Alison Suzanne Clay, MD

• Assistant Professor of Surgery
• Assistant Professor in Medicine

https://medicine.duke.edu/faculty/alison-suzanne-clay-md

Growth Monitoring the Indian Academy of Pediatrics has given guidelines to monitor growth during childhood (Table 2 antibiotic blue capsule generic minocycline 50 mg with amex. Later it can be integrated in to visits for vaccination virus 2014 respiratory virus generic 50 mg minocycline otc, minor illnesses or in to school health program bacteria antibiotics cheap minocycline express. Physical and sexual growth pattern of affluent Indian children from 5-18 yr of age can antibiotics for acne make it worse proven 50 mg minocycline. Steps in Assessment Familial Constitutional Pathological Undernutrition Chronic systemic illness Cerebral palsy Congenital heart disease virus worksheet purchase minocycline 50 mg overnight delivery, cystic fibrosis, asthma Malabsorption. For children below 2 yr, supine length should be measured using an infantometer with a rigid headboard on one side and a moveable footboard on the other side, while holding the infant straight on the horizontal board. For older children, height should be measured with a stadiometer, as explained in previous section. If height velocity is lower than expected for age, the child is likely to be suffering from a pathological cause of short stature. The height should be plotted on appropriate growth charts and expressed in centile or as standard deviation score. The height of the stool is subtracted from the reading obtained to get sitting height. For measuring arm span, child is asked to stand straight with both arms extended outwards parallel to the ground. Length between the tips of the middle finger of the outstretched hands is the arm span. Precious puberty can lead to early height spurt followed by premature epiphyseal fusion and ultimate short stature. On the other hand, delayed puberty can also present with short stature in adolescents as the height spurt is also delayed. Differential Diagnosis Diagnosis is based on a detailed history, examination and laboratory evaluation. Careful history and examination can w1ravel many clues to the etiology of short stature (Tables 2. The investigative work up to be done is guided by clues from history and physical examination. The appearance of various epiphyseal centers and fusion of epiphyses with metaphyses tells about the Table 2. Bone age is conventionally read from radiograph of the left hand and wrist using either Gruelich-Pyle atlas or Tanner-Whitehouse method. It gives an idea as to what proportion of the adult height has been achieved by the child and what is the remaining potential for height gain. Bone age is delayed compared to chronological age in almost all causes of short stature. Exceptions to this are familial short stature, in which bone age equals chronological age, and precocious puberty, in which bone age exceeds chronological age. In case of constitutional delay, undernutrition and systemic illness, bone age is less than chronological age and corresponds to height age. In cases of growth hormone deficiency and hypothyroidism, bone age may be lower than height age if the endocrine condition is diagnosed late. In addition, all children with disproportionate short stature require skeletal survey to rule out skeletal dysplasia and rickets. Essential screening investigations that should be done in all children with short stature are listed in Table 2. If these investigations are normal and bone age is delayed, level 2 investigations should be done. If these investigations are also normal, then the major diagnostic possibilities are growth hormone deficiency and malabsorption. These children show catch-down growth between birth and 2 yr of age, so that the height and weight come to lie on their target (mid-parental) centiles by the age of 2 yr. Subsequently, the growth velocity remains normal throughout childhood and adolescence. The body proportion is appropriate and Specific Etiologies Familial short stature the child is short as per definition -Table 2. Puberty is achieved at appropriate age and final height is within their target range. Constitutional growth delay these children are born with a normal length and weight and grow normally for the first 6-12 months of life. Their growth then shows a deceleration so that the height and weight fall below the 3rd centile. By 3 yr of age, normal height velocity is resumed and they continue to grow just below and parallel to the 3rd centile with a normal height velocity. The onset of puberty and adolescent growth spurt is also delayed in these children but final height is within normal limits. History of delayed puberty and delayed height spurt is usually present in one or both parents. Undernutrltion Stunted growth caused by chronic undernutrition is one of the commonest cause for short stature in our country. A detailed dietary history and presence of other features of malnutrition such as low mid upper arm circumference and low weight for height suggest the diagnosis. Skeletal dysplaslas Inborn errors in the formation of cartilage and bone, cause chondrodysplasias or skeletal dysplasias, inherited or sporadic conditions that are usually associated with abnormal skeletal proportions and severe short stature (except hypochondroplasia, where growth retardation is mild). C 16(63 62 15 61 60 76 19(75 74 77 these infants show catchup growth by 2 yr of age. Management the general principles of management for any child who presents with short stature include counseling of parents and dietary advice. Intake of a balanced diet containing the recommended amounts of macro- and micronutrients should also be recommended. For physiological causes, reassurance and annual monitoring of height and weight is sufficient. Dietary rehabilitation for undernutrition and treatment of underlying condition such as renal tubular acidosis or celiac disease are generally associated with good catchup growth. With any form of therapy, monitoring with regular and accurate recording of height is mandatory for satisfactory outcome. For skeletal dysplasias, limb lengthening procedures are offered at few orthopedic centers. The child falls to a lower centile in early childhood, grows below and parallel to 3rd centile in childhood, with an apparent downward deviation of growth curve during the normal time of pubertal growth, with later acceleration of growth and reaching target height (range indicated by vertical bold bar). Other syndromes associated with short stature are Down, Prader-Willi, Russell-Silver and Seckel syndromes. Psychosocial dwarfism this condition, also known as emotional deprivation dwarfism, maternal deprivation dwarfism or hyperphagic short stature, is seen in children in unhappy homes where the emotional needs of the child are totally neglected. Good catchup growth is usually seen when the child is placed in a less stressful environ ment and nurtured with love and affection. Prognosis If managed early and adequately, the prognosis for physical growth recovery is good. However, the outlook for cognitive, emotional and behavioral development is variable and less certain. Megalencephaly or enlargement of the brain parenchyma may be familial or associated with inherited syndromes or neurometabolic disease. Infants with benign familial megalencephaly have increased head size at birth that persists through infancy along the upper growth curve percentiles, and is associated with normal body size, neurologic examination and development. Most patients show postnatal rapid increase in head size and are symptomatic due to underlying disease or raised intracranial pressure (nausea, vomiting and irritability). Diagnosis History, physical examination and observation of parent child interaction are important. Management the goals of management are nutritional rehabilitation, treatment of organic causes if present, and remedial measures for psychosocial factors. Since head growth is driven by brain growth, microcephaly usually implies micro encephaly (except in craniosynostosis in which skull growth is restricted). Other associations include structural brain malformations, inherited syndromes, congenital or acquired infections, hypoxic ischemic insults and rarely, metabolic disorders. Careful history and physical examination are necessary, including development assessment and measurement of head size of parents. Need for neuroimaging is determined by the age at onset, severity of rnicrocephaly, head circumference in parents, history of antenatal insult(s) and associated clinical features. Children with asymptomatic familial megalencephaly or benign enlargement of the subarachnoid space do not require treatment. The term primary microcephaly is used to describe conditions associated with reduced generation of neurons during neural development and migration. Secondary microcephaly follows injury or insult to a previously normal brain causing reduction in the number of dendritic processes and synaptic connections. The prognosis depends upon the underlying cause, and is worse for secondary than primary microcephaly. The child should be managed in consultation with genetics and pediatric neurology services. Craniosynostosis Craniosynostosis is the premature fusion of one or more cranial sutures, either major. Cranial sutures normally fuse during early childhood, starting with the metopic suture (beginning at 2 months), followed by sagittal, coronal and lambdoid sutures (22-26 months), such that the frontonasal and frontozygomatic sutures close last (68-72 months). Premature fusion restricts the growth of the skull perpendicular to the affected suture. Compensatory skull growth occurs parallel to the affected suture in order to accommodate the growing brain. The resulting skull defor mity is termed as scaphocephaly, plagiocephaly or trigono cephaly based on the suture involved. Cloverleaf skull deformity is caused by the fusion of multiple sutures and is associated with hydrocephalus. Patients with tower skull or acrocephaly have combined sagittal, coronal and lambdoid synostosis, often as part of Apert or Crouzon syndrome. Oxycephaly or turricephaly refers to a tall cranium resulting from delayed repair ofbrachycephaly, and is often syndromic. Most patients have a high arched palate, malocclusion, cleft palate and complex syndactyly (mitten hand). Other findings are strabismus, conductive hearing loss, airway compromise and severe acne. The degree of facial deformity is milder than in Apert syndrome and patients do not show cleft palate, syndactyly and mental retardation. Other conditions associated with craniosynostosis are Carpenter syndrome and Pfeiffer syndrome. Development Ramesh Agarwal, Vandana Jain, Naveen Sankhyan Development refers to maturation of functions and acquisition of various skills for optimal functioning of an individual. The maturation and myelination of the nervous system is reflected in the sequential attainment of developmental milestones. Developmental milestones are important, easily identifiable events during the conti nuous process of development. Increasingly complex skills are learnt, matching the formation of new synapses in the brain. While development is a global process reflected in new motor abilities and language, social and cognitive skills, intelligence pertains to the part of the development dealing with cognitive or adaptive behavior. Rules of Development To understand the complex process of human development, some basic facts should be understood: 1. Development is a continuous process, starting in utero and progressing in an orderly manner until maturity. The child has to go through many developmental stages before a milestone is achieved. However, in absence of practice, the child may be unable to learn skills despite neural maturation, since the capability to perform the skills remains dormant. For example, all infants babble before they speak in words and sit before they stand. Hence, head control precedes trunk control, which precedes ability to use lower limbs. The control of limbs proceeds in a proximal to distal manner, such that hand use is learnt before control over fingers. Certain primitive reflexes have to be lost before relevant milestones are attained. For example, palmar grasp is lost before voluntary grasp is attained and the asymmetric tonic neck reflex has to disappear to allow the child to turnover. The initial disorganized mass activity is gradually replaced by specific and wilful actions. Hence, when shown a bright toy, a 3-4 month old squeals loudly and excitedly moves all limbs, whereas a 3-4 yr old may just smile and ask for it. Factors Affecting Development Development depends on a variety of mutually interactive factors such as hereditary potential, biological integrity, physical and psychosocial environment and emotional stimulation. The brain matures through a dynamic interplay of genetic, biological and psychosocial factors. Infancy and early childhood are the most crucial phases during which development takes place. Appropriate sensory inputs through hearing and vision, a secure environment and responsive parenting provide the bases for healthy patterns of learning, behavior and health. Poverty is among the most important risk factors associated with poor development. Poverty expo ses the child to many other risk factors such as lack of stimulation or excessive stress, malnutrition, exposure to environmental toxins, and concurrent diseases that adver sely affect development. Moreover, certain developmental patterns are observed to follow parental patterns like speech. Prenatal Factors Genetic factors Intelligence of parents has direct Prematurity Babies born before 37 weeks of gestation are more likely to have developmental impairment compared to term counterparts with babies born before 32 weeks gestation being at the highest risk.

Diseases

• Pericardium absent mental retardation short stature
• Hypoglycemia with deficiency of glycogen synthetase in the liver
• Familial hyperlipoproteinemia type IV
• Finnish type amyloidosis
• Xeroderma pigmentosum
• Pseudomonas stutzeri infection
• Pseudotumor cerebri
• Cerebelloolivary atrophy

Caution should be used in patients with peptic ulcer bacteria ua rare order 50 mg minocycline with mastercard, diabetes virus 1999 trusted 50 mg minocycline, liver disease topical antibiotics for acne side effects order minocycline 50 mg with mastercard, or a history of gout antibiotics non penicillin buy 50 mg minocycline overnight delivery. Impaired glucose tolerance and increased blood urate are reminiscent of thiazide side effects antibiotics list discount minocycline uk, also with an unknown basis. Hepatotoxicity may be linked to some long-acting preparations (extended-release capsules or tablets), whereas flushing and pruritus are reduced. Nicotinic acid and statin co-therapy gives a better effect on the lipid levels at the cost of an increased (albeit low) risk of hepatotoxicity and of myopathy. The Fibrates As a rule, none of the fibrates reduces blood cholesterol as much as do the statins or nicotinic acid. Like nicotinic acid, they are therefore suitable for use in atherogenic dyslipidemia. There are five warnings or reservations for this class of drugs, as found in the fenofibrate package insert. First, the early experience with clofibrate suggested that fibrates may increase mortality. This fear has not been borne out by trials of other fibrates, and gemfibrozil has significant coronary benefits. Second, hepatotoxicity may occur, with a pooled analysis of 10 placebo-controlled trials showing elevated transaminases in 5. Fourth, there is an important drug interaction with concomitant oral anticoagulants, so that the warfarin dose needs to be reduced. Fifth, combined therapy with statins should be avoided unless the potential beneficial effects on lipids outweigh the increased risk for myopathy (see later section on "Combination Therapy"). This agent was used in the large Helsinki Heart Study in a primary prevention trial on 2000 apparently healthy men with modest hypercholesterolemia observed for 5 years. Although the total death rate was unchanged, the study was not powered to assess mortality. This agent is currently licensed in the United States for treatment of the lipid triad. The dose is 1200 mg given in two divided doses 30 minutes before the morning and evening meals. When combined with statins, there is an increased risk for myopathy with myoglobinuria and a further rare risk for acute renal failure (for perspective, see "Combination Therapy" section). Bezafibrate this agent (Bezalip in the United Kingdom; not available in the United States) resembles gemfibrozil in its overall effects, side effects, and alterations in blood lipid profile. Hence plasma glucose tends to fall with bezafibrate, which may be useful in diabetics or those with abnormal glucose metabolic patterns. In patients with coronary artery disease, bezafibrate slows the development of insulin resistance. The dose is 200 mg two to three times daily; however, once daily is nearly as good, and there is now a slow-release formulation available (Bezalip-Mono, 400 mg once daily). The major problem with this agent is that, unlike gemfibrozil and the statins, there are as yet no major long-term outcome trials with clear results. Fenofibrate is also indicated for treatment of hypertriglyceridemia, although the effect on the risk for pancreatitis in patients with very high triglyceride levels, typically exceeding 2000 mg/dL, has not been well studied. The Trilipix formulation, which contains fenofibric acid rather than the ester, has an indication for mixed dyslipidemia in combination with statin therapy. Tablets are 48 or 145 mg for Tricor, but other formulations have slightly altered dosing. The dose for Tricor is 48 to 145 mg once daily (half-life of 20 hours), taken with food to optimize bioavailability. Predisposing diseases such as diabetes and hypothyroidism need to be excluded and treated. Weight reduction, increased exercise, and elimination of excess alcohol are recognized in the package insert as essential steps in the overall control of triglyceride levels. In addition, there is a warning that cyclosporine co-therapy may cause renal damage with decreased excretion of fenofibrate and increased blood levels. Note risk of bleeding in patients given warfarin (bold warning in package insert). Use with caution in older adults or patients with renal dysfunction (renal excretion). Cholesterol Absorption Inhibitors: Ezetimibe Cholesterol absorption inhibitors selectively interrupt intestinal absorption of cholesterol and other phytosterols. The first of this drug class to reach the market, ezetimibe (Zetia), acts at the brush border of the small intestine and inhibits the absorption of cholesterol, leading to decreased delivery of intestinal cholesterol to the liver,107 which reduces hepatic cholesterol and increases cholesterol clearance from the blood. Its clinical benefit in primary and secondary prevention has yet to be established. In homozygous familial hypercholesterolemia, ezetimibe may be combined with atorvastatin or simvastatin, used as an adjunct to other lipid-lowering treatments. Ezetimibe is indicated as adjunctive therapy to diet for the reduction of elevated sitosterol and campesterol levels in patients with homozygous familial sitosterolemia. The recommended dosage of ezetimibe is 10 mg once daily, administered with or without food. No dosage adjustment is necessary in patients with mild hepatic insufficiency, but the effects of ezetimibe have not been examined in patients with moderate or severe hepatic insufficiency. No dosage adjustment is necessary in patients with renal insufficiency or in geriatric patients. In primary prevention, for patients with severe hypercholesterolemia or familial combined hyperlipidemia with marked triglyceride elevations, combination of a statin with a fibrate is increasingly seen as an option. Two reservations are, first, the lack of any unambiguously favorable large-scale outcome studies with such combinations and, second, the fear of myopathy. The latter is now increasingly seen as a rather rare event during combination therapy. Hepatotoxicity seems to be a consistent but rare side effect of statins, also during statin-fibrate therapy. Both regimens were equally effective on blood lipids, and angiographically measured coronary stenosis was lessened, although side effects were worse on the nicotinic acid regimen. This agent is indicated for treating primary hypercholesterolemia and mixed dyslipidemias where the lipid triad is present. Two studies on carotid arterial lesions found that ezetimibe plus a statin (Vytorin) does less well than expected111 or has adverse effects. The 10-mg dose should not be exceeded in patients taking amiodarone, verapamil, and diltiazem. Niacin plus laropiprant (Tredaptive) is approved in the European Union as a modified-release tablet in a dose of 1 g nicotinic acid and 20 mg laropiprant for dyslipidemia and primary hypercholesterolemia. Because of the enormous popularity of the statins, it is likely that various other combinations will be considered in the future, such as a statin with low-dose aspirin and other cardioprotective drugs. Some experts have put forth the concept of a "polypill" that combines several heart-beneficial agents as a potential approach. In the light of the negative mega-studies showing no cardiovascular protection by vitamin E, either as primary or secondary prevention (see Chapter 12, p. A Mediterranean diet, which in the United States is associated with decreased all-cause mortality, is likely to contain adequate amounts of antioxidants mixed in the right proportions. Nonprescription fish oil may also be protective, at least in the postinfarct period and when the benefit is largely independent of any change of blood lipid levels and may relate to sodium channel blockade. Plant sterols can be converted to the corresponding stanol esters that interfere with the intestinal uptake of cholesterol, to cause "cholesterol malabsorption. In addition, red wine contains flavonoids that give experimental coronary vascular protection, perhaps by an antioxidant effect. However, the potential for abuse makes it difficult to give a whole-hearted endorsement to alcohol consumption as a preventive measure. Dealcoholized red wine has favorable vascular compliance effects when given to humans. In a variety of studies, red fruit juices such as cranberry juice, purple or red grape juice, black tea, and nuts have shown varying degrees of benefit on lipid profiles or vascular function. In primary prevention of cardiovascular disease, global risk factor assessment and correction is the current favored approach. Among the cardiac drugs tending to cause hyperlipidemias are b-blockers (especially propranolol) and thiazide diuretics; however, when these drugs are indicated, their protective effect overrides the relatively small changes in blood lipids, especially with statin co-therapy. The principle is to combine two different classes of agents with different mechanisms of action, such as a statin and a fibrate or nicotinic acid. Most sources warn against these combinations because of the fear of muscle or renal damage or hepatotoxicity. Nonetheless, there is a growing consensus that judicious use of combination therapy, when required, is likely to confer more benefits than harm. An additional combination, approved for use in chronic kidney disease, is that of simvastatin with a cholesterol absorption inhibitor, ezetimibe. Specifically, there are dose limitations for atorvastatin and rosuvastatin, with major contraindications for use with simvastatin and lovastatin. Hyperglycemia and new diabetes, first noted with rosuvastatin, are now recognized. Although this metabolic harm is more than outweighed by the overall cardiovascular benefits of statin therapy, periodic checks for glycemia are strongly advised. Dietary antioxidants may be obtained in adequate amounts by following the Mediterranean-type diet, whereas vitamin E supplements, in particular, have not given protection either in secondary prevention or as primary prevention in high-risk individuals. Cardiovascular event reduction and adverse events among subjects attaining low-density lipoprotein cholesterol,50 mg/dL with rosuvastatin. Markers of inflammation and cardiovascular disease: application to clinical and public health practice. A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Genetic loci associated with C-reactive protein levels and risk of coronary, heart disease. European guidelines on cardiovascular disease prevention in clinical practice: executive summary. Fourth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction. Intensive versus moderate lipid lowering with statins after acute, coronary syndromes. Relation between progression and regression of atherosclerotic left main coronary artery disease and serum cholesterol levels as assessed with serial longterm (. High density lipoproteins in the intersection of diabetes mellitus, inflammation and cardiovascular disease. Usefulness of atherogenic dyslipidemia for predicting cardiovascular risk in patients with angiographically defined coronary artery disease. Safety of Anacetrapib in patients with or at high risk for coronary heart, disease. Non-high-density lipoprotein cholesterol versus apolipoprotein B in cardiovascular risk stratification: do the math. Beyond low-density lipoprotein: defining the role of low-density lipoprotein heterogeneity in coronary artery disease. Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: executive summary. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Statins for the primary prevention of cardiovascular events in women with elevated high-sensitivity C-reactive protein or dyslipidemia. Prevention of coronary heart disease by diet and lifestyle: evidence from prospective cross-cultural, cohort, and intervention studies. Mediterranean diet: traditional risk factors, and the rate of cardiovascular complications after myocardial infarction. Diet and lifestyle recommendations revision 2006: a scientific statement from the American Heart Association Nutrition Committee. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. Basic science review: statin therapy-part I: the pleiotropic effects of statins in cardiovascular disease. Phospholipase A2 enzymes, high-dose atorvastatin, and prediction of ischemic events after acute coronary syndromes. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths. Strength of evidence for perioperative use of statins to reduce cardiovascular risk: systematic review of controlled studies. Intensive statin therapy compared with moderate dosing for prevention of cardiovascular events: a meta-analysis of. Meta-analysis of drug-induced adverse events associated with intensive-dose statin therapy. Statin use in patients with extremely low low-density lipoprotein levels is associated with improved survival. Risk of incident diabetes with intensive-dose compared with moderatedose statin therapy. Fluvastatin for prevention of cardiac events following successful percutaneous coronary intervention: a randomized controlled trial. Helsinki Heart Study: primary prevention trial with gemfibrozil in middleaged men with dyslipidemia. Gemfibrozil in the treatment of dyslipidemia: an 18-year mortality follow-up of the Helsinki Heart Study. Attenuation of progression of insulin resistance in patients with coronary artery disease by bezafibrate.

A girl who has not had menarche by 16 years of age virus 92014 purchase minocycline 50 mg online, or within 4 years after the onset of puberty antibiotic resistance farming order generic minocycline on line, is considered to have primary amenorrhea antibiotics names generic minocycline 50 mg overnight delivery. Secondary amenorrhea is diagnosed if more than 6 months have elapsed since the last menstrual period infection 4 weeks after wisdom teeth removal minocycline 50 mg buy on line, or if more than the length of three previous cycles has elapsed with no menstrual bleeding treatment for uti gram negative bacilli buy minocycline without a prescription. To sort out the many causes of amenorrhea, it is helpful to distinguish girls who produce sufficient estrogen from those who do not by performing a progesterone challenge. Girls who are producing estrogen will have withdrawal bleeding after 5 to 10 days of oral progesterone, whereas those who are estrogen-deficient will have very little or no bleeding. Those who do not have bleeding should be evaluated for hypogonadism as described previously. However, in two situations, girls who have sufficient estrogen will not have withdrawal bleeding: obstruction of the cervix and absence of the cervix or uterus. In Rokitansky syndrome, maldevelopment of the müllerian structures leads to an absent or hypoplastic uterus or cervix (or both). The production of antimüllerian hormone in patients with androgen insensitivity syndrome leads to regression of the müllerian structures and thus the absence of a uterus. The absence of a cervix is a diagnostic finding in both Rokitansky syndrome and complete androgen insensitivity syndrome. Consequently, a pelvic examination should be considered in all girls who present with amenorrhea, especially primary amenorrhea. Amenorrhea in girls who are producing normal or even elevated amounts of estrogen is a manifestation of anovulatory cycles. Irregular menses may also be a sign of chronic anovulation given that estrogen production, unopposed by progesterone, leads to endometrial hyperplasia and intermittent shedding. Because menarche is normally followed by a period of anovulatory cycles and irregular menses, many adolescents with a pathologic cause of amenorrhea may be missed. Consequently, it is important to evaluate all girls who do not have regular menses by 3 years after menarche. Boys with central precocity, however, have a much higher incidence of underlying central nervous system disorders. Precocious puberty must be distinguished from normal variants of early development, such as benign premature thelarche and benign premature adrenarche. The most useful diagnostic test to evaluate precocious puberty is a gonadotropin-releasing hormone stimulation test. Children with delayed puberty and normal linear growth will most likely have constitutional growth delay. After it has been determined that a child has abnormally delayed puberty, gonadotropin levels should be obtained. Kaplan S, Grumbach M: Pathophysiology and treatment of sexual precocity, J Clin Endocrinol Metab 71:785, 1990. Kulin H, Rester E: Managing the patient with a delay in pubertal development, Endocrinologist 2:231, 1992. Levine M: the McCune-Albright syndrome: the whys and wherefores of abnormal signal transduction, N Engl J Med 325:1738­1740, 1991. Matejek N, Weimann E, Witzel C, et al: Hypoleptinaemia in patients with anorexia nervosa and in elite gymnasts with anorexia athletica, Int J Sports Med 20:451­456, 1999. Rosenfield R: Diagnosis and management of delayed puberty, J Clin Endocrinol Metab 70:559­562, 1990. The normal testis has two functions: synthesis and secretion of testosterone from the Leydig cells and production of sperm from the seminiferous tubules. This condition can result from a disruption at one or more levels of the hypothalamic-pituitary-gonadal axis. Depending on the stage of development, hypogonadism may have varied manifestations. In utero androgen deficiency leads to a female phenotype or ambiguous genitalia, most commonly caused by a block in the production of testosterone secondary to congenital testosterone biosynthetic enzyme defects. Childhood androgen deficiency results in delayed, incomplete, or absent pubertal development. Common manifestations include the following: n Eunuchoid proportions (ratio of pubis to vertex/pubis to floor is, 0. A decrease in production of testosterone in adulthood is usually accompanied by a decline in production of sperm. The most frequent circumstance in which adult hypogonadism occurs is in the middle-aged or senescent man complaining of decreased libido or potency. Semen analysis is rarely performed in these men because they are usually not concerned with fertility. Other findings may include osteoporosis, diminished androgen production, and small prostate. If the onset of hypogonadism is acute, the patient may experience hot flushes and sweats. Equilibrium dialysis is the gold standard for measuring the free testosterone, but it is not commonly available and should be ordered to be performed only in a reliable reference laboratory. Liquid chromatography­ mass spectrometry or gas chromatography­mass spectrometry is used by some reference laboratories to measure testosterone. Analog methods for determining free testosterone are more widely available but are not accurate in the low ranges. The regulation of sperm production is complex and less clearly understood than is the regulation of testosterone production. The Sertoli cells within the seminiferous tubules seem to play an important coordinating role. Moreover, spermatogenesis depends on intratesticular production of testosterone mediated by androgen receptors within Sertoli cells. Failure of testicular function may result from a defect either at the testis or at the hypothalamicpituitary level. In men with secondary hypogonadism, fertility can generally be restored with appropriate hormonal treatment. Men with primary hypogonadism have fewer options and more limited success with improvement in fertility. In addition, the evaluation of secondary hypogonadism can reveal a pituitary mass or systemic illness as the underlying cause. If normal total testosterone but patient desires fertility, perform semen analysis; otherwise routine follow-up. When only biochemical criteria are used, the prevalence is higher (2%­6%) in that age range and 18% to 30% in men more than 70 years old. Further complicating the situation is the observation that there has been a population-level decrease in serum testosterone levels in men in the United States since the early 1990s. Any disease that affects the hypothalamic-pituitary axis can cause secondary hypogonadism. Such lesions include benign tumors and cysts, malignant tumors (both primary central nervous system tumors and metastatic tumors from distant sources), vascular aneurysms, infiltrative diseases. Drugs commonly used in the treatment of benign prostatic hypertrophy, the 5-alpha-reductase inhibitors finasteride and dutasteride, are among the iatrogenic causes of hypogonadism. Other drug-related causes include the use of narcotic analgesics and the abuse of anabolic steroids by athletes. The sense of smell in the patient (and his relatives) should be assessed by direct questioning. Loss of the testosterone-producing function of the testis may lead to loss of libido and erectile dysfunction, as well as diminution of secondary sexual characteristics, such as facial and pubic hair, and decrease in testicular volume. Decreased production of testosterone also may cause more generalized symptoms, such as decreased muscle mass and strength, malaise, and fatigue. In boys who develop hypogonadism before sexual maturation, delay or absence of the onset of puberty is typical. Numerous nonspecific symptoms are also commonly associated with hypogonadism, such as normochromic normocytic anemia, poor concentration, depressed mood, and increased body fat and body mass index. When the condition is associated with a low total or free testosterone level, the following questions are useful in establishing a diagnosis of clinical hypogonadism: n How frequently have you awakened with a full erection in the past month Osteoporosis is now a well-recognized result of both primary and secondary hypogonadism. Trabecular architecture (and bone strength) is even more severely disturbed than bone density in men with hypogonadism. Thus, it is not surprising that hypogonadism is found in up to 30% of men with vertebral fractures. Estradiol that is aromatized from testosterone may be the most important factor in preserving bone architecture and density in both men and women. However, androgen receptors are also found in bone and may explain the sexual dimorphism of bone density. The main functions of the testis, production of sperm and production of testosterone, are readily assessed by semen analysis and measurement of serum testosterone, respectively. Normal semen analysis values in men following 2 to 3 days of abstinence are 20 million sperm/mL and more than 60% motility of the sperm. Because sperm density is highly variable from day to day in all men, accurate assessment usually involves several semen analyses done with the same abstinence period each time. The best initial test for testosterone production is measurement of the fasting morning serum total testosterone level. Additional diagnostic testing should be based on clinical suspicion and the results of preliminary testing. Measurement of other pituitary hormones also may be appropriate to assess either possible tumoral hypersecretion. Similarly, the initial findings in primary hypogonadism may suggest additional tests. Measurement of serum estradiol levels may be helpful when feminization is prominent clinically, as in secondary hypogonadism related to production of estrogen by testicular or adrenal tumors. If infertility is the primary issue and no hormonal abnormality is found, genetic causes should be investigated. Testis biopsy rarely provides information that is useful in establishing a specific diagnosis, prognosis, or treatment. Hermaphrodite refers to someone who has both ovarian and testicular elements in the body. Pseudohermaphrodite refers to someone whose external genitalia are not consistent with his or her gonadal sex. Most often this results from genetic disorders of testosterone biosynthetic enzymes, the androgen receptor, or the 5-alpha-reductase enzyme; the severity of the phenotype depends on the severity of the genetic defect. The most common cause of this is congenital adrenal hyperplasia, which results in virilization of the female fetus in utero. For patients with secondary hypogonadism, the goal is a serum total testosterone level in the midnormal range. One study in older men with hypogonadism and impaired mobility was stopped early because of an increase in cardiovascular events. Abnormalities of liver function tests are uncommon with currently used injectable and transdermal preparations, but they can be seen with seldom-used oral preparations. A testosterone-induced increase in hematocrit is common, especially when testosterone injections are used, although clinically significant polycythemia is quite rare unless the drug is being abused. In boys who have not yet gone through puberty, the rapid increase in serum testosterone after initial treatment may lead to considerable psychological difficulties and physically aggressive behavior; initiating treatment with smaller doses may be helpful. Individual men may experience voiding symptoms along with this enlargement, which they should be advised to monitor. The outlook is much less pessimistic with secondary hypogonadism, particularly if the condition developed after puberty. The pretreatment size of the testis is often a clue to prognosis; larger testis size is associated with a better outcome. If microdeletions are found, the patient should be counseled about the possibility of transmittal to his male child. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hypogonadism in adult male patients: 2002 update. Hormone health article on rare endocrine disorders: adrenal insufficiency, hormone imbalance, and more. A reduction in testicular volume to less than 20 mL is the most common manifestation of hypogonadism and is seen in nearly all cases of long-standing hypogonadism. Classify hypogonadism as primary (a disorder at the level of the testes) or secondary (a disorder at the level of the hypothalamus or pituitary). Therapeutic goals are generally to correct testosterone to the midnormal range by topical preparations or by injection. Monitor patients receiving testosterone replacement therapy for polycythemia, sleep apnea, gynecomastia, psychological difficulties, prostate symptoms and size, and increases in prostate-specific antigen. Adverse events associated with testosterone administration, N Engl J Med 363:109­122, 2010. Testosterone replacement therapy in male hypogonadism, J Endocrinol Invest 26:481­489, 2003. Young J: Approach to the male patient with congenital hypogonadotropic hypogonadism, J Clin Endocrinol Metab 97: 707­718, 2012. Premature ejaculation may precede the development of impotence and is sometimes associated with drug therapy. Sexual desire (libido) is also usually preserved; loss of libido is suggestive of hypogonadism or severe systemic or psychiatric illness. The prevalence of impotence increases with age; about 2% of 40-year-old, 20% of 55-year-old, and 50% to 75% of 80-year-old men are impotent. There is a libido-potency gap in that many elderly men continue to have active libidos, but only 15% of them engage in sexual activity. Erection is primarily a vascular event that results from the complex interplay of the hormonal, vascular, and peripheral and central nervous systems. There is considerable psychiatric interplay in that underlying psychiatric conditions or medications can cause decreased erectile function. Conversely, undesired sexual symptoms can also adversely affect mood and self-perception.

Interventions to reduce stress and balance nutritional intake with degree of exercise should be attempted initially bacterial colony order generic minocycline line. If these interventions are unsuccessful antibiotics without food generic minocycline 50 mg with visa, estrogen replacement therapy (usually with oral contraceptives) can be instituted antibiotics for dogs with skin infections minocycline 50 mg buy low cost. However antibiotic resistance related to evolution buy 50 mg minocycline fast delivery, data are mixed on the protective effect of estrogen on bone health in women with anorexia nervosa antibiotic 5 year plan minocycline 50 mg fast delivery. Autoimmune destruction of the ovaries is characterized by a history of normal puberty and regular menses followed by the early onset of hot flashes, irregular menses, and eventual amenorrhea. Hyperandrogenic anovulation refers to the cluster of disorders that manifest with irregular menses or amenorrhea and signs of androgen excess, such as hirsutism and acne. Hirsutism and acne beginning in the teenage years are other common features of the disorder. Patients also frequently have signs of insulin resistance, including acanthosis nigricans, a velvety, hyperpigmented cutaneous lesion on the neck and in the axillae. Irregular, anovulatory menses lead to infertility, and the resultant unopposed estrogen exposure increases the risk of endometrial hyperplasia and carcinoma. The 1990 National Institutes of Health criteria were modified by the Rotterdam criteria in 2003. The Rotterdam criteria include two of the following three features: oligoovulation or anovulation, clinical or biochemical signs of hyperandrogenism, and polycystic ovaries by ultrasound examination. Birth control pills are the treatment of choice; an antiandrogen, such as spironolactone, may be added if hirsutism is a major problem. Intermittent cycling with progesterone (Provera or Prometrium) is an alternative for endometrial protection, but it does not suppress the elevated androgens and their ultimate impact on ovarian morphology and function. Fertility may be achieved with clomiphene citrate or human menopausal gonadotropins. Data show that clomiphene citrate is more efficacious than metformin for induction of ovulation and increased live births. There was a higher incidence of multiple births in the clomiphene group (5% versus 0%) than the metformin group. This trial was in contrast to other previous, smaller trials, which found similar rates in ovulation between the two medications but did not report live birth rates. The thiazolidinedione class of insulin sensitizers had shown promise, but weight gain and cardiovascular concerns limited their use. Predictors of responders to metformin may include patients with a family history of type 2 diabetes, history of rapid weight gain, and lack of severe obesity. Epidemiologic studies have not yet defined a clear-cut increase in cardiovascular events, but long-term studies are under way. Obesity-induced hyperandrogenic anovulation is suggested by a history of normal puberty and menses until progressive weight gain triggers the development of hirsutism, acne, oligomenorrhea, and, later, amenorrhea. Primary treatment with weight loss often results in restoration of normal reproductive function. Amenorrhea with estrogen deficiency can result in osteoporosis and premature cardiovascular disease. Hyperprolactinemia and hypothalamic amenorrhea are the most common causes of acquired amenorrhea with low estrogen and low follicle-stimulating hormone levels. Premature ovarian insufficiency is an autoimmune disease; affected patients are at risk for other autoimmune disorders, such as adrenal and thyroid disease, pernicious anemia, celiac sprue, and rheumatologic disorders. Polycystic ovary syndrome is the most common type of hyperandrogenic amenorrhea, associated with risks of infertility, endometrial cancer, the metabolic syndrome, and type 2 diabetes. Santoro N: Update in hyper- and hypogonadotropic amenorrhea, J Clin Endocrinol Metab 96:3281­3288, 2011. Hirsutism should be distinguished from hypertrichosis, which is a nonandrogen-dependent increase in vellus hair. Virilization consists of hirsutism, acne, and irregular menses along with signs of masculinization: deepening of the voice, increased muscle mass, temporal balding, clitoromegaly, and increased libido. Virilization results from high circulating levels of androgens, close to or in the male range, and is usually caused by an androgen-secreting tumor. Twenty-five percent of testosterone comes from the ovaries, 25% from the adrenal glands, and 50% from peripheral conversion of androstenedione, which is produced by both the ovaries and adrenals. Androgens transform the fine, downy, minimally pigmented vellus hair in androgen-sensitive areas in to coarse, pigmented, terminal hair. The hirsutism is gradually progressive, usually beginning at puberty, and most patients have irregular menses from the onset of menarche. However, in a study of hirsute patients with regular menses, 50% had polycystic ovaries. Familial hirsutism is an ethnic tendency to have a higher density of hair follicles per unit area of skin. Mediterraneans and Hispanics have increased hair density, whereas Asians have lower density. Patients with idiopathic or familial hirsutism usually have the onset of hirsutism shortly after puberty with a slow subsequent progression. All causes of Cushing syndrome may result in hypertrichosis because of increased vellus hair on the face, forehead, limbs, and trunk secondary to cortisol hypersecretion. Cushing syndrome resulting from an adrenal tumor also may produce hirsutism and virilization from increased secretion of androgens with cortisol. Phenytoin, cyclosporin, diazoxide, minoxidil, glucocorticoids, streptomycin, penicillamine, and psoralens can cause hypertrichosis. Hirsutism is the excessive growth of terminal hair and is frequently associated with irregular menses. Virilization consists of hirsutism and irregular menses associated with signs of masculinization. A patient with regular menses who shows significant concern about her hirsutism also may warrant a workup. Laboratory testing should be guided by the results of the history and physical examination. Many authors advocate against testing in patients with regular menses and only gradual progression of mild hirsutism. If no mass is found, iodocholesterol scanning of the adrenals or venous sampling of the ovaries or adrenals can be performed for localization before surgical removal. If clomiphene fails to induce ovulation, cyclic gonadotropin administration is often useful. In obese patients, weight reduction alone has been shown to increase the spontaneous ovulation rate. In patients resistant to medical management, surgical destruction of small sections of the ovaries induces ovulation in some patients. Wedge resection of the ovaries has been replaced by laparoscopic ovarian diathermy, in which laser or electrocautery is used to destroy portions of the ovaries. Preparations containing androgenic progestins, such as norgestrel and norethindrone, should be avoided. If hirsutism does not improve with these measures, the agents listed in questions 24 and 27 through 30 may be necessary. These problems should be addressed separately because they are not resolved by treating the hyperandrogenism alone. Thiazolidinediones have several side effects, including fluid retention, exacerbation of heart failure, increased osteoporotic fractures, and possible increased risk of cardiovascular events and bladder cancer, and therefore these drugs should be used with caution. Treatment with the regimens listed in questions 26 through 30 can hasten improvement of the hirsutism. Preparations containing the progestins desogestrel, norgestimate, drospirenone, and gestodene are believed to be the best because they are the least androgenic. Potential side effects include weight gain, bloating, nausea, emotional lability, breast pain, and deep venous thrombosis. Initial doses are 50 to 100 mg twice daily, tapered to 25 to 50 mg/day after an effect has been seen. Estrogen replacement must be given to avoid hot flashes, vaginal dryness, and bone density loss. Appropriate laboratory testing includes at least serum total testosterone, dehydroepiandrosterone sulfate, and 17-hydroxyprogesterone. Treatment of hirsutism is usually with a combination of oral contraceptive pills, spironolactone, eflornithine, and cosmetic measures; however, other antiandrogens and gonadotropin-releasing hormone agonists can be used. Patients with polycystic ovary syndrome may have improvement of symptoms if they are treated with insulin sensitizers. Treatment of virilization is surgical removal of the tumor or steroid treatment for congenital adrenal hyperplasia. In clinical trials, 58% of patients had marked improvement or some improvement as compared with 34% of controls after 24 weeks of treatment. The most common side effects are acne, pseudofolliculitis barbae, burning, tingling, erythema, or rash over the applied area. Generally, side effects resolve without treatment and rarely require discontinuation of the medication. Bleaching, shaving, plucking, waxing, depilating, and electrolysis are effective measures that can be used alone or in combination with the previously described treatments. They remove terminal hair that is already present while the patient waits for medications to decrease new growth and rate of transformation to terminal hair. It is an outpatient procedure that uses ruby, alexandrite, diode, or yttrium aluminum garnet lasers, or intense pulsed light therapy, all of which cause thermal injury to the hair follicle. The techniques result in removal of hair, and a period of 2 to 6 months before the regrowth of hair, which is thinner and lighter. Patients with light skin and dark hair have the best results with the fewest side effects. The side effects include minimal discomfort, local edema and erythema lasting 24 to 48 hours, rare petechiae, and infrequent hyperpigmentation lasting less than 6 months. No matter what therapy is chosen, the patient must be made aware that results will not be seen for at least 3 to 6 months. Unfortunately, most patients have a relapse of hirsutism approximately 12 months after discontinuation of medical therapy. Cosma M, Swiglo B, Flynn D, et al: Clinical review: insulin sensitizers for the treatment of hirsutism: a systematic review and metaanalyses of randomized controlled trials, J Clin Endocrinol Metab 93:1135­1142, 2008. Lapidoth M, Dierickx C, Lanigan S, et al: Best practice options for hair removal in patients with unwanted facial hair using combination therapy with laser: guidelines drawn up by an expert working group, Dermatology 221:34­42, 2010. Martin K, Chang R, Ehrmann D, et al: Evaluation and treatment of hirsutism in premenopausal women: an Endocrine Society clinical practice guideline, J Clin Endocrinol Metab 93:1105­1120, 2008. Moghetti P, Tosi F, Tosti A, et al: Comparison of spironolactone, flutamide, and finasteride efficacy in the treatment of hirsutism: a randomized, double blind, placebo-controlled trial, J Clin Endocrinol Metab 85:89­94, 2000. Practice Committee of the American Society for Reproductive Medicine: the evaluation and treatment of androgen excess, Fertil Steril 86:S241­S247, 2006. Smith S, Piacquadio D, Beger B, et al: Eflornithine cream combined with laser therapy in the management of unwanted facial hair growth in women: a randomized trial, Dermatol Surg 32:1237­1243, 2006. Unluhizarci K, Kaltsas G, Kelestimur F: Nonpolycystic ovary syndrome­related endocrine disorders associated with hirsutism, Eur J Clin Invest 42:86­94, 2012. A genetic component appears to be involved because women often experience menopause around the same time as their mother or sister, but there are numerous examples of circumstances when this does not hold true. It also appears that women in Asia may experience menopause at an earlier age (42­49 years old). In a woman who is more than 45 years old, 12 months of secondary amenorrhea is sufficient to diagnose menopause. Although a pelvic examination may reflect some atrophy of the vaginal mucosa, this is not always remarkable. Menopause should not be thought of as occurring suddenly, but rather as a transitional process over time. Ovarian failure is considered premature when it occurs in women who are less than 35 years old. There can be several causes of this condition, including autoimmune disorders, chromosomal defects, chemotherapy treatment, and some unknown causes. The hallmark symptom of menopause, which often occurs during the perimenopause transition, consists of hot flashes. During these episodes, which last seconds to minutes, the woman experiences a tremendous warming of her body, often with accompanying redness of the skin and sweat production. It is estimated that most women (approximately 85%) will experience some types of vasomotor symptoms with menopause. These can vary greatly in severity; the most severe symptoms usually occur in women who have had their ovaries surgically removed, thereby transitioning to what has been called "instant menopause. Generally, menopausal symptoms are worst during perimenopause or the first few years after menopause. Some women, however, continue to suffer from hot flashes and other menopause symptoms 10 years or longer after menopause occurs, at almost the same severity as when the symptoms first appeared. Loss of bone calcium, increased rates of coronary artery disease, skin and vaginal atrophy, hot flashes, and alterations in the lipid profile (mainly increased triglycerides and low-density lipoprotein cholesterol, and decreased high-density lipoprotein cholesterol) all occur through and after menopause. Women naturally have three different estrogens present in varying amounts: estrone (E1), estradiol (E2), and estriol (E3). Estradiol is the most potent of the three estrogens, binds equally to both the a- and b-estrogen receptors, and converts freely back and forth with estrone in the body. Some evidence suggests that estrone has a higher carcinogenic risk compared with the other estrogens, possibly because of its higher affinity to the a-estrogen receptor (approximately 5:1 a:b). Estriol is a metabolite of estradiol and estrone and will not convert back to E1 or E2 once formed, but rather is excreted out through the urine. During menopause, this production wanes and then stops, and estrone, or E1, becomes the dominant estrogen, converted in adipose tissue from androstenedione, which is secreted from the adrenal glands. Data showed an increased risk of invasive breast cancer, along with an increased incidence of coronary heart disease, pulmonary embolism, and stroke. The estrogen-alone arm of the trial also showed an increased risk of stroke and blood clots without preventing heart disease. Enrolling women 50 to 79 years old included a large number of women more than 60 years old, and this may have affected the results shown from the trial.

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