The Feria Journal of Medicine

Hematologic Laboratory facts

2012-02-06T19:10:00.000-08:00

In atypical automated blood cell counter, the blood sample is aspirated andseparated into two portions: one is lysed and diluted to permit measurement ofhemoglobin concentration and leukocyte enumeration, and the other is dilutedwithout lysis to enable counting and sizing of red cells and platelets

classicmethod to count and determine the volume of a particle or a cell is electricalimpedance in which a specific volume of an electrolyte solution containing adilute suspension of blood cells is aspirated through a small orifice acrosswhich a current is flowing. The electrical impedance produced as a cell passesthrough the orifice is registered as a particle for counting purposes and theheight of the pulse generated by the electrical impedance can be madeproportional to the volume of the particle. Automated hematology instrumentstoday rely heavily on analysis of light scattered at different angles from anincident laser beam striking passing cells. Cell count, volume, and internalstructure can be determined by multivariate analysis of these data.

Inelectronic instruments, the hematocrit (HCT) (proportion of blood occupied byerythrocytes) is calculated from the product of direct measurements of theerythrocyte count and the MCV (HCT [u1/100 u1] = RBC [x 10^–6/u1] x MCV [fl]/10). Falsely elevated MCV anddecreased red cell counts can be observed when red cell autoantibodies arepresent and retain binding capability at room temperature (cold agglutinins andsome cases of autoimmune hemolytic anemia).³ This causes redcells to clump and by affecting the accuracy of both red blood cell (RBC) countand MCV, also affects the resultant hematocrit.

The"spun" hematocrit includes plasma trapped between red cells in thepacked cell volume,⁵ typically about 2 to 3 percent of the packedvolume.⁶ Microhematocrits from polycythemic samples (HCT greaterthan 55) or blood containing abnormal erythrocytes (sickle cell anemia,thalassemia, iron deficiency, spherocytosis, macrocytosis) are increasedbecause of enhanced plasma trapping that generally is caused by increased redcell rigidity.^6,7 Therefore, although automated hematocrit valuesare adjusted to be equivalent to spun hematocrit for normal samples, inabnormal samples, the spun hematocrit may be artifactually elevated (up to 6%in microcytosis⁸). In general, the automated hematocrit is moreaccurate and easier to obtain than the spun hematocrit, although the hemoglobindetermination is preferred to either, because it is measured directly and isthe best indicator of the oxygen-carrying capacity of the blood.

Hemoglobinis intensely colored, and this property has been used in methods for estimatingits concentration in blood. Erythrocytes contain a mixture of hemoglobin,oxyhemoglobin, carboxyhemoglobin, methemoglobin, and minor amounts of otherforms of hemoglobin. To determine hemoglobin concentration in the blood, redcells are lysed and hemoglobin variants are converted to the stable compoundcyanmethemoglobin for quantitation by absorption at 540 nm.

The MCHC,the concentration of hemoglobin per unit with red cell volume, is calculated bythe formula MCHC (g/dl of red cells) = hemoglobin (g/dl) / hematocrit (ml/100dl) x 100. An MCHCgreater than 35 g/dl red cells is associated with hereditary spherocytosis,²³and a low MCHC is typical of iron deficiency,²⁴ but its diagnosticusefulness is limited.

Forexample, patients with sideroblastic anemia usually have a dimorphic bloodpicture, with both hypochromic and normochromic cells. The MCH and MCHC may bein the normal range, and the important finding of the mixed-cell population,both normochromic and hypochromic cells, would not be detected unless a bloodfilm is examined. A normal MCV might occur in the setting of iron deficiencycoupled with folate deficiency, but examination of the blood film would showcells characteristic of each, such as oval macrocytes and hypochromicmicrocytes. Another index, the red cell distribution width (RDW), isspecifically designed to reflect the variability of red cell size. It is basedon the width of the red blood cell volume distribution curve, with largervalues indicating greater variability. An elevated RDW may be an early sign ofiron-deficiency anemia^27,28 and although proposed as an aid indistinguishing iron deficiency from other causes of microcytic anemia,²⁹such as thalassemia, the RDW is not sufficiently specific to obviate the needfor more specific tests.³⁰ The RDW can be used in the laboratory asa flag to select those samples submitted for automated blood count that shouldhave manual review of the blood film for red cell morphology.

Thereticulocyte is a newly released anucleate red cell that enters the blood frommarrow with residual detectable amounts of RNA. The number of reticulocytes ina volume of blood permits an estimate of marrow erythrocyte production and isthus useful in evaluating the pathogenesis of anemia, distinguishing inadequateproduction from accelerated destruction (hemolysis). Various proprietarycombinations of light scatter and other parameters are used to minimizeinterferences such as nucleated red cells, nuclear remnants (Howell-Jollybodies), malaria parasites, or platelet clumps.

Thetheoretical advantage is that acute changes in red cell function would bedetected more rapidly and reliably in the reticulocyte fraction as opposed tothe whole red cell population

Mosthigh-end hematology analyzers now report some quantitative measure ofreticulocyte RNA content.³³ Increase in the immature reticulocytefraction (those with highest RNA content) is an early sign of marrow recovery³⁸and has been used as a marker of ineffective erythropoiesis, distinguishingmacrocytosis caused by megaloblastic anemia or myelodysplasia from othercauses.³⁹ A limitation at present is that both the methods andreference ranges for these parameters are instrument dependent.

Leukocyte counts are performed by automatedblood counters on blood samples appropriately diluted with a solution thatlyses the erythrocytes (e.g., an acid or a detergent), but preserves leukocyteintegrity. Manualcounting of leukocytes is used only when the instrument reports a potentialinterference or the count is beyond instrument linearity limits. Manual countsare subject to much greater technical variation than automated counts becauseof technical and statistical factors. Automated leukocyte counts may be falselyelevated as a result of cryoglobulins or cryofibrinogen,⁴¹ clumpedplatelets or fibrin from an inadequately anticoagulated or mixed sample,⁴²ethylenediaminetetraacetic acid (EDTA)-induced platelet aggregation,⁴³nucleated red blood cells,⁴² or nonlysed red cells. Theseinterferences cause a population of small-size particles to appear in theleukocyte volume histogram, and trigger a flag for manual review.

Plateletsare usually counted electronically by enumerating particles in the unlysedsample within a specified volume window (e.g., 2–20 fl), where volume may bemeasured by electrical impedance or light scatter. The platelet count was moredifficult to automate than the red cell count because of the small size,tendency to aggregate, and potential overlap of platelets with more numeroussmaller red cells.

Becauseplatelet volumes in health or disease follow a log-normal distribution,⁵⁷volume histograms inconsistent with such a distribution are flagged for manualreview. Automated platelet counting by current instrumentation is accurate andreliable, even in the thrombocytopenic range,⁵⁸ and far more precisethan manual methods.⁵⁸ Platelet counts by either manual or automatedmethods may be falsely decreased if the sample is incompletely anticoagulated(often indicated by small clots in the specimen or fibrin strands on thestained film). Infrequently, it may be necessary to confirm automated resultsby a manual (phase contrast) platelet count or platelet estimate from the bloodfilm when potential interferences are present. These include severemicrocytosis and leukocyte fragmentation (falsely elevated count) or platelet clumpingor "satellitism"(falsely decreased count). Platelet clumping, or platelet"satellitism" (adherence of platelets to neutrophils), mayoccur as a result of platelet-reactive antibodies,⁵⁹ which typicallycause no clinical symptoms. These antibodies recognize epitopes on adhesionmolecules which are exposed in the absence of divalent cations, and so becomeactivated in EDTA- or citrate-anticoagulated blood specimens.⁵⁹ Thiscondition occurs in approximately 0.1 percent of hospitalized patients and theorigin of the thrombocytopenia in such cases can be suspected by the appearanceof small particles (representing the platelet clumps) on the leukocyte volumehistogram.⁶⁰ Platelet counting under these conditions is difficult,but can be minimized by collecting blood in citrate⁶⁰ or estimatingplatelet count from a freshly prepared fingerstick blood smear.

The numberof platelets with high RNA content ("reticulated platelets"),measured using RNA-binding fluorescent dyes such as thiazole orange, is amarker of marrow megakaryopoiesis and has been proposed as a way ofdifferentiating hypoproductive from destructive causes of thrombocytopenia, inan analogous fashion to the reticulocyte count. The percentage, but not theabsolute number, of reticulated platelets is increased in destructivethrombocytopenias, whereas the absolute number, but not percentage, isdecreased in hypoproductive states.⁶⁸ Reticulated platelet number orRNA correlates with imminent platelet recovery after chemotherapy.

Microscopicexamination of the blood spread on a glass slide or coverslip yields usefulinformation regarding all the formed elements of the blood. The process ofpreparing a thin blood film causes mechanical trauma to the cells. Also, thecells flatten on the glass during drying, and the fixation and staining involveexposure to methanol and water. Some artifacts are inevitably introduced, butthese can be minimized by good technique. The optimal part of the stained bloodfilm to use for morphologic examination of the blood cells should besufficiently thin that only a few erythrocytes in a x100 field touch each other, but not so thinthat no red cells are touching. Selection of a portion of the blood film foranalysis that is too thick or too thin for proper morphologic evaluation is byfar the most common error in blood film interpretation. For example, leukemicblasts may appear dense and rounded and lose their characteristic features whenviewed in the thick part of the film. For specific purposes, the thick portion or side and"feathered" edges of the film are of interest (for instance, todetect microfilariae and malarial parasites or to search for large abnormalcells and platelet clumps).

The bloodfilm is first scanned at low magnification (x200) to confirm reasonably evendistribution of leukocytes, and check for abnormally large or immature cells inthe side and feathered edges of the film. The feathered edge is examined forplatelet clumps. Abnormal cells, red cell aggregation or rouleaux, backgroundbluish staining consistent with paraproteinemia, and parasites are all findingsthat can be suggested by medium magnification examination (x400). The optimal portion of thefilm is then examined at high magnification (x1000, oil immersion) tosystematically assess the size, shape, and morphology of the major celllineages.

Anisocytosis is the term that describesvariation in erythrocyte size, and is the morphologic correlate of the RDW. Themacrocyte, a red cell larger than normal, may be seen in a number ofdisease states, for example, folic acid or vitamin B12 deficiency. Cells areconsidered to be macrocytes if they are well hemoglobinized and their diametersexceed 9 um. Early ("shift" or "stress") reticulocytes(i.e., those with the most residual RNA) appear in stained films as large,bluish cells, referred to as polychromatophilic cells. These cellsroughly correspond to those quantitated by automated analyzers as the immaturereticulocyte fraction. Microcyte, a red cell smaller than normal, is theterm used to describe a cell less than 6 um in diameter.

Poikilocytosis is a term used to describevariations in the shape of erythrocytes. The predominant appearance of aspecific abnormality in red cell shape can be an important diagnostic clue inpatients with anemia. These are described in detail in Chap. 28. Erythrocyteswith evenly spaced spikes (crenated cells) can be an artifact caused byprolonged storage, or may reflect metabolic erythrocyte abnormalities. Spherocytesare more densely stained and appear smaller because of their rounded shape;they show decreased or absent central pallor. The hemoglobin may appear to beabnormally distributed in erythrocytes, particularly in a form of cell in whichthere is a spot or disc of hemoglobin in the center surrounded by a clear areawhich is, in turn, surrounded by a rim of hemoglobin at the outer edge of thecell, giving the appearance of a target—a target cell

Suchrouleaux formation is normal in the thicker part of the film; when found in theoptimal viewing portion of the film, it may be a result of the presence of anincrease in immunoglobulin (Ig), especially IgM, and suggests the diagnosis ofmacroglobulinemia. Occasionally, very high concentrations of IgA or IgG mayproduce noticeable pathologic rouleaux, as a manifestation of mieloma.

If theplatelet count is normal, approximately 8 to 15 platelets (individually or insmall clumps) should be visible in each oil-immersion (x1000) field. There should be 1 platelet present for about every20 erythrocytes. This is a valuable check when the automated plateletcount is in question or an unexpected result is obtained

Neutrophils areround cells ranging from 10 to 14 m in diameter (see Color Plate VII). The nucleus is lobulated, with two to five lobesconnected by a thin chromatin thread. The defining feature of thesegmented neutrophil is the round lobes with condensed chromatin, because thechromatin thread may overlie the nucleus and not be visible

Bands areidentical to mature polymorphonuclear leukocytes except that the nucleus isU-shaped or has rudimentary lobes connected by a band containing chromatinrather than by a thin thread (see Color Plate X-6). The nuclear chromatin is slightly less condensedthan the mature neutrophil.

Eosinophils are on the average slightly largerthan neutrophils. The nucleus usually has only two lobes. The chromatin patternis the same as that in the neutrophil, but the nucleus tends to be more lightlystained. Thedifferentiating characteristic of these cells is the presence of manyrefractile, orange-red granules that are distributed evenly throughout the celland may be visible overlying the nucleus (see Color Plate VII-3). Thesegranules are larger than those in the neutrophil and are more uniform in size.Occasionally, some of the granules in eosinophils stain light blue rather thanorange-red.

Basophils are similar to the otherpolymorphonuclear cells and are slightly smaller than neutrophils. The nucleusmay stain more faintly and usually is less segmented and has less distinctchromatin condensation than is the case in neutrophils. The large deeply basophilicgranules are fewer in number and less regular in size and shape than in theeosinophil.

Lymphocytes on blood films are usually small, about 10 m in diameter,but larger forms up to 20m in diameter are seen. The small lymphocyte, the predominant type innormal blood, is round and contains a relatively large, round, densely stainednucleus.

Monocytes are thelargest normal cells in the blood, usually measuring from 15 to 22 m indiameter. The nucleusis of various shapes—round, kidney-shaped,oval, or lobulated—and frequently appears to be folded (see Color Plates VII-1,2). The chromatin is arranged in fine strands with sharply defined margins. Thecytoplasm is light blue or gray, contains variable numbers of fine lilac orpurple granules, and is frequently vacuolated, especially in films made fromblood anticoagulated with EDTA.

In mucopolysaccharidoses, coarse, darkgranules may be found in the neutrophils (the Alder-Reilly anomaly) and largeazurophilic granules are often found in some lymphocytes (Gasser cells) andmonocytes. Hugemisshapen granules are found in the polymorphonuclear leukocytes, and giantazurophilic granules are present in the lymphocytes of patients exhibiting the Chédiak-Higashianomaly (see Chaps. 59 and 66).⁷⁴ Auer rods are sharplyoutlined, red-staining rods found in the cytoplasm in blast cells, andoccasionally in more mature leukemic cells, in the blood of some patients withacute myelogenous leukemia.

Light blue round or oval Döhle bodies,about 1 to 2 m in diameter, may be seen in the cytoplasm of neutrophils ofpatients with infections, burns, and other inflammatory states. The blue staining is caused by RNAof the rough-surfaced endoplasmic reticulum contained in Döhle bodies. Similarblue inclusions are seen in patients with the May-Hegglin anomaly.

Thisrefers to abnormal segmentation of the nuclei of leukocytes on the blood film,in which the lobes appear to radiate from a single point, giving a cloverleafor cartwheel picture. This change is common in cytocentrifuged preparations(i.e., from a body fluid), EDTA anticoagulated blood after excessive storage,or samples collected in oxalate.

Clinical Case

2012-01-17T21:36:00.000-08:00

A 75 years old man, who lives alone, is brought to emergency room of the hospital in coma. He is pale, with face, hands and foots swelling; hypotonia and generalized reflex absence without nerologic focal damage. His blood pressure is 80/50mmhg, Hr 55 bpm, Tº 34ºc. Laboratory results shows us: Hb: 11g/dl, White cells C:5300, Glucose: 61mg/dl, BUN: 20mg/dl, creatinine: 1.3mg/dl, Sodium: 129mEq/L, Potassium, 4.8mEq/L; pH:7.37, PaCO2: 49mmhg, Po2:65mmhg. A Head CT and a Chest X-ray are normal.

¿What would be your diagnose?

MYXEDEMA COMA

Myxedema coma, the extreme manifestation of hypothyroidism, is an uncommon but potentially lethal condition. Patients with hypothyroidism may exhibit a number of physiologic alterations to compensate for the lack of thyroid hormone. If these homeostatic mechanisms are overwhelmed by factors such as infection, the patient may decompensate into myxedema coma. Patients with hypothyroidism typically have a history of fatigue, weight gain, constipation and cold intolerance. Physicians should include hypothyroidism in the differential diagnosis of every patient with hyponatremia. Patients with suspected myxedema coma should be admitted to an intensive care unit for vigorous pulmonary and cardiovascular support. Most authorities recommend treatment with intravenous levothyroxine (T4) as opposed to intravenous liothyronine (T3). Hydrocortisone should be administered until coexisting adrenal insufficiency is ruled out. Family physicians are in an important position to prevent myxedema coma by maintaining a high level of suspicion for hypothyroidism.

Myxedema coma is an extreme complication of hypothyroidism in which patients exhibit multiple organ abnormalities and progressive mental deterioration. The term myxedema is often used interchangeably with hypothyroidism and myxedema coma. Myxedema also refers to the swelling of the skin and soft tissue that occurs in patients who are hypothyroid. Myxedema coma occurs when the body's compensatory responses to hypothyroidism are overwhelmed by a precipitating factor such as infection.

A common misconception is that a patient must be comatose to be diagnosed with myxedema coma. However, myxedema coma is a misnomer because most patients exhibit neither the nonpitting edema known as myxedema nor coma.1,2 Instead, the cardinal manifestation of myxedema coma is a deterioration of the patient's mental status.

When only comatose patients are considered, myxedema coma is exceedingly rare: one study reports 200 cases between 1953 and 1996.3 Applying a broader definition results in a significantly higher number of cases. While the actual prevalence of myxedema coma is unknown, its lethal nature demands recognition. Even with early detection and appropriate treatment, mortality ranges from 30 to 60 percent.3,4 Family physicians must be alert to the possibility of undiagnosed hypothyroidism in their patients.

Epidemiology

Hypothyroidism is four times more common in women than in men; 80 percent of cases of myxedema coma occur in females.5,6 Myxedema coma occurs almost exclusively in persons 60 years and older.5More than 90 percent of cases occur during the winter months.6 This seasonal presentation is probably due to age-related loss of the ability to sense temperature and lower heat production secondary to hypothyroidism.7

Historical Features

Patients with myxedema coma usually have longstanding hypothyroidism, although it may not have been previously diagnosed. They often demonstrate classic symptoms of hypothyroidism: fatigue; constipation; weight gain; cold intolerance; a deep voice; coarse hair; and dry, pale, cool skin. However, elderly patients with hypothyroidism often have atypical presentations, such as decreased mobility,8 and some patients with compensated hypothyroidism are asymptomatic.9

PRECIPITATING EVENT

Decompensation into myxedema coma occurs when the hypothyroid patient's homeostatic mechanisms are disrupted. Multiple factors can precipitate myxedema coma (Table 1).1–3,10–14 Some of the more common precipitating factors include infections, particularly pneumonia and urosepsis, and certain medications. Another potential risk factor is failure to reinstate thyroid replacement therapy during hospitalization.

TABLE 1
Factors Known to Precipitate Myxedema Coma

Burns
Carbon dioxide retention
Gastrointestinal hemorrhage
Hypoglycemia
Hypothermia
Infection
	Pneumonia
	Influenza
	Urinary tract infection/urosepsis
	Sepsis
Medications
	Amiodarone (Cordarone)
	Anesthesia
	Barbiturates
	Beta blockers
	Diuretics
	Lithium
	Narcotics
	Phenothiazines
	Phenytoin (Dilantin)
	Rifampin (Rifadin, Rimactane)
	Tranquilizers
Stroke
Surgery
Trauma

Information from references 1 through 3 and 10 through 14.

Physical Findings

Physical findings in myxedema coma (Table 2) may include the classic myxedematous face, which is characterized by generalized puffiness, macroglossia, ptosis, periorbital edema, and coarse, sparse hair. Nonpitting edema of the lower extremities is sometimes present. The findings from a thyroid examination are usually normal, but a goiter may be present in some patients. The presence of a scar on the neck might suggest postsurgical hypothyroidism and may be an important clue in the diagnosis of a patient who is comatose. A neurologic examination may reveal decreased reflex tendon relaxation and will invariably reveal altered mentation.

TABLE 2
Physical Findings in Myxedema Coma

Altered mentation
Alopecia
Bladder dystonia and distension
Cardiovascular
	Elevated diastolic blood pressure—early
	Hypotension—late
	Bradycardia
Delayed reflex relaxation
Dry, cool, doughy skin
Gastrointestinal
	Decreased motility
	Abdominal distension
	Paralytic ileus
	Fecal impaction
	Myxedema megacolon—late
Hyperventilation
Hypothermia
Myxedematous face
	Generalized swelling
	Macroglossia
	Ptosis
	Periorbital edema
	Coarse, sparse hair
Nonpitting edema

ALTERED MENTATION

All patients with myxedema coma display deterioration of their mental status. This decline may be subtle, manifesting as apathy, neglect or a decrease in intellectual function; more obvious changes include confusion, psychosis and, rarely, coma. While all patients with myxedema coma present with some degree of mental status change, few progress to coma. When there is doubt about a change in mental status, formal mental status testing should be performed.

Physicians should also be alert to the possibility of depression in the seemingly demented patient and perform depression screening in any patient with mental status changes. Lumbar puncture may also be clinically appropriate.

HYPOTHERMIA

Another common clinical feature of myxedema coma is hypothermia. The patient's temperature is usually less than 35.5�C (95.9�F).13 Conditions that may precipitate myxedema coma such as hypoglycemia and cold exposure may exacerbate the hypothermia. However, the patient's temperature is not always an accurate diagnostic aid because some patients present with a normal temperature.

BLOOD PRESSURE CHANGES

Patients with compensated hypothyroidism often exhibit diastolic hypertension. Decreased oxygen consumption and lowered body temperature result in peripheral vasoconstriction and central shunting.2Only when the patient has begun to decompensate do these neurovascular mechanisms fail. The patient may then display the hypotension characteristically associated with myxedema coma. Bradycardia, low cardiac output and overall blood volume deficit frequently exacerbate the hypotension.

HYPOVENTILATION

Hypoventilation in myxedema coma results from the body's decreased ventilatory response to hypoxia and hypercapnia.15 Respiratory dysfunction may lead to sleep apnea,16 and respiratory difficulties may be exacerbated by myxedematous infiltration of the tongue and pharynx.15,17 The diaphragmatic weakness induced by hypothyroidism is reversed by thyroid hormone replacement.16,18

Diagnostic Testing

Multiple diagnostic findings are reported in patients with myxedema coma. This disorder impacts thyroid hormone levels, electrolyte levels, creatine kinase (CPK) levels and other laboratory values (Table 3).

TABLE 3
Laboratory Abnormalities in Myxedema Coma

Anemia

Elevated CPK

Elevated creatinine

Elevated transaminases

Hypercapnia

Hyperlipidemia

Hypoglycemia

Hyponatremia

Hypoxia

Leukopenia

Respiratory acidosis

CPK = creatine kinase

THYROID HORMONE

Primary hypothyroidism results from the inability of the thyroid gland to produce adequate amounts of thyroid hormone. Typically, patients with myxedema coma have primary hypothyroidism manifested by low serum levels of thyroxine (T4) and triiodothyronine (T3) and a high thyroid stimulating hormone (TSH) level. However, primary hypothyroidism should be differentiated from secondary hypothyroidism, tertiary hypothyroidism and the low T4 level/low T3 level syndrome (euthyroid sick syndrome).

Secondary hypothyroidism is a result of pituitary dysfunction; tertiary hypothyroidism is caused by a hypothalamic abnormality. If the patient has hypopituitarism, the level of TSH is not increased. The findings of a low T4 level and low-normal or decreased TSH level mandate a search for pituitary abnormalities. However, a low level of serum T4 (and T3) with a normal TSH level may simply indicate that the patient's thyroid function tests have been altered as a result of illness unrelated to the thyroid (euthyroid sick syndrome).

ELECTROLYTE ABNORMALITIES

The hyponatremia seen in myxedema coma is a result of decreased free water clearance. Elevated levels of antidiuretic hormone and/or diminished blood flow to the kidneys are believed to be responsible for the inability to excrete free water.19,20 Hyponatremia is classically associated with a low serum osmolality. The level of serum creatinine is usually high, and while the level of calcium is generally low, it may be elevated.21 Hypoglycemia may be a result of the down-regulation of metabolism seen in hypothyroidism2; it may also indicate the possibility of adrenal insufficiency.

ELEVATED CREATINE KINASE

Patients with myxedema coma may be mis-diagnosed with myocardial infarction based on elevated CPK levels in association with nonspecific electrocardiographic (ECG) findings. Increased CPK and other transaminases are thought to result from altered membrane permeability.22 Fractionation of the CPK reveals a skeletal muscle source. ECG changes include bradycardia, decreased voltages, non-specific ST and T changes, varying types of block and a prolonged QT interval. Conversely, physicians should be alert to the possibility of myocardial infarction as a triggering event for myxedema coma.

OTHER ABNORMALITIES

Arterial blood gases often reveal respiratory acidosis, hypoxia and hypercapnia. Mild leukopenia and a normocytic anemia are also frequently present. However, macrocytic anemia and pernicious anemia caused by associated immune dysfunction are sometimes present.13,23 A chest radiograph may show cardiomegaly and pleural effusions. If cardiomegaly is present, an echocardiogram should be obtained to rule out a pericardial effusion. When performed, lumbar puncture typically reveals elevated protein levels13,15,24 and a high opening pressure. Results of electroencephalography are nonspecific.13

Treatment

The patient with myxedema coma should be admitted to the intensive care unit, and hypovolemia and electrolyte abnormalities corrected. Mechanical ventilation may be necessary. Cardiovascular status should be monitored carefully, especially after intravenous thyroid hormone replacement. Myocardial infarction must be ruled out and blood pressure stabilized. If possible, pressors and ionotropes should be avoided because of their tendency to provoke arrhythmias in the setting of intravenous thyroid replacement. Patients with hypothermia should be covered with regular blankets; the use of warming blankets should be avoided because the resulting peripheral dilatation may lead to hypotension and cardiovascular collapse.

THYROID HORMONE REPLACEMENT

Any patient with suspected myxedema coma should be treated presumptively with thyroid hormone. While there is concern regarding the precipitation of arrhythmias or myocardial infarction by administering large doses of intravenous levothyroxine, this concern must be balanced against T4's potentially life-saving and usually nondetrimental effect.25

While the necessity of intravenous thyroid hormone replacement is apparent, some controversy exists regarding the use and dosages of levothyroxine (T4) and liothyronine (T3). Because of the relatively small number of patients with myxedema coma, controlled studies comparing various dosages of T4 and T3 are lacking. Because T3 is more biologically active than T4, and because the conversion of 26,27 T4 to T3 is suppressed in myxedema coma, some have advocated T3 replacement. However, parental T3 is not only expensive and difficult to obtain, it may also contribute to increased mortality.27

Most authorities therefore recommend use of T4 alone.2,7,13,14,27 An initial levothyroxine dose of 100 to 500 μg administered intravenously should be followed by 75 to 100 μg administered intravenously daily until the patient is able to take oral replacement. The lower initial dose should be administered to patients who are frail or have other comorbidities, particularly cardiovascular disease. Elderly patients typically require 100 to 170 μg of oral levothyroxine daily.13

ANTIBIOTICS

Infection is often the cause of the patient's decompensation; therefore, an infectious etiology should be sought with blood and urine cultures as well as a chest radiograph. Some authorities advocate empiric therapy with broad-spectrum intravenous antibiotics.2

STEROIDS

Because of the possibility of secondary hypothyroidism and associated hypopituitarism, hydrocortisone should be administered until adrenal insufficiency has been ruled out. Hydrocortisone should be administered intravenously at a dosage of 100 mg every eight hours. Failure to treat with hydrocortisone in the face of adrenal insufficiency may result in the precipitation of adrenal crisis. A random cortisol level should be drawn prior to therapy, and if not depressed, the hydrocortisone can be discontinued without tapering. An adrenocorticotropic hormone stimulation test can be administered if clinically warranted.

Prognosis

The prognosis for patients with myxedema coma is difficult to define because of the small number of cases reported in the literature. The severity of the condition, however, is clear. One study reported a mortality rate of about 30 percent, while another suggests the mortality rate may be as high as 60 percent.3,4 Factors associated with a poor prognosis include advanced age, bradycardia and persistent hypothermia.27

Final Comment

Family physicians should be alert for myxedema coma, particularly in elderly women with mental status changes who present during the winter months. An accurate diagnosis generally follows a careful history, physical examination and laboratory evaluation. The most important elements in treatment of myxedema coma are early recognition, presumptive thyroid hormone replacement, hydrocortisone and appropriate supportive care. While myxedema coma carries a significant mortality rate even with appropriate testing and treatment, an early diagnosis of hypothyroidism may well save a patient's life.

Thanks Mr. Rondón for your participation.

Paragonimiasis - NEJM

2012-01-17T05:27:00.000-08:00

An 18-year-old man presented with a 1-year history of episodic hemoptysis. He otherwise felt well, with no dyspnea, fever, night sweats, weight loss, pedal edema, rash, or evidence of bleeding elsewhere. He took no medications. Laboratory examination revealed eosinophilia, with an eosinophil count of 3000 cells per microliter (reference range, 0 to 300). A chest radiograph (Panel A) and an axial computed tomographic image of the chest (Panel B) showed multiple nodules and cavitations (arrows). Eggs from the lung fluke paragonimus were discovered on microscopical examination of bronchoalveolar-lavage fluid (Panel C), confirming a diagnosis of pulmonary paragonimiasis. Paragonimus is acquired by humans through consumption of undercooked freshwater crabs or crayfish. Immature forms migrate through the duodenal wall, peritoneal cavity, and diaphragm to become encapsulated and mature within the pulmonary parenchyma. When the encapsulated cyst bursts, eggs are extruded into the bronchioles and subsequently are coughed up and swallowed, passing back into the environment with the stool. This patient was treated with a course of praziquantel, and the hemoptysis resolved within 2 months.

Marcos Arango Barrientos, M.D.

University of Antioquia School of Medicine, Medellin, Colombia

Alfonso Uriza Carrasco, M.D.
Hospital Universitario San Vicente de Paul, Medellin, Colombia
mabju@yahoo.com

Pelvic inflammatory disease - Williams review

2011-11-30T12:31:00.001-08:00

PelvicInflammatory Disease

Pelvicinflammatory disease (PID) is an infection of the upper reproductive tractorgans. Another diagnosis given to this disease is acute salpingitis. Although all may beinvolved, the organ of importance, with or without abscess formation, is the fallopian tube. Becauseof difficulty in accurately diagnosing this infection, its true magnitude isunknown. Many women report that they have been treated for PID when they didnot have it, and vice versa.

Microbiologyand Pathogenesis

The exactmicrobiologic pathogens in the fallopian tube cannot be known for any givenpatient. Studies have shown that transvaginal culture of the endocervix,endometrium, and cul-de-sac contents revealed different organisms from eachsite in the same patient. Inlaparoscopic studies, cervical pathogens and those recovered from the fallopiantube or cul-de-sac were not identical. For that reason, treatmentprotocols are designed so that most potential pathogens are covered byantibiotic regimens.

Classic salpingitis is that associated with andsecondary to N gonorrhoeae (Table 3-25). Another sexually transmitted disease species frequentlyrecovered from acutely symptomatic women is T vaginalis. The lower reproductive tractflora in those patients and in women with bacterial vaginosis are those inwhich anaerobic species predominate. However, Ness and colleagues (2004) andothers have shown that bacterialvaginosis is not a risk factor for development of PID. The sexually transmitted diseasespecies commonly recovered from women diagnosed with PID and reported inScandinavian studies is C trachomatis. It does not, however, cause anacute inflammatory response.

Upper tract infection is believed to be causedby bacteria from the lower reproductive tract that ascend into the upper tract. It is assumed that ascension of bacteria into the uppertract is enhanced during menstruation due to loss of endocervical barriers. Thegonococcus can cause a direct inflammatory response in the human endocervix,endometrium, and fallopian tube and is one of the true pathogens of humanfallopian tube epithelial cells. If normal human fallopian tube cells incell culture are exposed to potential pathogens such as E coli, Bacteroidesfragilis, or Enterococcus faecalis, no inflammatory responseresults. If the above bacteria are introduced into a fallopian tube cellculture in which gonococci are present and have caused inflammatory damage, anexaggerated inflammatory response results.

Incontrast, withintracellular C trachomatis, cell-mediated immune mechanisms may be responsible forresulting tissue injury. Little direct permanent damage results fromchlamydial tubal involvement (Patton, 1983). Tubal destruction in women withrepeated asymptomatic chlamydia may be the result of a delayed hyperimmuneresponse.

Women with pulmonary tuberculosis can developsalpingitis and endometritis. It is assumed that this pathogen is blood-borne,but ascension may still be a possible route. The fallopian tubes also can be infected bydirect extension from inflammatory gastrointestinal disease, especiallyruptured abscess, i.e., appendiceal or diverticular

Diagnosis

Pelvicinflammatory disease can be segregated into "silent" PID and PID. Of these, PID can be further subdividedinto acute and chronic.

SilentPelvic Inflammatory Disease

It is presumed that this condition results frommultiple or continuous low-grade infection in asymptomatic women. Silent PID is not a clinicaldiagnosis. Rather, it is an ultimate diagnosis given to women with tubal-factorinfertility who lack a history compatible with upper tract infection. Many ofthese patients have antibodies to C trachomatis and/or N gonorrhoeae.At laparoscopy orlaparotomy, these patients may have evidence of prior tubal infection such asadhesions, but for the most part the fallopian tubes are grossly normal.Internally, however, there are flattened mucosal folds, extensive deciliation,and secretory epithelial cell degeneration (Patton, 1989).

AcutePelvic Inflammatory Disease

Criteriafor Diagnosis of Acute Disease

In women who are symptomatic, symptoms developduring or following menstruation. The most recent recommended diagnostic criteria presented by the CDC(2006) are for sexuallyactive women at risk for STDs who have pelvic or lower abdominal pain and otheretiologies are not feasible. Their diagnosis should be PID if they have uterinetenderness, adnexal tenderness, or cervical motion tenderness. One or more ofthe following enhances diagnostic specificity: (1) oral temperature >38.3°C(101.6°F), (2) mucopurulent cervical or vaginal discharge, (3) abundant WBCs onsaline microscopy of cervical secretions, (4) elevated erythrocytesedimentation rate (ESR) or C-reactive protein (CRP), and (5) presence ofcervical N gonorrhoeae or C trachomatis

Symptomsand Physical Findings

Presentingsymptoms may include lower abdominal and/or pelvic pain, yellow vaginaldischarge, menorrhagia, fever, chills, anorexia, nausea, vomiting, diarrhea,dysmenorrhea, and dyspareunia. Patients also may have infective urinarysymptoms. Unfortunately, there is no single symptom or symptom associated witha physical finding that is specific for this diagnosis. Accordingly, otherpossible sources of acute pelvic pain should be considered (see Table 11-1).

In women with acute PID, leukorrhea ormucopurulent endocervicitis is common and is diagnosed microscopically. Inwomen suspected of having acute PID, endocervical testing for both Ngonorrhoeae and C trachomatis should be performed.

Duringbimanual pelvic examination, women with acute pelvic inflammatory disease willusually have pelvic organ tenderness. Cervical motion tenderness (CMT) is typicallyelicited by quickly displacing the cervix laterally with examining vaginalfingers. If a woman haspelvic peritonitis secondary to bacteria and purulent debris that has exudedfrom the fallopian tubes, this rapid peritoneal movement usually causes amarked pain response. Tapping the cul-de-sac with examining finger(s) will givethe examiner similar information. This maneuver usually causes a patientsignificantly less pain because less inflamed peritoneum is involved.

Abdominalperitonitis may be identified by deep probing and quick release of a handplaced on the abdomen. Alternatively, an examining hand may be positioned witha palm against a woman's mid-abdomen and gently and quickly moved back andforth (shake). This will identify abdominal peritonitis, often with lesspatient discomfort. In women with PID and peritonitis, usually only the lowerabdomen is involved. Ifall quadrants are involved, suspicion of a ruptured tubo-ovarian abscess shouldbe heightened

Laparoscopy

InScandinavian countries, women suspected of having acute PID undergo laparoscopyfor diagnosis. Tubalserosal hyperemia, tubal wall edema, and purulent exudate issuing from thefimbriated ends of the fallopian tubes and pooling in the cul-de-sac confirm thisdiagnosis.

Becauseof this routine practice, Hadgu and co-workers (1986) assembled criteria thatpreoperatively clinically predicted acute pelvic inflammatory disease andassessed their validity by the absence or presence of disease at laparoscopy. Criteriaincluded: (1) single status, (2) adnexal mass, (3) age younger than 25 years,(4) temperature >38°C, (5) cervical N gonorrhoeae, (6) purulentvaginal discharge, and (7) ESR >15 mm/hr. The preoperative clinicaldiagnosis of PID was 97-percent accurate if a woman met all seven criteria.Accordingly, due to the cost of laparoscopy, antimicrobial therapy based on aclinical diagnosis in patients with historical and physical findings suggestiveof acute PID is prudent.

Sonography

In womenwith marked abdominal pain and tenderness, appreciation of upper reproductivetract organs during bimanual examination may be limited. In these patients, vaginal sonography may be usedto identify tubo-ovarian abscess or exclude other pathology as the pain source(Figs. 2-15 and 2-16) (Molander, 2001). If sonography does not lead to a cleardiagnosis, computed-tomography (CT) scanning may be indicated

EndometrialBiopsy

In womensuspected of acute PID, some recommend endometrial biopsy to diagnoseendometritis. Polymorphonuclear leukocytes on the endometrial surface correlatewith acute endometritis, whereas plasma cells in the endometrium are found withchronic endometritis. However, women with uterine leiomyomas or endometrialpolyps and no PID frequently also have plasma cells present in the endometriumat endometrial biopsy, as do essentially all women in the lower uterinesegment. This, in the opinion of many, indicates that in women withmucopurulent secretions, an endometrial biopsy would not provide useful informationto alter the diagnosis or therapy (Achilles, 2005).

ChronicPelvic Inflammatory Disease

This diagnosis is given to women who describe ahistory of acute PID and who have pelvic pain. Accuracy of this diagnosis clinically isorders of magnitude less than for acute PID. A hydrosalpinx might qualify as a criterion for thisdiagnosis (Figs. 9–17 and 9–18). Realistically, however, it is ahistologic diagnosis (chronic inflammation) made by a pathologist. Thus, theclinical utility of this diagnosis is limited

Treatment

The mostbeneficial patient outcomes follow early diagnosis and prompt, appropriatetherapy. The primary goal of therapy is to eradicate bacteria, relievesymptoms, and prevent sequelae. Tubal damage or occlusion resulting from infection may lead toinfertility. Rates following one episode approximate 15 percent; two episodes,35 percent; and three or more episodes, 75 percent (Westrom, 1975). Also, ectopic pregnancy risk isincreased six- to 10-fold and may reach a 10-percent risk for those whoconceive. Othersequelae include chronic pelvic pain (15 to 20 percent), recurrent infection(20 to 25 percent), and abscess formation (5 to 15 percent).Unfortunately, women with mild symptoms may remain at home for days or weeksprior to presentation for diagnosis and therapy.

Exactlywhere a patient should be treated remains controversial. There are proposedcriteria that predict better outcome for certain patients with in-hospitalparenteral antimicrobial therapy (Table 3-26). However, the high cost ofin-hospital treatment prevents routine hospitalization for all women given thisdiagnosis

OralTreatment

In womenwith a mild to moderate clinical presentation, outpatient treatment andinpatient therapy yield similar results. Clinical treatment with oral therapy is also appropriatefor women with HIV infection and PID. These women have the same speciesrecovered compared with non-HIV infected patients and response to therapy is similar.

However,if women have more than moderate disease, they require hospitalization.Dunbar-Jacob and associates (2004) showed that women treated as outpatientstook 70 percent of prescribed doses, and for less than 50 percent of theiroutpatient treatment days. If patients are to be treated as outpatients, aninitial parenteral dose may be beneficial. If women do not respond to oraltherapy within 72 hours, re-evaluation is indicated and parenteral therapyshould be initiated either as an inpatient or as an outpatient if home nursingcare is available. This assumes that the diagnosis was confirmed atre-evaluation.

Specifictreatment recommendations from the CDC are found in Table 3-27. As mentionedearlier (Treatment), if patients have been recently to California, Hawaii, theeast coast, or other areas with increased quinolone-resistant strains of Ngonorrhoeae, quinolones should not be used. Anaerobes are believed by some to play animportant role in upper tract infection and should be treated. Althoughprospective clinical trials have established that quinolones alone haveexcellent cure rates, anaerobes are not predictably covered. Hence,metronidazole may be added to improve anaerobic coverage. If patients have BVor trichomoniasis, then metronidazole addition is required, although perhapsnot for 14 days

ParenteralTreatment

Any womanwho has criteria as outlined in Table 3-26 should be hospitalized for parenteral treatment for atleast 24 hours. Following this, if home parenteral treatment isavailable, this is a reasonable option. Alternatively, if a woman will beappropriately treated by one of the oral regimens in Table 3-27, then she canbe discharged on those medications.

Recommendationsfor parenteral antibiotic treatment of pelvic inflammatory disease are found inTable 3-28. Of these antibiotics, oral and parenteral routes of doxycyclinehave almost identical bioavailability, but parenteral doxycycline is caustic to veins. Manyprospective clinical trials have shown that either of the listed cephalosporinsalone, without doxycycline, will bring a clinical cure. For that reason, doxycycline administration couldbe reserved until the patient can take oral medication. Therecommendation is to continue parenteral therapy until 24 hours after thepatient clinically improves and the oral doxycycline should continue tocomplete 14 days of therapy. Alternatively, if the primary reason for providingdoxycycline is to eradicate chlamydia, a 1-g oral dose of azithromycin whilethe patient is in the hospital will also achieve that goal

For women with an abscess, some also administeroral clindamycin (450 mg every 6 hours) or metronidazole (as shown) to completetherapy. Treatment of apatient with an abscess should include parenteral antimicrobial therapy untilthe patient has been afebrile for at least 24 hours, preferably 48 to 72 hours.Surgery is rarely required.Although older recommendations for abscess include hysterectomy andadenexectomy, current antibiotics obviate most surgery. If antibiotic treatment fails, then abscessdrainage alone typically will suffice. Often this is possible percutaneously bya radiologist with CT guidance and should be considered initially for abscesseslarger than 8 cm.

References: Williams Ginecology 9th edition

Clinical Case Nº5

2011-10-30T21:44:00.000-07:00

A 24 years-old man arrives to emergency department complaining dyspnea, fever, coughing blood, astenia, pleuritic pain on the left chest. A Chest X-ray is taken inmediately (image). The leucocyte counting revealed 21.300 cells, with neutrophilia. PaO2 69 mmhg. After 3 days of continues antibiotic treatment with: oral cephalosporins, azytromicin and levofloxacine, the patient stills with the same symptoms. A Broncoscopy is performed without any results.

¿What is the Diagnose?

INTRALOBAR PULMONARY SEQUESTRATION

Intralobarpulmonary sequestration is an uncommon but distinct

clinical entity that may be the unrecognized

causeof recurrent pulmonary infections. Theterm seques-

tration, derived from the Latin verb sequestrure, “to sepa-

rate,” was coined by Pryce in 1946 [l] after his clear

description established intralobar sequestration as a dis-

tinct clinical entity. Generally regarded to result from

disturbed embryogenesis, a sequestration is encountered

in1% to 2% of all pulmonary resections [2]. This malfor-

mation is characterized by cystic nonfunctioning lung

tissuethat usually has no communication with the normal

bronchialtree and that receives its blood supply from an

anomalous systemic artery. The sequestration consistsof

normal lung elements in an abnormal and disorderly

arrangement with variable cartilage, bronchial glands,

a nd alveolar parenchyma. One or moremucus-filled cysts

result from mucous secretion into dilated, obstructed

bronchioles and alveoli, causing compression aletectasis

of surrounding parenchyma (Fig 1). Microscopic commu-

nicationswith adjacent normal lung allow air and, some-

times,bacteria to enter the cysts. If infection is superim-

posed, the cysts may contain purulent material. In the

usualcase there is extensive acute and chronic organizing

inflammation,usually so severe that little normal tissue

remains.Occasionally there is only a single large cyst or a

noncysticmass containing branching bronchi that run in

the direction of the aberrent artery. Apparently it takes

yearsfor these changes to occur, because the disease only

rarelybecomes apparent in early infancy.

Twotypes of pulmonary sequestration exist: an intra-

lobarsequestration, in which the abnormal tissue is partly

surrounded by normal lung and contained within the

visceralpleura, and less commonly, an extralobar type, in

which the abnormal lung tissue has its own distinct

pleural investment and maintains complete anatomical

and physiological separation from the adjacent normal

lung.

Severaltheories have attempted in the past to explain

theembryology of pulmonarysequestration [l, 31. How-

ever,they failed to offer a common pathogenesis to the

multitudeof different clinical presentations. Thepresence

of communications between the intestinal tract and se-

questrationsled Gerle and associates [4] to the develop-

ment of a unified theory of formation of intralobar and

extralobarsequestrations. This theory, supported by the

pathohistologicalstudies of Iwai and co-workers [5], pro-

posesthat an additional or accessory lung bud develops in

theearly embryo from the ventral aspect of the primitive

foregutdistal to the site of formation of thenormal lung

bud. The accessory lung bud migrates caudad with the

normallydeveloping lung and receives its blood supply

fromthe embryonic splanchnic plexus, which has numer-

ousconnections to the primitive dorsal aorta. The vascu-

lar connections to the dorsal aorta persist and form the

anomalousarterial supply of the developing pulmonary

sequestration.

Thetime at which the accessory lung bud develops in

theembryo determines whether the resulting malforma-

tionwill be intralobar or extralobar. The fact that only a

fewsequestrations maintain a patent connection with the

esophagus or stomach may be explained by inadequate mass.

Special interest in this malformation first arose in

blood supply to the communication resulting in itsinvo-

lution [4]. Simultaneously occurring intralobar andextra-

lobarpulmonary sequestrations in which the lesions were

notedto be communicating with the gastrointestinal tract

stronglysupport the common origin theory [6]. Albrecht-

sen[7j reported on a patient with an extralobar pulmo-

narysequestration connected by a narrow lung tissue

pedicle to the left lower lobe. This case represents a

definiteintermediate link between intralobar and extralo-

barsequestration, suggesting these lesionsare intimately

relatedin etiology and pathogenesis. Withregard to the

multitudeof anatomical variations, intralobar andextra-

lobarsequestrations represent part of aspectrum of mal-

formations,designated “bronchopulmonary-foregut mal-

formations”by Gerle and associates [4]. At one end of the

spectrumis a n anomalous arterial supply tonormal lung.

Atthe other end of the spectrum isabnormal pulmonary

tissue but without anomalous arterial supply; namely,

bronchogeniccyst, lobar emphysema, and adenomatoid

malformation.Between these two extremes lie the vari-

antsof sequestration. Recently Rodgersand co-workers

[8]have suggested that the term bronchopulmonary-foregut

malformation is best reserved for those abnormalities of

ventralforegut budding directly involving the pulmonary

parenchymaand originating from either the tracheobron-

chial tree or the gastrointestinal tract,such as bron-

chogeniccysts, sequestrations, and tracheallobes. They

didnot include lobar emphysema and cystic adenomatoid

malformations,which involve local aberrations of paren-

chymaldevelopment.

The presenting complaint in the majority of patients

harboring a sequestration is either repeated localized

pulmonary infections or an asymptomatic intrathoracic

1940when Harris and Lewis [9] reported operative injury

of an anomalous artery to a lower lobe,resulting in the

child’sdeath. Although death due to operativetrauma to

ananomalous artery has subsequently been reported [2],

most studies have shown that pulmonarysequestration

can be diagnosed accurately before operation and that

surgicalresection can usually be carried out safely. This

papersummarizes our clinical experience with the diag-

nosisand management of intralobar sequestration, em-

phasizingthe unfortunate delay in diagnosis often accom-

panyingthis malformation.

Charatecteristics and diferential Diagnose

The position of alesion and its persistence in a relatively young individual raises the index ofsuspicion that the underlying pathology may be the result of a sequesteredsegment. Demonstration of a dominant feeding vessel, usually from the aorta orits major vessels, and venous drainage to the pulmonary veins suggests thediagnosis.

Alternative venousdrainage patterns in ILS include a route directly into the left atrium via theazygos or hemiazygos systems, into intercostals veins, or into the inferiorvena cava (IVC) or superior vena cava (SVC).

The finding ofalternative venous drainage patterns separates pulmonary sequestration from otherdiagnoses, such as infection and tumor, round atelectasis, Bochdalek hernia,and pulmonary infarction. Enlargement of the associated abnormal feedingvessels is a constant feature, and the azygos vein is also frequently enlarged.

Multiple supplyarteries are found in 15% of sequestrations; 73% of sequestrations developblood vessels leading off the abdominal aorta, and 18% develop blood vesselsleading off the thoracic aorta. Rare documented origins include the ascendingaorta and the arch, subclavian, innominate, celiac, right coronary, andcircumflex arteries.

Extralobar sequestration

In ELS, 80% ofsequestrations lie between the lower lobe and the diaphragm. Lesions areusually located in the region of the posterior basal segments of the lowerlobes. Left-sided lesions are more common than right-sided lesions. The massmay be closely associated with the esophagus, and fistulae may develop.

SubdiaphragmaticELS lesions can mimic masses arising in various organs, such as the adrenalgland. In addition, ELS frequently is associated with other congenitalextrapulmonary anomalies. Venous drainage occurs via the systemic circulation.

Many patients withELS present in infancy with respiratory distress and chronic cough; somelesions are diagnosed coincidentally.

Intralobar sequestration

In ILS,sequestrations occur within pulmonary visceral pleurae and do not communicatewith the bronchial tree. ILS is seen in males and females in equal numbers. Thelesions of ILS may be solid, fluid, or hemorrhagic or may contain mucus. Cysticor emphysematous elements may be present, and adjacent atelectasis oftenexists.

Most lesionsappear hypervascular, because of abundant systemic vascularization. Super-addedinfection may lead to some consolidation in adjacent segments, and a chronicinflammatory process may induce localized reactive neovascularization. Mucoidimpaction of a bronchus surrounded by a hyperinflated lung is believed to becharacteristic of ILS.

Intrapulmonarysequestration is usually diagnosed later than ELS, being found in childhood oradulthood when the patient presents with an infection

Radiography

Conventional chest radiographic findings varydepending on the size of the lesion and whether the lesion is infected. Otherfactors that cause abnormal radiographic findings are the presence or absenceof communication with an airway or contiguous lung tissue and the presence ofassociated anomalies

An uninfected sequestration is seen as a well-definedmass or, less commonly, as a cyst in the medial aspect of a posterior lungbase. An infected sequestration tends to appear ill defined, may be associatedwith a parapneumonic effusion, and may contain one or more fluid levels.

Occasionally in ELS, a small bumpmay be seen on the hemidiaphragm or the inferior paravertebral region.

Rarely, a large sequestration maypresent with an opaque hemithorax, with or without ipsilateral effusion.

With a barium/contrast swallowstudy, communication between the GI tract and a sequestrated lung segment hasbeen described and may be demonstrated by means of a contrast-enhancedexamination of the esophagus.

Mass effect is demonstrated onbronchography as displacement of terminal bronchi by the sequestration.Contrast-agent filling of the sequestered segment in intralobar lesions isuncommon, even when air-fluid levels are present within the cyst. In somepatients, a blind intermediate portion of right bronchus may be seen because ofhypoplasia of the middle and lower lobes in ELS. CT scans can demonstrate thelack of bronchi entering a sequestration

Angiography

The blood supply of 75% of pulmonary sequestrations isderived from the thoracic or abdominal aorta. The remaining 25% ofsequestrations receive their blood flow from the subclavian, intercostal,pulmonary, pericardiophrenic, innominate, internal mammary, celiac, splenic, orrenal arteries. The arterial supply typically enters the lung via the pulmonaryligament if the artery originates above the diaphragm. Arteries originatingbelow the diaphragm reach the sequestration by piercing the diaphragm or viathe aortic or esophageal hiatus.

In the rare instance of sequestration in an upperlobe, arterial supply from the internal thoracic artery has been reported. Ifaortography (seen in the images below) is unrevealing, a coronary source shouldbe included in the preoperative search

References

- Medscape

- Intralobar sequestration: a missed diagnose. The annals of thoracic Surgery

Abnormal Uterine Bleeding - Williams Gynecology Review

2011-10-26T19:29:00.000-07:00

Definitions
Hypermenorrea or menorragia: More than 80ml or 7 days of menstrual bleeding
Polymenorrea: Cycles lasting less than 21 days
Metrorragia: Intercycle bleeding

Childhood

Bleeding prior to menarche should be investigated as an abnormalfinding. Initialevaluation should focus on determining the location of the bleeding, becausevaginal, rectal, or urethral bleeding can present similarly. In this agegroup, the vagina, rather than the uterus, is the most common source ofbleeding. Vulvovaginitis is the most frequent cause, but dermatologicconditions, neoplastic growths, or trauma by accident, abuse, or foreign bodymay also be reasons. In addition to vaginal sources, bleeding may alsooriginate from the urethra and may reflect urethral prolapse or infection

Perimenopause

Abnormal uterine bleeding is a frequent clinical problem, accounting for70 percent of all gynecologic visits by peri- and postmenopausal women. As with perimenarchal girls,anovulatory uterine bleeding from dysfunction of thehypothalamic-pituitary-ovarian axis becomes a more common finding in this group.Alternatively, the incidence of bleeding related to pregnancy and sexuallytransmitted disease decreases. With increasing age, there are greater risks ofbenign and malignant neoplastic growth.

Menopause

Bleeding after menopausetypically originates from benign disease. For example, Choo and colleagues(1985) found that the majority of cases resulted from atrophy of theendometrium. Benign endometrial polyps may also cause bleeding in this population.

Pathophysiology

The endometrium consistsof two distinct zones, the functionalis layer and the basalis layer (Fig.8-2). The basalis layer stretches beneath the functionalis, lies in directcontact with the myometrium, and is less hormonally responsive. The basalis serves as areservoir for the regeneration of the functionalis following menses. Incontrast, the functionalis layer lines the uterine cavity, undergoes dramaticchange throughout the menstrual cycle, and ultimately sloughs duringmenstruation. Histologically, the functionalis has a surface epitheliumand underlying subepithelial capillary plexus. Beneath these are organized stroma and glands in whichleukocyte populations are interspersed

Blood reaches the uterusvia the uterine and ovarian arteries (Fig. 38-13). From these, the arcuatearteries are formed and supply the myometrium. These in turn branch into theradial arteries, which extend toward the endometrium at right angles from thearcuate arteries (see Fig. 8-2). At the endometrium-myometrium junction, the radialarteries bifurcate to create the basal and spiral arteries. The basal arteriesserve the basalis layer of the endometrium and are relatively insensitive tohormonal changes (Abberton, 1999; Hickey, 2000b; Weston, 2000). The spiral arteries stretch tosupply the functionalis layer. Their arteriole branches are thought tobe critical in controlling menstruation. Prior to menses these arterioles display increasedcoiling with stasis of blood flow. Subsequently, vasodilatation and bleedingfrom the spiral arteriole and capillary walls ensues. As a result, mostmenstrual blood is lost through these vessels. This is followed by vasoconstriction which leads toendometrial ischemia and necrosis. This necrotic tissue is sloughed withmenstruation.

Postcoital Bleeding

Bleeding following intercourse most commonly develops in women aged 20to 40 years and in those who are multiparous. No underlying pathology is identified in up to twothirds (Rosenthal, 2001; Selo-Ojeme, 2004). If an identifiable lesion isfound, however, it typically is benign (Shalini, 1998). In a review of 248women with postcoital bleeding, Selo-Ojeme and co-workers (2004) found that afourth of cases were caused by cervical eversion (see Chap. 29, Cervix). Othercauses included endocervical polyps, cervicitis, and less commonly, endometrialpolyps.

In some women, postcoital bleeding may be from cervical or other genitaltract neoplasia. The epithelium associated with cervical intraepithelialneoplasia (CIN) and invasive cancer is thin and friable and readily detachesfrom the cervix. In womenwith postcoital bleeding, CIN was found in 7 to 10 percent, invasive cancer inabout 5 percent, and vaginal or endometrial cancer in <1 percent.

Painful intercourse andnoncyclic pain are less frequent in women with abnormal bleeding and usuallysuggests a structural or infectious cause. For example,Lippman and colleagues (2003) reported increased rates of dyspareunia andnoncyclic pelvic pain in women with uterine leiomyomas. Similarly, Sammour and co-workers(2002) correlated increasing pelvic pain with deepening myometrial invasionwith adenomyosis

The incidence and risk ofendometrial carcinoma increases with age and three fourths of women with thismalignancy are postmenopausal. Thus, in postmenopausal patients, the need to exclude cancerintensifies and endometrial biopsy is warranted. In the remaining 25 percent of premenopausal women withendometrial cancer, only 5 percent are less than 40 years of age(Peterson, 1968). Most of these premenopausal women are obese or have chronicanovulation, or both (Rose, 1996). Thus, obese or anovulatory women with abnormal bleeding should alsohave endometrial cancer excluded. The American College of Obstetriciansand Gynecologists (2000) recommends endometrial assessment in any woman olderthan 35 years with abnormal bleeding and in those younger than 35 years who aresuspected of having anovulatory uterine bleeding refractory to medicalmanagement.

Clinical Evaluation

Initially, the site of uterine bleeding must be confirmed becausebleeding may also come from the lower reproductive tract, gastrointestinalsystem, or urinary tract. This is more difficult when there is no activebleeding. In these situations, urinalysis or stool guaiac evaluation may behelpful adjuncts to a thorough examination

Hematologic and B-HCG Testing

A hemogram is useful to evaluate anemia from chronic blood loss as wellas the degree of blood loss in women with menorrhagia. An abnormally low serum ferritin level is asatisfactory predictor of blood loss >80 mL per menstrual cycle(Warner, 2004).

Pregnancy complications are quickly excluded with determination of urineor serum levels of human chorionic gonadotropin (-hCG). Miscarriages andectopic pregnancies may cause simple spotting or lead to life-threateninghemorrhage.

EndometrialBiopsy

Sampling and histologicevaluation of the endometrium in women with abnormal bleeding may discloseinfection or neoplastic lesions such as endometrial hyperplasia, cancer,polyps, or gestational trophoblastic neoplasia

For years, dilatation andcurettage (D&C) was used for endometrial tissue sampling (see Section41-16, Sharp Dilatation and Curettage). But because of the associated surgicalrisks, expense, postoperative pain, and need for operative anesthesia, othersuitable substitutes were evaluated. In addition,several investigators have demonstrated high rates of incomplete sampling andmissed pathology with D&C (Goldstein, 1997; Grimes, 1982; Stock, 1975).

Of suitable substitutesfor D&C, office techniques using metal curettes were implemented to obtainendometrial samples, and these showed significant positive correlations withhistologic results from hysterectomy specimens(Ferenczy, 1979; Stovall, 1989). The main disadvantages, however, were patientdiscomfort, cost, and procedural complications such as uterine perforation andinfection. To minimizethese, a variety of thin, flexible plastic samplers have been evaluated, withcomparable histologic findings from tissues obtained by D&C, hysterectomy,or stiff metal curette (Stovall, 1991). In their meta-analysis of endometrial biopsy tools,Dijkhuizen and co-workers (2000) found the Pipelle (CooperSurgical, Trumbull,CT) to be superior

Despite its advantages, there are limitations to endometrial samplingwith the Pipelle device. First, a tissue sample that is inadequate forhistologic evaluation or an inability to pass the catheter into the endometrialcavity is encountered in up to 28 percent of biopsy attempts (Smith-Bindman,1998). Cervical stenosis is the most common cause of obstruction. An incompleteevaluation necessitates further investigation with D&C, transvaginalsonography, or diagnostic hysteroscopy (Emanuel, 1995). Second, endometrial biopsy has acancer-detection failure rate of 0.9 percent. Thus, a positive histologic result is accurate todiagnose cancer, whereas a negative result does not necessarily exclude it.Therefore, if an endometrial biopsy with normal tissue is obtained, butabnormal bleeding continues despite conservative treatment or if the suspicionof endometrial cancer is high, then further diagnostic efforts are warranted(Clark, 2002; Hatasaka, 2005). Finally, endometrial sampling is associated with a greater percentageof false-negative results if the pathology is focal, such as with endometrialpolyps. Guido and associates (1995) reported false-negative results in11 of 65 patients—17 percent—undergoing Pipelle endometrial sampling forabnormal bleeding. Five of these 11 had malignant tissue present only inendometrial polyps, and another three patients had disease localized to lessthan 5 percent of the endometrial surface. Because of these limitations withendometrial sampling, investigators have evaluated the use of sonography,hysteroscopy, or both to replace or complement endometrial sampling.

TVU

Although the thickness of the endometrium varies, ranges have beenestablished. Granberg andco-workers (1991) found thickness measurements of 3.4 ± 1.2 mm inpostmenopausal women with an atrophic endometrium, 9.7 ± 2.5 mm in those withendometrial hyperplasia, and 18.2 ± 6.2 mm in those with endometrial cancer.Subsequently, a number ofinvestigations have focused on endometrial thickness as it relates to the riskof hyperplasia and cancer in postmenopausal women. Sensitivities of 95 to 97percent have been reported using a measurement of >4 mm for exclusion ofendometrial cancer. Thisguideline can be employed whether or not a patient is taking hormonereplacement therapy (Bakour, 1999; Karlsson, 1995; Tsuda, 1997). Womenwith endometrial thicknesses >5 mm warrant additional evaluation withsaline-infusion sonography (SIS), hysteroscopy, or endometrial biopsy.

Endometrial thicknessguidelines, however, have not been established for premenopausal women. Merz and colleagues (1996) foundthat the normal endometrial thickness in premenopausal women did not exceed 4mm on day 4 of the menstrual cycle, nor did it measure over 8 mm by day 8.In their review, Farquarand co-workers (1999) suggested that a persistent finding of endometrialthickness, independent of cycle day, measuring >12 mm should prompt furtherevaluation in these women, especially in those with risk factors forendometrial carcinoma (see Chap. 33). Risks include extended abnormal uterinebleeding, chronic anovulation, nulliparity, diabetes, obesity, hypertension,and tamoxifen use (Hatasaka, 2005).

Qualities other than endometrial thickness are also considered, andtextural changes may indicate pathology. For example, punctate cystic areas within the endometriummay indicate a polyp. Conversely,hypoechoic masses that distort the endometrium and originate from the innerlayer of myometrium most commonly are submucosal fibroids. Althoughthere are no specific sonographic findings that are characteristic ofendometrial cancer, some findings have been linked with greater frequency. Forexample, intermingled hypo- and hyperechoic areas within the endometrium mayindicate malignancy. Endometrial cavity fluid collections and an irregularendometrial-myometrial junction have also been implicated. Thus, even with a normalendometrial stripe width, endometrial biopsy or hysteroscopy with biopsy shouldbe performed to exclude malignancy when there is heterogeneous endometrial echogenicityor fluid collection.

A major limitation of TVSis the higher false-negative rate in diagnosing focal intrauterine pathology.This results in part from the physical inability of TVS to clearly assess theendometrium when there is concurrent uterine pathology such as leiomyomas orpolyps. These women warrant either saline-infusion sonography or hysteroscopyfor further evaluation.

To perform SIS, a small catheter is threaded through the cervical osinto the endometrial cavity. Through this catheter, sterile saline is infused,and the uterus is distended. Sonography is then performed using a traditionaltransvaginal technique. Saline-infusion sonography (SIS) has also been comparedwith hysteroscopy to detect uterine cavitary focal lesions. De Kroon andco-workers (2003) performed a meta-analysis of 24 studies and reported SIS to equal thediagnostic accuracy of hysteroscopy.

Another disadvantage to SIS is that it is best performed in theproliferative phase of the cycle to minimize false-negative and false-positiveresults. For example, focal lesions may be concealed in a thick, secretoryendometrium. Also, the amount of endometrial tissue that can develop during thenormal secretory phase can be mistaken for small polyps or focal hyperplasia(Goldstein, 2004). For many, SIS has more patient discomfort than TVS, andabout 5 percent of examinations cannot be completed because of cervicalstenosis or patient discomfort. As expected, stenosis is more prevalent inpostmenopausal women (De Kroon, 2003). This rate of incompletion mirrors thatof diagnostic hysteroscopy. Although accurate for identifying focal lesions,SIS may not add to the value of TVS alone to evaluate diffuse lesions such ashyperplasia and cancer. Therefore,in postmenopausal women with abnormal bleeding, and in whom the exclusion ofcancer is more relevant than evaluating focal intracavitary lesions, use of SISas an initial diagnostic tool may not have advantages over TVS alone.

Histeroscopy: This procedure involves inserting an optic endoscope,usually 3 to 5 mm in diameter, into the endometrial cavity (see Section 41-35,Hysteroscopy). The uterine cavity is then distended with saline or anothermedium for visualization. In addition to inspection, biopsy of the endometriumallows histologic diagnosis of visually abnormal areas and has been shown to bea safe and accurate means to identify pathology (van Dongen, 2007). In fact,for many studies done to investigate the accuracy of TVS or SIS for evaluationof intracavitary uterine pathology, hysteroscopy is used as the gold standard for comparison.

The main advantage of hysteroscopy is to detect intracavitary lesionssuch as leiomyomas and polyps that might be missed using transvaginalsonography or endometrial sampling (Fig. 8-10) (Tahir, 1999). In fact, some have advocatedhysteroscopy as the primary tool for the diagnosis of abnormal uterinebleeding. Although it is highly accurate for identifying endometrial cancer, itis less accurate for endometrial hyperplasia. Thus, some recommend endometrial biopsy orendometrial curettage in conjunction with hysteroscopy.

There are other limitations to hysteroscopy. Cervical stenosis sometimeswill block successful introduction of the endoscope, and heavy bleeding maylimit an adequate examination (Beukenholdt, 2003). The use of misoprostol, 100mg orally the evening before and the morning of hysteroscopy, is useful forcervical softening in patients with suspected cervical stenosis. Hysteroscopyis more expensive and technically challenging than TVS or SIS. Many performhysteroscopy in their office, whereas others prefer a day-surgery setting toprovide increased patient analgesia. Obviously, greater cost and anestheticrisks can attend completion in this latter setting. Although it can be painful,use of a 3.5-mm minihysteroscope instead of the conventional 5-mm endoscopesignificantly decreases patient discomfort during office hysteroscopy(Cicinelli, 2003). Associated infection and uterine perforation have beenreported with hysteroscopy, but fortunately their incidence is low.

There is concern that peritoneal seeding with malignant cells may takeplace during hysteroscopy in some women subsequently diagnosed with endometrialcancer (Obermair, 2000; Zerbe, 2000). Caution is advised with hysteroscopy inwomen at high risk for endometrial cancer, and some suggest a negativeendometrial biopsy result is necessary before hysteroscopy is done (Oehler,2003). Although there may be a risk of peritoneal contamination by cancer cellswith hysteroscopy, there is no evidence that the prognosis for patients isworsened.

There is no one clear sequence to use of endometrial biopsy, TVS, SIS,and hysteroscopy when evaluating abnormal uterine bleeding. None of these willdistinguish all anatomic lesions with high sensitivity and specificity. That said, TVS for severalreasons is a logical first step. It is well-tolerated, cost-effective,and requires relatively minimal technical skill. Additionally, it has theadvantage of reliably determining whether a lesion is diffuse or focal. Onceanatomic lesions have been identified, subsequent evaluation requiresindividualization. If endometrial hyperplasia or cancer is suspected, thenendometrial biopsy may offer advantages. Alternatively, possible focal lesionsmay be best investigated with either hysteroscopy or SIS. Ultimately, theselection of appropriate tests depends on their accuracy to characterize themost likely anatomic lesions.

Copper-Containing Intrauterine Device

These intrauterine devices (IUDs) have long been associated withmenorrhagia and metrorrhagia (see Chap. 5, Menorrhagia) (Milsom, 1995; Bilian,2002). Several explanations for this bleeding have been suggested. At the cellular level,unbalanced ratios of prostaglandins and thromboxane have been proposed as apotential source of IUD-induced menorrhagia

Initially, patients withIUD-related bleeding may be managed with empiric trials of NSAIDs (Table8-3). Persistent abnormal bleeding, however, may result from other gynecologicpathology and not from the IUD. These patients should be managed similarly toother women with the complaint of abnormal uterine bleeding. Althoughsonographic evaluation may be limited by IUD shadowing, endometrial biopsy withsmall catheters can be performed without removal of the device.

This system, marketed as Mirena (Berlex, Wayne, NJ) (see Fig. 5-5), canlead to abnormal uterine bleeding in some users.

Combination Hormonal Contraception

Bleeding associated with combination oral contraceptive pills (COCs) iscommon (see Chap. 5, Estrogen Plus Progestin Contraceptives). As many as 30 to50 percent of women experience abnormal uterine bleeding in the first monththat they use combination COCs (Hatcher, 2004). The presumed source of this bleeding stems fromendometrial atrophy, which is induced by the progestin component of COCs.During this process,spiral arterioles do not characteristically coil, and they become thinner andmore sinusoidal. In addition, venules become dilatated and prone tothrombosis. This often leads to local tissue infarction and is thought to bethe cause of breakthrough bleeding

Tamoxifen

This selective estrogen receptor modulator (SERM) is used as an adjunctfor treatment of estrogen-receptor–positive breast cancer. Although itdiminishes estrogen action in breast tissue, its effects on the endometrium stimulate proliferation(see Chap. 12, Breast Cancer Prevention). Tamoxifen use has been linked to endometrial hyperplasia,polyps, and carcinoma as well as uterine sarcomas (Cohen, 2004).

Screening women who use tamoxifen and do not have abnormal bleeding hasnot proved effective. Protocols using sonography or endometrial biopsy failedto effectively identify endometrial cancer in asymptomatic users (Barakat,2000; Love, 1999). As a result, women using tamoxifen should undergo evaluationfor endometrial cancer only when bleeding develops

Dysfunctional Uterine Bleeding

Once organic causes ofabnormal uterine bleeding have been excluded, the term dysfunctional uterinebleeding (DUB) is used. Up to one-half of women with abnormalbleeding will have DUB (Hickey, 2000b). In 80 to 90 percent of these, bleeding results from dysfunction ofthe hypothalamic-pituitary-ovarian axis, which leads to anovulation (seeChap. 16). Becauseanovulatory cycles produce no progesterone to stabilize cyclic withdrawal ofthe estrogen-prepared endometrium, bleeding episodes become irregular andamenorrhea, metrorrhagia, and menorrhagia are common. For example, manywomen with anovulation may have amenorrhea for weeks to months followed byirregular, prolonged, and heavy bleeding.

In the other 10 to 20percent of women with DUB, ovulation occurs cyclically, and menorrhagia isthought to originate from defects in the control mechanisms of menstruation.

Anovulatory DUB

No progesterone is produced when ovulation does not occur, and thusproliferative endometrium persists. At the tissue level, presistent proliferative endometrium is oftenassociated with stromal breakdown, decreased spiral arteriole density, andincreased dilated and unstable venous capillaries (Singh, 2005). At thecellular level, the availability of arachidonic acid is reduced, andprostaglandin production is impaired. For these reasons, bleeding associated with anovulationis thought to result from changes in endometrial vascular structure and inprostaglandin concentration, and from an increased endometrial responsivenessto vasodilating prostaglandins

Ovulatory DUB

Whereas anovulatory DUB results from alterations in vasculararchitecture and tone, ovulatoryDUB is thought to stem predominantly from vascular dilatation alone. Forexample, women with ovulatory bleeding lose blood at rates three times fasterthan women with normal menses, but the number of spiral arterioles is notincreased (Abberton, 1999).Thus in women with ovulatory DUB, it is thought that the vessels supplying theendometrium have decreased vascular tone and therefore increased rates of bloodloss resulting from vasodilatation (Rogers, 2003). A number of causesthat provoke this change in vascular tone have been suggested, andprostaglandins have been strongly implicated

Nonsteroidal Anti-Inflammatory Drugs

These medicines are effective and well-tolerated oral agents commonlyused for the treatment of DUB (see Table 8-3). The rationale for their usestems from the suspected role of prostaglandins in the pathogenesis of DUB. Anumber of investigators have documented the effectiveness of NSAIDs indecreasing DUB-related menorrhagia (Makarainen, 1986b; Marchini, 1995). AmongNSAIDs, there are no differences in clinical efficacy,

Women lose 90 percent of menstrual blood volume during the first 3 daysof menses (Haynes, 1977). Accordingly, NSAIDs are most effective if used withthe onset of menses or just prior to its onset and continued throughout itsduration. Therefore, oneadvantage to NSAIDs is that they are required only during menstruation.Another advantage is that commonly associated dysmenorrhea also improves withNSAIDs.

The so-called "conventional" NSAIDs nonspecifically inhibit bothcyclooxygenase-1 (COX-1), an enzyme critical to normal platelet function, andCOX-2, which mediates inflammatory response mechanisms. They are effectiveanalgesics, but their use with bleeding may not be ideal considering theirinhibitory effects on platelet function. The other class of NSAIDs inhibitsonly COX-2 and does not interfere with platelet aggregation and hemostasis(Leese, 2000). Some have proposed that COX-2 inhibitors might be more effectiveto treat menorrhagia, however, there have been no randomized trials thatvalidate this idea (Hayes, 2002). Additionally, there are now concerns thatlong-term use of COX-2 inhibitors is associated with increased myocardialinfarction, stroke, and heart failure (Solomon, 2005). As a result, furtherinvestigation is needed before routine use of COX-2 inhibitors is recommendedfor menorragia.

Tranexamic Acid

This is anantifibrinolytic drug that exerts its effects by reversibly blocking lysinebinding sites on plasminogen. The resulting decreased plasmin levelsdiminish fibrinolytic activity within endometrial vessels to prevent bleeding. The drug has no effect onother blood coagulation parameters such as platelet count, activated partialthromboplastin time, and prothrombin time (Wellington, 2003).

In women with DUB, there is increased fibrinolytic activity within theendometrium compared with women with normal menses (Gleeson, 1994). Clinically,the drug has been shown effective to reduce bleeding in up to half of womenwith DUB-related menorrhagia (Coulter, 1995; Lethaby, 2000). In addition, tranexamic acidrequires administration only during menstruation and has few minor reportedside effects. These are predominantly gastrointestinal anddose-dependent.

Oral Progestins

As discussed earlier, unopposed estrogen stimulation, resulting from anovulatory cycles,causes proliferation of the endometrium and erratic bleeding. Progestins halt endometrialgrowth and allow for an organized sloughing with their withdrawal(Saarikoski, 1990). Thus, progestin treatment of women with anovulatory DUB isusually successful. Of the oral progestins, either norethindrone—also known asnorethisterone—or medroxyprogesterone acetate may be used. For immediatecontrol of bleeding, norethindrone, 5 mg, is given two or three times daily, ormedroxyprogesterone acetate 10 mg is taken once daily for 10 days. This isfollowed by withdrawal bleeding 3 to 5 days after completion of the eithercourse. For long-term management, similar dosages of these drugs are givenduring days 16 through 25 following commencement of the most recent menstrualflow (Fraser, 1990). Again, withdrawal bleeding will follow cessation eachmonth

In contrast, ovulatorymenorrhagia is not due to a progestin deficiency but may result from alteredprostaglandin synthesis or disruption of hemostasis. As expected, ovulatorymenorrhagia is relatively unresponsive to cyclic administration of oralprogestins (Cameron, 1987, 1990; Preston, 1995; Singh, 2005).

Despite this, women withovulatory DUB may respond to longer treatment schedules. Norethindrone 5 mg ormedroxyprogesterone acetate 10 mg, each given three times orally daily for days5 to 26 of each menstrual cycle have been shown effective (Fraser,1990; Irvine, 1998). Unfortunately, prolonged use of high-dose progestins isoften associated with side effects such as mood changes, weight gain, bloating,headaches, and atherogenic changes in the lipid profile (Lethaby, 1998b). Forthese reasons, they are considered unacceptable by many women for long-term use

Combination Oral Contraceptive Pills

Evidence suggests that these hormonal contraceptives are effective inthe treatment of DUB, and when used long term, reduce flow by 40 to 70 percent(Agarwal, 2001; Fraser, 1991). Advantages to COC use include the additionalbenefits of reducing dysmenorrhea and providing contraception (see Chap. 5,Estrogen Plus Progestin Contraceptives). Their presumed method of action is endometrial atrophy.There may also be diminished prostaglandin synthesis and decreased endometrialfibrinolysis (Irvine, 1999).

In addition to chronic usefor the treatment of dysfunctional uterine bleeding, COCs can be used acutelyto manage menorrhagia. Pills containing at least 30 ug of ethinyl estradiolshould be prescribed. If there is active bleeding, the regimen begins with fourpills every 6 hours until the bleeding has stopped for at least 24 hours. An antiemetic may be needed tocontrol nausea. For most women, bleeding will cease within 48 hours. After the bleeding has stopped,the dosage of COC is decreased to three pills per day for the next 3 days,followed by two pills per day for 3 days. A once-a-day regimen is thencontinued for 21 days to be followed by withdrawal menses. At thispoint, COCs may be stopped or continued for cycle control (Rimsza, 2002).Alternatively, less frequent dosing or smaller doses may also be effective inthe acute management of menorrhagia

Androgens (Danazol and Gestrinone)

Danazol is an isoxazole derivative of the synthetic steroid 17-ethinyltestosterone (see Chap, 10, Androgens). The net effect of danazol creates a hypoestrogenic andhyperandrogenic environment, which induces endometrial atrophy. As aresult, menstrual loss is reduced by approximately half, and it may even induceamenorrhea in some women (Beaumont, 2002; Chimbira, 1980a; Higham, 1993).

For heavy menstrualbleeding, suggested dosing is 100 to 200 mg taken orally every day(Chimbira, 1980b). Unfortunately,this agent has significant androgenic side effects that include weightgain, oily skin, and acne.It is thus usually reserved as a second-line drug for short-term use prior tosurgery

Estrogens, GNH agonists

Levonorgestrel-Containing Intrauterine System

Intrauterine devices were developed for contraceptive purposes, but thelevonorgestrel-containing intrauterine system (LNG-IUS) also provides relief ofmenorrhagia for some women (see Chap. 5, Levonorgestrel-Containing IntrauterineDevice

The LNG-IUS can be used in all women as a first line of treatment ofmenorrhagia in place of oral medications. It is particularly useful forreproductive-aged women who also desire contraception

Dilatation and Curettage (D&C)

Curettage is rarely used for long-term treatment because its effects areonly temporary. In theoccasional woman, D&C is performed to arrest severe bleeding refractory tohigh-dose estrogen administration

Endometrial Destructive Procedures

Although medical therapy is generally used first, over half of womenwith menorrhagia undergo hysterectomy within 5 years of referral to agynecologist. In at least a third of these, an anatomically normal uterus isremoved (Coulter, 1991; Roy, 2004). As alternatives to hysterectomy, lessinvasive procedures have been devised that either destroy or resect theendometrium and lead to amenorrhea in a manner similar to Asherman syndrome

It is problematic that endometrial tissue has tremendous regenerativecapabilities. For this reason, to be successful, destructive procedures mustremove the endometrial functionalis and basalis as well as 3 mm of myometrialdepth. However, the persistence or regeneration of endometrium is possible.Therefore, premenopausal women should be counseled before surgery about theneed for adequate postoperative contraception.

In addition, the American College of Obstetricians and Gynecologists(2007) recommends endometrial sampling prior to surgery. Women with endometrialhyperplasia or cancer should not undergo ablation

Both first- and second-generation procedures require dilation of thecervix to admit the ablative device. They are typically performed using generalanesthesia or conduction analgesia. However, some have described the use ofparacervical block and/or intravenous sedation for second-generation procedures(Fernandez, 1997; Soysal, 2001; Wallage, 2003). Recently, Marsh and co-workers(2005) described the use of thermal balloon ablation using only preoperativeibuprofen.

HIsterectomy

Müllerian Defects

Congenital structural lesions of the reproductive tract may at timescause chronic intermenstrual bleeding superimposed upon normal menstrual cycles(see Chap. 18, Description and Patient Presentation). In such cases, an anomalous partial vaginal septummay collect blood behind it. Although sequestered, a small patent outflow fromthe collection typically allows chronic release. Patients thus describecyclic menses with light but persistent intermenstrual flow

Endometrial Polyp

These soft, fleshyintrauterine overgrowths are comprised of endometrial glands and fibroticstroma and are covered by a surface epithelium (Fig.8-10 and 8-11). Polyps are common, and their prevalence ranges from 10 to 30percent in women with abnormal bleeding (Bakour, 2000; Goldstein, 1997). Asshown in Figure 8-11, intact polyps may be single or multiple, may measure froma few millimeters to several centimeters, and may be sessile or pedunculatedwith a long and slender stalk (Kim, 2004). Most polyps are benign, but hyperplasia develops frequently.Moreover, malignant transformation develops in 1 to 2 percent of polyps

More than 70 percent ofwomen with endometrial polyps will complain of menorrhagia or metrorrhagia (Preutthipan, 2005;Reslova, 1999). It is thought that stromal congestion within the polyp leads tovenous stasis with apical necrosis and bleeding (Jakab, 2005). Althoughbleeding is common, with the introduction of transvaginal sonography, a largenumber of women with asymptomatic polyps have been identified during imaging forother indications

The few risk factors associated with development of endometrial polypsinclude hypertension and obesity as well as tamoxifen use (Reslova, 1999). Mostevidence does not support a link between hormone replacement therapy and polypformation.

Once a polyp has beenidentified, operative hysteroscopy is often the treatment of choice. The technique isdetailed in Section 41-38, Polypectomy. Hysteroscopy and polypectomy is recommended forsymptomatic women or for those with risk factors for malignant transformation(Savelli, 2003; Machtinger, 2005). Conversely, asymptomatic premenopausal women with polyps <1.5 cmcan be observed. There is only a small associated risk of malignanttransformation and high rates of spontaneous resolution.

Endocervical Polyp

These lesions represent overgrowths of benign endocervical stromacovered by epithelium. They appear as single, red, smooth elongated massesextending from the external os (see Fig. 4-13). Polyps vary in size and rangefrom several millimeters to 2 or 3 cm. These common growths are found morefrequently in multiparas and rarely in prepubertal females. Endocervical polypsare typically asymptomatic, but they can cause metrorrhagia, postcoitalbleeding, and symptomatic vaginal discharge.

Endocervical polyps are usually identified by visual inspection duringpelvic examination. In some instances, Pap smear findings of atypical glandularcells have been associated with endocervical polyps (Burja, 1999; Obenson,2000). Although typically benign, malignant transformation may develop in 1percent. Importantly,cervical cancer can present as polypoid masses and can mimic these benignlesions. For this reason, removal and histologic evaluation are recommended foran endocervical polyp.

Endocervical polyps are removed by grasping the polyp with a ring orpolyp forceps. The polyp is twisted repeatedly about the base of its stalk tostrangulate its feeding vessels. With repeated twisting the base will avulse.Monsel solution (ferric subsulfate) can be applied with direct pressure to theresulting stalk stub to complete hemostasis

VWD: Treatments for women with menorrhagia and vWD include desmopressin, plasmaconcentrates, hormonal contraception, antifibrinolytics, and surgery.Combination oral contraceptive pills have been noted to arrest uterinehemorrhage in 88 percent of women (Foster, 1995). Also, Kingman and co-workers(2004) reported that the LNG-IUS effectively decreased blood loss and inducedamenorrhea in 56 percent of women with inherited bleeding disorders.Preliminary success has been found with endometrial ablation for women withvWD-related menorrhagia (El-Nashar, 2007; Rubin, 2004). Hysterectomy, ofcourse, is curative and preoperative consultation with a hematologist isrecommended

Ovarian Cycle Review

2011-10-09T17:11:00.000-07:00

Modestsuppression of pituitary gonadotropin

secretionduring pill intake and recovery of FSH release

during thepill-free week creates a situation resembling the

earlyfollicular phase of the normal menstrual cycle and

allows forsubstantial residual ovarian activity.

Restingprimordial follicles continuously enter the growing

poolthroughout life (for review see Refs. 1–3). The magnitude

of depletion of the primordial follicle pool isdependent

on age and is most pronounced during fetal

development. Oocytes are detectable in fetalovaries after 16

weeks of gestational age. The great majority ofoocytes are

lost after the fifth month of intrauterinelife, when a maximum

of approximately 7 million germ cells have beenreported

(3). Thepresence of growing follicles in fetal ovaries

has beensubstantiated extensively (4). At birth, both ovaries

containapproximately 1 million primordial follicles. Reproductive

life starts with approximately 0.5 millionprimordial

follicles at menarche. Thereafter, loss offollicles takes place

at a fixed rate of around 1000 per month,accelerating beyond

the age of 35. Studies in the rat model suggest indeed

thatfollicle loss is inversely related to the number of primordial

folliclespresent in the ovaries (9). Once follicles are

stimulatedto grow, they can either reach full maturation and

ovulate orbecome atretic. Folliclesare present in the ovary

at different stages of development, and largenumbers of

follicles of different sizes can be observed atany given point

of the menstrual cycle (10). The distribution ofdevelopmental

stages offollicles entering atresia may vary with age (11).

It isgenerally believed that, especially at an early age, loss of

folliclesis largely due to atresia of primordial follicles (12).

It isunknown as yet which factors regulate initiation of

growth ofprimordial follicle (12, 13) and whether maturing

folliclesmay enter atresia at all developmental stages.

When primordial follicles enter the growthphase they

enlarge by an increase in size of the oocytetogether with

granulosa cell proliferation (primaryfollicle). Transition into

the secondary follicle stage involves alignmentof stroma

around the basal lamina and the development ofan independent

blood supply. The stroma subsequently differentiates

into a theca externa (similar to surroundingstroma cells)

and a theca interna layer. Theca interna cells express LH

receptors early on (15). Development of an antral cavity (at

a follicle size ;100 to 200 mm) dividesgranulosa cells in cells

surrounding the oocyte (cumulus) and cells thatborder the

basement membrane. During early preantralfollicle development,

FSH receptors also become detectable ongranulosa

cells. The time spanbetween a primary and an early

antral follicle in the human is unknown but isproposed to

be several months. Subsequent stages from earlyantral to

preovulatory follicles exhibit clearmorphological characteristics,

and the time interval is assessed to beapproximately 3 months.

An increasein the

number ofgranulosa cells is critically important for the advancement

indevelopmental stages of the follicle.

Under normal conditions, only about 400follicles reach the

mature preovulatory stage and ovulate in alifetime. Hence,

loss offollicles due to atresia — with apoptosis [i.e. programmed

cell death(18)] as the underlying cellular mechanism—

rather thangrowth and subsequent ovulation should

beconsidered the normal fate of follicles. The importance of

oxidativestress in inducing atresia (19) and gonadotropins

and variousgrowth factors (‘survival factors’) to suppress

apoptosis(20, 21) has been emphasized recently. FSH decreases

apoptosis in granulosa cells obtained fromhypophysectomized

rats (22) and prevents apoptotic changes ofcultured

preovulatory follicles.

In the human the process of initiation offollicle growth

and subsequent exhaustion of the resting poolof primordial

follicles appears to be regulated independentlyof stimulation

by gonadotropins (24). Follicles become dependent on

stimulationby FSH only at an advanced developmental

stage, aswill be discussed later.

Forinstance,

follicles grow up to the early antral stage inlong-term hypophysectomized

animals

It appears in the human that follicledevelopment

up to the antral stage continues throughoutlife until

depletion of follicles around menopause, evenunder conditions

in which endogenous gonadotropin release isdiminished

substantially (5, 29). Such conditions includeprepubertal

childhood (30 –33), pregnancy (34 –37), and theuse of

steroid contraceptives (see Section IV). In addition,follicle

growth upto the early antral stage has been described in

women withabsent gonadotropin secretion, either due to

hypophysectomy,as discussed by Block (1), or to hypothalamic/

pituitaryfailure.

In the rat

model it has been suggested that theca celldifferentiation

and early preantral follicle growth isdependent on subtle

stimulation byLH.

In contrast to early follicle development,stimulation by

FSH is an absolute requirement for developmentof large

antral preovulatory follicles. Duration and magnitude of FSH.

stimulation will determine the number offollicles with augmented

aromatase enzyme activity and subsequent E2biosynthesis.

High FSHlevels usually occurring during the luteo-

folliculartransition give rise to continued growth of a

limitednumber (cohort) of follicles. Subsequent development

of thiscohort during the follicular phase becomes dependent

oncontinued stimulation by gonadotropins.

in the human only a single follicle from thecohort is

selected to gain dominance and ovulate everycycle. Remaining

cohort follicles enter atresia due toinsufficient support

by reduced FSH levels. The only exception to this rule is

familial dizygotic twins in which ongoinggrowth and ovulation

of multiple follicles occur (46, 47). A reducedrate of

follicle atresia due to altered intrafollicularsteroidogenesis

independent from gonadotropins has recentlybeen proposed

as the underlying cause

Intrafollicularendocrine changes: Themajority of enzymes involved in the biosynthesis of

ovarian steroids belong to the cytochrome P-450gene family

(for review see Refs. 49 and 50). This group ofenzymes

includes: 1) Cholesterol side-chain cleavageenzymes (P-

450SCC), which convert cholesterol topregnenolone. 2) The

P-450C17 enzyme (involving both 17a-hydroxylaseand

C17,20-lyase activity) converts both progestins(pregnenolone

and progesterone) to androgens[dihydroepiandrosterone

and androstenedione (AD), respectively]. 3) Thearomatase

enzyme complex (P-450A ROM), converts androgens[AD

and testosterone (T)] to estrogens (estrone andE2, respectively)

Two enzymes that are not members of the P-450gene

family are also important for gonadal steroidsynthesis: 3bhydroxysteroid

dehydrogenase, converting D5-steroids

(such as pregnenolone) to D4-steroids (such asprogesterone),

and 17 ketosteroid reductase converting AD to Tand estrone

to E2.

The cholesterol side-chain cleavage enzymerepresents the

major rate-limiting step in steroid hormonesynthesis. Moreover,

proteinsinvolved in the acquisition of cholesterol (including

lipoproteinreceptors and enzymes involved in de

novocholesterol synthesis) have also been shown to be im-

In vitro studies using cells isolated fromhuman ovarian

follicles have demonstrated convincingly thattheca cells are

the source of follicular androgens (54, 55) — predominantly

AD(56, 57)—whereas granulosa cells only produceE2 when

androgens are added to the culture medium (58–60). In the

humanovarian follicle, immunocytochemistry (with the use

ofantibodies against specific enzymes, allowing direct visualization

of thedistribution of the enzyme in tissue) as well

as Northernblot analysis of RNA has shown the P-450C17

enzyme to be restricted to the theca cell layer (61, 62), consistent

with thenotion that these cells are the major site of

intrafollicularandrogen production. mRNA levels for

P-450C17are increased dramatically in preovulatory follicles

(63), whichcorrelate well with augmented 17a-hydroxylase

activity ofhuman theca cells in culture

. However,

appreciable quantities of mRNA (63, 65, 66) andthe aromatase

enzyme (62, 67) were observed in dominantfollicles

in the late follicular phase. Theseobservations are in keeping

with the high level of aromatase enzymeactivity expressed

in vitro by granulosa cells obtained frompreovulatory follicles

(59, 68).In addition, mRNA expression is in good agreement

withimmunolocalization of the aromatase enzyme

(66). Synthesis of the P-450AROMenzyme could also be

induced by FSH administration to humangranulosa cells in

culture (69). When follicles mature, granulosa cells also exhibit

elevated mRNA levels for P-450SCC, LH receptor,activin,

and inhibin (70).

The theca interna layer of developing folliclesresponds to

LH and synthesizes androgens (71, 72). AD and its immediate

metabolite T are transferred from the thecalayer to the

intrafollicular compartment. For this reasonthese steroids

are present in large quantities in ovarianfollicles of all sizes

and represent the main steroid produced byearly antral

follicles (73–75). Atretic follicles of all sizes (between 2 and

13 mm diameter) also contain high androgenlevels (57, 76)

and low E2 concentrations (77). Granulosa cells become responsive

to FSH only at more advanced stages ofdevelopment

and are capable of converting the thecacell-derived

substrate AD to E2 by induction of thearomatase enzyme.

This so-called ‘two-gonadotropin, two-cell’concept emphasizes

that adequate stimulation of both theca cellsby LH and

granulosa cells by FSH is required for adequateE2 biosynthesis,

as has been recognized since the 1940s

Large (.8 mm diameter) follicles in the mid-and late

follicular phase of the menstrual cycle containappreciable

(up to 10,000-fold) higher quantities of E2compared with

small follicles, as has been shown by numerous authors (60,

75, 76,83–87). Intrafollicular E2concentrations were up to

40,000-fold higher than those in peripheralplasma, and 20

It has

been demonstrated in IVF patients that acorrelation exists

between the E2/androgen ratio in follicle fluidand follicular

health and fertility potential of oocytes

The magnitude of E2 synthesized by granulosacells in vitro

is dependent on the size of the follicle fromwhich cells were

obtained, with AD metabolized to E2 only bygranulosa cells

from follicles beyond 8–10 mm in diameter (59, 68, 92). Follicle

fluid E2concentrations are also correlated with the

amount ofaromatase activity expressed in vitro (60). In addition,

granulosacells in culture produce larger quantities of

E2 inresponse to similar doses of FSH if cells were obtained

from larger(.8 mm) follicles (59, 68, 92), suggesting increased

sensitivity

Numerous in vitro studies have shown for therat model

that E2 plays important autocrine roles instimulating FSHinduced

granulosa cell proliferation (76, 96),aromatase enzyme

induction (97–99), production of inhibin (100),increase

in E2 and FSH receptors (101), and formation ofLH receptors

on granulosa cells (102, 103). In addition, E2exhibits a paracrine

action on adjacent theca cells by inhibitingandrogen

production.

Based onthese observations,

the concept has arisen that augmentedintrafollicular

E2 production is a conditio sine qua non forongoing

follicle maturation. In fact, absent induction of aromatase

enzyme activity has been widely accepted as theunderlying

cause of follicle maturation arrest andsubsequent anovulation

in PCOS.

In anotherpatient suffering from a

partialP-450C17 (17, 20-lyase step) deficiency, follicle growth

could alsobe achieved after the administration of exogenous

FSH despitelow intrafollicular E2 levels.

Despite a significant increase in serum

FSH levels, in the same order of magnitude asthe intercycle

rise in FSH during the normal menstrual cycle,serum E2

levels remained low. However, development ofmultiple preovulatory

follicles emerged within 14 days. In a single subject,

three large follicles between 13 and 18 mm indiameter

were aspirated, and extremely lowintrafollicular levels of

AD and E2 were found

Theseobservations in the human confirm the two-cell, twogonadotropin

concept foradequate E2 synthesis but also

demonstrateconvincingly that increased E2 production is not

mandatoryfor normal follicle growth up to the preovulatory

stage. It is still uncertain whetherestrogen receptors are present

on granulosa cells from higher primates,including the human.

Collectively,these data suggest that inthe human, E2 is not

required for follicle development. It appearsthat, under normal

conditions, augmented E2 synthesis is merelyassociated

with dominant follicle development, wheregrowth of the

follicle is, in fact, driven by othernonsteroidal (growth) factors.

During thefollicular phase of the normal menstrual cycle

E2 is clearly important for other crucialphysiological processes

such as stimulation of endometrialproliferation, cervical

mucus production, and induction of the midcycleLH

surge and subsequent ovulation. Whether oocytematuration

in the human requires exposure to estrogensremains unclear

at this stage

Ovarianresponse to exogenous

gonadotropins(as estimated by rising serum E2 levels)

was equal,regardless of whether gonadotropins were administered

in thefollicular or midluteal phase of the cycle

The dominant follicle requires continued

though reduced support by FSH. In fact, growthof a single

dominant follicle could be sustained in GnRHantagonisttreated

monkeys by the administration of exogenous FSHin

decremental doses (Fig. 4) (143), suggestingenhanced sensitivity

for FSH when the dominant follicle matures.

Early follicular phase administration of E2

caused a significant reduction in serum FSH anda lengthening

of the follicular phase (144). Moreover, administration

of antiestrogen antibodies in theearly to midfollicular phase

gives rise to elevated serum FSH levels, whichinterferes with

single dominant follicle selection resulting inongoing maturation

of additional cohort follicles

provide invivo evidence for

the conceptthat gonadotropin-responsive follicles are maintained

throughoutthe entire cycle. Follicles can be stimulated

to ongoingand gonadotropin-dependent development

when theappropriate endocrine signal (i.e. elevated serum

FSH levels)is operative. Under normalconditions, elevated

FSH concentrations are present during theluteo-follicular

transition only. Augmented E2 production by themost mature

(dominant) follicle starting around themidfollicular

phase causes a subsequent decrease in FSHlevels due to

negative feedback effects of E2 on the hypothalamic-pituitary

axis. The dominant follicle restricts ongoingmaturation of

other, less mature follicles from the cohortsince FSH levels

drop below their threshold for stimulation ofgonadotropindependent

growth. The dominantfollicle is spared from the

inhibitory influence of reduced FSH stimulationbecause of

increased sensitivity to FSH

FSH threshold and follicle recruitment. Due tothe demise of

the corpus luteum and the subsequent decreasein estrogen

production (148), FSH levels rise at the end ofthe luteal phase

of the human menstrual cycle (149). This intercycle rise is

closely synchronized with ovulation, and FSHlevels start to

increase 12 days after the preceding LH surge (150). As

mentioned previously, initiation of growth ofprimordial

follicles occurs continuously and in a randomfashion

only follicles that happen to be at a moreadvanced

stage of development during the intercycle risein

FSH will gain gonadotropin dependence. The concept that

FSHconcentrations above a certain level, referred to as the

‘FSHthreshold,’ are needed for ovarian stimulation was first

introducedby Brown in 1978 (151) and substantiated more

recently bySchoemaker and colleagues. Theindividual variation

in FSH serum levels at which follicle growthwas initiated

could be assessed to be between 5.7 and 12.0IU/liter

with the use of intravenous administration ofgonadotropins

in PCOS patients.

The threshold level should be

surpassed to ensure ongoing preovulatory follicledevelopment.

This process of rescue of a cohort of folliclesfrom

atresia by FSH stimulation is referred to bymost authors as

‘recruitment.’ The recruited cohort represents a group of

follicles at a comparable (but not identical)developmental

stage. This group offollicles, by chance, happened to leave

the pool of resting follicles around the sameperiod of time

several months before. In contrast, other investigators reserve

this termfor the initiation of growth of primordial

follicles. Morphological and endocrinestudies suggest that healthy

early antral follicles less than 4 mm indiameter are present

throughout the cycle (89), in keeping with theconcept that follicles are continuously available for stimulation by FSH

At the end of the luteal phase, the largesthealthy follicles

observed by morphological criteria have beendescribed to be

between 2 to 5 mm in diameter (10, 89, 154),and the number

of recruitable follicles present is believed tobe between 10

and 20 for both ovaries.

The largest healthy

follicles at the start of the follicular phaseof the cycle have

been reported to exhibit a diameter between 4and 8 mm (94,

155), andno morphological differences exist between these

follicles.These observations strongly suggest that the dominant

follicle isselected at a later stage of the follicular phase

of thecycle. Indeed, exogenousHMG administered during

different phases of the menstrual cycle is mosteffective in

stimulating follicle recruitment ifadministered during the

late luteal or early follicular phase.

Enucleation of the corpus luteum in 10 women

was followed by an immediate and rapid declineof E2 and

progesterone levels. This was followed byrising FSH levels,

renewed follicle growth, and ovulation within16–19 days

after enucleation (159). These experimental results are in full

If the intercycle rise in

serum FSH is shortened by the early tomidfollicular phase

administration of GnRH antagonist, folliclegrowth is arrested

and new follicle recruitment will follow oncemedication

is withdrawn

It may

be proposed that the follicle selected to gaindominance is the

one that has most rapidly acquired the highestsensitivity for

FSH. This may be the follicle that was at the most advanced

developmentalstage when recruited.

with morepronounced E2 production

by cellsobtained from larger follicles (59, 68, 92, 162).

Responsivenessto FSH stimulation is also increased in preovulatory

follicles(164). In addition, in thelate follicular

phase, steroidogenic function of granulosacells from the

dominant follicle is also stimulated by LH (165). Finally,

observations in the monkey suggest thatincreased vascularization

of individual follicles (resulting in thepreferential

exposure to circulating factors) may also beinstrumental in

the selective maturation of preovulatoryfollicles

The FSH ‘gate’ (168) or

‘window’ (169, 170) (Fig. 6, upper panel)concept has been

introduced to emphasize the significance of atransient elevation

of FSH above the threshold. This conceptemphasizes

the importance of time (i.e. duration ofelevated FSH levels)

rather than dose (magnitude of FSH elevation)for single

dominant follicle selection

However, it seems that the initiation

of declining serum FSH levels precedesaugmented

ovarian estrogen output. We have observed aclear association

between the magnitude of decrease in endogenousFSH

serum levels and the E2 rise, indicating thatthe duration of

FSH stimulation (duration of serum FSH abovethe threshold)

is a major determinant for ovarian E2production.

The magnitude of multiple

follicle growth in IVF patients has been shownto be

proportional to the late follicular phaseaccumulation of FSH

in serum (172). These experiments confirm that the duration

(related to the window concept) rather than themagnitude

(threshold concept) of FSH stimulationdetermines the number

of developing follicles.

Inhibin levels did not change during the early

follicular phase.

Follicularphase serum patterns of

inhibin Aappear to be comparable to previously used less

specificassays (175). In contrast,a profound rise in inhibin

B serum levels was observed early in thefollicular phase,

suggesting that it is secreted by recentlyrecruited cohort

follicles in response to FSH. This rapid rise in inhibin B occurs

just after the intercycle rise in FSH. It may be proposed that

inhibin B limits the duration of the FSH rise(narrowing the

FSH window) through negative feedback at thepituitary

level and may therefore be crucial for monofollicle development.

Folliclescould be visualized from

8–10mmonward(181), and usually two to three follicles per

ovary couldbe identified. Growth ofthe dominant follicle is generally

mentioned to be linear, with a mean dailygrowth rate

around 2–3 mm

TVU: Up to 11 follicles (.2 mm indiameter)

could be observed throughout the cycle in eachovary, and

a dominant follicle could be visualized from 10mm onward

(Fig. 9) oncycle day 9 (Table 1). Thesize of nondominant

follicles visualized by TVS always remainsbelow 11 mm.

Theultrasound observation of dominant follicle

selectioncorrelates strongly with a sudden increase in serum

E2concentrations

1.Heterogeneity of FSH. Variant forms of FSH are synthesized

andsecreted by the anterior pituitary, on the basis of differences

inoligosaccharide structure of these glycoproteins

as well asthe number of incorporated terminal sialic acid

residues.

Dependingon the sophistication of techniques

used, up to20 isoforms have been characterized for

human FSH. Heavily sialylated (more acidic)FSH has been

described to exhibit reduced receptor bindingand in vitro.

bioactivity, whereas circulating half-life ofthese forms is

extended. These forms may be desialylated in thecirculation.

In contrast, basic isoforms have been describedto be more

biopotent in vitro (2- to 5-fold), whereas thecirculating halflife

is significantly reduced.

It has been speculated that ovarian folliclesare

recruited in the early follicular phase (whengonadal steroid

feedback is low) predominantly by more acidicFSH isoforms,

whereas follicle selection and rupture laterduring the

follicular phase is dependent chiefly on morebasic FSH

isoforms

The majority of growth factors, such as

insulin-like growth factors (IGF) (226),transforming growth

factor-b, fibroblast growth factor, and activin(227), have

been shown to enhance FSH action in vitro. In contrast, other

growth factors have been shown to inhibit FSH-stimulatedE2

biosynthesis by cultured human or primategranulosa cells,

including inhibin (228), epidermal growthfactor (229 –231),

and IGF binding protein (IGFBPs) (232). Decreased follicle

fluidepidermal growth factor and transforming growth factor-

aconcentrations have been described when follicles mature

(233–235).Moreover, white blood cell-derived cytokines,

such aslike tumor necrosis factor, interferon, or

interleukins,have been proposed to be relevant for human

ovarianphysiology.

Expression of IGF-II and their

binding protein (IGFBPs), as well as IGFreceptors, has been

shown to be dependent on the developmentalstage of the

follicle (238, 239). IGFBP-3 was shown toexhibit structural

similarity with the FSH-binding inhibitor (240), and the IGFBP

profile infollicle fluid has been described to vary during

follicledevelopment, independent from changes in serum

(241).Moreover, proteases capable of specifically decreasing

the levelof IGFBP-4 could be demonstrated in estrogendominant

folliclefluid only

Ovarianmanipulation

HMGpreparations (FSH to LH activity ratio,

1:1), obtained from urine ofpostmenopausal women, are

administered to stimulate follicle growth,whereas pregnant

women provide the urine source for hCGpreparations (with

LH-like activity) to induce ovulation.

It should be stressed that the goal ofinduction of

ovulation is completely different from‘controlled’ ovarian

hyperstimulation for IVF, where the goal is tointerfere with

selection of a single dominant follicle toobtain multiple

oocytes for IVF.

The threshold level was arbitrarily

extrapolated from the first day a folliclebeyond 12mmcould

be observed by transabdominal ultrasound or TVS. No difference

in the FSHthreshold was observed, comparingHMG

vs. FSH.

For a given anovulatory woman, FSH levels‘within

the normal range’ may simply mean FSH levelsbelow the

threshold for ovarian stimulation. Hence, onlythe intercycle

rise in FSH above the threshold may be lackingin these

patients.

Normogonadotropic anovulatory women frequentlysuffer

from PCOS. This heterogeneous group of patients ischaracterized

by ovarianabnormalities (polycystic ovaries) combined

withdistinct endocrine features (elevated serum LH

and/orandrogen levels) (282). Variouslines of evidence

indicate that early follicle development isnormal in these

patients, whereas anovulation is caused bydisturbed dominant

follicle selection (74). This abnormal condition may be

caused by disturbed intraovarian regulation ofFSH action

(129), and therefore response to exogenous FSHmay be different

from normal. Hence, the presence or absence of ovarian

abnormalitiesin patients may influence treatment outcome

afterexogenously administered gonadotropins. This

may explain major differences in the FSHthreshold and

duration of stimulation needed to inducepreovulatory follicle

development in these patients.

Correlationsbetween serum

E2 levels and number and size of follicles havebeen studied

(194, 306), and it was shown that E2 productionis the net

result of all developing follicles. This is insharp contrast to

normal follicle development where estrogens areproduced

by a single dominant follicle only.

Concomitant medication, in addition togonadotropins,

may include: 1) dexamethasone suppression ofadrenal androgen

production (310); 2) GnRH agonists to suppressendogenous

release of LH (and FSH) (311, 312); 3) dopamine

agonists therapy in case of hyperprolactinemia;4) GH in an

attempt to improve ovarian responsiveness(313); and 5)

luteal support either by hCG or progestins.

1. Conventional step-up protocol. Conventionalstep-up dose

regimens for gonadotropin induction ofovulation are characterized

by initial daily doses of two ampoules (5 150IU of

bioactive FSH). Doses may be increased after 5days in the

event that ovarian response is judged to beinsufficient.

Low dose-regimen: step-up regimen forgonadotropin induction of ovulation has

been the preferred method of stimulation inEurope since

1990. This dose regimen is characterized by lowinitial daily

gonadotropin doses ranging between one-half andone ampoule

(38–75 IU of bioactive FSH), and doses are onlyincreased

by one-half ampoule per day after 14 days, incases

of insufficient ovarian response. Pharmacokinetic studies haveindicated that it takes approximately

5 daysbefore steady state FSH levels are reached

whensimilar gonadotropin doses are administered daily

through the intraperitoneal route

Initialdose finding studies have generated a dose regimen

that can beused in clinical practice. We have abandoned the

use of GnRHagonists since 1992 without any loss of clinical

efficacy. Asimilar FSH dose regimen is applied; i.e. a twoampoule/

day starting dose shortly after a spontaneousor

progestagen-induced bleeding, followed by adecrease to one

and one-half ampoules/day once a dominantfollicle can be

visualized by TVS (at least one follicle $ 10mm). The dose

is furtherdecreased to one ampoule/day 3 days after the first

dose reduction.

Reference

- Manipulation of Human Ovarian Function: Physiological

Concepts and Clinical Consequences-1997

Post-term Pregnancy Management Recomendations

2011-09-21T14:39:00.001-07:00

Fetal Growth Restriction - Williams 23th Review

2011-09-02T13:42:00.000-07:00

Each year,approximately 20 percent of the almost 4 million infants in the United Statesare born at the low and high extremes of fetal growth. Although mostlow-birthweight infants are preterm, approximately 3 percent are term

Lin andSantolaya-Forgas (1998) have divided cell growth into three consecutive phases.The initial phase ofhyperplasia occurs in the first 16 weeks and is characterized by a rapidincrease in cell number. The second phase, which extends up to 32 weeks,includes both cellular hyperplasia and hypertrophy. After 32 weeks, fetalgrowth is by cellular hypertrophy, and it is during this phase that most fetalfat and glycogen deposition takes place

The corresponding fetal-growth rates duringthese three phases are 5 g/day at 15 weeks, 15 to 20 g/day at 24 weeks, and 30to 35 g/day at 34 weeks

Forexample, there is considerable evidence that insulin and insulin-like growthfactor-I (IGF-I) and II (IGF-II) have a role in the regulation of fetal growthand weight gain

Fetal-GrowthRestriction

Low-birthweight infants who are small-for-gestational age are oftendesignated as having fetal-growth restriction. The term fetal-growthretardation has been discarded because "retardation" implies abnormalmental function, which is not the intent. It is estimated that 3 to 10 percent of infants aregrowth restricted.

Definition

In 1963, Lubchenco and co-workers published detailed comparisons ofgestational ages with birthweights in an effort to derive norms for expectedfetal size at a given gestational week. Battaglia and Lubchenco (1967) thenclassified small-for-gestational-age (SGA) infants as those whoseweights were below the10th percentile for their gestational age.

Because ofthese disparities, other classifications have been developed. Seeds (1984)suggested a definition based on birthweight below the 5th percentile. Usher andMcLean (1969) suggested that fetal-growth standards should be based on meanweights-for-age with normal limits defined by ±2 standard deviations. Thisdefinition would limit SGA infants to 3 percent of births instead of 10 percent.

Normativedata for fetal growth based on birthweight vary with ethnic and regionaldifferences. For example, infants born to women who reside at high altitudesare smaller than those born to women who live at sea level.

example, afetus with a birthweight in the 40^th percentile may not haveachieved its genomic growth potential for a birthweight in the 80^thpercentile. The rate or velocity of fetal growth can be estimated byserial sonographic anthropometry. Reports suggest that a diminished growthvelocity is related to perinatal morbidity.

Economidesand Nicolaides (1989a) found that the major cause of hypoglycemia in SGAfetuses was reduced supply rather than increased fetal consumption or diminishedfetal glucose production. These fetuses had hypoinsulinemia along withhypoglycemia.

Bycomparison, Economides and colleagues (1989b) measured the glycine:valine ratio in cord blood fromgrowth-restricted fetuses and found ratios similar to those observed in olderchildren with kwashiorkor. Moreover, protein deprivation correlated withfetal hypoxemia. Economides and associates (1990) then measured plasmatriglyceride concentrations in SGA fetuses and compared those with theconcentrations of appropriately grown fetuses. Growth-restricted fetuses demonstratedhypertriglyceridemia that was correlated with the degree of fetal hypoxemia.They hypothesized that hypoglycemic, growth-restricted fetuses mobilize adiposetissue and that hypertriglyceridemia is the result of lipolysis of their fat stores.

Elevated plasma concentrations ofinterleukin-10, placental atrial natriuretic peptide, and endothelin-1, as wellas a defect in epidermal growth factor function, have also been described ingrowth-restricted fetuses.In animals, chronic reduction in nitric oxide—an endothelium-derived,locally acting vasorelaxant—has been shown to result in diminished fetal growth(Diket and associates, 1994). Conversely, Giannubilo and co-workers (2008)showed that placenta-induced nitric oxide synthase was significantly increasedin growth restriction, possibly representing an adaptive response to placentalinsufficiency.

Risk is increased threefold at 26 weekscompared with only a 1.13-fold increased risk at 40 weeks.

Symmetricalversus Asymmetrical Growth Restriction

Campbell and Thoms (1977) described the use of the sonographicallydetermined head-to-abdomen circumference ratio (HC/AC) todifferentiate growth-restricted fetuses. Those who were symmetrical wereproportionately small, and those who were asymmetrical haddisproportionately lagging abdominal growth.

The onset or etiology of a particular fetal insult has beenhypothetically linked to either type of growth restriction. In the instance of symmetrical growth restriction,an early insult could result in a relative decrease in cell number and size.For example, global insults such as from chemical exposure, viral infection, or cellularmaldevelopment with aneuploidy may cause a proportionate reduction ofboth head and body size.

Asymmetrical growthrestriction might follow a late pregnancy insult such asplacental insufficiency from hypertension. Resultant diminished glucosetransfer and hepatic storage would primarily affect cell size and not number,and fetal abdominal circumference—which reflects liver size—would be reduced.Such somatic growth restriction is proposed to result from preferentialshunting of oxygen and nutrients to the brain, which allows normal brain andhead growth—so-called brain sparing. The fetal brain is normally relatively largeand the liver relatively small. Accordingly, the ratio of brain weight to liverweight during the last 12 weeks—usually about 3 to 1—may be increased to 5 to 1or more in severely growth-restricted infants.

Theseresearchers concluded that asymmetrical fetal-growth restriction representedsignificantly disordered growth, whereas symmetrical growth restriction morelikely represented normal, genetically determined small stature.

a womanbegins pregnancy weighing less than 100 pounds, the risk of delivering an SGAinfant is increased at least twofold.

concludedthat the environment provided by the recipient mother was more important thanthe genetic contribution to birthweight.

Poormaternal nutrition and social deprivation.

Mechanismsaffecting fetal growth appear to be different with each. Cytomegalovirus is associated with direct cytolysisand loss of functional cells. Rubella infection causes vascularinsufficiency by damaging the endothelium of small vessels, and it also reducescell división. HepatitisA and B are associated with preterm delivery but may also adverselyaffect fetal growth (Waterson, 1979). Listeriosis, tuberculosis, and syphilis havealso been reported to cause fetal-growth restriction. Paradoxically, withsyphilis, the placenta is almost always increased in weight and size due toedema and perivascular inflammation (Varner and Galask, 1984). Toxoplasmosisis the protozoan infection most often associated with compromised fetal growth.

In a studyof more than 13,000 infants with major structural anomalies, 22 percent hadaccompanying growth restriction.

According to Droste (1992), significantfetal-growth restriction is not seen with Turner syndrome (45,X) or Klinefeltersyndrome (47,XXY).

First-trimesterprenatal screening programs to identify women at risk for aneuploidy mayincidentally identify pregnancies at risk for fetal-growth restrictionunrelated to karyotype. In their analysis of 8012 women, Krantz and associates(2004) identified anincreased risk for growth restriction in those with extremely low free -humanchorionic gonadotropin (-hCG) and pregnancy-associated plasma protein-A(PAPP-A) levels despite normal chromosomes. Similar findings have alsobeen reported for second-trimester quad screening by the First- andSecond-Trimester Evaluation of Risk (FASTER) Trial Research Consortium

Placentary insufficiency

Reanl disease and prediabetes, multiplefetouses

Conditions associated with chronicuteroplacental hypoxia include preeclampsia, chronic hypertension, asthma,smoking, and high altitude

A number ofplacental abnormalities may cause fetal-growth restriction. These are discussedfurther throughout Chapter 27 and include chronic placental abruption, extensive infarction,chorioangioma, marginal or velamentous cord insertion, circumvallate placenta,placenta previa, and umbilical artery thrombosis. Growth failure inthese cases is presumed to be due to uteroplacental insufficiency.

Two classesof antiphospholipid antibodies—anticardiolipin antibodies and lupusanticoagulant—have been associated with fetal-growth restriction. Pathophysiological mechanismsappear to be caused by maternal platelet aggregation and placental thrombosis

Riskfactors, including a previous growth-restricted fetus, increase thepossibility of recurrence. Specifically, the rate of recurrence is believed tobe nearly 20 percent

1. Femur length (FL) measurement istechnically the easiest and the most reproducible

2. Biparietal diameter (BPD) andhead circumference (HC) measurements are dependent on the plane of section andmay also be affected by deformative pressures on the skull

3. Abdominal circumference (AC)measurement is more variable, but it is most commonly abnormal in cases offetal-growth restriction because mostly soft tissue is involved (Fig. 38-5).

An abdominal circumference within the normalrange for gestational age reliably excludes growth restriction, whereas ameasurement less than the 5^th percentile is highly suggestive ofgrowth restriction. Despiteits accuracy, sonography used for detection of fetal-growth restriction hasfalse-negative findings. Dashe and colleagues (2000) studied 8400 live birthsat Parkland Hospital in which fetal sonographic evaluation had been performedwithin 4 weeks of delivery. They reported that 30 percent of growth-restrictedfetuses were not detected.

DopplerVelocimetry

Abnormal umbilical arteryDoppler velocimetry—characterized by absent or reversed end-diastolic flow—hasbeen uniquely associated with fetal-growth restriction (see Chap. 16, Umbilical Artery). The use of Doppler velocimetryin the management of fetal-growth restriction has been recommended as apossible adjunct to techniques such as nonstress testing or biophysical profile.Abnormalities in Doppler flow characterize early versus severe fetal-growthrestriction and represent the transition from fetal adaptation to failure. Early changes inplacenta-based growth restriction are detected in peripheral vessels such asthe umbilical and middle cerebral arteries. Late changes are characterized byabnormal flow in the ductus venosus and aortic and pulmonary outflow tracts, aswell as by reversal of umbilical artery flow.

In a series of 604 neonates < 33 weeks whohad an abdominal circumference < 5^th percentile, Baschat andcolleagues (2007) found that the ductus venosus Doppler parameters were theprimary cardiovascular factor in predicting neonatal outcome. These late changes are felt to reflect myocardialdeterioration and acidemia, which are major contributors to adverse perinataland neurological outcome. In their longitudinal evaluation of 46 growth-restricted fetuses,Figueras and colleagues (2009) determined that Doppler flow abnormalities atthe aortic isthmus preceded those in the ductus venosus by one week.Similarly, Towers and co-workers (2008) prospectively observed 104 fetuses withabdominal circumference < 5^th percentile. They broadly identifiedtwo patterns of progression of Doppler abnormalities: (1) mild placentaldysfunction, which remained confined to umbilical and middle cerebralarteries, and (2) progressive placental dysfunction, which progressedfrom peripheral vessels to the ductus venosus at variable intervals dependingon gestational age. Both groups of investigators stressed that knowledge ofthese patterns of progression is critical for planning subsequent fetalsurveillance and timing of delivery

D Alloimmunization Management

2011-08-29T22:48:00.001-07:00

Algorithm for the overall management of the pregnant patient with RhD alloimmunization.

Rh, rhesus; MCA, middle cerebral artery; MoM, multiple of the median; Hct, hematocrit; EGA, estimated gestational age.

Moise. Rhesus Alloimmunization in
Pregnancy. Obstet Gynecol 2008.