Nuclear Medicine Imaging and Therapy: Gender Biases in Disease Valeria M. Moncayo, MD, John N. Aarsvold, PhD,*,† and Naomi P. Alazraki, MD*,† Gender-based medicine is medical research and care conducted with conscious consideration of the sex and gender differences of subjects and patients. This issue of Seminars is focused on diseases for which nuclear medicine is part of routine management and for which the diseases have sex- or gender-based differences that affect incidence or pathophysiology and that thus have differences that can potentially affect the results of the relevant nuclear medicine studies. In this first article, we discuss neurologic diseases, certain gastrointestinal conditions, and thyroid conditions. The discussion is in the context of those sex- or gender-based aspects of these diseases that should be considered in the performance, interpretation, and reporting of the relevant nuclear medicine studies. Cardiovascular diseases, gynecologic diseases, bone conditions such as osteoporosis, pediatric occurrences of some diseases, human immunodeficiency virus–related conditions, and the radiation dose considerations of nuclear medicine studies are discussed in the other articles in this issue. Semin Nucl Med 44:413-422 C 2014 Elsevier Inc. All rights reserved.

Introduction

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ex-based differences in disease are those related to biological and physiological factors (chromosomes, gonads, and hormones), whereas gender-based differences are those related to sociocultural, behavioral, and psychological factors. In gender-based medicine (also known as gender-biased medicine), issues such as how sex- and gender-based differences affect the natural history of a disease and the prognosis, treatment response, and outcome in management of a disease are considered. Nuclear medicine should be practiced as gender-based medicine, particularly in the management of certain diseases and when a practitioner seeks to apply personalized interventions, targeted therapies, and individualized preventions.

Thyroid Disease Thyroid disease, including hypothyroidism, hyperthyroidism, and thyroid cancer, is, in general, 3-5 times more common in *Division of Nuclear Medicine and Molecular Imaging, Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, GA. †Atlanta Veterans Affairs Medical Center, Nuclear Medicine Service, Decatur, GA. Address reprint requests to Valeria M. Moncayo, MD, Division of Nuclear Medicine and Molecular Imaging, Department of Radiology and Imaging Sciences, Emory University School of Medicine, 1364 Clifton Rd NE, Room D125A, Atlanta, GA 30322. E-mail: [email protected]

http://dx.doi.org/10.1053/j.semnuclmed.2014.06.004 0001-2998/& 2014 Elsevier Inc. All rights reserved.

women than in men. The natural history, severity, and response to therapy of thyroid conditions differ between the sexes. The role of nuclear medicine for thyrotoxicosis and thyroid cancer includes diagnostic imaging and thyroid uptake in benign conditions using sodium iodide-123 (123I) and technetium 99m (99mTc)-pertechnetate. 131I is used for imaging and therapy of patients with thyroid cancer after surgical thyroidectomy. At times, imaging may also include SPECT/CT with the aforementioned isotopes or PET/CT with 18F-FDG.1

Hypothyroidism and Goiter In iodine-depleted regions of the world, goiter is endemic. In regions where iodine deficiency is not an issue, the prevalence of spontaneous hypothyroidism is 1%-2%.2 Subclinical hypothyroidism is more common in elderly women and 10 times more common in women than in men. The greatest prevalence of goiter is in premenopausal women, and the ratio of women to men is at least 4:1.3 Further, it has been observed that women have a significantly higher prevalence of palpable goiter than men do.4 Imaging with 123I and 99mTc-pertechnetate is sometimes performed using a pinhole collimator on the scintillation camera. This imaging is performed with the objective of enlarging small regions of the thyroid gland in patients with goiter and thyroid nodules. If thyroid nodules are palpated or if there is a goiter, thyroid scintigraphy is used to characterize nodules as hypofunctioning, hyperfunctioning, or normal. 413

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414 Cold or hypofunctioning nodules are found to be malignant in 5%-35% of cases. They are often correlated with ultrasound images for biopsy.1 Thyroid scintigraphy is useful for evaluation of other disorders such as thyroid dysgenesis, including ectopic thyroid tissue. Such disorders are more frequent in childhood and are discussed in more detail in the article on pediatrics in this issue. Lingual thyroid is more prevalent in young adult women (4-7 times more frequent in women than in men). Planar and SPECT/CT are useful tools to evaluate lingual thyroid and other types of thyroid dysgenesis, particularly SPECT/CT, if it is determined that both anatomical and functional data would be useful.5

Hyperthyroidism and Graves Disease Gender-Focused Epidemiology in Graves Disease Parry, Graves,6 and von Basedow7 (in the mid-1800s) made the earliest descriptions of patients with thyrotoxicosis. Their descriptions of such disease were exclusively in women.8 Graves disease is seen in 0.5%-1% of the population, with a female-to-male preponderance of 5:1 to 10:1.2,9,10 It presents most commonly in the fourth decade of life. The strongest known risk factor is a family history of disease, seen in approximately 50% of patients.9,10 Autoimmune processes, including Graves disease, are in general more common in women.11,12 The fact that the phenomenon of autoimmune processes is more common in women has been postulated to be related to sexual dimorphism in the immune response and the influence of sex hormones.13 The etiology of Graves disease is multifactorial, encompassing genetic and environmental factors. In addition to female disease preponderance, it is well accepted that part of the genetic component of the inheritance pattern involves human leukocyte antigen genes, which encode for immune response–related proteins. The genes associated with the development of Graves disease are being studied. One of the most relevant is cytotoxic T-lymphocyte antigen 4. This is a negative regulatory molecule of the immune system that inhibits T-cell responses. It has been associated with many other autoimmune diseases.9,10 Research is also underway in the area of X chromosome inactivation as one of the factors influencing the female preponderance of Graves disease.10,14 Toxic multinodular goiter or autonomously functioning thyroid adenomas are also predominately seen in the female population; however, available data regarding gender prevalence are lacking.3 Thyroid-associated ophthalmopathy is the most common extrathyroidal manifestation of Graves disease. It occurs in 3%5% of patients with Graves disease. It has been described as more frequent in female patients, with a rate of 16 per 100,000 per year for women, as opposed to 2.9 cases per 100,000 per year for men. Severe graves ophthalmopathy is more frequent in male patients older than 60 years and in male or female patients who smoke cigarettes.8,15 Nuclear Medicine Imaging in Graves Disease Imaging with 123I and 99mTc-pertechnetate using a pinhole collimator on the scintillation camera has been used in the

workup of hyperthyroidism and Graves disease. If 123I is used, a study protocol generally provides iodine uptake values at 4-6 and 24 hours, (normal uptake is 10%-30% at 24 hours and less than 16% at 4 hours).16 123I is preferred over 99mTcpertechnetate because 123I is trapped and organified within the gland vs only trapping with 99mTc-pertechnetate. The uptake measurement is an important component for the differential diagnosis of hyperthyroidism. If the uptake at 24 hours is high, Graves disease is more likely than toxic nodular goiter. If the uptake is significantly low, subacute, postpartum thyroiditis or amiodarone toxicity should be considered. The pattern of iodine distribution and the size estimate of the gland are important for patient management.1,17 Radioiodine Therapy Considerations in Graves Disease Permanent therapy with 131I is a valuable noninvasive approach and an alternative to thyroid surgery or antithyroid medications. Calculation of appropriate doses for such therapies (there are several algorithms in use to accomplish this) requires appropriate information from thyroid uptake and thyroid imaging studies. Radiation safety precautions focus mainly on avoiding unnecessary exposures to family members and the public, particularly on limiting exposures to young children and pregnant women to levels o5 mSv (0.5 rem).18 In general, higher and faster cure rates for Graves disease are seen with orally administered doses of 15 mCi or more. Toxic multinodular goiter is usually treated with higher doses of 25-30 mCi.19 Women have a higher cure rate for Graves disease with radioactive iodine than men do.4 The only significant side effect of using 131I for permanent thyroid gland destruction is the gland destruction, which requires that a patient take thyroid hormone replacement for the rest of her or his life. Surgery is an alternative; it has the risk of hypoparathyroidism, recurrent laryngeal nerve injury that may result in vocal cord paresis or paralysis, bleeding, and anesthesia-related risks.20,21 Antithyroid medications have the risks of aplastic anemias and frequent recurrence of the disease if stopped.22,23

Thyroid Cancer Gender-Focused Epidemiology in Thyroid Cancer The incidence of thyroid cancer has increased in the last 30 years. The estimates for 2014 from the American Cancer Society are 62,980 new cases of thyroid cancer (47,790 in women and 15,190 in men). Although the death rate due to thyroid cancer is and has been low for many years, it is estimated that there will be approximately 1890 deaths due to thyroid cancer (1060 women and 830 men) in 2014.24 Although this malignancy is more prevalent in women, men have a higher rate of poor prognosis.25 The causes for the wellknown gender bias in thyroid cancer incidence remain unclear. Several mechanisms have been postulated as possible contributing factors. Androgen receptor and testosterone levels have been suggested as possible mechanisms, although such mechanisms are not well understood.26 Animal studies suggest that estradiol may influence the increase in size and function of the thyroid gland.27,28

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After the Chernobyl nuclear accident in Ukraine, a marked increase in the incidence of thyroid carcinoma occurred in children and adolescents. Between 1986 and 1997, the total number of thyroid carcinomas in Ukrainian children and adolescents was 577 (358 children and 219 adolescents), compared with 59 cases in the preceding 5 years. The femaleto-male ratio in these newly diagnosed thyroid carcinomas in this young population was approximately 2:1.29 Although radiation such as that at Chernobyl can cause thyroid cancer, it is the case that the best therapy for thyroid cancer is radioactive iodine therapy for destruction of the cancer and the thyroid. Radioiodine ablation for thyroid remnants in high-risk, differentiated thyroid cancer is a safe procedure. The procedure has limited effect on the female gonads and limited risk for development of a secondary tumor.30 Nuclear Medicine Imaging in Thyroid Cancer Nuclear medicine imaging for thyroid cancer includes pretherapy and posttherapy whole-body scans. Pretherapy scans may use 123I or 131I imaging, with anterior and posterior planar whole-body images. To maximize iodine uptake, patient preparation for pretherapy scans includes either thyroid hormone withdrawal or administration of recombinant human thyrotropin (Thyrogen; Genzyme Corporation, Cambridge, MA) injections for thyroid stimulating hormone stimulation.31 Posttherapy whole-body scans are acquired 8-10 days after radioiodine ablation and are more sensitive for the detection of metastatic disease compared with pretherapy whole-body scans, particularly in cases where thyroglobulin is elevated.32 123I or 131 I-SPECT/CT may be used, for example, when radioiodine activity is detected outside expected physiological distribution on a whole-body scan and further imaging is warranted.33,34 Female patients may demonstrate radioiodine uptake in breast tissue, uterus, and cervix depending on the menstrual cycle. Rillema et al35 described a possible upregulation effect of prolactin in the sodium iodide (Naþ/I) symporter. The 131Iwhole-body scan of a patient with thyroid cancer and a prolactinoma demonstrated bilateral symmetric breast uptake, as shown in Figure 1. The Naþ/I symporter is also under investigation for its possible role in the treatment of breast cancer.36 Figure 2 illustrates a case in which abnormal adnexal iodine uptake was noted and suspected to represent thyroid cancer metastasis. Further investigation, including tissue sampling, revealed an endometrioma. Naþ/I symporter expression has also been demonstrated in endometrial tissue.37 Figure 3 illustrates radioiodine activity in adnexal tissue that corresponded to the normal cervix in a female of reproductive age. The presence of the Naþ/I symporter results in radioiodine uptake that may be physiological or pathological; however, it may or may not correspond to metastatic thyroid cancer.38 Other possible instances of false-positive results of iodine taken up by tissues other than in the normal biodistribution are inflammatory lung disease, gastrointestinal tract, salivary gland, and simple contamination.39 In cases of dedifferentiated thyroid cancer, which may not be radioiodine avid, evaluation is also be possible using PET/ CT under withdrawal of thyroid hormone or Thyrogen stimulation.40

Figure 1 A 37year-old woman with papillary thyroid cancer (PTC) after total thyroidectomy. Anterior and posterior images acquired as 131 I (4 mCi) whole-body surveillance scan. The patient has a history of prolactinoma. There is no uptake in the thyroid bed; however, intense breast uptake is noted (arrows).

Nuclear Medicine and Gender Differences in Brain Physiology Gender differences in brain development, anatomy, function, and physiology have fascinated researchers for decades (particularly regarding the social implications of such differences). It is well known that the brain volume of men is approximately 10% greater than that of women. It is also known that women have a higher percentage of gray matter than men do, and thus that men have a higher percentage of white matter than women do.41,42 Nuclear medicine has proved to be useful in the study of brain function, and its use in such studies has enhanced our understanding of brain physiology and gender differences. Global cerebral blood flow is higher in women than in men. This has been demonstrated using several PET tracers to measure blood flow in the brain, for example Oxygen-15 (15O)–labeled water and 18F-FDG, and several SPECT tracers, for example, xenon 133, 99mTc-hexamethylpropylene amine oxime, and 99mTc-ethyl cysteinate dimer.43-50 Other studies have revealed that female and male brains are neurochemically distinct. Physiology in women that are absent from men include the menstrual cycle and the influences of estrogen in brain development and brain function.42 Neurotransmitters that can be imaged using radiotracers include serotonin (5-hydroxytryptamine [5-HT]) transporter, 5-HT1A receptor, and 5-HT2A receptor; dopamine (DA) D1 receptors and D2 receptors and the DA transporter (DAT); γ-aminobutyric acid-benzodiazepine receptors; β2-containing

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Figure 2 A 35-year-old woman with papillary thyroid cancer (PTC) after thyroidectomy. (A) Posttherapy scan 7 days after the administration of 150 mCi of 131I-NaI. Expected activity in the thyroid bed is visible. In addition, there are 2 foci of uptake in the pelvis. The larger is best appreciated on the posterior projection (arrows). (B) SPECT-CT images. The area of increased radiotracer uptake is localized to a left adnexal mass. The second focus of uptake on planar imaging seen superiorly corresponds to a loop of the bowel on SPECT/CT. (C) Transvaginal ultrasound in longitudinal view. A left adnexal hypoechoic mass with internal echoes and no internal blood flow is visible. This finding was stable during 6 months of follow-up. (D) Pathology section image of the left ovary. The image shows the lining of an endometriotic cyst consisting of glandular epithelium, stroma, and histiocytes with hemosiderin deposition, which are consistent with endometrioma.

Figure 3 A 58-year-old postmenopausal woman with papillary thyroid cancer (PTC) with regional and nodal metastatic recurrence after second ablation with 215 mCi of 131I-NaI. (A) Posttherapy whole-body scan obtained 10 days after ablation demonstrates expected uptake in the salivary glands and liver. Uptake in the right adnexal region is noted (arrow). (B) SPECT-CT axial images localize the areas of increased uptake to the right adnexal region; the region is suggestive of metastatic focus. (C) MRI of the pelvis with contrast. The axial T2 image shows that the area of iodine activity on wholebody scan corresponds to normal cervix where no enhancing tumor was identified.

Nuclear medicine imaging and therapy nicotinic acetylcholine receptors; and μ opioid receptors.42,51,52 In a study using 99mTc-ethyl cysteinate dimer on healthy volunteers, significantly higher uptake in the right parietal cortex was observed in women than in men, whereas higher uptake in the cerebellum and the left anterior temporal and orbitofrontal cortex were observed in men than in women.53

Alzheimer Disease Gender-Focused Epidemiology in Alzheimer Disease More than 5 million individuals are affected with Alzheimer disease (AD)54 in the United States.55-57 The prevalence rate of AD in females is nearly twice that of males; this significant difference is seen only in AD and not in other types of dementias.58 In fact, men are at higher risk for mild cognitive impairment, which is an intermediate stage between normal aging and dementia, but women are disproportionally affected with AD, corresponding to almost two-thirds of subjects with the diagnosis. Along these lines, several studies across multiple continents have found that women demonstrate a higher incidence of AD after the ages of 80-85 years.59-61 A contributing factor may be that men die earlier of other causes than women do.57 Gender-Related Risk Factors in AD Testosterone and estrogen have been studied as factors in the development of AD. It has been suggested that after menopause the decreased levels of estrogen may contribute to the increased prevalence of AD in women.62 In support of this is research in which it was observed that patients who took estrogen replacement therapy in the years immediately following menopause or after bilateral salpingo-oophorectomy demonstrate decreased incidence of AD and showed improved cognition with this therapy.63 One of the possible explanations is that estrogen protects against mitochondrial toxicity of β-amyloid.64 There is controversy about the role of hormonal replacement therapy and its effects in AD, especially when the timing of therapy is considered. Estrogen can have no effect or even detrimental effects in cognitive function if the replacement is started 5 or more years after the onset of natural menopause. In this regard, it has been suggested that estrogen’s effects are only seen on healthy neurons, therefore, if the mitochondria are damaged, which is seen in normal aging, estrogen will not provide benefit and may even damage the cells. A hypothesis explaining the lack of effect in some studies proposes that longterm estrogen depletion leads to decreased levels of estrogen receptors. Therefore, if the estrogen replacement treatment is started too late, these receptors are downregulated.57,65 Genetic factors, such as the apolipoprotein E-epsilon-4 (APOEε4) allele, have been extensively studied as risk factors for the development of AD.66 A family history of dementia is generally considered an established risk factor for AD. The presence of one or more APOE-ε4 alleles confers a substantially greater risk of AD in women than in men.66-68 Individuals who have at least 2 firstdegree relatives with AD and the APOE-ε4 allele had a higher risk of dementia and AD than those who did not.66,69

417 Cardiovascular risk for the development of AD is currently an area of growing interest. Women older than 75 years have higher rates of hypertension, hyperlipidemia, and diabetes than similarly aged men do.70 Lack of cognitive reserve is also thought to be a risk factor for AD. Historically, men have had more opportunities in education and occupation, particularly for the generation of individuals currently older than 70 years, a high-risk group for AD.57 Historical and social changes resulting in changes in the roles of family members and in increased educational opportunities for women may, in the future, result in changes in gender differences in AD prevalence. Nuclear Medicine Imaging in AD Progressive formation and accumulation of extracellular βamyloid plaques and intracellular tau neurofibrillary tangles are pathological hallmarks of AD, although it is also well known that these can accumulate in the brain before cognitive decline is clinically evident.71 There is extensive literature on radiotracers developed for the potential early detection of AD. The most studied radiotracer is 11C-Pittsburgh compound B (PiB), which targets amyloid plaques. In vivo PiB studies demonstrate a roughly 2-fold increase in tracer retention in patients with AD in comparison with cognitively normal elderly subjects.72 PiB has high sensitivity and specificity for the detection of B-amyloid plaques; however, when it is used for the detection of AD, the specificity is measurably lower, as PiB has been found in up to 30% of patients with no measurable cognitive impairment.73 18 F-FDG is the most widely used radiotracer for the investigation of metabolism. It has also been used to study AD. Images of AD typically show decreased glucose metabolism in the posterior parietal-temporal regions.46,74 Currently, there are 3 Food and Drug Administration (FDA)–approved PET radiotracers for the evaluation of β-amyloid deposition in the clinical evaluation of AD. Amyvid (18F-florbetapir; Lilly), a fluorine-18–radiolabeled small molecule, was approved by the FDA in 2012 for the evaluation of amyloid plaque volume using PET. Figures 4 and 5 demonstrate examples of female patients with normal and abnormal Amyvid scans, respectively. Two other tracers, Neuraceq, (18F-florbetaben; Piramal Imaging) and Vizamyl, (18F-flutemetamol; GE Healthcare) were approved by the FDA in 2013 and 2014, respectively. These 3 radiotracers share similar radiopharmaceutical characteristics and identify patients with increased amyloid deposition in the brain, which correlates with AD but not absolutely.75 18 F-2-(1-{6-[(2-[fluorine-18]fluoroethyl)(methyl)amino]-2naphthyl}-ethylidene)malononitrile (FDDNP) is another tracer that targets β-amyloid and tau protein deposits in the brain. Braskie et al studied 18F-FDDNP radiotracer distributions in cognitively intact subjects with mild AD.76 Their findings support the postmortem pathological findings of the classic Braak and Braak description of neurofibrillary tangles and neuropil threads pattern distribution, which affects the lateral, temporal, parietal, and frontal cortices.71,76,77 Recently, tau protein, which is found in neurofibrillary tangles in the brains of patients with AD, has also been the

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Figure 4 A 75-year-old woman with memory loss. The 18F-florbetapir (Amyvid) PET/CT scan axial images demonstrate homogeneous distribution of radiotracer bilaterally. No cortical white-gray matter differentiation is present; this is consistent with amyloid plaque deposition.

target of basic and human research for the development of PET-based imaging tracers. Deposition of tau protein is closely associated with neuronal loss; therefore, it is thought to represent an in vivo target that will detect correlation between tau protein load and cognitive decline. As such, this tracer may be useful78,79 for the evaluation of disease progression and therapeutic effect. 18F-labeled arylquinoline derivatives, 18FTHK-5105 and 18F-THK-5117, have also been developed and tested in mice as tau imaging PET tracers.78 An in vitro evaluation of 18F THK-523 showed superior binding to tau protein compared with PiB or 18F-FDDNP. No binding to β-amyloid was observed.79

Trials on therapies and preventive measures in AD should have adequate sample size to account for effects in men and women separately, given the extensive differences encountered in pathophysiology, response to therapy, and risk factors of the disease; however no gender-based differences in imaging patterns have been observed as yet.

Parkinson Disease Gender-Focused Epidemiology in Parkinson Disease Parkinson disease (PD) is the second most common neurodegenerative disorder. It is second to AD. It is more frequent in

Figure 5 An 82-year-old woman with depression and cognitive decline. The 18F-florbetapir (Amyvid) PET/CT scan axial images demonstrate adequate cortical white-gray matter differentiation that is compatible with the absence of amyloid plaque deposition in the cortex.

Nuclear medicine imaging and therapy men than in women. The male-to-female ratio is approximately 2:1.80,81 The incidence rates range between 1.5 and 22 per 100,000 person-years. If restricted to individuals aged 65 years and more, the median incidence rate is higher, 160 per 100,000 person-years, predicting an estimated 59,000 new cases per year in the United States.80,81 Most studies reveal a prevalence between 100 and 300 per 100,000 person-years.80 Clinical characteristics that appear in men more often than in women include rigidity and rapid eye movements, whereas characteristics that appear more often in women include dyskinesias and depression.82 A milder phenotype of PD has been observed in women.83 The prevalence and severity of nonmotor symptoms in PD (fatigue, mood, sexual and digestive problems, pain, restless legs, and daytime sleepiness) appear to be significantly different between men and women.84 Multiple studies have suggested a neuroprotective role of estrogen in the dopaminergic neurons.85-87 Nuclear Medicine Imaging in PD Traditionally, MRI has been used to detect structural changes and PET or SPECT has been used for functional neurochemical and metabolic manifestations associated with these disorders. The dopaminergic terminals in the posterior dorsal putamen are initially affected in PD, then those in the anterior putamen followed by those in the head of the caudate. Many PET and SPECT tracers have been developed for the evaluation of DA function in the striatum and putamen.88 123 I-ioflupane (DaTSCAN; GE Healthcare) was approved by the FDA for the evaluation of the integrity of the nigrostriatal structures in patients with suspected PD in 2011. This radiotracer can be used to distinguish essential tremor from other parkinsonian syndromes.89 Typically, the assessment is qualitative, when clear, accepted criteria exist. However, in some cases, quantitative assessment is desired. Recently, a large database of 123I-ioflupane SPECT scans in healthy controls was generated for the European Normal Control Database of DaTSCAN study. The investigators of this study concluded that women have greater availability of DAT90 compared with men and concluded that there is a decrease in DAT availability of 5.5% per decade for both genders as was also previously reported.91 The greater availability of DAT in women has been a source of controversy in the literature. One thought is that the greater availability is related to hormonal effects that result from higher DA transmission or turnover or to striatal volume and concentration of receptors or to a combination of both.92 Men have striata with higher volumes than those in women, therefore the concentrations in men could be less than those of women.93

Gallbladder Disease Gender-Focused Epidemiology and Risk Factors in Gallbladder Disease Gallbladder disorders are found worldwide, with the most common asymptomatic condition being cholelithiasis—a condition that affects approximately 10% of the adult population in the United States. In Western countries, the prevalence of gallstone disease reportedly ranges from 7.9%

419 in men to 16.6% in women.94 Some ethnic groups demonstrate higher incidences of gallbladder disease, for example, the incidence is 73% in Pima Native American women, 64.1% in Native American women in general, and 26.7% in Mexican American women.94 The clear female predominance of gallstone disease is thought to be related to estrogen. Data suggest that there is an increase in the number of gallstones in pregnancy and with use of estrogen therapy and oral contraceptives.95 Other risk factors for gallstones include obesity, dyslipidemias, and type 2 diabetes. The pathophysiology of gallbladder disorders appears to be multifactorial.95 Nuclear Medicine Imaging in Gallbladder Disease In acute settings of gallbladder diseases, nuclear medicine plays an important role in the diagnosis of acute cholecystitis. One of the most common complications of cholelithiasis is acute cholecystitis, which manifests as an obstruction of the cystic duct. Its diagnosis is mainly accomplished clinically; however, imaging is frequently used to support a clinical diagnosis. Among the various imaging modalities, ultrasound is most often used to evaluate the gallbladder. This is because it is relatively easy to perform in this context and because it is readily available, is low cost, and has high sensitivity.95 Findings suggestive of acute cholecystitis in ultrasound include thickening of the gallbladder wall, pericholecystic fluid, and a sonographic Murphy sign, which is essentially a modified Murphy maneuver using the ultrasound probe to produce pressure in the right upper quadrant. Ultrasound is also used to investigate right upper quadrant pain with or without the history of cholelithiasis.96 Biliary scintigraphy is performed using 99mTc-disofenin (2,6-diisopropylacetanilido iminodiacetic acid) or 99mTcmebrofenin (bromo-2,4,6-trimethylacetanilido iminodiacetic acid). The diagnosis of acute cholecystitis can be effectively excluded if radiotracer is seen within the gallbladder and the bowel. This test has  98% sensitivity and  90% specificity. Awareness of the possibilities of false-positive or false-negative results is crucial. In acalculous cholecystitis, gall bladder may be nonvisualized (functional cystic duct obstruction due to edema and vasculitis) or visualized. Biliary scintigraphy can be used as a guide to direct surgical or medical therapy. In the absence of cholelithiasis and clinical features of acute gallbladder inflammation, if biliary scintigraphy shows the absence of gallbladder filling, the treatment is most likely surgical or if the gallbladder is visualized, it is medical.97 In addition to diagnosis of acute cholecystitis in which nuclear medicine images demonstrate nonvisualization of the gallbladder due to cystic duct obstruction, other uses of biliary scintigraphy include imaging of bile leaks, biliary-enteric anastomosis patency, and recurrent pain in the patients after cholecystectomy.98

Gastric Motility Evaluation of patients with symptoms that suggest gastroparesis, such as early satiety, nausea, vomiting, bloating, postprandial fullness, and upper abdominal discomfort, may

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420 include imaging studies. Gastric motility can be studied with multiple imaging modalities such as dynamic contrast radiography, magnetic resonance, and ultrasound.99-101 The role of nuclear medicine in the quantification of gastric emptying has been well established. Different methodologies in the meal administered have made it difficult to standardize gastric emptying studies, although practice guidelines are in place. The gastric-emptying breath test using a radiolabeled meal with carbon 13 and a wireless motility capsule are nonimaging, less commonly used tests to evaluate gastric motility.99 The observation that women empty both solids and liquids from their stomachs more slowly than men has been confirmed in several studies, although the results are difficult to compare owing to the lack of uniform methodology.90,102,103 In a study conducted in 1987 that enrolled 15 men and 15 women, a standard meal of 150 g of radiolabeled beef stew and 150 g of radiolabeled orange juice was provided.90 The beef stew was labeled with 99mTc and the orange juice was labeled with 111 Indium to detect differences for solid and liquid emptying, respectively. Gastric emptying half-times were lower for women than for men, and the differences were statistically significant. It is well known that pregnant women have delayed gastrointestinal transit, with high levels of estradiol and progesterone being the most likely cause, as these hormones have a direct effect on the smooth muscle of the gastrointestinal tract.104 This is also more evident in the third trimester when the hormonal levels are the highest as compared with such levels for the first and second trimester. Similar findings have been observed in nonpregnant women during the luteal phase of the menstrual cycle.105 Diabetes is a known predisposing factor for gastric motility abnormalities; within this group of patients, there is a female preponderance of delayed emptying.103

Conclusion Nuclear medicine plays an important role in several clinical conditions affected by gender bias. Benign and malignant thyroid disease in general is more prevalent in women, although disease response to therapy is in general better in women than in men. In the evaluation of patients with thyroid cancer, it is important to recognize particular extrathyroid sources of iodine uptake, as they may correlate with femalespecific anatomy and physiology. In thyroid imaging, locations of radioiodine uptake indicated on planar images may be further imaged with SPECT/CT for more accurate assessment and localization. Although there are no particular gender differences in imaging of patients with AD, there is clear female predominance in incidence and of severity of the disease. Women appear to demonstrate a protective factor toward PD likely because of the effect of estrogen. PD is more frequent and more severe in male patients. Delayed gastric emptying and gallbladder diseases are more common in women. Estrogen undoubtedly plays a role in all these diseases in some way, although in most cases, this role is still incompletely understood.

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