenal hormones, DHEA and Cortisol also play an important role in aging related cognitive decline.

Applying Research - Hormone Replacement Strategies: The HRT may improve cognitive changes and consists of either combined hormone treatment having estrogen plus a progestin (HT) or estrogen alone (ET). The thyroxine (L-T4) treatment administered both sub- chronically and chronically, has been demonstrated to improve cognitive function, possibly mediated by an enhancement of cholinergic activity. But, as documented in clinical practice, the L-T4 treatment may not always completely restore normal cognitive functioning in patients with hypothyroidism. The use of thyroid hormone should be clinically relevant. Higher levels of thyroxine can potentiate oxidative stress and damage neurons, and are associated with accelerated cognitive decline. The replacement therapy for androgens is ridden with controversies, and the studies document that testosterone replacement therapy in a hypogonadal men does not have a positive effect on cognitive functions.

Conclusion-Finding the Solutions: The aim of hormone therapy is to suitably replenish the hormonal deficiencies that come with aging and to take care of their fallouts in the aging man or woman to maintain cognitive health. The hormonal replacement (HR) for a failing hormone is a grossly simple concept. But, then it will affect the altered feedback loops, attenuated receptors, and atrophied neurones. In all, the recent research provides various possibilities, but also puts various limitations and restraints on the therapeutic choices.

Keywords: Neurological Aging; Hormonal Homeostasis; Estrogen; Progesterone; Menopause; Testosterone; Andropause; DHEA; Thyroid Hormone; Cortisol; Calcium Homeostasis; Growth Hormone; Somatopause; Cognitive Decline; Alzheimer's Disease; Hormonal Replacement Therapy; ET; HRT

Abbreviations: ADL: activities of daily living; QOL: quality of life; AD: Alzheimer's disease; MCI: Mild Cognitive Impairment; NTMs: Neurotransmitters; ERs: Estrogen Receptors; HPG: Hypothalamus-Pituitary-Gonadal; BDNF: Brain-Derived Neurotrophic Factor; MAP: Mitogen- Activated Protein; pAkt: Phosphorylated Akt; CAlsr: CA1 Stratum Radiatum; dlPFC: Dorsolateral Prefrontal Cortex; WHI: Women's Health Initiative; WHIMS: WHI Memory Study; CEE: Conjugated Equine Estrogen; MPA: Medroxy Progesterone Acetate; HRT: Hormone Replacement Therapy; HT: Hormone Therapy; PADAM: Partial Androgen Deficiency in Aging Male; THs: Thyroid Hormones; Ach: Acetylcholine; T1DM: Type 1 Diabetes Mellitus; WMH: White Matter Hyperintensity; T2DM: Type 2 Diabetes Mellitus; GH: Growth Hormone; HR: Hormonal Replacement

The Neurohormonal Aging

The aging and underlying pathophysiological alterations are the gradual but heterogeneous. Simultaneously, there are declines of physiological functions, often accompanied by cognitive decline. These alterations are orchestrated through various molecular mechanisms, which complexly interact to alter the homeostasis. The endocrine system is involved in all of the integrative aspects of life, including cognitive faculties. The endocrine functions undergo major changes during aging, and include alterations in hormonal networks and signaling, and concomitant hormonal deficits/excess, augmented by decreased sensitivity of receptors and tissues to their action [1]. These hormonal alterations occur across lifespan, and affect the health, activities of daily living (ADL) and quality of life (QOL) during later years.

The demographic studies suggest that there is significant increase in the prevalence of Alzheimer's disease (AD) in older adults, of which 68% are female and 32% are male [2]. Further, because women have a longer life expectancy than men, the absolute number of women with AD exceeds that of men. In fact, the women are 1.5 times more likely to develop AD than age- matched men [3]. Traditionally, the aging process, including the development of physical frailty and a gradual loss in cognitive function during later years of life, has been considered to be physiological and unavoidable. In recent years, however, it has become evident scientifically and we can reject the grim stereotype of aging as an unalterable process of physical and cognitive decline, and optimistically can look forward to healthy and successful aging with good quality of life [4].

Essential Hormonal Alterations

With aging, the levels of various hormones undergo alterations [5]. Most of the hormones decrease with aging, like estrogen (in women), testosterone (in men), growth hormone and melatonin. The gonadal steroid hormones include androgen, estrogen, and progesterone, which decrease with aging. These hormones transduce their effects via hormone-specific receptors which are localized throughout the brain. The androgen, estrogen, progesterone, and the glucocorticoid receptors have been identified in brain regions associated with learning and memory areas such as the hippocampus [6]. In women, the acute decline in estrogen levels leads to menopause. In men, testosterone levels decrease gradually. Apart from, reproductive functions, estrogen, progesterone and testosterone play a critical role in modulation of cognition with aging and protect from loss of memory, cognition and progression of dementia [7].

The sex hormones estrogen, testosterone, and progesterone decline with age, while hormones regulating the HPA axis, such as corticosteroids have been shown to increase with age. The gonadal steroid hormones appear to act in concert with each other. The testosterone can be aromatized to estrogen, thus the loss of testosterone may also result in a reduction in estrogen. Further, the progesterone receptor contains an imperfect estrogen-binding site, thus loss of estrogen can potentially impact actions initiated through the progesterone receptor. The role of gonadal steroid hormones in cognition has been studied using both animal models and clinical trials [8]. Mood swings, memory loss, Mild Cognitive Impairment (MCI) and dementia are common symptoms and signs indicating that estrogen, progesterone and testosterone levels are declining [9].

The thyroid hormones decrease and subclinical hypothyroidism is common in older adults. There is evidence from animal models and observational human studies that thyroid hormone has an important influence on cognitive function, not only in childhood and adolescence but also in younger adults and the elderly [10]. The clinical undiagnosed hypothyroidism may present as difficulty in concentration, short-term memory loss and brain fog. The decreased levels of growth hormone lead to decreased muscle mass and strength, and affect cognitive functions; whereas the decreased melatonin levels play a role in the loss of normal sleep-wake patterns and affect the biological clock [11].

Some hormones tend to remain at physiological levels as in younger adults, like cortisol and insulin except in disease conditions. But, even when hormone levels do not change, endocrine function suffers with age because the hormonal receptors and tissues may become less sensitive [12]. This way an imbalance results especially with regard to Neurotransmitters (NTMs) like dopamine and serotonin, and hormones like cortisol, epinephrine and norepinephrine. Because of increased resistance and decreased production, the same is true for insulin, availability of which becomes chronically low in the brain in older adults and affects the cognitive functions and appetite regulation [13]. Cognitive performance is dependent on adequate glucose supply to the brain. Insulin, which regulates systemic glucose metabolism, has recently been shown both to regulate hippocampal metabolism and to be a mandatory component of hippocampally-mediated cognitive performance.

In addition, the adiposity with age increases serum triglycerides, which affects various bioactive molecules and hormones including leptin. The obese individuals appear to be more responsive to stress. Stress activates the sympathetic nervous system and the adipose-tissue cytokine leptin has been shown to stimulate SNS activity in animals. There is evidence that individuals with greater adiposity and/or higher plasma leptin would be more stress-responsive [14]. Apart from leptin, some hormones increase in absolute or a relative ratio and include FSH, LH, norepinephrine, epinephrine and parathormone.

Physiological Vs. Abnormal Homeostasis

The brain is part of a larger integrated biological system, which relies on signaling and neurotransmission throughout the body. There are balanced interactions between organs that release hormones and the nervous system which acts through neurotransmission in purview of the integrated biological system. Certain areas of brain are concerned with various cognitive functions. Whereas the hippocampus is concerned with short term memory, the temporal lobe is concerned with memory, emotions, hearing and language. The amygdola also shares emotions and social behaviour, whereas the frontal lobe is important for decision making, problem solving and planning [15].

Among the hormones, testosterone is Crucial for maintaining mental sharpness and clarity. The testosterone, along with estrogen and progesterone act directly on neurones in the brain, facilitating neurotransmission, and protect neurones from neurotoxins and free radicals, and enhance cerebral vasodilatation and blood flow. Estrogen facilitates higher cognitive functions by exerting effects on brain regions such as the prefrontal cortex and hippocampus. It induces spinogenesis and synaptogenesis in these two brain regions and also initiates a complex set of signal transduction pathways via Estrogen Receptors (ERs). The estrogen effects are mediated by activation of ER α and ER β, which in turn act on nuclear DNA, which leads to gene expression and protein synthesis, and enhance the NTM, associated functions by NTM associated proteins, spines and neurotrophins [16]. Progesterone stimulates the GABA receptors in brain, the feel-good, calming NTM, and has an overall calming effect on the CNS. A decreased progesterone level or the altered receptors lead to altered cognitive function [17].

The Pathophysiology Of Endocrinological Alterations

Estrogen

The HPG Axis: Estrogen plays an important role in the neurobiology of aging, and both endocrine and neural senescence overlap and is intertwined in complex feedback loops. The brain controls estrogen release through the Hypothalamus-Pituitary- Gonadal (HPG) axis. The GnRH neurons in the hypothalamus release RH, a decapeptide, which acts on the pituitary gland, to release the gonadotropins LH and FSH, which act on their receptors on the ovary to regulate production of sex steroid hormones, which are released into the circulation to exert feedback actions on the hypothalamus and pituitary gland. But, the brain also responds to estrogen through ERa and ERp receptors, which are distributed throughout the brain [18]. The neuroendocrine function is initiated in the hypothalamus and the circuitry responding to estrogen includes neocortex, hippocampus and brainstem (Figure 1). With the drop in circulating estrogens at menopause and the brain being a target organ for estrogen, women are prone for neurological changes, the cognitive dysfunctions and risk for depression, at menopause and in post-menopausal period [19].

Estrogen and Aging: The major estrogen from ovaries is 17-β-estradiol. The process of reproductive aging in women has several unique features and occurs in stages spread over few years. In fact, the menopause transition represents a complex interplay of actions at all levels of the hypothalamic- pituitary-ovarian axis [20]. Another aspect is the impact of falling concentration of the reproductive hormones on brain function and behaviour during the menopause transition. For the majority of women, the reproductive aging is not associated with either depressive symptoms or the syndrome of significant cognitive decline.

But, in a minority of women, progress through the menopause transition and during the post-menopausal period, symptoms of depression, decreased concentration and memory decline are common [21]. There appears a probability that the declining ovarian estrogen secretion exacerbates the age-related decrement in episodic memory [22,23]. Several longitudinal and community-based studies have also documented an association between the menopause transition and an increased risk for depression [24]. Some recent longitudinal studies that followed women with no past history of depression demonstrated an increased risk of depressions during the menopause transition [25] .

The Neurological Mechanisms

a) The Estrogen Receptors (ERs): The brain undergoes many structural and functional changes during aging, some of which are regulated by estrogens which act mainly through the intracellular estrogen receptors, ERa and ERp. The expression of these receptors depends upon several factors including their own ligand estrogen, and others such as growth hormone and thyroid hormone. The levels of these factors also decrease during aging and affect cognitive functions. Another important factor, the nucleotide polymorphisms of ERa has been documented with an increased risk of cognitive dysfunction and dementia [26] .

b) Behavioural Alterations and Cognitive Decline: The age-related changes in estradiol concentrations affect function in hypothalamus and cortex, thalamus, amygdala, brainstem, cerebellum, and most other brain regions through ERs. Though, the GnRH cell numbers do not change with aging, the inputs to GnRH neurons from NMDA (N-methyl-D-aspartate) receptors though glutamate and other neurotransmitters, which regulate GnRH gene expression and biosynthesis, cause age-associated changes in GnRH output [27,28]. These changes in NMDARs may also contribute to, other dysfunctions including alterations in sexual behaviour and/or libido, and decline in cognitive function [29]. In other brain regions such as hippocampus and frontal cortex, the loss or change in estradiol signaling may be manifested by morphological and behavioural changes.

c) Loss of Neuroprotection: The efficacy of neurological function and preventing neurodegeneration depends on the binding of estradiol and other estrogenic ligands to membrane- associated, mitochondrial, and nuclear estrogen receptors in hippocampal and cortical neurons [30,31]. Estrogen-activated cellular signaling cascade promotes enhanced mitochondrial function, leading to increased calcium load tolerance, enhanced electron transport chain efficiency, and promotion of antioxidant defence mechanisms pivotal to sustaining calcium homeostasis and the estradiol-induced cascade that leads to neurotrophic and neuroprotective benefit [32]. Thus, the postmenopausal fall in estrogen levels have effects on the neuronal aging and cognitive performance. Consistent with these alterations, incidence of depression, cognitive dysfunction and dementia, including AD, has been reported in observational studies.

d) The miRNA levels: It is thought that menopause associated rapid age-related decline of circulating 17 β-estradiol levels alters the miRNA levels in an age- and brain region- dependent manner. This results in differential gene expression involving genes that are important for memory and stress regulation, such as Brain-Derived Neurotrophic Factor (BDNF), glucocorticoid receptor, and SIRT-1, and consequently alter neuronal function [33].

The Research Studies

a) The Animal Studies: The studies in rodents and NHP have provided evidence that estrogen favourably modifies synaptic circuitry in hypothalamus, hippocampus and neocortex and is neuroprotective [34,35]. The hippocampus is a forebrain structure and consists of the subiculum, CA1, CA2, CA3 and dentate gyrus regions. The studies in female rodents provide evidence that the synaptic effects of estrogen in hippocampus and prefrontal cortex influence cognitive aging through synaptic circuitry of CA1 in the hippocampus which is NMDAR dependent. These hippocampal circuits sub-serve memory functions. Effects of estradiol on GABAergic and cholinergic systems augment the glutamatergic impact on hippocampal function. In addition, estradiol rapidly stimulates signaling cascades such as the Mitogen-Activated Protein (MAP) kinase family and the phosphotidylinositol 3-kinase (PI3K), pathway leading to the phosphorylation of Akt, a key signaling molecule. Furthermore, Phosphorylated Akt (pAkt) is present in CA1 dendrites, spines, and synapses and is increased by the presence of estradiol [36-38].

Further, the synaptic effects and behavioural impact of estrogen in CA1 differ in young and aged female rats. There is an age-related attenuation of the beneficial cognitive effects of estrogen modulations in rats [39]. This is related to age and duration of loss of estrogen, after which ET is less effective. The activated signaling molecules such as pAkt, which is present in CA1 dendrites and spines play a critical role in estradiol-induced synaptic alterations. In addition, synaptic pAkt thought to be activated by ERα is also decreased dramatically in aged CA1 axospinous synapses as is ERβ suggesting that several key players in the local synaptic response to estradiol are compromised with age in female rats [40,41].

In young and aged rhesus monkeys, as compared to female rats, estrogen increases axospinous synapses in CA1. The studies using an NHP model have revealed the cognitive and neurobiological effects of ET in the context of aging [42]. The studies in rhesus monkeys used a regimen of cyclic exposure to estradiol in an attempt to replicate a pulsatile peak. Initially, the total number of spines in CA1 Stratum Radiatum (CA1sr) of both young and aged monkeys, showed an increase of 35%. Also, long-term cyclical ET enhances cognitive performance and spine density in the Dorsolateral Prefrontal Cortex (dlPFC) of aged rhesus monkeys. The dlPFC is an area in the prefrontal cortex of the brain involved in executive functions. It is one of the most recently evolved parts of the human brain and undergoes a prolonged period of maturation which lasts until adulthood and is highly vulnerable in aging and AD.

b) Observation and Clinical Studies: Numerous studies have documented beneficial effects of HT/ET regimens on cognition [43]. The trials demonstrated the beneficial effects of short-term (i.e., 2-12 weeks) ET on measures of verbal learning and memory [44]. There were beneficial effects of HT/ET on several domains of cognitive function, like verbal memory, vigilance, reasoning, and motor speed, in symptomatic perimenopausal women and in women in whom hypogonadism was recently induced by medical or surgical interventions.

The Women's Health Initiative (WHI) studies published in 2003 failed to collaborate these findings. Simultaneously, the WHI Memory Study (WHIMS) concluded that this HT regimen did not improve cognitive function but increased the risk for probable dementia in postmenopausal women aged 65 or older [45,46]. Other related WHIMS studies with ET also failed to protect against cognitive decline, although this regimen did not carry the same risk for increased incidence of dementia [47]. But, there were two notable points, these studies used the pharmaceutical formulations which different from the natural hormones estradiol and progesterone, and the HRT was initiated in women 65 years or older, which may be too late to expect the neurological benefits of ET or combined HT [48,49].

Both observational- and clinic-based studies have suggested that combined HT and unopposed ET in hypogonadal women improve cognition, lessen the risk for the development of dementia, and possibly, improve the severity and course of dementia [50]. Estrogen seems to enhance neuronal function, improve neuronal resilience, and serve as a neuro protective agent. In addition to the potential beneficial effects of estrogen on episodic memory, there is evidence to suggest that HT reduced the risks of both MCI and dementia including AD. The therapeutic response to estradiol was observed in both major and minor depression as well as in women with and without hot flushes in perimenopausal women. In the observational studies, the early initiation and adherence to HT/ET treatment were related to the ongoing relief of the affective, cognitive, and behavioral symptoms.

The impact of declining reproductive function on sexual function is variably expressed in women. Many of postmenopausal symptoms reported in women, such as vasomotor symptoms, vaginal dryness, etc. are directly attributable to low circulating estradiol. These may have correlation with loss of libido and sexual dysfunction in postmenopausal period. However, estradiol fails to restore sexual functioning. Some recent RCTs reported improvements in libido after testosterone therapy in hypogonadal women [51].

Hormone Therapy for the Cognitive Decline: The HRT may improve cognitive changes and consists of either combined hormone treatment having estrogen plus a progestin (HT) or estrogen alone (ET). The neuro-selective estrogen receptor modulator (NeuroSERM) and phyto-selective estrogen receptor modulator (PhytoSERM) molecules appear to be safe and efficacious estrogen alternatives for preserving neurological function and preventing neurodegenerative disease. The research indicates that a low dose estradiol exerts neuroprotection in the perimenopausal period in acute, continuous or intermittent mode [52].

Whereas, a high estradiol dose is ineffective at inducing neuroprotection regardless of pattern of dose, and in fact, exacerbate neurodegeneration. The mechanism by which high estradiol exacerbates neurodegeneration is likely through dysregulation of calcium homeostasis. Thus, estrogen-induced calcium signaling pathways both promote neuronal function and could exacerbate neuronal apoptosis in neurodegenerative states. The epidemiological studies indicate that women receiving ET at the time of menopause, in a prevention mode well before age-associated degeneration is prevalent, have a lower risk of developing AD than women who have never received ET or HT.

The retrospective studies have investigated the issue of ET or HT formulation as a determinant of the adverse outcomes of treatment trials. The results of a frequently prescribed combined estrogen/progestin formulation, Conjugated Equine Estrogen (CEE) plus Medroxy Progesterone Acetate (MPA) - Depo-Provera or PremPro - have documented that MPA is neither neuroprotective nor synergistic with estradiol. In fact, MPA antagonized estradiol-induced neuroprotection [53]. Moreover, MPA exacerbated glutamate induced excito-toxic neuronal death [54]. Results of the WHIMS trial in which the hormone therapy group (CEE plus MPA) documented a twofold risk of developing dementia strongly suggest that the addition of MPA has deleterious outcomes for the brain [55].

The evidence from various studies endorse that in the hypogonadal states, the Hormone Therapy (HT) or Hormone Replacement Therapy (HRT) is likely to prevent and reverse age- related alterations in the relevant neural circuitry. The HRT is protective against cognitive decline and AD, has no detrimental effect on cognitive function and has shown benefits on memory, attention and reasoning [56]. The observational data also suggest that HRT may reduce the risk of cognitive decline and dementia. In a population cohort of older women, lifetime HRT supplementation was associated with improved global cognition and attenuated decline over a 3-year interval [57]. A 2011 meta-analysis study concluded that the overall data from epidemiologic studies, observational studies and clinical trials of HRT, indicate that the age-related hormone decline plays an important role in the pathogenesis of cognitive decline and risk for Alzheimer's disease and there was a decreased risk of dementia in HRT users [58].

As per the latest research on HRT, last updated on Oct 12, 2017 with over 713 News and research items available on the subject online - 'Hormone Replacement Therapy News Widget', the postmenopausal estrogen-based hormone therapy lasting longer than ten years was associated with a decreased risk of AD in a large study [59]. Finally, the HT has very limited effect when administered to postmenopausal women with AD, as an adjuvant with anti-cholinesterasic treatment, HT was only efficient when administered before the onset of dementia and most therapeutic trials conducted to date have been unable to conclude that HT could significantly prevent the development of AD or decrease its severity [60,61].

The identification of the hormonal determinants of cognitive and neurodegenerative disorders in the older adults and the characterization of sub-groups of 'hormone-responsive' subjects potentially at risk may open up the possibility of offering tailor- made therapies based on hormones favouring natural steroids. The natural formulations (micronized progesterone, transdermal 17-β-estradiol) are preferable because of their fewer side effects, especially when given at the peri-menopause and have potentially greater impact on neuropsychiatric disorders [62]. For the postmenopausal hormone treatment, there is prognostic importance of the following parameters: women's age, age at start of hormone use, duration of therapy, dosage, route of administration, and the exact type and combination of estrogen and progestogen.

Testosterone

Testosterone and Cognitive Function: The testosterone secretion and serum levels gradually decline with age after attaining a peak in early twenties (Figure 2). Also, the advancing age is the most significant risk factor for the onset of general cognitive decline [63]. But, the decline is variable among individuals. Though, the underlying neuro- pathogenic mechanisms for cognitive decline with age are not fully understood, there is a mounting evidence, that it may also be related to the declining testosterone in men, like estrogen in women. Testosterone, an androgen, is a precursor of certain neurotransmitters. The testosterone appears to be neuroprotective by mediating neuronal and vascular aging in neuronal cells of the hippocampus and other areas which are involved in cognitive function [64]. The results from cell culture and animal studies support testosterone as neuroprotective hormone [65].

With aging, both cognitive functions and testosterone levels decline. Further, a recent meta-analysis, in 2016, documented that most men with AD and other cognitive disorders have low testosterone. Also, the testosterone levels are lower in men with AD compared with controls. In fact, the low testosterone levels may precede onset of AD by many years. Further, there is a documented evidence to prove that testosterone therapy in older men may improve cognitive functions [66].

Mechanism of neuroprotective action: A recent animal study evaluated a possible mechanism by which testosterone may inhibit cognitive decline is via the influence on neuronal and vascular aging in hippocampal cells. In the mouse model with hypogonadism and cognitive impairment, the treatment with testosterone decreased senescent changes in hippocampal vascular endothelial cells and inhibited cognitive decline. At the sub cellular level, key enzyme, SIRT1, an NAD+-dependent acetylase, was induced by testosterone therapy and led to decreased oxidative stress-induced endothelial senescence [67].

In a cross-sectional study, the OPTIMA trial, the testosterone levels were significantly lower in the older cohort, aged~80 years with AD than in controls. Also, a younger cohort with AD aged~66 years; the testosterone levels were significantly lower than the controls without AD [68]. The studies have investigated the probability of lower testosterone levels as an independent risk factor for AD. In the large and well-designed Baltimore Longitudinal Study of Aging, it was documented that the free testosterone serum levels at 2, 5, and 10 years before diagnosis of AD were documented to be reduced [69]. In another study, using post-mortem data, documented that in preclinical male AD cases, testosterone brain levels were lower than in controls [70]. These studies indicate that testosterone may play a part in early, preclinical phases of AD, suggesting a causative role. Evidence supporting this is the high densities of androgen receptors in hippocampus and nearby regions [71]. Further, these regions also exhibit the earliest functional declines in AD. As suggested in another study testosterone may modulate neuronal damage caused by oxidative stress and it probably decreases neuronal apoptosis, a key step in both AD and age-related cognitive decline [72].

Testosterone Deficiency States: The studies show the testosterone replacement therapy in hypogonadal men does not have a positive effect on cognition. Certain other factors also appear to influence the neuroprotective effect of testosterone and include sex-hormone-binding globulin, thyroid hormone, gonadotrophins and estrogen levels. An imbalance or deficiency of these factors may affect testosterone's neuroprotective actions and lead to cognitive decline. Evidence of the relationship between androgen deficiency and male depression also comes from studies that have assessed depression in hypogonadal subjects, the association between low testosterone levels and male depressive illness, and the antidepressant action of androgen replacement. The etiology of depressive symptoms of Partial Androgen Deficiency in Aging Male (PADAM) is multifactorial, and results from the interaction of the biological and psychosocial changes that take place during the mid-life transition [73].

Recently, a preliminary study of testosterone therapy in older men with low levels of the hormone and clinical conditions related to low testosterone, found that restoring levels to those of healthy young men improved sexual function. The treatment had a smaller effect on other aspects of health, such as the ability to walk or the sense of vitality [74]. The positive effect on cognitive functions was not documented. The PADAM is responsible for a variety of behavioural symptoms, such as weakness, decreased libido and erectile dysfunction, lower psychological vitality, depressive mood, anxiety, insomnia, difficulty in concentrating, and memory impairment. The psychological and behavioural aspects of PADAM may overlap with signs and symptoms of major depression [75].

Testosterone Therapy for Cognitive Dysfunction: Testosterone is an important modulator of cerebral functions. It appears to activate the cortical network, the ventral processing stream, during spatial cognition tasks, and the addition of testosterone improves spatial cognition in younger and older hypogonadal men. In addition, reduced testosterone is associated with depressive disorders. In the hypogonadal men, testosterone supplementation enhances vigor and energy and many aspects of mood and cognition [76].

Androgens play a neuroactive role during the aging process when it affects hippocampal spine synapse density, suggesting a role for androgen in the modulation of cognitive function and development of neurodegenerative disease. The sex steroids modulate brain function and the ability of the brain to process, store and retrieve sensory information [77]. The maintenance of neural elements in brain systems that support memory, such as synapse formation in prefrontal cortex and hippocampus, are critical for cognitive health in aging. There is a biological basis for androgens as neuro-protectants or neuromodulators and the importance of androgens for memory. The androgen deprivation causes significant loss of synapses in the hippocampus in rodent and nonhuman primates, increases amyloid deposition in human and rodent models and causes changes in neurotransmission in prefrontal cortex in rodent models.

The research suggests that these changes modify age-related cognitive loss, particularly to memory in men. In addition, the conversion of testosterone to its androgen metabolites or to estradiol may play a special role in the preservation of memory in aging [78]. Androgen deficiency has been reported to cause changes in mood and cognitive function and the preliminary evidence suggests that testosterone loss may be a risk factor for cognitive decline and possibly for dementia. Conversely, the maintenance of higher testosterone levels may prove beneficial for cognitive and brain function in elderly men. Large-scale placebo-controlled intervention studies are required to resolve ambiguities in the literature [79].

Thyroid Hormone

Thyroid Dysfunction and Cognitive Decline: The concentration of Thyroid Hormones (THs) declines with age. The cognitive decline is often concomitant with aging and the physiological changes in thyroid function might be causally related to changes in cognition during aging [80]. There is a continuum from low to increased concentrations of THs in which cognitive dysfunction can result (Figure 3). The clinical hypothyroidism has effects on cognition and mood, and there is evidence that subclinical hypothyroidism may be a predisposing factor for depression, cognitive impairment, and dementia. Subclinical hypothyroidism is common in the older adults, particularly in women. Further, the older adults are more vulnerable to the effects of subclinical hypothyroidism because of age-related changes to the hypothalamic-pituitary-thyroid axis [81].

The hyperthyroidism in older adults is also associated with decreased cognitive functioning, especially memory, visuospatial retention, attention, and reaction time. Thus, there is potentially increased risk of cognitive decline with thyroid dysfunction, and it is plausible to theorize that the thyroid status contributes to a risk, at least in part, to AD. In fact, hypothyroidism and hyperthyroidism have both been associated with cognitive impairment and dementia [82]. Even the mild variations of thyroid function can have significant consequences for cognitive function in the elderly, and the older adults with cognitive impairment should be assessed for hypothyroidism [83].

Mechanism of Cognitive Impairment in Hypothyroidism: The THs regulate cellular metabolic activity and neuronal development and function [84]. In fact, there exists interdependence between THs and Acetylcholine (Ach), nerve growth factor and hippocampal function. There occurs a decreased cerebral blood flow in mild hypothyroidism in regions mediating attention, motor speed, memory, and visuospatial processing. The THs regulate systemic glucose metabolism and may also be involved in regulation of brain glucose metabolism.

It may also decrease glucose metabolism in brain, thus, prevents the brain from adequately utilizing the energy needed for neurotransmission, memory, and other higher brain functions. Low brain uptake of glucose is commonly associated with deteriorating cognition and AD and can be present decades before clinical evidence of the disease occurs. Thus, brain hypo-metabolism is a precursor lesion increasing the risk of at least some forms of cognitive decline [85]. Further, the THs imbalance is often encountered in combination with metabolic disorders such as diabetes, and may cause additional metabolic dysregulation and hence worsening of disease states. THs may also modulate memory processes, at least in part by modulation of central insulin signaling and glucose metabolism.

Thyroid Replacement Therapy:

a) The results from animal studies: The L-T4 treatment administered both sub-chronically and chronically, significantly enhances the ability of rats to learn a spatial memory task, compared with controls. Moreover, both short-term and longterm L-T4 treatment reduced the cognitive-impairing effects of scopolamine. Improvements in performance were shown to occur along with increased cholinergic activity in frontal cortex and hippocampus of treated animals. These findings demonstrate an augmentative effect of L-T4 upon cognitive function, possibly mediated by an enhancement of cholinergic activity. The results support a relationship between L-T4 and acetylcholine, and the possible mechanisms by which disorders of thyroid function may be associated with cognitive decline.

b) The Results from Clinical Studies: As documented by clinical research, the L-thyroxine treatment may not always completely restore normal cognitive functioning in patients with hypothyroidism [86]. The use of thyroid hormone should be clinically relevant. Higher levels of thyroxine can potentiate oxidative stress and damage neurons, and are associated with accelerated cognitive decline. Therefore treatment with thyroxine in those without thyroid disease is not recommended. In fact, the optimal therapeutic level in the older adults may be normally a bit on lower side because of the physiological slowdown of tissue metabolism.

Insulin

In the Type 1 Diabetes Mellitus (T1DM) patients, cerebral micro vascular damage is common. As life expectancy in patients with T1DM has increased because of better therapeutic modalities, living longer and the longer exposure to disease- related factors, contributes to cerebral micro vascular disease. Clinically relevant White Matter Hyperintensity (WMH) lesions are evident earlier among middle-aged patients with T1DM and lead to the slower information processing and cognitive decline [87]. Brain imaging in T1DM patients having cognitive dysfunctions, especially those with neuropathies, may delineate cerebral micro vascular lesions [88]. Signs of accelerated aging that are related to slower information processing are evident in the brains of middle-aged adults with T1DM. As the people with T1DM are now living longer than ever before and as the incidence of T1DM is increasing annually, the impact of the disease is seen more often and they increasingly present with accelerated brain aging and cognitive decline.

In Type 2 Diabetes Mellitus (T2DM) also, aging is associated with a deranged metabolic function, insulin resistance, increased incidence of neurodegenerative diseases, and memory or cognitive dysfunction [89]. The onset of type 2 diabetes in older adults appears to affect late-life cognition by reducing brain volume, as revealed by MRI studies in a population- based cohort without dementia. But, the T2DM onset after age 64 does not seem to impact brain pathology or cognitive functions, suggesting that the deleterious impact of diabetes on memory and other cognitive aspects develops over decades. The older adults with pre-diabetes and T2DM may suffer from an accelerated decline in brain volume and cognitive functions over as short as two years period, suggesting that other factors also play a role. Further, the aging brain is vulnerable to worsening blood sugar levels even before T2DM is diagnosable [90].

The researchers have documented that older adults having pre-diabetes and T2DM, may lose almost two and a half times more brain volume than the controls over two years. The reduction in size of the frontal lobe, associated with higher mental functions like decision-making, emotional control, and long term memory, has a significant impact on cognitive function and quality of life. The Sydney Memory and Ageing Study, compared MRI scans in older adults taken from the beginning and end of a two-year period. The participants were elderly aged between 70 and 90 years old (54% were male) and free from dementia. At the start of the study 41% had pre-diabetes and 13% had type 2 diabetes. The researchers found that a person's blood sugar status after two years can significantly predict their decline in brain volume [91].

The older adults with T2DM and hypertension may be found to have cortical or subcortical infarctions, WMH, and hippocampal and whole brain volume loss on MRI scanning, and cognitive decline with reduced performance in executive function during cognitive testing, and have a higher risk for AD. In addition, the older adults with T2DM show a two-fold increase in MCI risk as compared with those having no diabetes. The dysfunctional insulin signaling and altered glucose metabolism in the brain of diabetics appears to increase tau phosphorylation, increase insulin binding to insulin-degrading enzyme, decrease beta-amyloid clearance, and lead to neurodegeneration [92].

Growth Hormone

The Growth Hormone (GH) levels also decline with age and may contribute to the cognitive dysfunction typical of aging [93]. GH has a pulsatile pattern of release by the pituitary gland, and the normal pulsatile secretion may be lost before there develops actual GH deficiency. The decline in the overall GH level with age is called somatopause. The signs of somatopause in adults include decrease in lean body mass, decreased joint cartilage, decrease in cardiac endurance, delayed rate of wound healing and decreased sleep duration and quality. The recent clinical research suggests that somatropin or human GH is useful as an anti-aging hormone. The low GH has also been linked to chronic fatigue syndrome, fibromyalgia and osteoporosis.

The low GH states that may benefit from GH replacement therapy include obesity and plaque buildup leading to cardiovascular disease. Tesamorelin is a synthetic version of growth-hormone-releasing hormone, or GHRH. The drug stimulates the production of HGH. In a 20 week double blind study, the researchers found that supplemental GHRH had a positive effect on cognition and healthy brain function not only in healthy older adults but also in adults at increased risk of cognitive decline and dementia [94]. Other research works have also documented that GH supplementation in low GH states may be useful in treating cognitive decline [95].

Cortisol and Dhea

Cortisol is involved in balancing blood glucose levels, immune system responses, bone turnover rate, mood and thought, sleep and protein catabolism. Elevated cortisol is associated with anxiety, insulin resistance, obesity, osteoporosis, sex hormone imbalance, onset insomnia, accelerated aging and immune suppression and disrupts gastrointestinal microflora levels causing dysbiosis. Low cortisol levels, on the other hand, relate to CFS, depression, PMS, menopause, fibromyalgia, impotence in men, fertility and maintenance insomnia [96]. An increase in cortisol levels experienced during prolonged stress, will inhibit release of GH. Also there will be a reduction in the release of LH and testosterone. Cortisol also influences the activity of insulin and THs. Decreased sleep causes an increase in cortisol, a decrease in GH and testosterone. Also the release of melatonin will be affected and this further reduces the production of GH and quality of sleep. The sleep disturbances can exacerbate age- related changes in the brain through the endocrine system [97].

The cortisol levels increase with age (Figure 4). Adrenal hormones DHEA and Cortisol also play an important role in aging related cognitive decline. DHEA, the principle adrenal androgen, and its sulphonated ester DHEA-S, decrease with age [98]. In addition to its androgenic function, DHEA has been reported to have other functions such as improving carbohydrate metabolism, neurological function and general well-being. Low levels of DHEA-S are involved in the decline in immunity, chronic fatigue, nonspecific arthritis, insomnia, decreased libido, obesity, depression and osteoporosis. The hippocampal region of the brain show plasticity and resilience of brain cells to stress hormone action and aging. There is vulnerability of the aging hippocampus in relation to stress and AD [99]. Mechanisms of neuronal death or apoptosis in aging brain and AD include the role of endocrine-mediated altered calcium homeostasis [100].

Applying Recent Research For Action Plan

Research, Results and Concepts

The biological research including the animal studies and clinical research, and various related discoveries have led to wider understanding about hormonal homeostasis, hypothalamic- pituitary axis for hormonal control, the feedback loops which auto-adjust and auto-regulate and role and impact on brain and neurotransmitters, and cognitive functions [101]. The results have led to formulation of theories and concepts through which we can understand and act. The Hormonal Replacement (HR) for a failing hormone is a grossly simple concept. But, then it will affect the altered feedback loops, attenuated receptors, and atrophied neurones. In all, the recent research provides various possibilities, but also puts limitations on therapeutic choices.

HR: Controversies and Restrictions

As for the postmenopausal or perimenopausal women with the hypogonadal states, the HT is likely to prevent and reverse age-related cognitive alterations, and protect AD, but should not have any detrimental effect on other physiological functions [102]. It should also be free from serious side-effects and aftereffects. Further, the research indicates that a low dose estradiol exerts neuroprotection in acute, continuous or intermittent mode, but a high estradiol dose is ineffective at inducing neuroprotection regardless of pattern of dose and may have significant side-effects. Various clinical studies have provided mixed results, and have failed to endorse a unified therapeutic approach. Thus, the wonderful possibilities of HT have been put on back-foot, and lie vastly under-utilized.

The testosterone replacement therapy in PADAM in older men is also ridden with unclarified and mixed results from various clinical studies, hence the therapeutic controversies and confusion [103]. The DHEA treatment is equally controversial [104]. The androgen deficiency leads to mood disorders and cognitive dysfunction and predispose to dementia. A suitable replacement dose may help, but the maintenance of higher testosterone levels have been shown to be beneficial for cognitive and brain function in aging male. TH has a role is in regulating brain glucose metabolism and modulating hippocampal cognitive processes. The THs gradually declines with age and hypothyroidism is common. In fact, TH replacement is the most common in hormonal treatment in clinical practice. But, the L-T4 treatment may not always completely restore normal cognitive functioning in patients with hypothyroidism. On the other hand, higher levels of thyroxine can potentiate oxidative stress and damage neurons, and are associated with accelerated cognitive decline. Therefore, TH replacement should be regularly monitored.

Conclusion: Way Out of the Research Smog

Dissecting Data for Uniformity

With aging, various tissues and organs including the brain gradually fail. The latter is manifested as cognitive decline, MCI and AD. The cognitive decline with aging is part due to wear and tear processes in various neurones and faltering hormonal homeostasis including alterations in the concerned receptors and their impact on neuronal functioning. Over the year, animal studies as well as clinical trials and therapeutic practice have generated vast but diverse data. They provide a gamut of results from varying methodology with differing subjects. These data at times are lope-sided and contradictory. Many a time, the research deals with one aspect of the totality and fails to generate a wholesome inference. The conclusions drawn in various studies restricted and biased, and may preclude further research in the area. Thus, it is required that the research works are dissected out to find and develop relevancy for clinical applicability.

Finding Solutions and Final Words

The biological systems in an organism are regulated by brain through neurotransmitters and hormone releasing factors, influencing hormones secretion. The hormones communicate between organs and tissues by binding to specific receptors for physiological regulation. They also communicate with brain for physiologic and metabolic modulation by the feedback loops and through various receptors on different parts of the brain for behavioral modulation. The aim of hormone therapy, which aims to suitably replenish all the hormonal deficiencies which come with aging, is to prevent and treat their fallouts in the aging man or woman to maintain cognitive health. The hormone therapy needs to address to cognitive decline, and improve ADL and QOL.

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