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or maturation of the follicle into a corpus luteum, as well as the production of ovarian estradiol.

in both males and females, the HPG axis is relatively dormant before the onset of puberty. the onset of puberty in girls occurs approximately 2 years before boys. in girls, the average age at which breast development starts is 10.5 years, and menses starts at about 12 years of age. in boys, the peak growth rate and beginning of voice change are about the age of 14 years, whereas facial hair appears on average at the age of 15 years. in men, from late puberty until about age 60 years, the serum testosterone levels are relatively constant and begin to decline gradually thereafter. in women, serum estradiol levels vary widely over the course of the menstrual cycle, but after menopause (average age is 50 years), serum estradiol levels become very low and gonadotropin (lH and FsH) levels are elevated.PrECOCiOuSPubErTy,DElayEDPubErTy,anDhyPOGOnaDiSMin both males and females, precocious puberty, delayed puberty, and hypogonadism are clinical diagnoses, made by early or late signs of secondary sexually differentiation or loss of sexual characteristics.90 Pubertal development is measured clinically by a staging system developed by tanner.91 this assesses the development stage of breasts and pubic hair in girls and the pubic hair, testes, and penile length in boys. Puberty is generally considered precocious in boys if it starts before age 10 years and in girls before age 8.5 years or delayed if there are no signs of sexual development by the age of 13 years in girls and 14 years in boys.

once a clinical diagnosis of gonadal dysfunction is estab-lished (see table 12), the next step is to determine if the pathophysiologic process is in the gonads (primary), pituitary (secondary), hypothalamus (tertiary), or, in the case of precocious puberty, an ectopic (or exogenous) source of hormone. Gonadal testing usually involves measuring the appropriate sex steroid (testosterone or estradiol) and the pituitary gonadotropins lH and FsH. the most common cause of precocious puberty in boys and girls is early onset of pituitary hormone production, central precocious puberty. if the end-organ hormones are elevated, and the gonadotro-pins are suppressed (gonadotropin-independent precocious puberty), this suggests primary (autonomous) gonadal dys-function. Finally, the adrenal gland also produces androgens that can lead to early puberty in boys and masculinization in girls.

Premature ovarian failure is the onset of menopause, often including hot ashes, before the age of 40 years. the most common associated problem is cessation of menstrual cycles. Hypogonadism in men presents with a loss of libido and decreased growth rate of facial hair and can lead to osteo-porosis and fractures. Premature ovarian failure is diagnosed by the early loss of menstrual cycles in the setting of an elevated serum FsH. Hypogonadism in men is diagnosed by a low serum testosterone level.

replacement of the primary gonadal steroid (testosterone or estradiol or one of its analogues) in men and women

is straightforward. However, replacement of the missing hormone will not return fertility, which is often a major issue. if the gonad is still functional but loss of pituitary hormones led to loss of function, the pituitary hormones can be replaced using a very sophisticated treatment approach.

OralManifestationsofGonadalDisordersHypersecretion of female sex hormones commonly occurs in pregnancy. several unusual oral manifestations may occur in a pregnant woman, such as bilateral brown facial pigmenta-tion (melasma), which disappears after delivery of the new-born baby. High levels of female sex hormones cause increased capillary permeability, making them susceptible to gingivitis (pregnancy gingivitis), gingival hyperplasia, and pyogenic granuloma (pregnancy tumor). these factors may complicate preexisting periodontal disease. a decrease in gonadal hor-mones at menopause is associated with a decrease in salivary ow and salivary composition. these may predispose indi-viduals to dental caries, glossodynia, dysgeusia, unpleasant metallic taste, and oral candidiasis. Gingival tissues become atrophic; there is a higher tendency for plaque accumulation and increased risks of gingivitis and periodontitis. after dental extractions, unrestored edentulous ridges rapidly undergo resorption. Postmenopausal women have increased suscepti-bility to osteoporosis, so dental radiographs may demonstrate hypocalcied bone. there is also an increase in the incidence of several systemic disorders, including sjgrens syndrome, pemphigus vulgaris, burning mouth syndrome, and trigem-inal neuralgia, but the direct relationship of these with gonadal insufciency has not been established.92

DentalManagementthe specic dental management concerns in patients with gonadal disorders are focused on the associated secondary disorders. the pregnant patient is susceptible to gestational diabetes since insulin action is antagonized by estrogens and progesterone. the dental care practitioner should consult with the patients physician if dental care is required and determine if the patient has been diagnosed with gestational diabetes. elective and stressful dental procedures should be avoided during the rst trimester and the last half of the third trimester. the second trimester is the safest period to provide dental care during pregnancy. During this time, emphasis should be on prevention, maintenance of optimal oral health, and treatment of dental concerns that may lead to complica-tions in late stages of pregnancy.93 injudicious use of medica-tions should be avoided in pregnancy; choice of medication should be guided by Food and Drug administration pregnancy classications for prescription drugs to avoid those with possible teratogenic effects.94 it is also important to carefully evaluate panoramic radiographs for the presence of a carotid atheroma in postmenopausal women; if found, the patient should be promptly referred for further evaluation.95

ParathyroidGlandandMetabolicDisordersPtH is secreted by four parathyroid glands closely associated with the thyroid gland in the neck region. secretion of the

532 Diabetes Mellitus and Endocrine Diseases

PtH is in response to the level of serum ionized calcium. low serum ionized calcium stimulates PtH secretion, whereas high serum ionized calcium suppresses PtH secretion. another major regulator of PtH is the active form of vitamin D3 (1, 25-dihydroxyvitamin D3 or calcitriol). it suppresses PtH synthesis by its ability to promote intestinal calcium absorption. PtH protects the body from chronic low serum calcium (hypocalcemia); therefore, an individual with hypo-calcemia and vitamin D deciency may develop parathyroid gland hyperplasia.

hyPErParaThyrOiDiSMHyperparathyroidism is chronic excessive secretion of the PtH by the parathyroid glands. it results in uncontrolled chronic high serum calcium (hypercalcemia). the condition occurs in 0.1% of adult patients, is more common within the third to fth decades of life, and is three times more prevalent in women than men. the vast majority (90%) of patients with hypercalcemia have either primary hyperparathyroidism or hypercalcemia of malignancy. Modern immunoradio-metric and chemiluminometric assays can distinguish between the two since PtH is usually elevated or normal in primary hyperparathyroidism but suppressed when hypercalcemia is caused by a malignancy unrelated to the parathyroid glands.

When excessive PtH secretion arises from one or more parathyroid glands, it is referred to as primary hyperparathy-roidism. it is usually caused by a solitary adenoma (80% of cases), whereas 15% are due to hyperplasia and 1% are due to carcinoma of the parathyroid glands. Postmenopausal women are more commonly affected by primary hyperparathy-roidism. the amount of PtH secreted usually correlates with the size of glandular enlargement. However, pathologic para-thyroid gland enlargement may affect more members of the same family, resulting in familial hyperparathyroidism. this type may also be associated with the Men syndrome types 1, 2a, and 2b or the hyperparathyroid jaw tumor syndrome (HPt-Jt). HPt-Jt is a rare autosomal dominant disorder consisting of parathyroid cystic adenomas or carcinomas, multiple ossifying bromas of the mandible and maxilla, and renal disorders that may include cysts, hamartomas, and Wilms tumors. the risk of developing parathyroid carci-noma is much higher in HPt-Jt syndrome. another condi-tion, secondary hyperparathyroidism, may also occur due to compensatory glandular enlargement in response to unusual hypocalcemia induced by metabolic disorders such as renal failure, deciency of 1,25-dihydroxyvitamin D or malabsorp-tion of calcium found in rickets, and some forms of osteoma-lacia. PtH secretion from enlarged parathyroid glands may become autonomous (secreting without control or response to feedback inhibition), leading to tertiary hyperparathyroidism.

the pathophysiology of hyperparathyroidism is related to the tight control of ionized calcium in the extracellular uid by PtH and vitamin D and the central role of extracellular

calcium in both cellular physiology and regulation of metab-olism. specically, the PtH can be referred to as the bodys defense against hypocalcemia. it binds specic receptors on the surface of PtH-responsive cells such as osteoblasts and renal tubular cells. PtH acts on osteoblastic cells to express ranKl (receptor activator of nuclear factor kb ligand), an inducer of osteoclastic bone resorption. to further maintain normal serum calcium, PtH stimulates renal tubular reab-sorption of calcium and magnesium while inhibiting renal tubular reabsorption of phosphate and bicarbonate. this allows elimination of phosphates released from bone during osteoclastic bone resorption so as not to bind to serum ion-ized calcium. in the kidneys, PtH activates 1-a-hydroxylase, an enzyme that converts inactive vitamin D (25-hydroxyvi-tamin D) to the active form, 1,25-dihydroxyvitamin D. active vitamin D acts to promote intestinal absorption of calcium. therefore, excessive PtH secretion causes diffuse bone resorption, hypercalcemia, and excessive renal excretion of calcium and phosphate. the severity of hypercalcemia increases calcium in the glomerular ltrate, a process that eventually leads to hypercalciuria and formation of kidney stones. chronic bone resorption eventually results in patchy cystic bone lesions and pathologic fractures.

Many cases of hyperparathyroidism may be asymptom-atic and only detected by serum analysis during routine serologic evaluations. clinically, the patients have manifesta-tions of skeletal and renal disorders and hypercalcemia. they complain of bones, stones, abdominal groans, psychic moans, and psychic overtones.

skeletal presentations include bone demineralization that manifests as reduction in bone mass. Patients complain of bone pains and arthralgia and may develop pathologic frac-tures. bone radiographs show well-circumscribed unilocular or multilocular radiolucent lesions known as brown tumor of hyperparathyroidism, but brown tumors are now rare occurrences in modern medicine because of early detection. if brown tumors occur, they contain abundant hemorrhagic tissue and hemosiderin, which give it a characteristically dark reddish-brown color. Degeneration of brown tumor leads to patchy osteoclastic bone resorption, cystic lesions, and replacement of bone with abundant vascular cellular brous tissue. this transformation is referred to as osteitis brosa cystica. in addition, skull radiographs show patchy regions of demineralization (salt and pepper appearance). Due to routine screenings and early detection of hypercalcemia, skeletal presentation is now commonly osteopenia without the classic features of brown tumor and osteitis brosa cystica. brown tumors may be seen in developing countries and in patients with parathyroid carcinoma. in patients with HPt-Jt syndrome, the multiple bro-osseous jaw tumors and parathyroid adenomas can occur in isolation. However, unlike brown tumors of hyperparathyroidism, jaw tumors of HPt-Jt are distinct because they do not resolve after parathyroidectomy.

renal presentations include polyuria and polydypsia as a result of hypercalcemia-induced Di, and 10 to 15% of patients

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may develop kidney stones consisting of calcium phosphate or calcium oxalate. nonspecic presentations of hyper-calcemia include abdominal groans of constipation, indigestion, weight loss, nausea, vomiting, peptic ulcer, and pancreatitis, as well as psychic moans of lethargy, fatigue, depression, loss of memory, paranoia, neuroses, change in personality, confusion, stupor, and coma. Metastatic calcium precipitation in the cornea may cause keratitis and conjuncti-vitis, and if in soft tissues, it may cause calciphylaxis.

the most common laboratory nding is high alkaline phosphatase in patients with bone lesions. serum calcium is elevated (>10.5 mg/dl), but phosphate may vary from low-normal (

534 Diabetes Mellitus and Endocrine Diseases

mucocutaneous candidiasis may be present in an acute or chronic form.

if hypoparathyroidism occurs when teeth are still devel-oping, there will be abnormalities in the appearance and eruption pattern. there may be enamel hypoplasia, single or parallel horizontal bands on the enamel, and poorly mineral-ized dentin. other dental ndings include malformed teeth, anodontia, short blunt root apices, elongated pulp chambers (some occluded by pulp stones, even in the primary dentition), impacted teeth, and mandibular exostoses. if hypoparathyroidism occurs after dental development, there are no abnormalities seen in erupted teeth.

DentalManagementofPatientswithParathyroidGlandDisordershyPErParaThyrOiDiSMclinicians must be careful to avoid iatrogenic jaw fractures during oral surgical procedures due to the presence of lytic bone lesions and cortical bone loss. Following successful treatment of hyperparathyroidism, recalcication of the skeleton occurs and serum calcium levels return to normal. surgical intervention of giant cell tumors is not necessary except to correct large deformities or remove displaced or resorbed teeth.

hyPOParaThyrOiDiSMlow serum calcium levels may precipitate cardiac arrhythmias, convulsions, laryngospasm, or bronchospasm. therefore, consultation with the patients physicians is required to ascertain level of metabolic control and update serum calcium and phosphate levels as well as the PtH level. Patients with dental abnormalities require frequent oral examinations due to increased caries risk associated with hypoplastic teeth. Periodic dental radiographs are required to screen for dentigerous cysts that may develop at sites of impacted teeth.

rickets,Osteomalacia,andvitaminDDeficiencyrickets is failure of mineralization of endochondral new bone formed at the growth plates in children, whereas osteoma-lacia is failure of mineralization of newly formed organic bone matrix (osteoid mineralization) at sites of bone turn-over. therefore, osteomalacia is usually found in adults, whereas rickets and osteomalacia may coexist in children whose growth plates have not fused. rickets/osteomalacia and osteoporosis are referred to as metabolic bone diseases because they cause generalized decrease in bone density (osteopenia) and bone strength. unlike osteoporosis, which is characterized by a decrease in bone matrix and minerals, the bone matrix is normal in rickets/osteomalacia. abnormalities in vitamin D metabolism or resistance to the actions of vitamin D can cause rickets or osteomalacia because the primary actions of vitamin D are to increase absorption of calcium and phosphate from the intestine.

ergocalciferol or vitamin D2 derived from plants is insuf-cient in major food items, so the human daily requirement is supplemented by formation of cholecalciferol or vitamin

D3 in the skin. Dermal synthesis of vitamin D can be impaired by inadequate sunlight in geographic regions of extreme latitude or in cultural regions that wear extensive clothing to cover the whole body. Hepatic and renal disorders can also affect vitamin D metabolism.

clinical and radiologic presentations of rickets are skeletal pain, fracture of abnormal bone, bone deformity such as bowing of the long bones, scoliosis, bell-shaped thorax, and basilar invagination of the skull. Patients with osteomalacia also experience diffuse skeletal pain, especially the weight-bearing areas. the radiographic presentations are usually nonspecic but may include osteopenia, poorly dened trabecular bone, and masking of the junction between the cortical and trabecular bone. it is common to observe bilat-eral and symmetric pseudofractures called loosers zones on several bones (femur, pelvis, ribs, and scapula). although bone biopsy is usually not necessary for diagnosis, these microfractures are also visible in undecalcied histologic bone sections (Figure 15).

clinical and radiologic presentations of rickets are usually obvious in children, but diagnosing and identifying the cause of osteomalacia are more challenging. the serum calcium level is usually low to normal and serum phosphorus is low, but serum alkaline phosphatase and PtH levels are elevated because of secondary hyperparathyroidism and increased bone resorption. a low level of 1,25-dihydroxyvitamin D3 conrms vitamin D deciency, but sometimes the vitamin D level is normal. bone biopsy and histomorphometric analysis may be necessary but not required to diagnose osteomalacia.

Vitamin D deciency is treated with vitamin D and calcium supplements at doses dependent upon the severity

FIGUrE 15 Undecalcied,plasticembeddedsectionsofnormalandosteomalacicbonestainedwithGiemsa(blue)andVonKossa(black)revealhistological featuresofosteomalacia.Thenormalbone(leftpanel)demon-stratescompletemineralizationof the trabeculae (black)whereasosteo-malacicbone(rightpanel)ispoorlymineralizedasdemonstratedbyathicklayerofun-mineralizedosteoid(stainedblue,redstar)aroundirregularbonetrabeculae.Thereissmoothcontinuityofnormalbonetrabeculaecomparedwith irregulardiscontinuous trabeculaeormicrofracture inosteomalacicbone(redarrow).