What are endocrine disruptors. How do they affect our bodies. Where are endocrine disruptors commonly found. What research is being conducted on endocrine-disrupting chemicals. How can we minimize exposure to these harmful substances.

The Basics of Endocrine Disruptors: Definition and Sources

Endocrine disruptors are chemicals that interfere with the body’s hormonal system, potentially causing a wide range of health issues. These substances can be both natural and synthetic, found in various everyday products and environmental sources.

Common sources of endocrine disruptors include:

• Plastic bottles and food containers
• Metal food can linings
• Detergents and cleaning products
• Flame retardants
• Certain foods (e.g., those containing phytoestrogens)
• Toys
• Cosmetics and personal care products
• Pesticides

One of the concerning characteristics of many endocrine disruptors is their persistence in the environment. This property makes them potentially hazardous over extended periods, as they can accumulate in ecosystems and living organisms.

Common Endocrine Disruptors and Their Sources

To better understand the prevalence of endocrine disruptors in our daily lives, it’s crucial to identify some of the most common culprits:

Bisphenol A (BPA)

BPA is widely used in the production of polycarbonate plastics and epoxy resins. It’s found in numerous plastic products, including food storage containers and water bottles.

Phthalates

These chemicals are used to increase the flexibility of plastics. They’re present in food packaging, cosmetics, children’s toys, and some medical devices.

Perfluoroalkyl and Polyfluoroalkyl Substances (PFAS)

PFAS have widespread industrial applications, including non-stick cookware coatings, water-resistant textiles, and firefighting foams.

Polybrominated diphenyl ethers (PBDE)

PBDEs are commonly used as flame retardants in household products such as furniture foam and carpets.

Dioxins

These chemicals are byproducts of various industrial processes, including herbicide production and paper bleaching. They can also be released during waste burning and wildfires.

The Impact of Endocrine Disruptors on Human Health

While extensive research has demonstrated adverse effects of endocrine disruptors in animals, the full extent of their impact on human health is still being investigated. However, several potential health problems have been associated with exposure to these chemicals:

• Developmental issues
• Reproductive problems
• Brain and neurological disorders
• Immune system dysfunction
• Hormonal imbalances
• Certain types of cancer

Do endocrine disruptors pose a risk even at low doses? Yes, research suggests that even small amounts of these chemicals may be unsafe. The endocrine system is highly sensitive, with normal functioning involving minute changes in hormone levels. This sensitivity has led scientists to believe that exposure to endocrine-disrupting chemicals, even in low quantities, can disrupt the body’s delicate hormonal balance and potentially lead to health issues.

Mechanisms of Action: How Endocrine Disruptors Affect the Body

Endocrine disruptors can interfere with the body’s hormonal system in several ways:

1. Altering hormone levels: They can decrease or increase the normal levels of hormones in the body.
2. Mimicking natural hormones: Some endocrine disruptors can imitate the body’s natural hormones, potentially triggering false responses.
3. Modifying hormone production: These chemicals can alter the natural production of hormones in the body.

How do these mechanisms manifest in the body? When absorbed, endocrine disruptors can bind to hormone receptors, block hormone binding, or interfere with hormone synthesis, transport, or metabolism. This interference can lead to a range of physiological effects, from subtle changes in gene expression to more pronounced developmental abnormalities.

Exposure Pathways: How Endocrine Disruptors Enter the Body

Understanding how we come into contact with endocrine-disrupting chemicals is crucial for minimizing exposure. The main pathways of exposure include:

• Diet: Consuming food and beverages that contain or have been in contact with endocrine disruptors
• Air: Inhaling airborne endocrine disruptors, particularly in industrial areas or from household products
• Skin contact: Absorption through the skin from personal care products, cosmetics, or contaminated surfaces
• Water: Drinking water contaminated with endocrine-disrupting chemicals

What makes assessing the health effects of endocrine disruptors challenging? One of the primary difficulties lies in the fact that people are typically exposed to multiple endocrine disruptors simultaneously. This complex exposure scenario makes it challenging to isolate the effects of individual chemicals and accurately assess their public health impact.

Research Initiatives: NIEHS and the Study of Endocrine Disruptors

The National Institute of Environmental Health Sciences (NIEHS) has been at the forefront of research on endocrine disruptors for over three decades. Their work has significantly contributed to our understanding of how these chemicals may harm health and cause disease.

Key aspects of NIEHS research on endocrine disruptors include:

• Developing new models and tools to better understand the mechanisms of endocrine disruptors
• Creating and applying high-throughput assays to identify substances with endocrine-disrupting activity
• Conducting animal and human studies to assess the health effects of exposure
• Investigating the long-term consequences of endocrine disruptor exposure, particularly during critical developmental periods

What was one of the earliest and most significant studies on endocrine disruptors? The research on diethylstilbestrol (DES) was a landmark in the field. DES, a drug used from the 1940s to the 1970s to prevent miscarriage, was later linked to rare vaginal cancers and other health issues in the children of women who took the drug during pregnancy. NIEHS experiments successfully replicated and predicted these health problems, providing valuable insights into the mechanisms of endocrine disruption.

Recent Developments in Endocrine Disruptor Research

The field of endocrine disruptor research is continuously evolving, with new discoveries and methodologies emerging regularly. Some recent developments include:

Key Characteristics Framework

In 2019, NIEHS was involved in developing a consensus statement on the key characteristics of endocrine-disrupting chemicals. This framework provides scientists with a structured approach to evaluate potential endocrine disruptors, enhancing the consistency and reliability of research in this field.

Epigenetic Effects

Emerging research is exploring how endocrine disruptors may cause epigenetic changes – alterations in gene expression that don’t involve changes to the DNA sequence itself. These epigenetic modifications could potentially explain some of the long-term and transgenerational effects observed with certain endocrine disruptors.

Mixture Effects

Given that humans are typically exposed to multiple endocrine disruptors simultaneously, there’s increasing focus on studying the combined effects of these chemical mixtures. This research aims to better reflect real-world exposure scenarios and their potential health impacts.

Minimizing Exposure: Practical Steps to Reduce Contact with Endocrine Disruptors

While it’s nearly impossible to completely avoid endocrine disruptors in the modern world, there are several steps individuals can take to minimize their exposure:

• Choose glass or stainless steel containers over plastic for food storage
• Avoid heating food in plastic containers
• Filter tap water
• Eat organic produce when possible to reduce pesticide exposure
• Read labels on personal care products and avoid those containing phthalates, parabens, and triclosan
• Dust and vacuum regularly to reduce exposure to flame retardants in household dust
• Choose naturally flame-resistant materials like wool instead of chemically treated ones
• Minimize consumption of canned foods to reduce exposure to BPA in can linings

Can completely eliminating exposure to endocrine disruptors guarantee protection from their effects? While reducing exposure is beneficial, it’s important to note that some endocrine disruptors are ubiquitous in the environment and difficult to avoid entirely. Additionally, the long-term persistence of certain endocrine disruptors means that past exposures may continue to have effects. Therefore, a combination of individual actions, regulatory measures, and ongoing research is necessary to address the challenge of endocrine disruptors comprehensively.

The Future of Endocrine Disruptor Research and Regulation

As our understanding of endocrine disruptors grows, so does the need for more comprehensive research and regulatory approaches. Future directions in this field may include:

Improved Testing Methods

Developing more sensitive and specific methods for detecting endocrine-disrupting activity in chemicals, particularly at low doses that mimic environmental exposures.

Comprehensive Screening Programs

Implementing large-scale screening programs to identify endocrine-disrupting chemicals in consumer products and environmental samples.

Regulatory Updates

Revising and updating regulations based on the latest scientific evidence to better protect public health and the environment from the effects of endocrine disruptors.

Alternative Development

Encouraging the development of safer alternatives to known endocrine disruptors in consumer products and industrial applications.

How might advances in technology contribute to endocrine disruptor research? Emerging technologies such as high-throughput screening, advanced analytical techniques, and computational modeling are likely to play increasingly important roles in identifying and characterizing endocrine disruptors. These tools can help researchers process large amounts of data more quickly and efficiently, potentially accelerating the pace of discovery in this field.

In conclusion, endocrine disruptors represent a complex and ongoing challenge in environmental health. While significant progress has been made in understanding these chemicals and their effects, much work remains to be done. Continued research, public awareness, and regulatory action will be crucial in mitigating the potential health risks associated with endocrine-disrupting chemicals and ensuring a healthier future for both humans and the environment.

Endocrine Disruptors

Introduction

Many chemicals, both natural and man-made, may mimic or interfere with the body’s hormones, known as the endocrine system. Called endocrine disruptors, these chemicals are linked with developmental, reproductive, brain, immune, and other problems.

Endocrine disruptors are found in many everyday products, including some plastic bottles and containers, liners of metal food cans, detergents, flame retardants, food, toys, cosmetics, and pesticides.

Some endocrine-disrupting chemicals are slow to break-down in the environment. That characteristic makes them potentially hazardous over time.

Endocrine disrupting chemicals cause adverse effects in animals. But limited scientific information exists on potential health problems in humans. Because people are typically exposed to multiple endocrine disruptors at the same time, assessing public health effects is difficult.

What are some common endocrine disruptors?

• Bisphenol A (BPA) — used to make polycarbonate plastics and epoxy resins, which are found in many plastic products including food storage containers
• Dioxins — produced as a byproduct in herbicide production and paper bleaching, they are also released into the environment during waste burning and wildfires
• Perchlorate — a by-product of aerospace, weapon, and pharmaceutical industries found in drinking water and fireworks
• Perfluoroalkyl and Polyfluoroalkyl Substances (PFAS) — used widely in industrial applications, such as firefighting foams and non-stick pan, paper, and textile coatings
• Phthalates — used to make plastics more flexible, they are also found in some food packaging, cosmetics, children’s toys, and medical devices
• Phytoestrogens — naturally occurring substances in plants that have hormone-like activity, such as genistein and daidzein that are in soy products, like tofu or soy milk
• Polybrominated diphenyl ethers (PBDE) — used to make flame retardants for household products such as furniture foam and carpets
• Polychlorinated biphenyls (PCB) — used to make electrical equipment like transformers, and in hydraulic fluids, heat transfer fluids, lubricants, and plasticizers
• Triclosan — may be found in some anti-microbial and personal care products, like liquid body wash

How do people encounter endocrine-disrupting chemicals?

People may be exposed to endocrine disruptors through food and beverages consumed, pesticides applied, and cosmetics used. In essence, your contact with these chemicals may occur through diet, air, skin, and water.

Even low doses of endocrine-disrupting chemicals may be unsafe. The body’s normal endocrine functioning involves very small changes in hormone levels, yet we know even these small changes can cause significant developmental and biological effects. This observation leads scientists to think that endocrine-disrupting chemical exposures, even at low amounts, can alter the body’s sensitive systems and lead to health problems.

When absorbed in the body, an endocrine disruptor can decrease or increase normal hormone levels (left), mimic the body’s natural hormones (middle), or alter the natural production of hormones (right).

What is NIEHS Doing?

For more than three decades, NIEHS has been a pioneer in conducting research on the health effects of endocrine disruptors. NIEHS-supported research leads to a greater understanding of how endocrine-disrupting chemicals may harm our health and cause disease.

This work began with studies on the endocrine-disrupting effects of the drug diethylstilbestrol (DES). From 1940s through 1970s, DES was used to treat women with high-risk pregnancies, with the mistaken belief that it prevented miscarriage. In 1972, prenatal exposure to DES was linked to the development of a rare form of vaginal cancer in daughters whose mothers took DES, and with numerous noncancerous changes in both sons and daughters. NIEHS experiments on DES successfully replicated and predicted health problems, which was useful in discovering how DES may harm wellbeing.

NIEHS was involved in developing a consensus statement in 2019 on the key characteristics of endocrine-disrupting chemicals, which provides a framework to help scientists evaluate potential endocrine disruptors.

NIEHS leads cutting-edge research projects on endocrine disrupting chemicals to understand how they work and define their role in health and disease. Research areas in progress include:

• Developing new models and tools to better understand how endocrine disrupters work
• Developing and applying high throughout assays to identify substances with endocrine disrupting activity
• Conducting animal and human health research to define linkages between exposure to endocrine disrupters and health effects
• Developing new assessments and biomarkers of exposure and toxicity
• Identifying and developing new intervention and prevention strategies

Related work of the National Toxicology Program

In 2000, an independent panel of experts convened by NIEHS and the National Toxicology Program (NTP), which is housed at NIEHS, concluded there was credible evidence that very low doses of some hormone-like chemicals can adversely affect bodily functions in test animals.

NTP is evaluating endocrine disrupters including pesticides, perfluorinated chemicals, compounds that may replace BPA in the marketplace, and components of flame-retardants for how they may affect body tissues such as breast, uterus, fat cells, male reproductive tract, and liver. In addition, they conduct laboratory studies that help them prioritize endocrine disrupting chemicals for further toxicity testing.

NTP scientists collaborate with researchers from the U.S. Environmental Protection Agency (EPA) to develop and validate integrated, high throughput testing strategies to detect substances that could disrupt endocrine functions by interacting with the hormones estrogen and androgen. In addition, they created a comprehensive database from thousands of scientific studies on how different substances interact with hormones.

The multi-agency Tox 21 program, in which NIEHS participates, is developing and applying new models and tools using robotics to predict endocrine disrupting activity for environmental substances.

What has NIEHS discovered?

NIEHS-supported research has discovered links between endocrine-disrupting chemicals and the ways in which wellbeing may be harmed, as shown by the following examples:

• Attention. Attention-deficit/hyperactivity disorder (ADHD) is one of the most common childhood disorders, which can continue through adolescence and into adulthood. ADHD symptoms include difficulty staying focused, paying attention, and controlling behavior. Researchers reported in JAMA that ordinary exposure to certain phthalates, as found in urine samples, was associated with ADHD-related behaviors in adolescence. The drug DES may be linked to an increased chance of developing ADHD in the grandchildren of women who used it during pregnancy.
• Immunity. Children exposed to high levels of PFAS had a diminished immune response to vaccines.
• Metabolism. Long-term exposure to arsenic can disrupt metabolism, increasing the risk of diabetes and other metabolic disorders.
• Puberty. Chemicals in lavender oil and tea tree oil are potential endocrine disruptors. Researchers found that persistent exposure to lavender oil products is associated with premature breast development in girls, and abnormal breast development in boys.
• Reproduction. DES can cause epigenetic changes, altering the way genes are turned on and off, in reproductive organs of mice. The findings provide a possible explanation for how endocrine disruptors affect fertility and reproduction.

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Gender Dysphoria/Gender Incongruence Guideline Resources

Full Guideline: Endocrine Treatment of Gender-Dysphoric/Gender-Incongruent Persons: An Endocrine Society Clinical Practice Guideline
JCEM September 2017
Wylie C. Hembree (Chair), Peggy T. Cohen-Kettenis, Louis Gooren, Sabine E. Hannema, Walter J. Meyer, M. Hassan Murad, Stephen M. Rosenthal, Joshua D. Safer, Vin Tangpricha, Guy G. T’Sjoen

The 2017 guideline on endocrine treatment of gender dysphoric/gender incongruent persons:

• Establishes a framework for the appropriate treatment of these individuals
• Standardizes terminology to be used by healthcare professionals
• Reaffirms the role of the endocrinologist
• Emphasizes that a broader healthcare team is needed to provide mental health services and other treatments, such as gender-affirmation surgery

Endocrine Treatment of Gender Incongruent/Gender Dysphoric Persons: An Endocrine Society Clinical Practice Guideline

Essential Points

• Diagnosing clinicians, mental health providers for adolescents, and mental health professionals for adults all should be knowledgeable about the diagnostic criteria for gender-affirming treatment, have sufficient training and experience in assessing related mental health conditions, and be willing to participate in the ongoing care throughout the endocrine transition
• Gender-dysphoric/gender-incongruent persons should receive a safe and effective hormone regimen that will suppress the body’s sex hormone secretion, determined at birth and manifested at puberty, and maintain levels of sex steroids within the normal range for the person’s affirmed gender.
• Hormone treatment is not recommended for pre-pubertal gender-dysphoric /gender-incongruent persons;
• For the care of youths during puberty and older adolescents, an expert multi-disciplinary team comprised of medical professionals and mental health professionals should manage treatment;
• For adult gender-dysphoric/gender-incongruent persons, the treating clinicians (collectively) should have expertise in transgender-specific diagnostic criteria, mental health, primary care, hormone treatment, and surgery, as needed by the patient;
• All individuals seeking gender-affirming medical treatment should receive information and counsel on options for fertility preservation prior to initiating puberty suppression in adolescents and prior to treating with hormonal therapy in both adolescents and adults;
• Removal of gonads may be considered when high doses of sex steroids are required to suppress the body’s secretion of hormones, and/or to reduce steroid levels in advanced age; and
• During sex steroid treatment, clinicians should monitor, in both transgender males (female to male) and/or transgender females (male to female), prolactin, metabolic disorders, and bone loss, as well as cancer risks in individuals who have not undergone surgical treatment

Summary of Recommendations

+ 1. 0 Evaluation of Youth and Adults

1.1. We advise that only trained mental health professionals (MHPs) who meet the following criteria should diagnose gender dysphoria (GD)/gender incongruence in adults: (1) competence in using the Diagnostic and Statistical Manual of Mental Disorders (DSM) and/or the International Statistical Classification of Diseases and Related Health Problems (ICD) for diagnostic purposes, (2) the ability to diagnose GD/gender incongruence and make a distinction between GD/gender incongruence and conditions that have similar features (e.g., body dysmorphic disorder), (3) training in diagnosing psychiatric conditions, (4) the ability to undertake or refer for appropriate treatment, (5) the ability to psychosocially assess the person’s understanding, mental health, and social conditions that can impact gender-affirming hormone therapy, and (6) a practice of regularly attending relevant professional meetings. (Ungraded Good Practice Statement)
1.2. We advise that only MHPs who meet the following criteria should diagnose GD/gender incongruence in children and adolescents: (1) training in child and adolescent developmental psychology and psychopathology, (2) competence in using the DSM and/or the ICD for diagnostic purposes, (3) the ability to make a distinction between GD/gender incongruence and conditions that have similar features (e. g., body dysmorphic disorder), (4) training in diagnosing psychiatric conditions, (5) the ability to undertake or refer for appropriate treatment, (6) the ability to psychosocially assess the person’s understanding and social conditions that can impact gender-affirming hormone therapy, (7) a practice of regularly attending relevant professional meetings, and (8) knowledge of the criteria for puberty blocking and gender-affirming hormone treatment in adolescents. (Ungraded Good Practice Statement)
1.3. We advise that decisions regarding the social transition of prepubertal youths with GD/gender incongruence are made with the assistance of an MHP or another experienced professional. (Ungraded Good Practice Statement).
1.4. We recommend against puberty blocking and gender-affirming hormone treatment in prepubertal children with GD/gender incongruence. (1 |⊕⊕OO)
1.5. We recommend that clinicians inform and counsel all individuals seeking gender-affirming medical treatment regarding options for fertility preservation prior to initiating puberty suppression in adolescents and prior to treating with hormonal therapy of the affirmed gender in both adolescents and adults. (1 |⊕⊕⊕O)

+ 2.0 Treatment of Adolescents

2.1. We suggest that adolescents who meet diagnostic criteria for GD/gender incongruence, fulfill criteria for treatment, and are requesting treatment should initially undergo treatment to suppress pubertal development. (2 |⊕⊕OO)
2.2. We suggest that clinicians begin pubertal hormone suppression after girls and boys first exhibit physical changes of puberty. (2 |⊕⊕OO)
2.3. We recommend that, where indicated, GnRH analogues are used to suppress pubertal hormones. (1 |⊕⊕OO)
2.4. In adolescents who request sex hormone treatment (given this is a partly irreversible treatment), we recommend initiating treatment using a gradually increasing dose schedule after a multidisciplinary team of medical and MHPs has confirmed the persistence of GD/gender incongruence and sufficient mental capacity to give informed consent, which most adolescents have by age 16 years. (1 |⊕⊕OO).
2.5. We recognize that there may be compelling reasons to initiate sex hormone treatment prior to the age of 16 years in some adolescents with GD/gender incongruence, even though there are minimal published studies of gender-affirming hormone treatments administered before age 13. 5 to 14 years. As with the care of adolescents ≥16 years of age, we recommend that an expert multidisciplinary team of medical and MHPs manage this treatment. (1 |⊕OOO)
2.6. We suggest monitoring clinical pubertal development every 3 to 6 months and laboratory parameters every 6 to 12 months during sex hormone treatment. (2 |⊕⊕OO)

+ 3.0 Hormonal Therapy for Transgender Adults

3.1. We recommend that clinicians confirm the diagnostic criteria of GD/gender incongruence and the criteria for the endocrine phase of gender transition before beginning treatment. (1 |⊕⊕⊕O)
3.2. We recommend that clinicians evaluate and address medical conditions that can be exacerbated by hormone depletion and treatment with sex hormones of the affirmed gender before beginning treatment. (1 |⊕⊕⊕O)
3.3. We suggest that clinicians measure hormone levels during treatment to ensure that endogenous sex steroids are suppressed and administered sex steroids are maintained in the normal physiologic range for the affirmed gender. (2 |⊕⊕OO)
3.4. We suggest that endocrinologists provide education to transgender individuals undergoing treatment about the onset and time course of physical changes induced by sex hormone treatment. (2 |⊕OOO)

+ 4.0 Adverse Outcome Prevention and Long-Term Care

4.1. We suggest regular clinical evaluation for physical changes and potential adverse changes in response to sex steroid hormones and laboratory monitoring of sex steroid hormone levels every 3 months during the first year of hormone therapy for transgender males and females and then once or twice yearly. (2 |⊕⊕○○)
4.2. We suggest periodically monitoring prolactin levels in transgender females treated with estrogens. (2 |⊕⊕OO)
4.3. We suggest that clinicians evaluate transgender persons treated with hormones for cardiovascular risk factors using fasting lipid profiles, diabetes screening, and/or other diagnostic tools. (2 |⊕⊕OO)
4.4. We recommend that clinicians obtain bone mineral density (BMD) measurements when risk factors for osteoporosis exist, specifically in those who stop sex hormone therapy after gonadectomy. (1 |⊕⊕OO)
4.5. We suggest that transgender females with no known increased risk of breast cancer follow breast-screening guidelines recommended for non-transgender females. (2 |⊕⊕OO)
4.6. We suggest that transgender females treated with estrogens follow individualized screening according to personal risk for prostatic disease and prostate cancer. (2 |⊕OOO)
4.7. We advise that clinicians determine the medical necessity of including a total hysterectomy and oophorectomy as part of gender-affirming surgery. (Ungraded Good Practice Statement)

+ 5.0 Surgery for Sex Reassignment and Gender Confirmation

5.1. We recommend that a patient pursue genital gender-affirming surgery only after the MHP and the clinician responsible for endocrine transition therapy both agree that surgery is medically necessary and would benefit the patient’s overall health and/or well-being. (1 |⊕⊕OO)
5.2. We advise that clinicians approve genital gender-affirming surgery only after completion of at least 1 year of consistent and compliant hormone treatment, unless hormone therapy is not desired or medically contraindicated. (Ungraded Good Practice Statement)
5.3. We advise that the clinician responsible for endocrine treatment and the primary care provider ensure appropriate medical clearance of transgender individuals for genital gender-affirming surgery and collaborate with the surgeon regarding hormone use during and after surgery. (Ungraded Good Practice Statement)
5.4. We recommend that clinicians refer hormone-treated transgender individuals for genital surgery when: (1) the individual has had a satisfactory social role change, (2) the individual is satisfied about the hormonal effects, and (3) the individual desires definitive surgical changes. (1 |⊕OOO)
5.5. We suggest that clinicians delay gender-affirming genital surgery involving gonadectomy and/or hysterectomy until the patient is at least 18 years old or legal age of majority in his or her country. (2 |⊕⊕OO).
5.6. We suggest that clinicians determine the timing of breast surgery for transgender males based upon the physical and mental health status of the individual. There is insufficient evidence to recommend a specific age requirement. (2 |⊕OOO)

Comprehensive Type 2 Diabetes Management Algorithm (2020) – EXECUTIVE SUMMARY

This algorithm for the comprehensive management of persons with type 2 diabetes (T2D) was developed to provide clinicians with a practical guide that considers the whole patient, his or her spectrum of risks and complications, and evidence-based approaches to treatment. It is now clear that the progressive pancreatic beta-cell defect that drives the deterioration of metabolic control over time begins early and may be present before the diagnosis of T2D (1-3). In addition to advocating glycemic control to reduce microvascular complications, this document highlights obesity and prediabetes as underlying risk factors for the development of T2D and associated macrovascular complications. In addition, the algorithm provides recommendations for blood pressure (BP) and lipid control, the two most important risk factors for atherosclerotic cardiovascular disease (ASCVD).

Since originally drafted in 2013, the algorithm has been updated as new therapies, management approaches, and important clinical data have emerged. The current algorithm includes up-to-date sections on lifestyle therapy and all classes of obesity, antihyperglycemic, lipid-lowering, and antihypertensive medications approved by the U.S. Food and Drug Administration (FDA) through December 2019. In addition, the algorithm is formulated to be consistent with American Association of Clinical Endocrinologists (AACE) position statements on adiposity- and dysglycemia-based chronic disease models for early and sustainable preventive care.

This algorithm supplements the AACE and American College of Endocrinology (ACE) 2015 Clinical Practice Guidelines for Developing a Diabetes Mellitus Comprehensive Care Plan (6) and is organized into discrete sections that address the following topics: the founding principles of the algorithm, lifestyle therapy, obesity, prediabetes, management of hypertension and dyslipidemia, and glucose control with noninsulin antihyperglycemic agents and insulin. In the accompanying algorithm, a chart summarizing the attributes of each antihyperglycemic class appears at the end.

READ EXECUTIVE SUMMARY
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The Nervous System and the Endocrine System – Introduction to Psychology – 1st Canadian Edition

Learning Objectives

1. Summarize the primary functions of the CNS and of the subsystems of the PNS.
2. Explain how the electrical components of the nervous system and the chemical components of the endocrine system work together to influence behaviour.

Now that we have considered how individual neurons operate and the roles of the different brain areas, it is time to ask how the body manages to put it all together. How do the complex activities in the various parts of the brain, the simple all-or-nothing firings of billions of interconnected neurons, and the various chemical systems within the body work together to allow the body to respond to the social environment and engage in everyday behaviours? In this section we will see that the complexities of human behaviour are accomplished through the joint actions of electrical and chemical processes in the nervous system and the endocrine system.

Electrical Control of Behaviour: The Nervous System

The nervous system (see Figure 4.16, “The Functional Divisions of the Nervous System”), the electrical information highway of the body, is made up of nerves — bundles of interconnected neurons that fire in synchrony to carry messages. The central nervous system (CNS), made up of the brain and spinal cord, is the major controller of the body’s functions, charged with interpreting sensory information and responding to it with its own directives. The CNS interprets information coming in from the senses, formulates an appropriate reaction, and sends responses to the appropriate system to respond accordingly. Everything that we see, hear, smell, touch, and taste is conveyed to us from our sensory organs as neural impulses, and each of the commands that the brain sends to the body, both consciously and unconsciously, travels through this system as well.

Figure 4.16 The Functional Divisions of the Nervous System. [Long Description]

Nerves are differentiated according to their function. A sensory (or afferent) neuron carries information from the sensory receptors, whereas a motor (or efferent) neuron transmits information to the muscles and glands. An interneuron, which is by far the most common type of neuron, is located primarily within the CNS and is responsible for communicating among the neurons. Interneurons allow the brain to combine the multiple sources of available information to create a coherent picture of the sensory information being conveyed.

The spinal cord is the long, thin, tubular bundle of nerves and supporting cells that extends down from the brain. It is the central throughway of information for the body. Within the spinal cord, ascending tracts of sensory neurons relay sensory information from the sense organs to the brain while descending tracts of motor neurons relay motor commands back to the body. When a quicker-than-usual response is required, the spinal cord can do its own processing, bypassing the brain altogether. A reflex is an involuntary and nearly instantaneous movement in response to a stimulus. Reflexes are triggered when sensory information is powerful enough to reach a given threshold and the interneurons in the spinal cord act to send a message back through the motor neurons without relaying the information to the brain (see Figure 4.17, “The Reflex”). When you touch a hot stove and immediately pull your hand back, or when you fumble your cell phone and instinctively reach to catch it before it falls, reflexes in your spinal cord order the appropriate responses before your brain even knows what is happening.

Figure 4.17 The Reflex. The central nervous system can interpret signals from sensory neurons and respond to them extremely quickly via the motor neurons without any need for the brain to be involved. These quick responses, known as reflexes, can reduce the damage that we might experience as a result of, for instance, touching a hot stove.

If the central nervous system is the command centre of the body, the peripheral nervous system (PNS) represents the front line. The PNS links the CNS to the body’s sense receptors, muscles, and glands. As you can see in Figure 4.18, “The Autonomic Nervous System,” the peripheral nervous system is itself divided into two subsystems, one controlling internal responses and one controlling external responses.

The autonomic nervous system (ANS) is the division of the PNS that governs the internal activities of the human body, including heart rate, breathing, digestion, salivation, perspiration, urination, and sexual arousal. Many of the actions of the ANS, such as heart rate and digestion, are automatic and out of our conscious control, but others, such as breathing and sexual activity, can be controlled and influenced by conscious processes.

The somatic nervous system (SNS) is the division of the PNS that controls the external aspects of the body, including the skeletal muscles, skin, and sense organs. The somatic nervous system consists primarily of motor nerves responsible for sending brain signals for muscle contraction.

The autonomic nervous system itself can be further subdivided into the sympathetic and parasympathetic systems. The sympathetic division of the ANS is involved in preparing the body for behaviour, particularly in response to stress, by activating the organs and the glands in the endocrine system. The parasympathetic division of the ANS tends to calm the body by slowing the heart and breathing and by allowing the body to recover from the activities that the sympathetic system causes. The sympathetic and the parasympathetic divisions normally function in opposition to each other, with the sympathetic division acting a bit like the accelerator pedal on a car and the parasympathetic division acting like the brake.

Figure 4.18 The Autonomic Nervous System. The autonomic nervous system has two divisions: The sympathetic division acts to energize the body, preparing it for action. The parasympathetic division acts to calm the body, allowing it to rest. [Long Description]

Our everyday activities are controlled by the interaction between the sympathetic and parasympathetic nervous systems. For example, when we get out of bed in the morning, we would experience a sharp drop in blood pressure if it were not for the action of the sympathetic system, which automatically increases blood flow through the body. Similarly, after we eat a big meal, the parasympathetic system automatically sends more blood to the stomach and intestines, allowing us to efficiently digest the food. And perhaps you have had the experience of not being at all hungry before a stressful event, such as a sports game or an exam (when the sympathetic division was primarily in action), but suddenly finding yourself feeling starved afterward, as the parasympathetic takes over. The two systems work together to maintain vital bodily functions, resulting in homeostasis, the natural balance in the body’s systems.

The Body’s Chemicals Help Control Behaviour: The Endocrine System

The nervous system is designed to protect us from danger through its interpretation of and reactions to stimuli. But a primary function of the sympathetic and parasympathetic nervous systems is to interact with the endocrine system to elicit chemicals that provide another system for influencing our feelings and behaviours.

A gland in the endocrine system is made up of groups of cells that function to secrete hormones. A hormone is a chemical that moves throughout the body to help regulate emotions and behaviours. When the hormones released by one gland arrive at receptor tissues or other glands, these receiving receptors may trigger the release of other hormones, resulting in a series of complex chemical chain reactions. The endocrine system works together with the nervous system to influence many aspects of human behaviour, including growth, reproduction, and metabolism. And the endocrine system plays a vital role in emotions. Because the glands in men and women differ, hormones also help explain some of the observed behavioural differences between men and women. The major glands in the endocrine system are shown in Figure 4.19, “The Major Glands of the Endocrine System.”

Figure 4.19 The Major Glands of the Endocrine System. The male is shown on the left and the female on the right.

The pituitary gland, a small pea-sized gland located near the centre of the brain, is responsible for controlling the body’s growth, but it also has many other influences that make it of primary importance to regulating behaviour. The pituitary secretes hormones that influence our responses to pain as well as hormones that signal the ovaries and testes to make sex hormones. The pituitary gland also controls ovulation and the menstrual cycle in women. Because the pituitary has such an important influence on other glands, it is sometimes known as the “master gland. ”

Other glands in the endocrine system include the pancreas, which secretes hormones designed to keep the body supplied with fuel to produce and maintain stores of energy; the pineal gland, located in the middle of the brain, which secretes melatonin, a hormone that helps regulate the wake-sleep cycle; and the thyroid and parathyroid glands, which are responsible for determining how quickly the body uses energy and hormones, and controlling the amount of calcium in the blood and bones.

The body has two triangular adrenal glands, one atop each kidney. The adrenal glands produce hormones that regulate salt and water balance in the body, and they are involved in metabolism, the immune system, and sexual development and function. The most important function of the adrenal glands is to secrete the hormones epinephrine (also known as adrenaline) and norepinephrine (also known as noradrenaline) when we are excited, threatened, or stressed. Epinephrine and norepinephrine stimulate the sympathetic division of the ANS, causing increased heart and lung activity, dilation of the pupils, and increases in blood sugar, which give the body a surge of energy to respond to a threat. The activity and role of the adrenal glands in response to stress provide an excellent example of the close relationship and interdependency of the nervous and endocrine systems. A quick-acting nervous system is essential for immediate activation of the adrenal glands, while the endocrine system mobilizes the body for action.

The male sex glands, known as the testes, secrete a number of hormones, the most important of which is testosterone, the male sex hormone. Testosterone regulates body changes associated with sexual development, including enlargement of the penis, deepening of the voice, growth of facial and pubic hair, and the increase in muscle growth and strength. The ovaries, the female sex glands, are located in the pelvis. They produce eggs and secrete the female hormones estrogen and progesterone. Estrogen is involved in the development of female sexual features, including breast growth, the accumulation of body fat around the hips and thighs, and the growth spurt that occurs during puberty. Both estrogen and progesterone are also involved in pregnancy and the regulation of the menstrual cycle.

Recent research has pinpointed some of the important roles of the sex hormones in social behaviour. Dabbs, Hargrove, and Heusel (1996) measured the testosterone levels of 240 men who were members of 12 fraternities at two universities. They also obtained descriptions of the fraternities from university officials, fraternity officers, yearbook and chapter house photographs, and researcher field notes. The researchers correlated the testosterone levels and the descriptions of each fraternity. They found that the fraternities with the highest average testosterone levels were also more wild and unruly, and one of these fraternities was known across campus for the crudeness of its behaviour. On the other hand, the fraternities with the lowest average testosterone levels were more well behaved, friendly and pleasant, academically successful, and socially responsible. Banks and Dabbs (1996) found that juvenile delinquents and prisoners who had high levels of testosterone also acted more violently, and Tremblay and colleagues (1998) found that testosterone was related to toughness and leadership behaviours in adolescent boys. Although testosterone levels are higher in men than in women, the relationship between testosterone and aggression is not limited to males. Studies have also shown a positive relationship between testosterone and aggression and related behaviours (such as competitiveness) in women (Cashdan, 2003).

Keep in mind that the observed relationships between testosterone levels and aggressive behaviour that have been found in these studies do not prove that testosterone causes aggression — the relationships are only correlational. In fact, there is evidence that the relationship between violence and testosterone also goes in the other direction: playing an aggressive game, such as tennis or even chess, increases the testosterone levels of the winners and decreases the testosterone levels of losers (Gladue, Boechler, & McCaul, 1989; Mazur, Booth, & Dabbs, 1992), and perhaps this is why excited soccer fans sometimes riot when their team wins.

Recent research has also begun to document the role that female sex hormones may play in reactions to others. A study about hormonal influences on social-cognitive functioning (Macrae, Alnwick, Milne, & Schloerscheidt, 2002) found that women were more easily able to perceive and categorize male faces during the more fertile phases of their menstrual cycles. Although researchers did not directly measure the presence of hormones, it is likely that phase-specific hormonal differences influenced the women’s perceptions.

At this point you can begin to see the important role the hormones play in behaviour. But the hormones we have reviewed in this section represent only a subset of the many influences that hormones have on our behaviours. In the chapters to come we will consider the important roles that hormones play in many other behaviours, including sleeping, sexual activity, and helping and harming others.

Key Takeaways

• The body uses both electrical and chemical systems to create homeostasis.
• The CNS is made up of bundles of nerves that carry messages to and from the PNS.
• The peripheral nervous system is composed of the autonomic nervous system (ANS) and the peripheral nervous system (PNS). The ANS is further divided into the sympathetic (activating) and parasympathetic (calming) nervous systems. These divisions are activated by glands and organs in the endocrine system.
• Specific nerves, including sensory neurons, motor neurons, and interneurons, each have specific functions.
• The spinal cord may bypass the brain by responding rapidly using reflexes.
• The pituitary gland is a master gland, affecting many other glands.
• Hormones produced by the pituitary and adrenal glands regulate growth, stress, sexual functions, and chemical balance in the body.
• The adrenal glands produce epinephrine and norepinephrine, the hormones responsible for our reactions to stress.
• The sex hormones, testosterone, estrogen, and progesterone, play an important role in sex differences.

Exercises and Critical Thinking

1. Recall a time when you were threatened or stressed. What physiological reactions did you experience in the situation, and what aspects of the endocrine system do you think created those reactions?
2. Consider the emotions that you have experienced over the past several weeks. What hormones do you think might have been involved in creating those emotions?

References

Banks, T., & Dabbs, J. M., Jr. (1996). Salivary testosterone and cortisol in delinquent and violent urban subculture. Journal of Social Psychology, 136(1), 49–56.

Cashdan, E. (2003). Hormones and competitive aggression in women. Aggressive Behavior, 29(2), 107–115.

Dabbs, J. M., Jr., Hargrove, M. F., & Heusel, C. (1996). Testosterone differences among college fraternities: Well-behaved vs. rambunctious. Personality and Individual Differences, 20(2), 157–161.

Gladue, B. A., Boechler, M., & McCaul, K. D. (1989). Hormonal response to competition in human males. Aggressive Behavior, 15(6), 409–422.

Macrae, C. N., Alnwick, K. A., Milne, A. B., & Schloerscheidt, A. M. (2002). Person perception across the menstrual cycle: Hormonal influences on social-cognitive functioning. Psychological Science, 13(6), 532–536.

Mazur, A., Booth, A., & Dabbs, J. M. (1992). Testosterone and chess competition. Social Psychology Quarterly, 55(1), 70–77.

Tremblay, R. E., Schaal, B., Boulerice, B., Arseneault, L., Soussignan, R. G., Paquette, D., & Laurent, D. (1998). Testosterone, physical aggression, dominance, and physical development in early adolescence. International Journal of Behavioral Development, 22(4), 753–777.

Long Descriptions

Figure 4.16 long description: The nervous system is made up of two parts: The central nervous system consisting of the brain and spinal cord and the peripheral nervous system. The peripheral nervous system is both autonomic (controlling internal activities of organs and glands) and somatic (controlling external actions of skin and muscles). [Return to Figure 4.16]

[Return to Figure 4.18]

The American Association of Endocrine Surgeons Guidelines for Definitive Management of Primary Hyperparathyroidism | Endocrine Surgery | JAMA Surgery

Importance 
Primary hyperparathyroidism (pHPT) is a common clinical problem for which the only definitive management is surgery. Surgical management has evolved considerably during the last several decades.

Objective 
To develop evidence-based guidelines to enhance the appropriate, safe, and effective practice of parathyroidectomy.

Evidence Review 
A multidisciplinary panel used PubMed to review the medical literature from January 1, 1985, to July 1, 2015. Levels of evidence were determined using the American College of Physicians grading system, and recommendations were discussed until consensus.

Findings 
Initial evaluation should include 25-hydroxyvitamin D measurement, 24-hour urine calcium measurement, dual-energy x-ray absorptiometry, and supplementation for vitamin D deficiency. Parathyroidectomy is indicated for all symptomatic patients, should be considered for most asymptomatic patients, and is more cost-effective than observation or pharmacologic therapy. Cervical ultrasonography or other high-resolution imaging is recommended for operative planning. Patients with nonlocalizing imaging remain surgical candidates. Preoperative parathyroid biopsy should be avoided. Surgeons who perform a high volume of operations have better outcomes. The possibility of multigland disease should be routinely considered. Both focused, image-guided surgery (minimally invasive parathyroidectomy) and bilateral exploration are appropriate operations that achieve high cure rates. For minimally invasive parathyroidectomy, intraoperative parathyroid hormone monitoring via a reliable protocol is recommended. Minimally invasive parathyroidectomy is not routinely recommended for known or suspected multigland disease. Ex vivo aspiration of resected parathyroid tissue may be used to confirm parathyroid tissue intraoperatively. Clinically relevant thyroid disease should be assessed preoperatively and managed during parathyroidectomy. Devascularized normal parathyroid tissue should be autotransplanted. Patients should be observed postoperatively for hematoma, evaluated for hypocalcemia and symptoms of hypocalcemia, and followed up to assess for cure defined as eucalcemia at more than 6 months. Calcium supplementation may be indicated postoperatively. Familial pHPT, reoperative parathyroidectomy, and parathyroid carcinoma are challenging entities that require special consideration and expertise.

Conclusions and Relevance 
Evidence-based recommendations were created to assist clinicians in the optimal treatment of patients with pHPT.

The surgical treatment of primary hyperparathyroidism (pHPT) has undergone extensive change in the past 2 decades. The presentation, diagnosis, and medical management have been previously addressed by an international workshop.^1-4 To meet the need for a detailed focus on operative management, the American Association of Endocrine Surgeons (AAES) developed evidence-based guidelines to delineate the safe and effective practice of parathyroidectomy to achieve definitive treatment.

A multidisciplinary panel of endocrinologists, pathologists, surgeons, and radiologists established PubMed search parameters for the worldwide medical literature from January 1, 1985, to July 1, 2015, using the National Library of Medicine Medical Subject Headings and keywords (hyperparathyroidism, primary; parathyroid neoplasms; and hyperparathyroidism) linked by boolean operators. The writing group adopted the American College of Physicians grading system for evidence-based guidelines,⁵ which uses a validated scale to critically evaluate the strength and quality of the evidence. Recommendations are designated strong when benefits clearly outweigh risks and/or the recommendation should be applied to all or most patients without reservation, weak for equivalent risks or uncertainty, and insufficient when evidence is conflicting or of poor quality. Evidence quality is graded high for randomized clinical trials or overwhelming evidence, moderate for randomized clinical trials with significant limitations or large observational studies, and low for small observational or case studies.

In guidelines construction, the evidence was rigorously examined, recommendations were graded, and text was amended to achieve consensus. Feedback was sought from an independent group of nonauthor clinicians, the AAES membership, and other expert sources.

These guidelines present a process for the evaluation and surgical treatment of pHPT based on evidence at the time of writing. They do not represent the only approach to the management of adult pHPT and are not meant to replace an individual physician’s judgment. Adherence to the guidelines is not mandatory, may require adaptation in practice settings with barriers to implementation, and does not constitute a legal standard of care. The writing group had complete independence from the AAES in the production of the evidence-based guidelines.

The full evidence statements supporting the recommendations appear in the eAppendix and eTable 1 in the Supplement. The Supplement also includes additional details, technical descriptions, discussions of controversy, and expert advice on the surgical management of pHPT.

Primary hyperparathyroidism is a common disorder that arises from autonomous overproduction of parathyroid hormone (PTH) by abnormal parathyroid glands. The disease is characterized by the persistent elevation of total serum calcium levels with corresponding elevated or inappropriately normal (ie, nonsuppressed) PTH levels. The diagnosis of pHPT is biochemical. The clinical presentation is heterogeneous, and the associated symptoms overlap with those of aging and disease. Patients with symptomatic pHPT have overt signs and symptoms; however, the definition of symptomatic disease is still evolving. Patients with asymptomatic pHPT have no disease-specific symptoms.

Normocalcemic pHPT is a recently recognized, incompletely characterized variant that presents with high PTH levels and normal total and ionized serum calcium levels. Some, but not all, patients may progress over time to hypercalcemic pHPT.⁶

Establishing the Diagnosis: Laboratory Testing

In pHPT, patients may occasionally have normal total and/or ionized calcium levels but are hypercalcemic most of the time. Thus, repeated measurements of calcium are required.³ Total serum calcium levels are reported in milligrams per deciliter (to convert to millimoles per liter, multiply by 0.25) and should be corrected for serum albumin (eAppendix in the Supplement). Although pHPT and malignant tumors are the most common causes of hypercalcemia in adults, other causes should be considered. Patients with normocalcemic pHPT have normal serum and ionized calcium levels; thus, measurement of ionized calcium is necessary to establish the diagnosis of normocalcemic, but not hypercalcemic, pHPT.

In pHPT, PTH levels are high or inappropriately normal (ie, not suppressed despite hypercalcemia). Diagnosis of normocalcemic pHPT requires the exclusion of other causes of secondary elevation of PTH (eTable 2 in the Supplement). Nonparathyroid causes of hypercalcemia are associated with suppressed PTH. Renal function and vitamin D status should be assessed preoperatively.

• Quiz Ref IDRecommendation 1-1: The biochemical evaluation of suspected pHPT should include serum total calcium, PTH, creatinine, and 25-hydroxyvitamin D levels (strong recommendation; moderate-quality evidence).

A 24-hour urinary calcium level is important to distinguish pHPT from familial hypocalciuric hypercalcemia, which is an autosomal dominant disorder of the renal calcium-sensing receptor that can mimic pHPT. Familial hypocalciuric hypercalcemia should be considered in patients with long-standing hypercalcemia, urinary calcium levels less than 100 mg/24 hours, and a calcium to creatinine clearance ratio less than 0.01 (eAppendix in the Supplement).

Investigation of Symptoms, Features, and Complications

A careful history should be performed for objective renal and skeletal manifestations, including nephrolithiasis, fragility fractures, and osteoporosis. Subjective symptoms, including neuropsychiatric, cognitive, musculoskeletal, and gastrointestinal complaints (eAppendix in the Supplement), should be documented because parathyroidectomy may lead to improvement or resolution of these symptoms. Certain medications can cause biochemical changes that mimic pHPT (eAppendix in the Supplement). In 3% to 5% of patients, pHPT occurs as a component of an inherited syndrome (eAppendix in the Supplement).^7-9

Patients with otherwise asymptomatic pHPT may have nephrocalcinosis or silent nephrolithiasis; both are indications for parathyroidectomy.⁴

Primary hyperparathyroidism causes site-specific reduction in bone mineral density (BMD) and may predispose patients to fragility fractures.⁴ Dual-energy x-ray absorptiometry (DXA) examination is appropriate for all patients with pHPT and should be performed to screen for clinically relevant skeletal manifestations.⁴

• Quiz Ref IDRecommendation 1-5: Bone mineral density should be measured at the lumbar spine, hip, and distal radius, preferably using DXA (strong recommendation; high-quality evidence).

In patients with pHPT attributable to a hereditary syndrome, the timing and extent of parathyroidectomy are affected by the presence and specific type of mutation present (eAppendix in the Supplement).⁹

Epidemiology and Pathogenesis

The recognition of pHPT increased in the 1970s with automated routine calcium testing, and prevalence continues to increase today. Incidence appears to increase with age and is 2 to 3 times higher in women (eAppendix in the Supplement). Primary hyperparathyroidism remains underdiagnosed and undertreated.

Safe and effective parathyroidectomy requires mastery of the anatomical and pathophysiologic features of pHPT (eAppendix in the Supplement). Autonomous PTH secretion may be attributable to hyperfunction of 1 or more glands and is caused by 3 different pathologic conditions: adenoma, hyperplasia, or carcinoma. The overall frequency of MGD is 6% to 33% (eAppendix in the Supplement).

Lithium-associated pHPT occurs in up to 15% of long-term users, with increased rates of MGD.¹⁰ Molecular alterations also affect the pathophysiologic mechanisms and rates of MGD (eAppendix in the Supplement). Germline inactivating mutation of the MEN1 gene (OMIM 613733) causes multiple endocrine neoplasia type 1, and somatic events occur in sporadic tumors; germline activating mutations of the RET (OMIM 188550) proto-oncogene result in multiple endocrine neoplasia type 2; the somatic PRAD1 (OMIM 168461) rearrangement upregulates cyclin D1 in sporadic adenomas; and inactivating mutations of CDC73 (formerly HRPT2) (OMIM 607393) occur as germline alterations in hyperparathyroidism–jaw tumor syndrome and familial isolated hyperparathyroidism and as somatic events in sporadic parathyroid cancer (PCA) (eAppendix in the Supplement).

Indications and Outcomes of Intervention

Parathyroidectomy is the only definitive treatment of pHPT. Symptomatic patients are expected to derive clear benefits from curative parathyroidectomy, and patients considered to be asymptomatic frequently report improvement in quality-of-life indexes.^11-14 Observation and pharmacologic therapy are less effective and less cost-effective than surgery, even when the patient is considered asymptomatic.¹⁵ Long-term hypercalcemia should be avoided because of potential deleterious effects (eAppendix in the Supplement).^16-18 Referral to an experienced parathyroid surgeon is advised to determine whether the likelihood and benefits of cure outweigh the anticipated risks of the procedure.

• Quiz Ref IDRecommendation 3-1: Parathyroidectomy is indicated, and is the preferred treatment, for all patients with symptomatic pHPT (strong recommendation; high-quality evidence).

• Recommendation 3-2: Parathyroidectomy is indicated when the serum calcium level is greater than 1 mg/dL above normal, regardless of whether objective symptoms are present or absent (strong recommendation; low-quality evidence).

After successful parathyroidectomy, the development of new kidney stones decreases markedly.¹⁹ Although renal insufficiency and nephrocalcinosis do not resolve, surgery may prevent a further decline in the glomerular filtration rate (eAppendix in the Supplement).

• Recommendation 3-3: Parathyroidectomy is indicated for objective evidence of renal involvement, including silent nephrolithiasis on renal imaging, nephrocalcinosis, hypercalciuria (24-hour urine calcium level >400 mg/dL) with increased stone risk, or impaired renal function (glomerular filtration rate <60 mL/min) (weak recommendation; low-quality evidence).

Primary hyperparathyroidism causes a decrease in BMD, most pronounced at cortical bone sites, such as the distal third of the radius. Parathyroidectomy improves BMD and appears to reduce fracture rate, even for normal or osteopenic bone (eAppendix in the Supplement).¹⁶

• Recommendation 3-4: Parathyroidectomy is indicated in patients with pHPT and osteoporosis, fragility fracture, or evidence of vertebral compression fracture on spine imaging (strong recommendation; high-quality evidence).

Patients 50 years or younger at diagnosis require prolonged monitoring and compared with older patients have a higher incidence of progression (eAppendix in the Supplement).²⁰

The preoperative diagnosis of PCA may be difficult. If PCA is suspected, patients should be treated surgically because this is the only potentially curative treatment (eAppendix in the Supplement).

Patients who choose not to undergo surgery should undergo annual biochemical evaluation and periodic DXA. If the patient does not have the means or desire to adhere to a planned observation schedule, parathyroidectomy should be offered (eAppendix in the Supplement).¹⁴

Patients with pHPT frequently have neurocognitive and neuropsychiatric symptoms. With varying response patterns, 3 randomized clinical trials demonstrated neurocognitive benefits of surgery vs observation.^13,14,21

Patients with pHPT may have higher rates of myocardial infarction, hypertension, stroke, congestive heart failure, diabetes, and mortality (eAppendix in the Supplement). Observational studies in mild pHPT have yielded conflicting data about the improvement of cardiac parameters after parathyroidectomy. It is prudent to weigh the possibility of mitigating cardiovascular morbidity and mortality on a case-by-case basis.

Observational studies¹⁶ suggest that several nontraditional and/or newly studied symptoms improve after successful parathyroidectomy, including muscle strength, functional capacity, gastroesophageal reflux, sleep patterns, and fibromyalgia (eAppendix in the Supplement).

• Recommendation 3-10a: The nontraditional symptoms of muscle weakness, functional capacity, and abnormal sleep patterns should be considered in the decision for parathyroidectomy (weak recommendation; moderate-quality evidence).

• Recommendation 3-10b: The nontraditional features of gastroesophageal reflux and fibromyalgia symptoms may be considered in the decision for parathyroidectomy (insufficient evidence).

The success rate for surgeons who perform fewer than 10 parathyroidectomies per year is lower than for experienced surgeons (eAppendix in the Supplement). Volume of operations inversely correlates with complications, cost, and length of stay.²²

Although many pharmacologic agents have been used in an attempt to reduce the serum calcium level or stabilize BMD, none have improved both (eAppendix in the Supplement). In formal cost-effectiveness analyses, pharmacologic treatment is not optimal at any life expectancy.^15,23

Parathyroidectomy for pHPT is not recommended when the risks of surgery or anesthesia are outweighed by the anticipated benefits of cure, as with severe or overriding medical illness (eAppendix in the Supplement). In patients who meet none of these indications for surgical intervention, refuse surgery, or are considered prohibitively high risk, medical intervention aimed at mitigating specific sequelae should be used.² For many patients, mild disease will progress over time.²⁴

Parathyroid Localization Modalities: What Imaging to Perform and When

1. Imaging has no utility in confirming or excluding the diagnosis of pHPT.

2. Imaging results should not be used to select patients for surgical referral. Patients with negative imaging results remain candidates for parathyroidectomy.

3. There is marked regional variability in imaging accuracy. When imaging with initially negative results is performed again at high-volume centers, the sensitivity of localization improves to as high as 92%.²⁵

4. Imaging is performed after deciding to proceed with parathyroidectomy and is performed for operative planning.

5. Parathyroid imaging is significantly less accurate for MGD.²⁶

6. Recommendation 4-1: Patients who are candidates for parathyroidectomy should be referred to an expert clinician to decide which imaging studies to perform based on their knowledge of regional imaging capabilities (strong recommendation; low-quality evidence).

7. Recommendation 4-2: Patients who are candidates for surgery and have negative or discordant imaging results should still be referred to a parathyroid surgeon for evaluation (strong recommendation; low-quality evidence).

Cervical ultrasonography performed by an experienced parathyroid sonographer is the least costly imaging modality and, when combined with sestamibi or 4-dimensional computed tomography, is the most cost-effective strategy (eAppendix in the Supplement).^26-28 Preoperative ultrasound-directed fine-needle aspiration biopsy of parathyroid lesions is highly specific but is rarely necessary and can have undesirable consequences (eAppendix in the Supplement).

• Recommendation 4-3: Cervical ultrasonography is recommended to localize parathyroid disease and assess for concomitant thyroid disease (strong recommendation; low-quality evidence).

• Recommendation 4-4: Preoperative parathyroid fine-needle aspiration biopsy is not recommended except in unusual, difficult cases of pHPT and should not be performed if PCA is suspected (insufficient evidence).

Technetium Tc 99m sestamibi is the dominant radioisotope in parathyroid scintigraphy. Each sestamibi protocol (dual-phase, iodine 131 subtraction, single-photon emission computed tomography) has individual strengths and weaknesses (eAppendix in the Supplement). Sensitivity in MGD is poor. Combined ultrasonography and sestamibi imaging increases localization accuracy and improves sensitivity (eAppendix in the Supplement). Although traditional computed tomography has little utility, the 4-dimensional computed tomography protocol has emerged as a useful modality, although sensitivity in MGD is limited.

• Recommendation 4-5: An experienced clinician should help determine which type of imaging to use based on knowledge of their region’s imaging capabilities (strong recommendation; moderate-quality evidence).

• Recommendation 4-6: Magnetic resonance imaging and venous sampling can be considered in cases of subsequent operation, difficult localization, or ionizing radiation contraindication (weak recommendation; low-quality evidence).

A daily intake of 1000 to 1200 mg of calcium is recommended for adults and appears appropriate for patients with pHPT as well. Dietary restriction of calcium is not advised in pHPT. Preoperative vitamin D repletion is advised and should be performed carefully in patients with hypercalciuria (eAppendix in the Supplement).

• Recommendation 5-1: Most patients with pHPT should follow Institute of Medicine guidelines for calcium intake (strong recommendation; moderate-quality evidence).

• Recommendation 5-2: Before parathyroidectomy, patients with pHPT who are vitamin D deficient can safely begin vitamin D supplementation (weak recommendation; low-quality evidence).

Subjective assessment of voice quality is an essential component of preoperative examination. Additional objective evaluation is recommended for subjective changes, surgeon-identified abnormalities, or any history of prior operations in which the vagus nerve or recurrent laryngeal nerve (RLN) was at risk (eAppendix in the Supplement).

• Recommendation 5-3: Preoperative voice evaluation should include specific inquiry about subjective voice changes, with additional evaluation for significant voice changes or a history of prior at-risk surgery (strong recommendation; low-quality evidence).

Hypercalcemic crisis is defined by a rapid-onset, albumin-corrected serum calcium level greater than 14 mg/dL and signs or symptoms of multiorgan dysfunction.²⁹ Intravenous fluid resuscitation and pharmacologic management are used to stabilize patients before expeditious parathyroidectomy. The presence of PCA should be considered (eAppendix in the Supplement).

Intraoperative PTH Monitoring

Intraoperative PTH monitoring (IPM) provides real-time assessment of parathyroid function and has a major effect on focused operations when the surgeon removes an image-identified abnormal gland without additional dissection. The success of focused operations guided by IPM has been excellent, with cure rates as high as 97% to 99% (eTable 3 in the Supplement).³⁰ Focused operations guided solely by imaging studies without IPM can miss MGD, with failure rates that may be higher than accepted standards (eAppendix in the Supplement). For initial image-guided surgery, positive imaging directs where to start exploration, and the results of intraoperative PTH monitoring help to terminate it.

The accuracy of IPM depends on the protocol used. Surgeons should use a protocol that is practical, accurate, and reproducible and be aware of potential sources of error (eAppendix in the Supplement). In addition, IPM is useful in differential jugular venous sampling and ex vivo parathyroid aspiration (eAppendix in the Supplement).

Minimally Invasive Parathyroidectomy

Approximately 85% of patients with pHPT have a solitary adenoma, the resection of which results in durable cure. Thus, surgeons have adapted a variety of methods to streamline parathyroidectomy and reduce the risk of complications, collectively termed minimally invasive parathyroidectomy (MIP). All MIP techniques are designed to limit dissection, hasten recovery, reduce postoperative discomfort, and reduce incision length. These techniques typically require preoperative imaging and other adjuncts.

Regardless of MIP technique, specific strategies are advised to improve the likelihood of success (eAppendix in the Supplement), including selection by imaging results. Minimally invasive parathyroidectomy can achieve cure in 97% to 99% of selected patients when adjunctive IPM is used to confirm adequacy of resection (eAppendix in the Supplement).³¹ During MIP, if IPM suggests residual hypersecreting tissue, conversion to bilateral exploration (BE) is warranted and has equivalent cure rates to planned BE.

• Quiz Ref IDRecommendation 7-1: Defined as a focused dissection, MIP is ideally used in patients who appear clinically and by imaging to have a single parathyroid adenoma. It is not routinely recommended in patients with known or suspected high risk of MGD (strong recommendation; high-quality evidence).

• Recommendation 7-2: Ex vivo PTH aspiration or frozen section analysis may be used to confirm the resection of parathyroid tissue (weak recommendation; low-quality evidence).

• Recommendation 7-3: During MIP, the discovery of MGD, the inability to identify an abnormal gland, or the failure to achieve an appropriate IPM decrease should prompt conversion to BE (strong recommendation; high-quality evidence).

In BE, all parathyroid glands should be identified and compared to deduce the presence of a single adenoma or MGD. Bilateral exploration has long-term success rates greater than 95% and low complication rates.^22,32 Familiarity with parathyroid anatomy, the locations of eutopic (normal position) and ectopic glands (Figure 1), and the appearance of normal and abnormal glands (eAppendix in the Supplement) is essential.

• Quiz Ref IDRecommendation 8-1: Bilateral exploration provides a time-tested standard of efficacy and safety in the definitive treatment of pHPT (strong recommendation; high-quality evidence).

• Recommendation 8-2: Planned BE is the preferred operative strategy in situations of discordant or nonlocalizing preoperative imaging, when there is a high suspicion of MGD, when IPM is not available, or at the discretion of the surgeon (strong recommendation; moderate-quality evidence).

• Recommendation 8-3: Bilateral exploration is defined by a standard technique in which all parathyroid glands are identified with exploration of expected and, if necessary, ectopic cervical locations (strong recommendation; moderate-quality evidence).

• Recommendation 8-4: In lithium-induced pHPT, the surgical approach may be BE or MIP guided by imaging and IPM (weak recommendation; low-quality evidence).

In patients with a genetic predisposition for pHPT (eAppendix in the Supplement), the high likelihood of MGD and recurrent hypercalcemia necessitate a distinctive surgical approach with the goals of achieving eucalcemia for as long as possible, avoiding hypoparathyroidism, and facilitating potential subsequent operation for recurrence. Lifelong follow-up is critical.

• Recommendation 9-1: In patients with multiple endocrine neoplasia type 1–associated pHPT, subtotal parathyroidectomy is recommended as the index operation (strong recommendation; moderate-quality evidence).

• Recommendation 9-2: In multiple endocrine neoplasia type 2A–associated pHPT, resection of only visibly enlarged glands is recommended (weak recommendation; low-quality evidence).

The most widely used surgical adjunct is IPM. Other adjuncts (eAppendix in the Supplement) can assist with confirmation of resected parathyroid tissue (frozen section analysis, ex vivo parathyroid aspiration), gland visualization (methylene blue, near infrared fluorescence or infrared spectroscopy), and gland localization (intraoperative ultrasonography, bilateral jugular venous sampling, or γ-probe guidance). Monitoring of the RLN is used less often in parathyroid than thyroid surgery but may play a role in subsequent operation. Adjuncts cannot replace judgment and experience.

In patients with pHPT, concomitant thyroid disease is frequent (12%-67%) (eAppendix in the Supplement). Concurrent thyroidectomy may be performed for thyroid disease that requires resection, suspicion of PCA, removal of an abnormal intrathyroidal parathyroid gland, or improved access.

• Recommendation 11-1: Patients undergoing parathyroidectomy should have preoperative thyroid evaluation because of the high rate of concomitant disease, which may require thyroid resection (strong recommendation; moderate-quality evidence).

Compared with intraoperative thyroid examination, preoperative ultrasonography is more sensitive and specific for clinically significant thyroid disease and is associated with a 5-fold lower rate of thyroid resection.³³ Preoperative identification of thyroid disease may facilitate performance of the most appropriate index operation, reduce complications, and avoid future reoperation (eAppendix in the Supplement).

• Recommendation 11-2: In patients with concomitant pHPT and thyroid disease that requires resection, thyroid resection should be performed at the time of parathyroidectomy (strong recommendation; moderate-quality evidence).

• Recommendation 11-3: Evaluation for concomitant thyroid disease in patients undergoing parathyroidectomy for pHPT should follow evidence-based guidelines (strong recommendation; high-quality evidence).

• Recommendation 11-4: The indications for thyroidectomy for concomitant thyroid disease during parathyroidectomy for pHPT are the same as those for patients with isolated thyroid disease and should follow evidence-based guidelines (strong recommendation; high-quality evidence).

Parathyroid cancer accounts for approximately 1% of all cases of pHPT and typically presents with very high PTH and calcium levels (eTable 4 in Supplement).³⁴ Parathyroidectomy is the only curative treatment for PCA.

• Recommendation 12-1: The diagnosis of PCA should be considered in patients with pHPT with markedly elevated PTH levels and severe hypercalcemia (strong recommendation; low-quality evidence).

• Recommendation 12-2: With intraoperative suspicion of parathyroid carcinoma, complete resection avoiding capsular disruption improves the likelihood of cure and may require en bloc resection of adherent tissues (strong recommendation; low-quality evidence).

• Recommendation 12-3: Prophylactic central or lateral neck dissection should not be performed for parathyroid carcinoma (insufficient evidence).

• Recommendation 12-4: The histologic diagnosis of PCA relies on identification of unequivocal angioinvasion and can be assisted by biomarkers (strong recommendation; moderate-quality evidence).

• Recommendation 12-5: Adjuvant external beam radiotherapy should not be routinely performed after surgical resection of PCA and is reserved as a palliative option (strong recommendation; low-quality evidence).

• Recommendation 12-6: Patients with functional PCA should undergo regular surveillance by testing serum calcium and PTH levels (strong recommendation; low-quality evidence).

Autotransplantation and Cryopreservation

Autotransplantation is the most reliable method to preserve function when a gland cannot be kept viable on its vascular pedicle. The arterial perfusion of parathyroid glands that have been manipulated but are left in situ should be assessed. All efforts should be made to preserve the maximal amount of normal parathyroid tissue and to treat each parathyroid gland as carefully as if it were the last (eAppendix in the Supplement).

Immediate Postoperative Care

Although a common finding, especially in vitamin D–deficient patients or those with malabsorption for any reason (eg, celiac disease or prior bariatric surgery), symptomatic hypocalcemia is typically transient and managed as an outpatient.^32,35,36 Patients undergoing BE have significantly higher rates of mild and severe hypocalcemic symptoms.^37,38 The reported rates of moderate postoperative hypocalcemia range from 5% to 47%.³⁹ After initial parathyroid surgery, permanent hypoparathyroidism is rare (0%-3.6%).^32,35-37

• Recommendation 14-1: The operative note should detail the findings and events of parathyroidectomy (insufficient evidence).

• Recommendation 14-2: After parathyroidectomy, patients should be observed in a monitored setting for the development of cervical hematoma. Evidence of compressive hematoma after parathyroidectomy should prompt emergency decompression (strong recommendation; low-quality evidence).

• Recommendation 14-3: Short-term calcium and/or vitamin D supplementation for prophylaxis against hypocalcemia should be considered after parathyroidectomy (weak recommendation; low-quality evidence).

Outpatient parathyroidectomy can be performed in selected patients. An overnight stay may be appropriate for patients undergoing subsequent operation, extensive exploration, or subtotal parathyroidectomy or those with profound vitamin D deficiency, social issues, or expected nonadherence.

The assessment of cure and complications (prolonged hypoparathyroidism, permanent RLN paralysis) requires evaluation for at least 6 months. Longitudinal testing should include calcium, PTH, and 25-hydroxyvitamin D levels. Achieving normal vitamin D levels postoperatively will help absorption of calcium and normalization of PTH levels and may improve BMD (eAppendix in the Supplement).

• Recommendation 14-5: After apparently successful parathyroidectomy, calcium intake should follow the Institute of Medicine Dietary Reference Intakes (strong recommendation; moderate-quality evidence).

• Recommendation 14-6: Patients who are vitamin D deficient should receive vitamin D supplementation after apparently successful parathyroidectomy (strong recommendation; moderate-quality evidence).

• Recommendation 14-7: At 6 months, surgeons individually or in conjunction with the multidisciplinary care team should assess postparathyroidectomy patients for cure and evidence of long-term complications (strong recommendation; low-quality evidence).

The goal of parathyroidectomy is cure. Cure rates for parathyroidectomy in sporadic pHPT should approach 95% to 99%. Although there is no role for routine PTH measurement in the normocalcemic patient in the immediate postoperative period, failure to normalize PTH levels at 6 months or longer can signify early operative failure. In normocalcemic pHPT, the PTH level must also normalize to indicate cure. In patients with inherited forms of pHPT, a different end point of care pertains (eAppendix in the Supplement).

• Recommendation 15-1a: Cure after parathyroidectomy is defined as the reestablishment of normal calcium homeostasis lasting a minimum of 6 months (strong recommendation; high-quality evidence).

• Recommendation 15-1b: Patients with normocalcemic pHPT who have persistently elevated PTH levels after parathyroidectomy should be evaluated and treated for causes of secondary HPT and, if none are present, monitored for recurrent disease (strong recommendation; low-quality evidence).

• Recommendation 15-2: Surgeons should choose an operative approach that in their hands carries a high cure rate, low-risk profile, and cost comparable to other available techniques (strong recommendation; low-quality evidence).

• Recommendation 15-3: In normocalcemic pHPT, the definition of cure must include normal calcium and PTH levels more than 6 months after surgery (insufficient evidence).

Operative failure remains the most common complication of parathyroidectomy. Failure may be predicted by an incomplete decrease in IPM levels or kinetic analysis. Diagnosis of failure requires discontinuation of calcium use and a stepwise evaluation (eAppendix in the Supplement). Surgeons should be cognizant of their failure rates.

• Recommendation 15-4: Persistent pHPT should be defined as a failure to achieve normocalcemia within 6 months of parathyroidectomy. Recurrent pHPT is defined by recurrence of hypercalcemia after a normocalcemic interval at more than 6 months after parathyroidectomy (strong recommendation; high-quality evidence).

Management of Other Complications

Laryngeal reinnervation does not restore normal vocal fold movement, but it may improve voice strength, reduce the risk of aspiration, and decrease the need for postoperative vocal cord medialization and injections.

The symptoms of postoperative hypoparathyroidism include perioral numbness and fingertip paresthesias, which can also occur in euparathyroid bone hunger or transient hypoparathyroidism (eAppendix in the Supplement). Severe postoperative hypocalcemia is rare. Patients may require temporary postoperative calcium administration and calcitriol to avoid such symptoms (eAppendix in the Supplement). In contrast, prolonged hypoparathyroidism is a chronic condition of such diminished parathyroid function that ongoing calcium and calcitriol treatment is required for 6 to 12 months.⁴⁰

• Recommendation 16-2: Patients with transient hypoparathyroidism after surgery should be treated with calcium and, if necessary, calcitriol supplements, which should be weaned as tolerated. Patients with prolonged hypoparathyroidism may be considered for recombinant PTH therapy (weak recommendation; low-quality evidence).

Reoperative parathyroidectomy is defined as any prior cervical operation that placed the RLN at risk. In persistent or recurrent pHPT, subsequent operation is often recommended to achieve biochemical cure. Because cure rates are lower (82%-98%) (eAppendix in the Supplement) and risks are higher, many surgeons use stricter indications for subsequent operation than for initial surgery.^41,42 A careful data evaluation, assessment for surgical indications beyond the biochemical diagnosis, and positive imaging results are essential; this algorithm is detailed in Figure 2. Intraoperative PTH monitoring and other adjuncts are often used.

• Recommendation 17-1: The evaluation of persistent or recurrent pHPT should include confirmation of biochemical diagnosis, assessment of indications for surgery, review of prior records if available, and evaluation of RLN function (strong recommendation; low-quality evidence).

• Recommendation 17-2: Patients with persistent or recurrent pHPT should be evaluated by an experienced parathyroid surgeon before the decision to proceed with surgery or nonoperative management (strong recommendation; low-quality evidence).

• Recommendation 17-3: Intraoperative PTH monitoring should be considered in patients undergoing reoperative parathyroidectomy for pHPT (strong recommendation; low-quality evidence).

Because the surgical treatment of pHPT has undergone extensive change in the last 2 decades, the AAES determined the need to develop evidence-based clinical guidelines to enhance the safe, definitive treatment of pHPT. These evidence-based guidelines provide a broad-based approach to the clinical spectrum of pHPT and, although they do not represent the only acceptable approach, serve as a sound template for the effective surgical management of pHPT to achieve cure as safely and efficiently as possible.

Corresponding Author: Scott M. Wilhelm, MD, Department of Surgery, University Hospitals/Case Medical Center, 11100 Euclid Ave, Cleveland, OH 44118 ([email protected]).

Accepted for Publication: May 19, 2016.

Published Online: August 10, 2016. doi:10.1001/jamasurg.2016.2310

Conflict of Interest Disclosures: None reported.

Additional Information: Dr Carty is the chair of the AAES Parathyroidectomy Guidelines Writing Group.

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ASCO Reading Room | Excellent Summary of Adjuvant Endocrine Tx for Premenopausal Breast Cancer Patients

The majority of people diagnosed with breast cancer will have hormone receptor (HR) positive disease (also referred to as luminal-like subtypes). Almost every individual diagnosed with HR-positive early stage breast cancer will be a candidate for adjuvant endocrine therapy, either with tamoxifen or an aromatase inhibitor (AI). In premenopausal women, the challenge lies between intensifying treatment to improve outcomes when necessary while trying to avoid overtreating, as breast cancer treatments can negatively impact a patient’s quality of life and may result in lowered treatment adherence.

The authors of a review in the ASCO Educational Book provide an excellent summary of the current options for adjuvant therapy in premenopausal women, while highlighting existing challenges and unanswered treatment questions that remain.

There have been many recent advances in adjuvant endocrine therapy for premenopausal women, and this review details treatments that are currently the standard of care. There are several tools that are available to help risk stratification for breast cancer recurrence and aid with treatment decision-making, including gene expression assays (i.e., Oncotype Dx assay RS, MammaPrint, and The Breast Cancer Index) and online calculators (CancerMath and National Health Service Predict tool). For patients who require chemotherapy, the choice of treatment is typically a taxane-based or an anthracycline/taxane-based regimen.

The decision to use a particular regimen depends on multiple factors including HR and lymph node status.

With regards to endocrine therapy, premenopausal women should be considered for 5 to 10 years of endocrine therapy. Newer data over the last decade have demonstrated the additional benefit of 10 years of tamoxifen or 5 years of ovarian function suppression (OFS) combined with either tamoxifen or an AI when compared with 5 years of tamoxifen alone.

OFS can be achieved by either pharmacologic methods (reversible, gonadotropin-release hormone agonists such as goserelin and leuprolide) or surgery via a bilateral salpingo-oophorectomy.

A key point made by the authors is that prior to initiating systemic therapy, premenopausal women should receive genetic testing and counseling and if appropriate, be offered fertility preservation. Patients should be encouraged to maintain ideal body weight and be physically active. Bone health should be monitored throughout treatment.

These recent updates in the standard of care have raised additional questions. The key topics that need more study include the appropriate timing of initiating OFS (following chemotherapy or concurrently with chemotherapy), the optimal duration of OFS, interruption of endocrine therapy to attempt pregnancy, the role of tamoxifen alone in very young women with favorable breast cancers, and the addition of CDK 4/6 inhibitors in the adjuvant setting. The review authors provide excellent consensus guidelines to aid clinicians who are treating this patient population.

Finally, it is well established that endocrine therapy is associated with certain adverse events that have the potential to affect medication adherence and a person’s quality of life. The most common side effects of endocrine therapy include but are not limited to musculoskeletal symptoms, vasomotor symptoms, worsening bone health, sexual dysfunction, vulvovaginal symptoms, fatigue, insomnia, weight gain, and cognitive impairment. Rare side effects of tamoxifen include venous thromboembolic events and endometrial cancer.

Extension of endocrine therapy beyond 5 years can result in prolonged duration of those side effects and higher incidences of rare side effects. The addition of OFS can worsen the side effect profile. The most common reasons for drug discontinuation appear to be poor drug tolerability and uncontrolled adverse events from the medications. Decreased adherence and compliance have been associated with worse breast cancer clinical outcomes.

It is imperative that clinicians ask about treatment adherence and recommend interventions to mitigate side effects whenever possible.

In conclusion, this review is an excellent summary of adjuvant endocrine therapy for premenopausal women including current treatment options, what remains unknown, and a thorough discussion of treatment-related side effects.

Future directions must focus on further individualizing treatment to improve not only clinical outcomes but also quality of life in this patient population.

Eleonora Teplinsky, MD, is head of Breast Medical Oncology at Valley Health System in Paramus, New Jersey, and clinical assistant professor at Icahn School of Medicine at Mount Sinai.

Read the study here and an interview about it here.

Summary of the Endocrine System – Anatomy and Physiology – BM41055 –

Summary of the book Human Anatomy & Physiology for the course Anatomy and Physiology at TU…Bekijk meer

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The Endocrine System Chapter 16 The endocrine system is one of the two major control systems The nervous and endocrine systems are the major controlling systems of the body. The nervous system exerts rapid controls via nerve the endocrine system exerts are prolonged effects via hormones. Hormonal regulated processes include reproduction growth and development maintaining electrolyte, water, and nutrient balance regulating cellular metabolism and energy balance and mobilizing body defenses There are two kinds of glands: Exocrine glands produce substances, such as sweat and saliva, and have ducts that carry these substances to a membrane Figure 1: Location of selected endocrine organs of the body face. Endocrine glands, also called ductless glands, produce hormones and lack ducts. Typically wellvascularized glands that release hormones directly into the blood or lymph. They are small and widely separated in the body. The purely endocrine organs are the pituitary, thyroid, parathyroid, adrenal, and pineal gland. The hypothalamus is a neuroendocrine organ. The pancreas, gonads, and placenta also have endocrine tissue. Local chemical messengers, not generally considered part of the endocrine system, include autocrines, which act on the cells that secrete them, and paracrines, which act on a different cell type near. Hormones act through second messengers or activating specific genes Hormones alter cell activity stimulating or inhibiting characteristic cellular processes of their target cells. Cell responses to hormone stimulation may produce one or more of the following changes: Change of plasma membrane permeability or membrane potential. Stimulates synthesis of enzymes and other proteins within the cell. Activates, or deactivates enzymes. Induces secretory activity. Stimulates mitosis. 1 mechanisms employing G proteins and intracellular second messengers are a common means which amino hormones interact with their target cells. In the cyclic AMP system, the hormone binds to a plasma membrane receptor that couples to a G protein. When the G protein is activated, it couples to adenylate cyclase, which catalyzes the synthesis of cyclic AMP form ATP. Cyclic AMP initiates reactions that activate protein kinases and other enzymes, leading to cellular responses. The PIP2 signaling mechanism is another important system. Other second messengers are cyclic GMP and hormones) Steroid hormones (and thyroid hormone) enter their target cells and effect responses activating DNA, which initiates messenger RNA formation leading to protein synthesis.(Lipidsoluble hormones) Three types of stimuli cause hormone release Figure 2: Three types of endocrine gland stimuli Endocrine Gland Stimuli Humoral, neural, or hormonal stimuli activate endocrine organs to release their hormones, see figure 2. Negative feedback is important in regulating hormone levels in the blood. Nervous System Modulation The nervous system, acting through hypothalamic controls, can in certain cases override or modulate hormonal effects. For example blood glucose levels rise, when your body is under severe stress. In this way, the nervous system ensures that body cells have sufficient fuel in case vigorous activity is required. 2 Figure 3: Pituitary Hormones: Summary of Regulation and effects Growth Hormone (GH) Somatrotropic cells of the anterior lobe produce growth hormone (GH), it is an anabolic hormone that stimulates growth of all body tissues but especially skeletal muscle and bone. Direct Actions on Metabolism Acting directly, GH exerts metabolic effects. It mobilizes fats from fat depots for transport to cells, increasing blood levels of fatty acids and encouraging their use for fuel. It decreases glucose uptake and metabolism, conserving glucose. In the liver, it encourages glycogen breakdown and release of glucose to the blood. GH increases amino acid uptake into cells and their incorporation into proteins. Indirect Actions on Growth GH mediates most of its growth enhancing effects indirectly via proteins called growth factors (IGFs). The liver, skeletal muscle, bone, and other tissues produce IGFs in response to GH. IGFs stimulate the uptake of nutrients from the blood and their incorporation into proteins and DNA, allowing growth cell division, and Formation of collagen and deposition of bone matrix. Regulation of Secretion Its secretion is regulated growth hormone (GHRH), and growth hormone (GHIH), or somatostatin. GHRH is triggered the feedback of GH and IGFs. GH is highest when sleeping. Hypersecretion causes gigantism 4 in childeren and acromegaly in hyposecretion in children causes pituitary dwarfism. Figure 4: Pituitary Hormones: Summary of Regulation and continued(DO NOT STUDY FSH LH) Homone (TSH) hormone (TSH) or thyrotropin is a tropic hormone that promotes normal development and activity of the thyroid gland. hormone (TRH) stimulates release of TSH from thyrotropic cells of the anterior negative feedback of thyroid hormone inhibits it. Adrenocorticotropic Hormone(ACTH) Adrenocoricotropic hormone (ACTH) or corticotropin stimulates the adrenal cortex to release corticosteroids. Corticotropin releasing hormone (CRH) triggers ACTH rising glucocorticoids levels inhibit it. Internal and external factors that alter the normal ACTH rhythm triggering CRH release include fever, hypoglycemia (low blood glucose), and stressors of all types. Prolactin (PRL) Prolactin (PRL), simular to GH produced prolactin cells. Promotes milk production in humans. Its secretion is primarily controlled an inhibitory hormone, hormone (PIH), or dopamine. 5 Figure 6: Synthesis of thyroid hormone. heat production. Factors that inhibit TSH release include GHIH, dopamine, and rising levels of glucocorticoids. Also high blood iodide concentrations inhibit TH release. disease is the most common cause of hyperthyroidism. Hyposecretion causes cretinism in infants and myxedema in adults. Calcitonin The parafollicular (C) cells of the thyroid gland produce calcitonin. It is not normally important in calcium homeostasis. At pharmacological levels, it inhibits bone matrix resorption and enhances calcium deposit in bone. Can help to reduce osteoporosis, further no known physiological role in humans. The parathyroid glands are primary regulators of blood calcium levels The parathyroid glands, located on the dorsal aspect of the thyroid gland, secrete parathyroid hormone (PTH), which increases blood calcium levels. The glandular cells are arranged in thick, branching cords containing scattered oxyphil cells and large numbers of smaller parathyroid cells, the function of the oxyphil cells is unclear. PTH targets bone, the kidneys, and the small intestine (indirectly via vitamin D activation). PTH is the key hormone for calcium homeostasis. Falling blood calcium levels trigger PTH rising blood calcium levels inhibit its release. PTH release: Stimulates osteoclasts Enhances reabsorption of the kidneys. activation of vitamin D, there increasing absorption of intestinal mucosal cells. Vitamin D is required for absorption of calcium from food. Hyperparathyroidism results in hypercalcemia and extreme bone wasting. Hypoparathyroidism 7 Figure 7: The parathyroid glands leads to hypocaclemia, evidenced tetany and respiratory paralysis. The adrenal glands produce hormones involved in electrolyte balance and stress response The paired adrenal (spurarenal) glands sit atop the kidneys. Each adrenal gland has two functional portions, the cortex, part of the sympathetic nervous system), and the medulla. Figure 8: Microscopic structure of the adrenal gland 8 Figure 9: Overview fo the Adrenal Gland Hormones sponse to sympathetic nervous system stimulation. Catecholamines enhance and prolong the response to stressors. Hypersecretion leads to symptoms typical of sympathetic nervous system The pineal gland secretes melatonin The pineal gland is located in the diencephalon. Its primary hormone is melatonin, which influences daily rhythms, peaks in the night makes us drowsy, and may have an antigonadotropic effect in humans(may affect the timing of puberty and inhibit precocious sexual maturation). The pancreas, gonads, and most other organs secrete hormones The Pancreas The pancreas, located in the abdomen close to the stomach, is both an exocrine and an endocrine gland. The endocrine portion (pancreatic islets) releases insulin and glucagon and smaller amounts of other hormones to the blood. Glucagon, released alpha cells when blood levels of glucose are low, stimulates the liver to release glucose to the blood. Insulin is released beta cells when blood levels of glucose (and amino acids) are rising. It increases the rate of glucose uptake and metabolism most body cells. Factors that influence Insulin release are Elevated blood glucose levels, rising blood levels of amino acids and fatty acids, Acetylcholine released parasympathetic nerve fibers, and hyperglycemice hormones. Hyposecretion or hypoactivity of insulin results in diabetes cardinal signs are polyruria, polydipsia, and polyphagia. 10

Environmental summary – Newspaper Kommersant No. 71 (294) dated 17.04.1993

& nbsp Environmental summary

Mutant tomatoes have come to Moscow stores
Chemistry brings together the news of the week from the field of applied ecology. In Moscow, they began to sell fresh tomatoes with nitrates and other, completely undesirable for domestic consumption, chemistry. Milk chocolate Rica + Don appeared in St. Petersburg this week, for some reason it has a laxative effect.And in butter, which arrived in Norilsk straight from America, the local sanitary and epidemiological supervision found heavy metals.

Be careful when buying fresh tomatoes. This week, Moscow stores received tomatoes, which contain a lot of chemicals.
Their color is somewhat different from the usual – it is not even red, but pale. An irregular shape of tomatoes can also give out an abundance of chemistry – there are growths, depressions; also tomatoes are somewhat elongated as a whole or in one direction.All these are signs of a mutation that occurred as a result of the qualitative and quantitative effects of chemical elements. As for the taste, it is almost completely absent from such tomatoes. The abundance of nitrates, pesticides and other unwanted chemical “impurities” in vegetables is harmful to health. In particular, the consumption of significant amounts of such “impurities” can adversely affect the activity of the endocrine system. It should be borne in mind that sellers, after some selection of a low-quality batch, can throw out the most non-standard fruits and achieve an almost decent appearance of tomatoes on the counter.Therefore, before making a purchase, carefully study what exactly you are going to buy. Harmful tomatoes were seen in Sokolniki, Tushino, throughout Profsoyuznaya Street and in the area of ​​the Polezhaevskaya metro station (less often in the center).
Take a closer look at the fresh cabbage that has appeared in the shops of the center and south-west of Moscow. It can also be of poor quality, albeit harmless.
The cabbage was delivered from the Moscow region. It is not harmful to health, however, and left all its taste qualities in vegetable stores, where it seems that they were cool about observing storage conditions.A poor-quality head of cabbage is loose, there is a lot of free space between its leaves; upon close examination, you can find signs of decay.
This week brought to St. Petersburg the milk chocolate Rica + Don, which has an uncharacteristic ability for ordinary chocolate – and indeed high-quality products – to disrupt gastrointestinal activity.
Rica + Don is packaged in blue and red 50 gram packs. Judging by the inscriptions, the chocolate was made in Germany, but I don’t really want to believe this unconditionally – many, having eaten one or two servings per day, noted signs of mild gastrointestinal disturbances (fortunately, they do not require medical attention) …There are no specific indications for taking the product on its packaging. Its chemical analysis has not yet been carried out, and what caused the “laxative” properties of chocolate is still a mystery (it is possible, for example, the use of low-quality water or milk in its manufacture, but this alone, most likely, would not be enough). Chocolate is sold mainly in the city center, but it can also be found on the outskirts.
And the outgoing week brought a message that heavy metals are found not only in domestic food (Ecosvodka reported about the St. Petersburg macaroni saturated with them in the fall).Now they are found in butter from America.
It should not reach Moscow and, moreover, St. Petersburg – a batch of this product came directly from the United States to Norilsk. Heavy metal additives were found by the local sanitary and epidemiological station: tests showed that the oil, in addition to the usual components, contains heavy metals in quantities exceeding any maximum permissible norms – even according to Russian standards. The sale of this oil is, of course, prohibited – despite the fact that the product has a quality certificate.The influence of heavy metals and their salts on the human body has been reported in the “Ecosystem” more than once. Let us recall only the most dangerous – these are unpredictable and uncontrolled gene mutations.

ALEXANDER B-OVCHARENKO

Operational Bulletin

04/06/2020

According to the Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing, more than 697 thousand studies on coronavirus have been carried out in the Russian Federation.In total, 5389 cases of coronavirus infection have been registered in Russia today in 78 regions. For the entire period, 355 people were discharged after recovery. For 05.04.2020, 658 cases of coronavirus infection were confirmed. In the Republic of Bashkortostan, a total of 10 cases were registered; for the period from 04/03/2020 to 04/05/2020, not a single new case of coronavirus infection was registered in the republic.

What category of people is subject to laboratory testing for coronavirus?

Diagnosis of a new coronavirus infection is carried out by molecular genetic methods – PCR (polymerase chain reaction).For the study, a swab from the nose and oropharynx is taken, as well as other tests as prescribed by the doctor.

Self-delivery of tests for coronavirus is currently not provided. The test for the presence of coronavirus is prescribed only by a doctor of a medical organization (clinic, hospital) and only for medical and epidemiological indications. The following category of persons are subject to examination:

1. Persons with signs of respiratory diseases who crossed the border within the last 14 days

2.Persons diagnosed with community-acquired pneumonia

3. Persons over 60 years of age who seek medical care with symptoms of respiratory disease

4. Persons with signs of respiratory diseases and chronic comorbidities (cardiovascular diseases, diabetes mellitus, oncological diseases, diseases of the endocrine system)

5. Those who came into contact with a patient with COVID-2019,

6.healthcare workers at risk of contracting COVID-2019 in the workplace

A single test is not enough to make a diagnosis. If a person does not have symptoms of respiratory diseases, then he is tested 2 times. In the presence of symptoms of respiratory diseases, studies are carried out at least 3 times

Government documents – Government of the Saratov Region

90,067 90,132 90,000 Over the past day, 273 cases of coronavirus infection were detected in Kuzbass

Synopsis as of 11:00 am, October 26th.90,026 Over the past day, 273 cases of coronavirus infection were detected in Kuzbass: Kemerovo – 36, Novokuznetsk – 33, Prokopyevsk – 31, Belovo – 30, Mezhdurechensk – 25, Yurga – 22, Myski – 21, Anzhero-Sudzhensk – 20, Kaltan – 9 , Osinniki – 9, Kiselevsk – 6, Belovskiy MO – 6, Leninsk-Kuznetskiy – 5, Novokuznetskiy MR – 4, Kemerovo MO – 3, Berezovskiy – 2, Krasnobrodskiy – 2, Guryevskiy MO – 2, Leninsk Kuznetskiy MO – 2, Tashtagolskiy MR – 2, Prokopyevskiy MO – 1, Topkinskiy MO – 1, Yurginskiy MO – 1.

5 patients died. A woman born in 1939 developed bilateral polysegmental pneumonia. The disease proceeded against the background of pathology of the cardiovascular system, the central nervous system. She lived in Mezhdurechensk. A woman born in 1958 developed bilateral polysegmental pneumonia. The disease proceeded against the background of pathology of the cardiovascular system, diabetes mellitus. She lived in Prokopyevsk. A man born in 1961 has bilateral polysegmental pneumonia.The disease proceeded against the background of neurological pathology, pathology of the central nervous endocrine system, central nervous system, and chronic kidney disease. He lived in the Yurginsky municipal district. A woman born in 1953 developed bilateral polysegmental pneumonia. The disease proceeded against the background of pathology of the cardiovascular system, diabetes mellitus, and pathology of the central nervous system. He lived in Anzhero-Sudzhensk. A woman born in 1964 developed bilateral polysegmental pneumonia.The disease proceeded against the background of diabetes mellitus. She lived in Kemerovo. 90,027 90,026 204 patients recovered. Thus, in Kuzbass, 59,074 people have recovered from the coronavirus. In total, 1,647 patients diagnosed with COVID-19 receive regional assistance. There are 16,433 people in medical hospitals, observatories and 14-day isolation at home. The situation is under the control of the Kuzbass government.

Screening for Endocrine Activity in Water Using Commercially-available In Vitro Transactivation Bioassays

The activities of environmental estrogens such as estradiol-17ss are well documented. (E2) guarantees screening for these chemicals at concentrations ng / L ^23.24. In this study, the ER response for wastewater treatment (BEQ range: 2.3 to 17 ng E2 / L) was slightly higher than reported for the secondary effluent from Australian WWTP ^20, while BEQs for surface waters (<0.5 to 4 ng E2 / L) were within the range indicated on the surface and storm waters elsewhere (<1 to 11 ng E2 / L) ^16. Despite the low level of ER activity measured in samples surface water, this analysis represents an appropriate screening endpoint for assessing water quality.Estrogens such as surfactants based on bisphenol A and alkyl phenols are often found in aqueous media, but can be difficult to quantify using conventional analytical chemistry. ER cell assays may also be useful for screening current and newly registered pesticides, as shown by Kojima et al ^25.

GR activity was orders of magnitude greater than ER activity in all 4 analyzed wastewater samples in this study (table 2). This trend is consistent with previous studies on wastewater treatment ^14, and the range for GR-BEQs reported here is slightly higher but comparable to that for other secondary wastewater using the same bioassay in vitro ^12. Using different bioassay cells, the range for GR-BEQs for wastewater from wastewater treatment plants in Japan was lower (<3 to 78 ng Dex / L) than reported for the secondary effluent in this study ^22. With the exception of a sample of one water surface, which recorded a maximum GR response of 30 ng Dex / L (Table 2, sample E), GR activity in the remaining surface water samples corresponded to reported low activity for Dutch surface waters ²¹ . less, the environmental pact GR of active chemicals is less well characterized than for ER active chemicals ^26, , which makes the assessment of the potential for higher effects of the order of the challenge.

As with conventional chemical analysis, adherence to written protocols and validation of measurements using a performance-based QA / QC approach improves data quality and reliability. Although the verification of cellular biosamples adapted to assess the quality of water will continue to evolve and improve, the measurement of QA / QC parameters first set out in Mehinto and al. ¹⁴ and in relation to this study showed that our results were within the predetermined values ​​of the guidelines (Table 1 ).The calibration curve parameters for these mirror bioassays are used to calibrate other assay protocols (e.g. GC-MS), with the addition of criteria that assess the viability of cells (e.g. cytotoxicity) representing the main difference. Another operational distinction made possible by the use of cells in a high-throughput format is the inclusion of multiple dilutions of samples illustrating the concentration-dependent response expected when bioactivity is measured (Fig.2). When considering sample measurements, the lower ER and GR responses for tertiary effluents (Sample D) compared to three secondary effluent samples (AC) provides additional evidence of the relative accuracy of the bioassay screening results in Table 2 . Inclusion of controls or reference samples that represent a matrix of interest, in this case water, will further enhance the ability to compare the results of bioanalysis internally and especially through measurements of individuals.

The responses of the ER and GR transactivation cell lines used in this study were expressed relative to the potency of the potent agonists E2 and dexamethasone, respectively. This allows a quantitative assessment of bioactivity expressed as a bioassay equivalent concentration (BEQ). This further allows for the study of chemicals that facilitate the reaction of bioassays, i.e. direct comparison of BEQs with individual agonist concentrations determined using routine analytical chemistry.This concept emphasizes the added value of guiding biological screening to the diagnostic study of pathogens, also known as guided effects analysis.

Since SPE is commonly used to isolate a wide variety of pharmaceuticals and other “new contaminants” from water, we used the previously published protocol ^{9, 20} , which showed a sorbent designed to capture both hydrophilic and hydrophobic chemicals in water …Although we assume quantitative capture of all bioactive organic compounds using this technique, more work is needed to fully standardize and validate the effectiveness of such extraction methods. The type of cell assay used in this study may represent another limitation. These assays measure interactions between pollutants and nuclear receptors and do not take into account other possible interactions such as the chemo-membrane receptor.Thus, it is possible that the screening responses measured here were underestimated. Like sample extraction, there are no standardized methods for data analysis, cell analysis and different approaches may lead to different results. Linear regression used in this study to simulate the response at the bottom of the calibration curve may not be appropriate for all cell assays, especially if the simulated response extends beyond the relatively narrow range specified in this study.Further investigation of the above issues is needed to understand the extent to which these tools can be applied as a reliable monitoring tool.

While much of the groundwork is for ER and GR as screens for endocrine reactive chemicals, researchers are expanding the scope of bioanalytical tools to include other appropriate modes of action, for example, androgenicity, genotoxicity, neurotoxicity and immunotoxicity ^9.27. A more comprehensive set of tools will expand the possibilities for screening biologically active chemicals, including the conversion products of known and / or unknown chemicals that can occur ^28, now and in the future, in various aquatic environments ^19.

Subscription Required. Please recommend JoVE to your librarian. 90,027 90,000 On November 9, 1783 cases of COVID-19 were confirmed in the Samara region

On November 9, 1783 cases of a new coronavirus infection were confirmed in the region:

• 673 in St.Samara
• 388 in Togliatti
• 94 in Novokuibyshevsk
• 73 in Syzran
• 70 in Otradny
• 51 in Kinel
• 37 in Neftegorsk District
• 262 9016 Sergievsky District 27 in Stavropol District
• 22 in Volzhsky District
• 24 in Chapayevsk
• 25 in Kinel-Cherkassky District
• 20 in Pokhvistnevo
• 21 in Privolzhsky District
• 19 in Bogatovsky District
• 16
• 14 in Bolsheglushitsky district
• 15 in g.Oktyabrsk
• 14 in Pestravsky district
• 12 in Pokhvistnevsky district
• 11 in Klyavlinsky district
• 10 in Isaklinsky district
• 13 in Krasnoyarsk district
• 13 in Koshkinsky district
• 10 in Krasnoarmeysk district 13
• 12 in the Bolshechernigovsky district
• 10 in the Khvorostyansky district
• 8 in the Alekseevsky district
• 6 in the Borsky district
• 8 in the Elkhovsky district
• 7 in the Chelnovershinsky district
• 5 902 in the Bezenchuksky district 6 4 in Shigonsky district
• 3 in Shentalinsky district
• 3 in Syzran district

1656 people were examined with a diagnosis of community-acquired pneumonia and acute respiratory viral infections.

127 people were identified during a preventive examination of persons without clinical manifestations. 90,027 90,026 A cumulative total of 147,883 cases of coronavirus were recorded in the region.

4863 people died (cumulative total), including 30 over the last day:

• man 56, 67, 83, 83 years old, women 62, 63, 72, 74, 80 years old, suffered from diseases of the cardiovascular system;
• men 49, 57, 58, 64, 66, 66, 83 years old, women 66, 71, 71, 83, 83 years old, suffering from diseases of the cardiovascular and endocrine systems;
• women 58, 67, 71, 81, 83, 86 years old;
• women 39, 51 years old, suffering from diseases of the endocrine system and respiratory organs;
• A 75-year-old woman who suffered from diseases of the cardiovascular and endocrine systems, cancer.

Mortality rate per 100 thousand population in the region – 152.3, in the country – 170.7.

The mortality rate in the region is 3.29, in the country – 2.