Total T 4 and T 3 : i concentrations, corresponding to rise in TBG \200 Free T 4 and T 3 : small rise in concentration in \201 rst trimester due to hCG stimulation then fall into normal range. During the second and third trimesters, FT 4 concentration is often just bel ow the normal reference range. Thyroid-stimulating hormone (TSH) is within normal limits in preg- nancy. However, it is suppressed in 13.5% in the \201 rst trimester, 4.5% in the second t rimester, and 1.2% in the third trimester due to hCG thyrotropic effect. There is a positiv e correlation between free T 4 and hCG levels and a negative correlation between TSH and hC G levels in the \201 rst half of pregnancy. Thyrotropin-releasing hormone (TRH) is normal. \200 TSH receptor antibodies: When present in high concentrations in mater- nal serum these may cross the placenta. Antibody titer de creases with progression of the pregnancy. Fetal thyroid function TRH and TSH synthesis occurs by 8 \200\22310 weeks \200\231 gestatio n, and thyroid hor- mone synthesis occurs by 10 \200\22312 weeks \200\231 gestation. TSH, total and freeT 4 and T 3 , and TBG concentrations increase progres- sively throughout gestation. Maternal TSH does not cross the placenta, and although TRH crosses the placenta, it does no t regulate fetal thyroid function. Iodine crosses the placenta and excessive quantities may induce fetal hypothyroidism. Maternal T 4 and T 3 cross the placenta in small quantities a nd are important for fetal brain development in the \201 rst half of gestation. 62-Draznin-Chap62.indd 346 3/31/2011 3:25:37 PM MATERNAL HYPERTHYROIDISM 347 Maternal hyperthyroidism b See Thyrotoxicosis in pregnancy (p. 31). Incidence This condition affects 0.2% of pregnant women. Most patients are diag- nosed befo re pregnancy or in the \201 rst trimester of pregnancy. In women with Graves \200\231 disease in remission, exacerbation may occur in the \201 rst trimester of pregnancy. Graves \200\231 disease The most common scenario is pregnancy in a patient with pre-existin g Graves \200\231 disease on treatment, as fertility is low in patients with untreated thyr otoxicosis. Newly diagnosed Graves \200\231 disease in pregnancy is unusual. Aggravation of disease occurs in the \201 rst trimester with amelioration in second half of pregnancy b ecause of a decrease in maternal immunological activity at that time. Symptoms of thyrotoxicosis are dif \201 cult to differentiate from those of normal pregnan cy. The most sensitive symptoms are weight loss and tachycardia. Goiter is found in most pa tients. Management Risks of uncontrolled hyperthyroidism to mother include heart failure and arryht hmias. Antithyroid drugs (ATDs) are the treatment of choice but cross the placenta. Propylthiourac il is preferred, although the risk of aplasia cutis, a rare fetal scalp defect, with carbim azole is negligible. There is also less transfer to breast milk. Avoid B -blockers, as they may be associated with fetal growth impair- ment with prolonged use. They can be used initially for 2 \200\2233 weeks while antithyroid drugs take affect. Most patients will be on a maintenance dose of an ATD. A high dose of ATD may be necessary initially to achieve euthyroidism as quickly as possible (carbimazole 20 \200\22340 mg/day or propylthiouracil 200 \200\223400 mg/day) in newly diagnosed patients, then the minimal d ose of ATD can be used to maintain euthyroidism. Do not use a block-replace regime, as higher doses of ATDs are required and there is minima l transplacental transfer of T 4 , thereby risking fetal hypothyroidism. Monitor TFTs every 4 \200\2236 weeks. Aim to keep FT 4 at the upper limit of normal and TSH low \200\223normal. In approximately 30% of women, ATDs may be discontinued at 32 \200\223 36 weeks \200\231 gestation. Consider doing this if the patient is euthyroid for at least 4 weeks on the lowest dose of propylthiouracil, but continue to monitor TFTs frequently. Pre sence of a large goiter or ophthalmopathy suggests severe disease; the chances of remission are low, so do not stop the ATD. Risks of neonatal hypothyroidism and goiter are reduced if the woman is on 200 mg propylthi ouracil or less (or carbimazole 20 mg) in the last few weeks of gestation. 62-Draznin-Chap62.indd Sec1:347 3/31/2011 3:25:37 PM CHAPTER 62 Thyroid disorders 348 Propylthiouracil (PTU) is secreted in negligible amounts in breast milk. Carbimazole is sec reted in higher amounts. Breast-feeding is not contrain- dicated if the mother is on <150 m g PTU or 5 mg carbimazole. Give in divided doses after the feeds and monitor neonatal thyro id function. Surgical management of thyrotoxicosis is rarely necessary in pregnancy. The only indication is serious ATD complication (e.g., agranulocytosis) or drug resistance. There is a possibl e i risk of spontaneous abortion or pre- mature delivery associated with surgery during pre gnancy. Radioiodine therapy is contraindicated in pregnancy and for 4 months beforehand. Infants born to mothers with Graves \200\231 disease Risks to fetus of uncontrolled thyroto xicosis \200 i Risk of spontaneous abortion and stillbirth \200 Intrauterine growth res triction (IUGR) \200 Premature labor \200 Fetal or neonatal hyperthyroidism. Follow-up of babies born to mothers on ATDs shows normal weight, height, and intellectual f unction. Fetal hypothyroidism This may occur following treatment of a mother with high doses of ATDs (>200 mg PTU/day), particularly in the latter half of pregnancy. This condi- tion is rare and may be diagnosed by demonstrating a large fetal goiter on fetal US in the presence of f etal bradycardia. Fetal hyperthyroidism This may occur after week 25 of gestation. It results in IUGR, fetal goiter, and tachycardia (fetal heart rate >160 bpm). It may develop if the mother has high titers of TSH-stimulating antibodies (TSAb). Treat by giving the mother an ATD, and monitor fetal heart rate (aim <140 bpm), growth, and goiter size. Neonatal thyrotoxicosis This develops in 1% of infants born to thyrotoxic mothers. It is du e to pla- cental transfer of TSAb. It is transient, usually subsiding by 6 months, but ther e is up to 30% mortality if left untreated. Treat with ATD and B -blockers. Hyperemesis gravidarum (gestational hyperthyroidism) \200 Characterized by severe vomitin g and weight loss. Cause unknown \200 Begins in early pregnancy (week 6 \200\2239 of gest ation) and tends to resolve spontaneously by week 20 of gestation Biochemical hyperthyroidism in two-thirds of affected women, but T 3 is less commonly eleva ted. Mechanism: hCG has TSH-like effect, thus stimulating the thyroid gland and suppressing TSH secretion Degree of thyroid stimulation correlates with severity of vomiting. \200 No other evidenc e of thyroid disease, i.e., no goiter or history of thyroid disease, no ophthalmopathy, and negative thyroid autoanti- bodies Antithyroid drugs are not required and do not improve symptoms of hyperemesis. 62-Draznin-Chap62.indd Sec1:348 3/31/2011 3:25:37 PM MATERNAL HYPOTHYROIDISM 349 Causes of maternal hyperthyroidism \200 Graves \200\231 disease (85% of cases) \200 Tox ic nodule \200 Toxic multinodular goiter \200 Hydatidiform mole Maternal hypothyroidism Prevalence \200 2.5% subclinical hypothyroidism \200 1 \200\223 2% overt hypothyroidism Risks of suboptimal treatment during pregnancy \200 Spontaneous abortion: 2-fold i risk. \200 Pre-eclampsia: 21% of suboptimally treated mothers have pregnancy- induced hypertension (PIH). Also, i risk of anemia during pregnancy and postpartal hemorrhage \200 Risk of impaired f etal intellectual and cognitive development \200 i Risk of perinatal death \200 Other r isks to fetus include those associated with PIH (IUGR, premature delivery, etc). The risk of congenital malformations is not thought to be i . Management Spontaneous pregnancy in overtly hypothyroid women is unusual, as hypo- thyroid women are likely to have anovulatory menstrual cycles. \200 Levothyroxine therapy: Start on 150 mcg. Measure TSH 4 weeks later. \200 If already on T 4 before pregnancy, assess TS H at 6 \200\2238 weeks \200\231 gestation, then between weeks 16 \200\22320, then again between weeks 28 \200\22332 of gestation. Aim : TSH \200\224lower part of normal range; FT4 \200\224upper end of normal \200 Increa se T 4 dose by 30% (an average of 25 \200\22350 mcg) when pregnancy is con \201 rmed. Afte r delivery, thyroid requirements decrease to pre- pregnancy levels. Do not give FeSO 4 simu ltaneously with T 4 \200\224this reduces its ef \201 cacy. Separate times for drug ingest ion by at least 2 hours. Causes of maternal hypothyroidism \200 Hashimoto \200\231s thyroiditis (most common cause ) \200 Previous radioiodine therapy or thyroidectomy \200 Previous postpartum thyroidit is \200 Hypopituitarism Positive thyroid antibodies but euthyroid \200 2-Fold excess risk of spontaneous abortion \200 No other complications \200 No risk of neonatal hypothyroidism \200 Risk of PIH not i \200 The occasional mother will develop hypothyroidism toward the end of the pregnancy, so check TSH between weeks 28 \200\22332 of gestation. i Risk of postpartum thyroiditis, so check TSH at 3 months postpartum 62-Draznin-Chap62.indd 349 3/31/2011 3:25:37 PM CHAPTER 62 Thyroid disorders 350 Postpartum thyroid dysfunction Prevalence \200 5 \200\22310% of women within 1 year of de livery or miscarriage \200 3 \227 more common in women with type 1 diabetes mellitus Etiology \200 Chronic autoimmune thyroiditis ( b see Other types of thyroiditis, p. 49) Clinical presentation Hyperthyroidism (32%) \200 Within 4 months of delivery \200 The m ost common symptom is fatigue. \200 Usually resolves spontaneously in 2 \200\2233 months Hypothyroidism (43%) \200 Develops 4 \200\2236 months after delivery \200 Symptoms may be mild and nonspeci \201 c. \200 There may be an i risk of postpartum depression. Hyperthyroidism followed by hypothyroidism (25%) \200 Spontaneous recovery in 80% within 6 \200\22312 months of delivery Differential diagnosis Graves \200\231 disease may relapse in the postpartum period. This is differentiated from postpartum thyroiditis by a high upta ke on radioiodine scanning. Lymphocytic hypophysitis may cause hypothyroidism. However, serum TSH concentrations are inappropriately low. Investigation Thyroid peroxidase antibodies are positive in 80%. Radionuclide uptake scans are rarely necessary. However, there is low uptake during the thy rotoxic phase, differentiating it from Grave \200\231s disease where uptake is increased. Management \200 B -blockers if thyrotoxic and symptomatic until TFTs normalize. Antithyroid medication is unnecessary. Levothyroxine if TSH>10 or if TSH between 4 \200\22310 and symptomatic There is no consensu s on how long to treat with thyroxine. There are two options: \200 Halve the dose at abou t 12 months postnatal and check TFTs 6 weeks later. If normal, then withdraw T 4 and check TFTs 6 weeks later. Withdraw treatment 1 year after completion of family. Prognosis There is recurrence in future pregnancies in 70% of women. Permanent hypothyroidi sm develops in up to 50% of women within 10 years. If treatment is withdrawn, then annual T SH measurements are essential. 62-Draznin-Chap62.indd 350 3/31/2011 3:25:37 PM THYROID CANCER IN PREGNANCY 351 Thyroid cancer in pregnancy b See Thyroid cancer and pregnancy (p. 77). Further reading Abalovich M, Amino N, Barbour LA, et al. (2007).Management of thyroid dysfu nction during preg- nancy and postpartum: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 92(8 Suppl):S1 \200\223S47. Alexander EK, Marqusee E, Lawrence J, et al. (2004). Timing and magnitude of increases in l evothyroxine requirements during pregnancy in women with hypothyroidism. N Engl J Med 351(3 ):241 \200\223249. Lazarus JH, Kokandi A (2000). Thyroid disease in relation to pregnancy: a decade of change. Clin Endocrinol 53:265 \200\223278. LeBeau SO, Mandell SJ (2006). Thyroid disorders during pregnancy. Endocr Metab Clin North A m 35:117 \200\223136. Poppe K, Glinoer D (2003). Thyroid autoimmunity and hypothyroidism before and during preg- nancy. Hum Reprod Update 9(2):149 \200\223161. Stagnaro-Green A (2002). Postpartum thyroiditis. J Clin Endocrinol Metab 87(9):4042 \200 \2234047. 62-Draznin-Chap62.indd 351 3/31/2011 3:25:37 PM CHAPTER 63 Pituitary disorders 352 Pituitary disorders Normal anatomical changes during pregnancy \200 Prolactin (PRL)-secreting cells: marked l actotrope hyperplasia during pregnancy Gonadotropin-secreting cells: marked reduction in size and number \200 TSH and ACTH-secre ting cells: no change in size or number \200 Anterior pituitary: Size increases by up to 70% during pregnancy. It may take 1 year to shrink to near pre-pregnancy size in nonlactating women. Gradual slight increase in size with each pregnancy MRI: enlarged anterior pituitary gland, but stalk is midline. Posterior pituitary gland may not be seen in late pregnancy. 63-Draznin-Chap63.indd 352 3/31/2011 3:27:06 PM NORMAL PHYSIOLOGY DURING PREGNANCY 353 Normal physiology during pregnancy Serum PRL Concentrations increase markedly during pregnancy and fall again to pre-pregnancy levels approximately 2 weeks postpartum in nonlactating women. Serum LH and FSH There are undetectable levels in pregnancy and a blunted response to GnRH because of negative feedback inhibition from high levels of sex hor- mones and PRL. Serum TSH, T 4 , and T 3 TSH may be suppressed in the \201 rst trimester of pregnancy. Fr ee thyroid hormones usually within the normal range. Growth hormone (GH) and IGF-I There are low maternal GH levels and a blunted response to hy poglyc- emia due to placental production of a GH-like substance. IGF-I levels are normal or high in pregnancy. ACTH and cortisol CRH, ACTH, and cortisol levels are high in pregnancy, as both CRH and ACT H are produced by the placenta. In addition, estrogen-induced increase in cortisol-binding globulin (CBG) synthesis during pregnancy will further increase maternal plasma cortisol co ncentrations. During the latter half of pregnancy there is a progressive increase of ACTH and cortisol le vels, peaking during labor. Incomplete suppression of cortisol occurs following dexamethaso ne suppression test, along with an exaggerated response of cortisol to CRH stimulation. How ever, normal diurnal variation persists. 63-Draznin-Chap63.indd 353 3/31/2011 3:27:06 PM CHAPTER 63 Pituitary disorders 354 Prolactinoma in pregnancy Effect of pregnancy on tumor size Risk of signi \201 cant tumor enlargement (i.e., resulting in visual \201 eld distur- bances or headaches): \200 Micr oadenoma (1 \200\2232%) \200 Macroadenoma (15 \200\22335%) \200 Macroadenoma treated wi th surgery and/or radiotherapy before pregnancy (4 \200\2237%) Effect of dopamine agonists on the fetus Bromocriptine Over 6000 pregnancies have occurred in women receiving bromocriptine in early pregnancy, and the incidence of complications in these pregnancies with regard to fetal outcome is similar to that of the normal population, indicating that bromocriptine is probably safe in early pregnancy. Data are available on children whose mothers received bromocriptine throughout pregnancy, a nd again the incidence of congenital abnormalities is negligible. Cabergoline This is also probably safe in early pregnancy, with no i risk of fetal loss or congenital abnormalities, although fewer data are available. It is thus recommended that wo men with prolactinomas seeking fertility receive bromocriptine to induce ovulation, as ther e are more data on the long- term safety of bromocriptine. Cabergoline is being used increa singly, as it is better tolerated. Management Microprolactinoma Initiate dopamine agonist therapy to induce normal ovulatory c ycles and fertility. Stop bromocriptine as soon as pregnancy is con \201 rmed. Assess for visual symptoms and headache at each trimester, although the risk of complicatio ns is low (<5%). Serum PRL levels are dif \201 cult to interpret during pregnancy, as they are normally elevated and are thus are not routinely measured. MRI is indicated in the occasional patient who becomes symptomatic. In the postpartum perio d, recheck serum PRL level after cessation of breast-feeding. Reassess size of microprolact inoma by MRI only if the serum PRL level is higher than pre-pregnancy concentrations. There is a 40 \200\22360% chance of remission of microprolactinoma following pregnancy. Macroprolactinoma Management is controversial and must therefore be individualized. There a re three possible approaches: \200 Bromocriptine may be used throughout pregnancy to redu ce the risk of tumor growth. The patient is monitored by visual \201 elds at each trimest er, or more frequently if symptoms of tumor enlargement develop. This is probably the safes t and thus preferred approach. 63-Draznin-Chap63.indd 354 3/31/2011 3:27:06 PM PROLACTINOMA IN PREGNANCY 355 Bromocriptine or cabergoline may be used to induce ovulation and then stopped after conception. However, the patient must be monitored very carefully du ring pregnancy with monthly visual \201 eld testing. If symptoms of tumor enlargement develop or there is deterioration in visual \201 elds, an MRI should be performed to assess tumor growth. If signi \201 ca nt tumor enlargement develops, bromocriptine therapy should be initiated. Alternatively, the patient may undergo surgical debulking of the tumor and/or radiotherapy before seeking fertility. This will signi \201 cantly reduce the risk of complications associated with tumor growth. However, this approach may render them gonad otropin de \201 cient. These patients should again be monitored during pregnancy using reg ular visual \201 elds. There is no contraindication to breast-feeding. \200 MRI should be performed in the postp artum period in women with macroprolactinomas to look for tumor growth. 63-Draznin-Chap63.indd 355 3/31/2011 3:27:06 PM CHAPTER 63 Pituitary disorders 356 Cushing \200\231s syndrome Pregnancy is rare in women with untreated Cushing \200\231s synd rome, as 75% of them will experience oligo- or amenorrhea. The diagnosis of Cushing \200\231s syndrome is dif \201 cult to establish during preg- nan cy. However, the presence of purple striae and proximal myopathy should alert the physician to the diagnosis of Cushing \200\231s syndrome. If suspected, the investigation of Cushing \200\231s syndrome should be car- ried out as in the nonpregnant state. However, high urinary free cortisols and nonsuppression of cortisol production on a low-dose dexamethasone suppression test may be features of a normal pregna ncy. The diurnal vari- ation of cortisol secretion is preserved in normal pregnancy. Diagnosis is important, as pregnancy in Cushing \200\231s syndrome is associated with a high risk of maternal and fetal complications ( b see Table 63.1). Adrenal disease is the most common cause of Cushing \200\231s syndrome developing in pregnancy, responsible for over 50% of reported cases. Management First trimester \200 Offer termination of pregnancy and instigate treatment, p articularly if adrenal carcinoma Alternatively, surgical treatment early in the second trimester Second trimester \200 Surgery, e.g., adrenalectomy or pituitary adenomectomy. There is a minimal risk to the fetus. Third trimester \200 i Risk of diabetes mellitus \200 Deliver baby as soon as possible (preferably by vaginal delivery to minimize the risk of poor wound healing following a Caesarian section) and instigate treatm ent. Table 63.1 Complications of Cushing \200\231s syndrome in pregnancy Maternal complications Incidence (%) Fetal complications Incidence (%) Hypertension 70 Spontaneous abortion 12 Diabetes mellitus 27 Perinatal death 18 Congestive cardiac failure 7 Prematurity 60 Poor wound healing 6 Congenital malformations Low risk; no risk of virilization Death 4 63-Draznin-Chap63.indd 356 3/31/2011 3:27:06 PM ACROMEGALY 357 Metyrapone used in doses of <2g/day appears to be safe in pregnancy. Postoperative glucocor ticoid replacement therapy will be required. Treatment of Cushing \200\231s syndrome in pregnancy may reduce maternal and fetal morbidity and mortality. Acromegaly Fertility in acromegaly is reduced, partly due to hyperprolactinemia (if present ) in addition to secondary hypogonadism. However, there have been several reported cases of pregnancy in acromegaly. Acromegaly increases the risk of gestational diabetes and hypertension. However, in the abs ence of diabetes mellitus, there does not appear to be an excess of perinatal morbidity or mortality in babies born to women with acromegaly. Signi \201 cant tumor enlargement occasionally occurs together with enlargement of the nor mal pituitary lactotropes, so monthly visual \201 eld testing is recommended. It may be t reated with bromocriptine until there are more safety data on other forms of treatment. How ever, treatment may be deferred until after delivery in the majority of patients. Few data are available on the use of somatostatin analogs during preg- nancy, so their rout ine use is currently not recommended as they cross the placenta. However, there have been a few reports of uneventful preg- nancies in patients treated with octreotide. 63-Draznin-Chap63.indd 357 3/31/2011 3:27:06 PM CHAPTER 63 Pituitary disorders 358 Hypopituitarism in pregnancy Pre-existing hypopituitarism This is most commonly due to surg ical treatment of and/or radiotherapy for a pituitary adenoma. Ovulation and thus conceptio n may be induced by gonadotropin stimulation. Lymphocytic hypophysitis b See also Lymphocytic hypophysitis (p. 137). \200 Rare disorder thought to be autoimmune in origin \200 Characterized by pituitary enlargement on imagin g and variable loss of pituitary function Most commonly seen in women in late pregnancy or in the \201 rst year postpartum. Symptoms are due to pressure effects, e.g., visual \201 eld defects and headaches, or to hormonal de \201 ciency. The most common hormonal de \201 ciencies are as follows: \200 ACTH and vasopressin de \201 ciency \200 TSH de \201 ciency may also exist. \200 Gonadotropins and GH levels a re usually normal. \200 PRL levels may be mildly elevated in a third, and low in a third. Differential diagnosis \200 Pituitary adenoma \200 Sheehan \200\231s syndrome MRI often reveals diffuse homogenous contrast enhancement of the pitu- itary gland. However , the diagnosis is often only made de \201 nitively by pitu- itary biopsy. There is an association with other autoimmune diseases, particularly Hashimoto \200\231s thyroiditis. The course is variable. Pituitary function may deteriorate or improve with time. Management \200 Pituitary hormone replacement therapy as required \200 Surgical decompr ession if pressure symptoms persist \200 A course of high-dose steroid therapy is controv ersial, with mixed results. Causes of hypopituitarism during pregnancy \200 Pre-existing hypopituitarism \200 Pitui tary adenoma \200 Lymphocytic hypophysitis \200 Sheehan \200\231s syndrome 63-Draznin-Chap63.indd 358 3/31/2011 3:27:06 PM HYPOPITUITARISM IN PREGNANCY 359 Management of pre-existing hypopituitarism during pregnancy Hydrocortisone The dose may nee d to be i in the third trimester of pregnancy by 10 mg/ day as the increase in CBG will red uce the bioavailability of hydrocorti- sone. Parenteral hydrocortisone in a dose of 100 mg IM every 6 hours should be given during labor and the dose reduced back to maintenance leve ls in the postpartum period (24 \200\22372 hours). Thyroxine Requirements may increase as t he pregnancy progresses. Monitor free T 4 each trimester and increase T 4 dose accordingly. GH There are few data on the effects of GH on pregnancy, but case reports do not suggest a detrimental effect on fetal outcome. However, until more data accrue, GH should be stopped prior to pregnancy. Moreover, as the placenta synthesizes a GH variant, GH therapy is unne cessary. Vasopressin The placenta synthesizes vasopressinase, which breaks down vasopressin but not desmopressin. Women with partial diabetes insipidus may there- fore require desmop ressin treatment during pregnancy. Those already receiving desmopressin may require a dose increment during pregnancy. Vasopressinase levels fall rapidly after delivery. Sheehan \200\231s syndrome Postpartum pituitary infarction or hemorrhage results in hypopit uitarism. This syndrome is increasingly uncommon in developed countries with improvements i n obstetric care. Pathogenesis The enlarged pituitary gland of pregnancy is susceptible to any compro- mise to its blood supply. Investigations will con \201 rm hypopituitarism. Risk factors \200 Postpartum hemorrhage \200 Type 1 diabetes mellitus \200 Sickle cel l disease Clinical features \200 Failure of lactation \200 Involution of breasts \200 Fatigue, lethargy, and dizziness \200 Amenorrhea \200 Loss of axillary and pubic hair \200 Sym ptoms of hypothyroidism \200 Diabetes insipidus is rare. Management \200 Pituitary hormone replacement therapy ( b see Background, p. 98) 63-Draznin-Chap63.indd 359 3/31/2011 3:27:06 PM CHAPTER 63 Pituitary disorders 360 Further reading Kovacs K (2003). Sheehan syndrome. Lancet 361:520 \200\223522. Molitch M (1999). Medical treatment of prolactinomas. Endocrinol Metab Clin North Am 28(1): 143 \200\223169. Molitch M (2006). Pituitary disorders in pregnancy. Endocrinol Metab Clin North Am 35:99 \200\223116. Sam S, Molitch M (2003). Timing and special concerns regarding endocrine surgery during pre g- nancy. Endocrinol Metab Clin North Am 32:337 \200\223354. 63-Draznin-Chap63.indd 360 3/31/2011 3:27:06 PM NORMAL CHANGES DURING PREGNANCY 361 Adrenal disorders during pregnancy Normal changes during pregnancy Changes in maternal adrenocortical function Markedly iconcentrations of all adrenal steroid s are due to i synthesis and d catabolism. Fetoplacental unit Fetal adrenal gland DHEAS is produced in vast quantities by the fetal ad renal gland. This is the major precursor for estrogen synthesis by the placenta. The fetal adrenal gland has a large capacity for steroidogenesis. Stimulus for fetal adrenal gland is unknown \200\224possibly hCG or PRL. Placenta Maternal glucocorticoids are largely inactivated in the placenta by 11B HSD. Mater nal androgens are converted to estrogens by placental aromatase, thus protecting the female fetus from virilization. 64-Draznin-Chap64.indd 361 3/31/2011 3:28:40 PM CHAPTER 64 Adrenal disorders during pregnancy 362 Addison \200\231s disease in pregnancy There is no associated fetal morbidity in women who have pre-existing primary adrenal insuf \201 ciency, as the fetus produces and regulates i ts own adrenal steroids. Management of Addison \200\231s disease does not differ in pregnancy. Glucocorticoids metab olized by placental 11B HSD are preferred (i.e., prednisolone or hydrocortisone), to avoid fetal adrenal suppression. Increase hydrocortisone dose by about 10 mg during the third trimester of pregnancy and at any time in case of intercurrent illness. High-dose intramuscular hydrocortisone should be given at the time of delivery to cover the stress of labor. Doses may be tapered to normal maintenance doses in the postpartum period ( b see Box 64.1 ). Addison \200\231s disease developing in pregnancy may result in an adrenal cri- sis, particularly at the time of delivery, because of a delay in diagnosis. In early pregnancy, vomiting, fatigue, and hyperpigmentation and low BP may be wrongly attr ibuted to pregnancy. However, persisting symptoms should alert the clinician. If suspected, the diagnosis is con \201 rmed by the presence of low serum cortisol concent rations with failure to rise following ACTH stimulation, and high ACTH levels. However, the normal ranges for serum ACTH and cortisol concentrations have not been established in preg nancy. Chronic maternal adrenal insuf \201 ciency may be associated with intrau- terine fetal growth restriction. There is no i risk of developing Addison \200\231s disease in the immediate post- partum period. Box 64.1 Management of adrenal insuf \201 ciency during pregnancy \200 Hydrocortisone 20 \200\22330 mg PO in divided doses, as per pre-pregnancy dose Fludrocortisone 50 \200\223200 mcg PO, as per pre-pregnancy dose During uncomplicated labor \200 Hydrocortisone 100 mg IM q6h for 24 hours, then reduce to maintenance dose over 72 hours \200 Keep the patient well hydrated. \200 Fludrocortison e may be discontinued while on high doses of hydrocortisone. 64-Draznin-Chap64.indd 362 3/31/2011 3:28:40 PM CONGENITAL ADRENAL HYPERPLASIA 363 Congenital adrenal hyperplasia Fertility is reduced, particularly women with the salt-wasti ng form of CAH. Reasons for this are as follows: \200 Inadequate vaginal introitus despit e reconstructive surgery \200 Anovulation as a result of hyperandrogenemia \200 Adverse effects of elevated progestagen levels on endometrium From 60 to 80% of women with CAH and an adequate vaginal introitus are fertile. Fertility may be maximized by optimal suppressi on of hyperandro- genism by glucocorticoid therapy ( b see Management, p. 244). No major co mplications in pregnancy are known in women with CAH, apart from a possibly i incidence of pre-eclampsia. However, women are more likely to require Cesarean section for cephalopelvic disproportion. Management is the same as in the nonpregnant woman, and steroids are i at the time of delivery as for Addison \200\231s disease ( b p. 203). Monitor serum testosterone and electrolytes every 6 \200\2238 weeks. Risk to fetus \200 There is no risk of virilization from maternal hyperandrogenism, as th e placenta will aromatize androgens to estrogens. Glucocorticoids do not increase the risk of congenital abnormalities. \200 If the partner is a heterozygote or homozygote for CAH, the fetus has a 50% risk of CAH. Prenatal treatme nt with dexamethasone will then be necessary to avoid virilization of a female fetus ( b se e Management of pregnancy in CAH, p. 245). 64-Draznin-Chap64.indd 363 3/31/2011 3:28:40 PM CHAPTER 64 Adrenal disorders during pregnancy 364 Pheochromocytoma This condition is rare but potentially lethal in pregnancy. Maternal morta lity may still be as high as 17%, with 30% fetal mortality if not treated promptly. The hig hest risk of hypertensive crisis and death is during labor. Suspect pheochrocytoma in women with hypertension, persistent or intermittent, especially i n the absence of proteinuria or edema, hyperten- sion developing before 20 weeks \200\231 g estation, or persistent glycosuria. Suspect it if paroxysmal symptoms are present: palpitations, sweating, and headache. Prenatal screening is recommended in high-risk women, e.g., those with a history or family history of MEN-2 or von Hippel \200\223Lindau syndrome. Diagnose by 24-hour urinary catecholamine collection. Tumor localization is important \200 \224MRI is the imaging of choice in pregnancy. Management A -blockade Phenoxybenzamine reduces fetal and maternal morbidity and mortality. It appears to be safe in pregnancy. The starting dose is 10 mg q12h and is built up gradua lly to a maximum of 20 mg every 8 hours. B -blockade Propranolol is given only after adequa te A-blockade. It may increase the risk of intrauterine fetal growth restriction if started in the third trimester. Give in a dose of 40 mg q8h. Surgery This is controversial. Some clinicians offer surgical removal of pheochro- mocytoma before 24 weeks \200\231 gestation (which is relatively safe following A- and B -blockade) . After 24 weeks \200\231 gestation, surgery should be deferred until fetal maturity, and t hen it can be combined with Cesarean section with removal of the tumor. Ensure adequate adrenergic blockade before surgery. Operate after safe delivery of the fetus. Further reading Hadden DR (1995). Adrenal disorders of pregnancy. Endocrinol Metab Clin Nor th Am 24(1):139 \200\223151. Sam S, Molitch M (2003). Timing and special concerns regarding endocrine surgery during pre g- nancy. Endocrinol Metab Clin North Am 32:337 \200\223354. 64-Draznin-Chap64.indd 364 3/31/2011 3:28:40 PM Part 6 Calcium and bone metabolism Sol Epstein 65 Calcium and bone physiology 66 Investigation of bone 67 Investigation of calcium, phosph ate, 366 369 and magnesium 68 Hypercalcemia 69 Hypocalcemia 70 Rickets and osteomalacia 71 Hypomagnesemi a 72 Osteoporosis 73 Paget \200\231s disease 74 Inherited disorders of bone 373 376 389 396 403 405 421 427 65-Draznin-Chap65.indd 365 3/31/2011 3:29:45 PM CHAPTER 65 Calcium and bone physiology 366 Calcium and bone physiology Bone turnover In order to ensure that bone can undertake its mechanical and metabolic funct ions, it is in a constant state of turnover (see b Fig. 65.1 ). \200 Osteoclasts , derive d from the hematopoetic stem cell series, resorb bone. Osteoblasts , derived from the mesenchymal cell precursors, make bone. Osteocytes , buried osteoblasts, sense mechanical strain and secrete factors important in bone homeostasis. Lining cells Bone lining cells o i d Formation d o s t c Osteoclasts e e r aliz Mineralized bone m i n n U Osteocytes Resorption 21 21 Days of remodeling cycle 100 Fig. 65.1 Bone turnover during remodeling cycle. 65-Draznin-Chap65.indd 366 3/31/2011 3:29:45 PM BONE MASS DURING LIFE 367 Bone mass during life b See Fig. 65.2. Bone is laid down rapidly during skeletal growth at puberty. Following this there is a peri od of stabilization of bone mass in early adult life. After the age of 40, there is a grad ual loss of bone in both sexes. This occurs at the rate of approximately 0.5% annually. However, in women after the menopause there is a period of rapid bone loss. The accelerated loss is maximal immediately after the cessa- tion of ovarian function but remains increase d throughout life. The excess bone loss associated with the menopause is of the order of 10 % of skeletal mass. This menopause-associated loss coupled with lower peak bone mass largely explains why osteo porosis and its associated fractures are more common in women. 120 ) 100 k a e p s s a m e n o B 80 e l a m e f 60 40 % ( 20 0 0 20 40 Age (years) 60 80 Fig. 65.2 Bone mass and age. 65-Draznin-Chap65.indd 367 3/31/2011 3:29:46 PM CHAPTER 65 Calcium and bone physiology 368 Calcium Roles of calcium \200 Skeletal strength \200 Neuromuscular conduction \200 St imulus secretion coupling Calcium in the circulation Circulating calcium exists in several forms ( b see Fig. 65.3 ). \200 Ionized \200\224biologically active \200 Complexed to citrate, phosphate etc. \200\224biologically active \200 Bound to protein, mainly albumin \200\224inactive Ionized Complexed Protein bound 45% 50% 5% Fig. 65.3 Forms of circulating calcium. 65-Draznin-Chap65.indd 368 3/31/2011 3:29:47 PM BONE TURNOVER MARKERS 369 Investigation of bone Bone turnover markers These may be useful in \200 Assessing overall risk of osteoporotic fracture. \200 Judging response to treatments for osteoporosis. Resorption markers Collagen cross-links These make use of the fact that when collagen is laid down in bone, th e \201 bers are held in trimers by covalent links. These links are chemically very stable and are speci \201 c to the type of collagen. The excretion of fragments containing these cross-links is a much better indicator of bone turnover. It can be measured either as the excretion of the linking molecules themselves, known as de oxypyridinoline cross-links , or as small fragments of the ends of the collagen molecule in cluding these cross-links, known as telopeptides . These latter markers can be derived from either the N- or the C-terminal of the collagen molecule, and separate assays are availabl e for each. Assays are available for both blood and urine, although the former are subject to less error and are preferred. Urinary hydroxyproline This relies on the fact that hydroxyproline is unique to collagen, t hus any hydroxyproline in urine must come from collagen breakdown. Unfortunately, this is n ot speci \201 c to bone (type 1) collagen; furthermore, hydroxyproline is variably metabol ized before excretion and so its urinary levels are not a true index of collagen destructio n. It has accordingly been superseded. Formation markers Total alkaline phosphatase is not speci \201 c; it is also found in the liver, intestine, and placenta. It is relatively insensitive to small changes in bone turno ver and has only found general use in the monitoring of the activity of Paget \200\231s dis ease. Bone-speci \201 c alkaline phosphatase is more speci \201 c but its clinical utility is not yet clear. Osteocalcin is a vitamin K \200\223dependent protein that accounts for about 1% of bone mat rix. The serum level of osteocalcin appears to re \202 ect oste- oblast activity. However, the results obtained with bone-speci \201 c alkaline phosphatase and osteocalcin do not a lways correlate. This is particularly true in Paget \200\231s disease, where the osteocalci n is frequently scarcely ele- vated despite the marked increase in bone turnover. 66-Draznin-Chap66.indd 369 3/31/2011 3:43:44 PM CHAPTER 66 Investigation of bone 370 P1NP is a procollagen fragment released from the N terminal as type 1 collagen is laid down . When measured in the serum it is the most sensi- tive and speci \201 c marker of bone fo rmation, although its clinical utility is as yet unclear. Bone imaging Skeletal radiology This is useful for the following: \200 Diagnosis of fract ure \200 Diagnosis of speci \201 c diseases (e.g., Paget \200\231s disease and osteomala cia) \200 Identi \201 cation of bone dysplasia It is not useful for assessing bone densi ty. Isotope bone scanning Bone-seeking isotopes, particularly 99m technetium-labeled bisphospho - nates, are concentrated in areas of localized i bone cell activity. They are useful for i dentifying localized areas of bone disease such as fracture, metastasis, or Paget \200\231s disease. However, isotope uptake is not selective, and so i activity on a scan does not indicate the nature of the underlying bone disease. Hence, sub- sequent radiology of affected regions i s frequently needed to establish the diagnosis. Isotope bone scans are particularly useful in Paget \200\231s disease to establish the extent of skeletal involvement and the underlying disease activity. 66-Draznin-Chap66.indd 370 3/31/2011 3:43:45 PM BONE MASS MEASUREMENTS 371 Bone mass measurements b See Table 66.1. Interpretation of results The differences in normal ranges between the machines of differen t manufacturers has led to the practice of quoting bone mass measure- ments in terms of the number of standard deviations (SDs) they lie from an expected mean. This can be done in tw o ways: T score and Z score; b see Table 66.2. It is generally accepted that a reduction of 1 SD in bone density will approximately double the risk of fracture. The WHO has developed guidelines for the diagnosis of osteoporosis in postmenopausal women ( b see Table 66.3). No similar criteria have been set in males, but the same thresholds are generally accepted.