Bone Marrow Failure 

Updated: Dec 11, 2019
Author: Srikanth Nagalla, MD, MS, FACP; Chief Editor: Koyamangalath Krishnan, MD, FRCP, FACP 

Overview

Practice Essentials

The bone marrow failure syndromes include a group of disorders than can be either inherited or acquired. These diseases are disorders of the hematopoietic stem cell that can involve either 1 cell line or all of the cell lines (erythroid for red cells, myeloid for white blood cells, megakaryocytic for platelets). The lymphocytes, which are involved in lymphoproliferative disorders, are usually spared (see the image below). (See Etiology.)

This bone marrow film at 400X magnification demons This bone marrow film at 400X magnification demonstrates a complete absence of hemopoietic cells. Most of the identifiable cells are lymphocytes or plasma cells. Photographed by U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland (http://www.aum.iawf.unibe.ch/).

The inherited bone marrow failure syndromes (IBMFS) include Fanconi anemia, dyskeratosis congenita, Diamond-Blackfan anemia, and other genetic disorders.[1] The most common cause of acquired bone marrow failure is aplastic anemia. (See Etiology, Presentation, Workup, and Treatment.)[2]

Diseases that can present in a manner similar to acquired bone marrow failure include myelodysplastic syndromes, paroxysmal nocturnal hemoglobinuria, and large granular lymphocytic leukemia. (See DDx.)

For patient education information, see Anemia.

Etiology

Bone marrow failure can be inherited or acquired and can involve a single hematopoietic stem cell line or all three cell lines. These etiologies involve the following:

  1. A decrease in or damage to the hematopoietic stem cells and their microenvironment, resulting in hypoplastic or aplastic bone marrow
  2. Maturation defects, such as in vitamin B12 or folate deficiency
  3. Differentiation defects, such as myelodysplasia

Damage to hematopoietic stem cells can be congenital or acquired. Mechanisms include the following:

  • An acquired stem cell injury from viruses, toxins, or chemicals (eg, chloramphenicol, insecticides[3] ) that leads to a quantitative or qualitative abnormality

  • Abnormal humoral or cellular control of hematopoiesis

  • An abnormal or hostile marrow microenvironment

  • Immunologic suppression of hematopoiesis (ie, mediated by antibodies, T cells [or cellularly], or lymphokines)

  • Mutations in genes, causing inherited bone marrow failure syndromes; identification of these relevant mutations has led to progress in defining the precise functions of the corresponding proteins in normal cells

Inherited bone marrow failure syndromes

The genetic abnormalities in the inherited bone marrow failure syndromes (IBMFS) have been identified in the following disorders[4, 5] :

  • Dyskeratosis congenita
  • Shwachman-Diamond syndrome
  • Diamond-Blackfan anemia
  • Amegakaryocytic thrombocytopenia
  • Congenital neutropenia
  • Telomere biology disorders
  • GATA2 deficiency syndrome

Fanconi anemia is inherited in either an autosomal recessive or X-linked fashion. Twelve Fanconi anemia (FANC) genes have been identified. These genes collaborate in a complicated pathway (FA pathway) that is responsible for the repair of DNA damage. One of these genes (FANCD1) is the breast/ovarian susceptibility gene (BRCA2).

Dyskeratosis congenita is inherited in an X-linked recessive, autosomal dominant, or autosomal recessive manner. Patients with the X-linked form have mutations in DKC1 at band Xq28, a gene that encodes for dyskenin, in a protein involved in the telomere maintenance pathway. Other patients have mutations in band 3q26 in TERC, a part of the telomerase complex, and still others have mutations in the telomerase reverse transcription (TERT) enzyme.[6]

Shwachman-Diamond syndrome is an autosomal recessive disorder in which the majority of patients have a mutation in the Shwachman Bodian Diamond syndrome gene (SBDS), located at band 7q11.

Amegakaryocytic thrombocytopenia is an autosomal recessive disorder with biallelic mutations in the thrombopoietin receptor, MPL, at the band 1p34 location.

Diamond-Blackfan anemia is an autosomal dominant disease in which 25% of patients were found to have a mutation in the gene for small ribosomal protein (RPS19), located at band 19q13.2.

In half of the patients, severe congenital neutropenia is associated with dominant mutations in neutrophil elastase (ELA2, located at band 19p13.3), while a few patients have mutations in GFI-1.

Thrombocytopenia absent radii syndrome is associated with bone marrow failure, but no genetic defect for bone marrow failure has been identified in this autosomal recessive disorder.

Germline mutations in GATA2 cause an autosomal dominant heterogeneous IBMFS characterized by susceptibility to infection, pulmonary and vascular/lymphatic dysfunction, autoimmunity, and malignancy. Wlodarski  and colleagues identified germline GATA2 mutations in 28 (7%) of 426 children age 18 years or younger with sporadic MDS in Germany.[7]

Next-generation sequencing has broadened the spectrum of possible etologic germline mutations. In a cohort of 179 patients (from 173 families) with bone marrow failure of suspected inherited origin, genomic DNA from skin fibroblasts using whole-exome sequencing were analyzed. Causal or likely causal germ line mutations were assigned in 86 patients (48.0%), involving a total of 28 genes. These included genes in familial hematopoietic disorders (GATA2, RUNX1), telomeropathies (TERC, TERT, RTEL1), ribosome disorders (SBDS, DNAJC21, RPL5), and DNA repair deficiency (LIG4).[8]

Many patients had an atypical presentation, and the mutated gene was often not clinically suspected. Mutations in genes seldom reported in IBMFS were also identified, such as SAMD9 and SAMD9L (N = 16 of the 86 patients, 18.6%), MECOM/EVI1 (N = 6, 7.0%), and ERCC6L2 (N = 7, 8.1%), each of which was associated with a distinct natural history; SAMD9 and SAMD9L patients often experienced transient aplasia and monosomy 7, whereas MECOM patients presented early-onset severe aplastic anemia, and ERCC6L2 patients, mild pancytopenia with myelodysplasia.[8]  

Constitutional causes

Constitutional aplastic anemia is associated with chronic bone marrow failure, congenital anomalies, familial incidence, or thrombocytopenia at birth. Constitutional causes of aplastic anemia include the following conditions:

  • Fanconi anemia - Characterized by familial aplastic anemia, chromosomal breaks, and, in some cases, congenital anomalies of the thumb or kidneys

  • Dyskeratosis congenita - Another rare disorder, dyskeratosis congenita has a characteristic dermatologic manifestation of nail dystrophies and leukoplakia; patients with this disease develop aplastic anemia in their second decade of life

  • Shwachman-Diamond syndrome - This disorder consists of exocrine pancreatic insufficiency and bone marrow failure; occasionally, cartilage and hair hypoplasia occur, resulting in short stature and dysostosis

Single cytopenias

Pure red cell aplasia may be a secondary disorder caused by a thymoma. It may also occur transiently, resulting from a viral infection, as with parvovirus B19. Pure red cell aplasia also may be permanent, as a result of viral hepatitis. Finally, it may arise from lymphoproliferative diseases (eg, lymphomas, chronic lymphocytic leukemia) or collagen vascular diseases (eg, systemic lupus erythematosus, refractory anemia), or it may occur during pregnancy.

Amegakaryocytic thrombocytopenic purpura has been reported to occur as a result of causes similar to those for pure red cell aplasia.

Early forms of myelodysplastic syndrome initially can manifest as a single cytopenia or, more often, as a bicytopenia.

Pancytopenia

A decrease in all three cell lines is the most common manifestation of bone marrow failure. Aplastic or hypoplastic anemia can be idiopathic in nature, or it can develop from secondary causes. Myelodysplastic anemia also can cause pancytopenia. Myelophthisic anemia may result from marrow destruction because of tumor invasion or granulomas.

Epidemiology

The prevalence of bone marrow failure resulting from hypoplastic or aplastic anemia is low in the United States and Europe (2-6 cases per million persons) compared with the prevalence of bone marrow failure resulting from acute myelogenous leukemia and multiple myeloma (27-35 cases per million persons). The frequency of myelodysplasia, on the other hand, has increased from 143 cases reported in 1973 to about 15,000 cases annually in United States. This is an underestimation of the actual prevalence, which is believed to be about 35,000-55,000 new cases a year.

In Japan and the Far East, the frequency of bone marrow failure is at least 3 times higher than it is in the United States and Europe. Mexico and Latin America also have high occurrence rates, which are attributed to the liberal use of chloramphenicol. Environmental factors and the pervasive use of insecticides have been implicated as causes of this disease. The incidence of myelodysplasia has been estimated to be around 4-5 per 100,000 population per year in Germany and Sweden.

Prognosis

The prognosis of bone marrow failure depends on the duration of the marrow function abnormality. Most inherited forms of bone marrow failure, such as Fanconi anemia, are associated with transformation into leukemia several years later. Viral causes, such as parvoviruses, are usually self-limiting.

Acquired idiopathic aplastic anemia is usually permanent and life threatening. Half of the patients die during the first 6 months.

Morbidity and mortality

Bone marrow failure resulting in failure to produce one, two, or all three blood cell lines increases patient morbidity and mortality.

Morbidity and mortality from pancytopenia are caused by low levels of mature blood cells. Severe anemia can cause high-output cardiac failure and fatigue. Neutropenia can predispose individuals to bacterial and fungal infections. Thrombocytopenia can cause spontaneous bleeding and hemorrhage.

The severity and extent of cytopenia determine prognosis. Severe pancytopenia is a medical emergency, requiring rapid institution of definitive therapy (ie, early determination of supportive care and bone marrow transplant candidates).

Transfusion complications

Over time, the transfusion of packed red cells increases the patient’s total iron load. Increased levels of iron are toxic to various organs, including the heart, and iron toxicity can cause arrhythmia by blocking the bundle of His, diabetes by damaging the islets of Langerhans in the pancreas, and liver cirrhosis. (Iron can also produce bronze coloration in fair-skinned individuals.) Therefore, it is necessary to measure a patient’s iron stores (in the form of ferritin).

Administering a chelating agent is an effective method of removing excess iron. Chelating agents are composed of molecules that bind tightly with free iron and remove the iron by carrying it as the agents are excreted from the body.

Desferrioxamine is the iron chelator available in parenteral form. If given intravenously, its activity is short and it is excreted rapidly by the kidneys. A subcutaneous infusion given continuously by a portable pump for 3-4 hours every 12 hours is the preferred method. It optimizes the binding of the chelator to the free iron. As more free iron is excreted, storage iron is mobilized into the free form. This treatment can be performed in an outpatient setting.

Monitoring serum ferritin levels and measuring total iron urinary excretion can determine the effectiveness of therapy. Most tissue damage can be reversed with timely chelation, except for cirrhosis of the liver (once it has set in).

 

Presentation

History

Patients with bone marrow failure present with low blood counts. Low platelet counts predispose patients to spontaneous bleeding in the skin and mucous membranes. Neutropenia places the patient at risk for serious infections. Bleeding complications are usually the most alarming symptom, and infections prompt individuals to visit the emergency department.

Weakness and fatigue resulting from anemia can develop slowly. Months may elapse before the patient seeks medical help for these symptoms.

Family and personal medical histories can help to distinguish inherited causes from acquired causes. Inherited bone marrow failure is usually diagnosed in young adults but may be missed until their fifth or sixth decade of life. These diseases should be considered if any of the following are present: subtle, but characteristic, physical anomalies; hematologic cytopenias; unexplained macrocytosis; myelodysplastic syndrome or acute myelogenous leukemia; or squamous cell cancer even in the absence of pancytopenia or a positive family history.

Cases in which siblings of a patient with known Fanconi anemia have developed abnormal blood counts should be investigated. Exposure to toxins, drugs, environmental hazards, and recent viral infections (eg, hepatitis) should be noted.

Physical Examination

The manifestations of bone marrow failure relate to the clinical effects of low blood counts. Patients with severe anemia may present with pallor and/or signs of congestive heart failure, such as shortness of breath. Bruising (eg, ecchymoses, petechiae) on the skin, gum bleeding, or nosebleeds frequently are associated with thrombocytopenia. Fever, cellulitis, pneumonia, and sepsis can be complications of severe neutropenia.

Fanconi anemia, a form of inherited bone marrow failure, has characteristic physical developmental anomalies, including absent thumbs, absent radius, microcephaly, renal anomalies, short stature, and abnormal skin pigmentation (ie, café-au-lait and hypopigmented or hyperpigmented spots). However, as many as half of all patients with Fanconi anemia may not exhibit obvious developmental or cutaneous manifestations, and it is increasingly clear that the diagnosis should be considered in adults with bone marrow failure, myelodysplastic syndrome, or early onset of epithelial cancer.

 

DDx

Diagnostic Considerations

Conditions to consider in the differential diagnosis of bone marrow failure include the following:

  • Myelodysplastic syndromes

  • Large granular lymphocytic leukemia.

  • Immune pancytopenias in connective tissue disorders  (eg, refractory anemia in systemic lupus erythematosus)

An evaluation for IBMFS should be considered for all patients presenting with AA, MDS, acute myeloid leukemia (AML), and chronic unexplained cytopenias. This assessment is likely most critical for patients who are younger than age 40 years at presentation, but diagnoses of some patients with IBMFSs have been reported into their 50s or older. Patients with excess hematologic or other toxicities during treatment of an early-onset solid tumor characteristic of the IBMFSs also warrant an evaluation.[5]

Differential Diagnoses

 

Workup

Approach Considerations

Laboratory features of bone marrow failure include a single cytopenia, as in pure red cell aplasia, and amegakaryocytic thrombocytopenic purpura or pancytopenia, as in aplastic anemia.

Peripheral blood findings

Anemia is common, and red cells appear morphologically normal. The reticulocyte count usually is less than 1%, indicating a lack of red cell production. Occasionally, the mean cell volume is elevated, with macrocytosis.

Platelet counts are lower than normal, with a paucity of platelets in the blood smear. Platelet size is normal, but a low platelet count may cause greater heterogeneity in size.

Agranulocytosis (ie, a decrease in all granular white blood cells, including neutrophils, eosinophils, and basophils) and a decrease in monocytes are observed. A relative lymphocytosis occurs (ie, increased percentage) without an increase in numbers.

Ham test

The Ham test, or sucrose hemolysis test, result may be positive in a patient with underlying paroxysmal nocturnal hemoglobinuria, but a recent transfusion with packed red blood cells may induce a false-negative test result (ie, testing normal, transfused red cells). Folate, vitamin B-12, and serum erythropoietin levels usually are increased.

Fanconi anemia screening

Fanconi anemia should be considered in all young adults and children with hypoplastic or aplastic anemia[9] or cytopenia, unexplained macrocytosis, myelodysplastic syndrome, acute myelogenous leukemia, epithelial malignancies, or subtle, but characteristic, physical anomalies.

The criterion standard screening test for Fanconi anemia is based on the characteristic hypersensitivity of Fanconi anemia cells to the crosslinking agents (eg, mitomycin C, diepoxy butane [DEB], cisplatin). Expose a culture of replicative cells (ie, phytohemagglutinin [PHA]–stimulated peripheral blood lymphocytes or skin fibroblasts) to low doses of mitomycin C or DEB. Then examine the cells in metaphase, looking for evidence of chromosomal breaks and radial chromosomes.

Identification of gene mutations

Mutated genes can be identified by retroviral complement studies, by direct sequencing, or by denaturing high-performance liquid chromatography (DHLP).

Dyskeratosis congenita screening

Screening for dyskeratosis congenita should be considered in children and adults who have (1) bone marrow failure, acute myelogenous leukemia, or myelodysplastic syndrome; (2) negative mitomycin C and DEB test results, which would rule out Fanconi anemia; and either (3) hypopigmented macules, reticulated hypopigmentation, dystrophic nails, or oral leukoplakia or (4) evidence in their family history, obtained via genomic deoxyribonucleic acid (DNA) screening, of X-linked or autosomal dominant forms of dyskeratosis congenita (DKC1-3).

Diamond-Blackfan anemia and Shwachman-Diamond syndrome characteristics

Diamond-Blackfan anemia is a pure red cell aplasia and usually manifests in early infancy. Shwachman-Diamond syndrome is a syndrome of bone marrow failure (classically neutropenia), exocrine pancreatic insufficiency, and metaphyseal dysostosis that also manifests in early childhood.

Histologic findings

Bone marrow studies provide information to definitively diagnose failure, and the status of precursor cells of each cell line can be examined. Pure red cell aplasia characteristically affects erythroid progenitor cells; amegakaryocytic thrombocytopenia is evidenced by a lack of megakaryocytes. A finding of hypoplastic bone marrow differentiates aplastic anemia from aleukemic leukemia, which produces blast cells in the marrow.[10]

Imaging Studies

Bone marrow activity can be measured by radiographic methods. Ferrokinetic studies have been conducted using a radioactive label, such as iron-59 or indium-111, both of which are taken up by erythroid cells. Radioactive iron is no longer available in the United States.

Magnetic resonance imaging (MRI) can be used to differentiate densities and intensity signals of bone marrow fat cells from densities and intensity signals of hematopoietic cells.

Positron emission tomography (PET) scanning with radiolabeled oxygen can measure the metabolic activity difference between hypoplastic marrow and cellular marrow.

Bone Marrow Aspirate and Biopsy

A bone marrow aspirate and biopsy should be performed to assess the cellularity and morphology of the residual cells. In general, the marrow is replaced with fat cells and stromal cells are replaced with lymphocytes, with very few hematopoietic cells. Occasionally, localized pockets of marrow are present (ie, from a sampling error), which can be misleading. To evaluate cellularity, the core biopsy specimen should be at least 1 cm long.

Residual erythroid cells may show evidence of dysplasia with nuclear-cytoplasmic maturation dissociation (commonly described, in the absence of a folate or vitamin B-12 deficiency, as megaloblastoid features).

 

Treatment

Approach Considerations

Supportive care is essential for patient survival. In patients with bone marrow failure, the resulting cytopenia can lead to life-threatening symptoms.

Anemia can cause fatigue and can impair the patient's ability to function in daily activities. Impaired heart function can be aggravated into congestive heart failure by increasing oxygen demands on the heart and other tissues.

If clinically indicated, initiate a blood transfusion using specific cells, such as packed red cells for anemia and platelets for thrombocytopenia. Clinical indications for red cell transfusions are symptoms secondary to anemia and bleeding from thrombocytopenia. Supportive care gives only temporary relief of symptoms and does not treat the primary disease.

Bone marrow transplantation (BMT) candidates are patients who are younger than age 55 years who have severe disease and a matched, related donor.[11] With current BMT regimens, most patients with severe aplastic anemia have a 60-70% long-term survival rate. Survival rates of higher than 80% are reported for patients in more favorable subgroups. Using matched, unrelated donors still is less favorable (11-20% survival rates).

Patients with inherited bone marrow failure and a matched sibling are excellent candidates for hematopoietic stem cell transplantation (HSCT). A caveat is the patients’ extraordinary sensitivity to chemotherapeutic agents and radiation used in conditioning regimens, which must both be reduced to avoid fatal toxicities. Consider saving cord blood from healthy siblings when identified.

Consultations

Hematologists should manage patients with bone marrow failure. Additionally, an infectious disease specialist may be necessary. In severe cases, early consideration for BMT should be initiated.

Pharmacologic Therapy

Infections resulting in neutropenia should be treated as emergencies. After blood is drawn and other cultures are taken, broad-spectrum antibiotics should be started empirically in the presence of febrile neutropenia. Coverage for the most common gram-positive and gram-negative organisms should be considered. With the new broad-spectrum antibiotics, a single antibiotic generally is sufficient. The choice can be altered later, depending on the results of sensitivity tests from positive cultures.

Sepsis, pneumonias, urinary tract infections, and cellulitis with bacterial organisms are common complications of neutropenia. The risk is moderate with actual or total neutrophil counts of 500-1000, and the risk is high at levels below 500.

The addition of antifungal agents should be considered in the presence of persistent fever despite adequate antibacterial coverage. Liposomal amphotericin B is indicated if renal dysfunction is present because of toxicity resulting from the drug in another form.

Patients with severe aplastic anemia who receive antithymocyte globulin (ATG) or antilymphocyte globulin (ALG) but do not receive BMT have a 41% response rate and a 1-year survival rate of 55%.[12] The addition of androgens increases response rates to 70%, with a 1-year survival rate of 76%. Although their roles are unknown, ATG or ALG should be given with corticosteroids to prevent serum sickness.

High-dose corticosteroids, using methylprednisolone (20 mg/kg/day with rapid taper), have been administered in countries where ATG or ALG is expensive; response rates are 38%. Cyclosporine therapy at 200-400 mg/day (maintain serum trough levels at 100-250 ng/mL) has a reported 85% hematologic remission rate.

Androgens were used in the past, but most are masculinizing and poorly tolerated by females and children. A variety of androgen formulations have been used, from testosterone propionate and nandrolone decanoate to oxymetholon and oxandrolone. Danazol is a nonmasculinizing androgen that may be useful. The response rate is limited to approximately 45%, and results may require 6-10 months of therapy. Androgen treatment may result in liver dysfunction, adenomas, and adenocarcinomas, and patients should have liver function tests performed every 3 to 6 months and hepatic lesions assessed by ultrasonography every 6 months. Hematologic responses to oxymetholone and danazol are comparable, but liver toxicity appears to be more common with oxymetholone.[13]

Hematopoietic growth factors, such as granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF), may be useful in patients with neutropenia who have infections, without requiring a white blood cell transfusion.

Mucosal bleeding from the nose, gums, or teeth may be easily controlled with oral aminocaproic acid (Amicar 500-mg tab or 500 mg/mL elix). The dose of aminocaproic acid can be as high 6-8 g/day, in divided doses every 6-8 hours. Hypotension is the dose-limiting symptom. Disseminated intravascular coagulation (DIC) and clots in the urinary tract are contraindications. This therapy is useful in the long-term maintenance of severe thrombocytopenia in patients with bone marrow failure.

Transfusion

Transfuse packed red cells to maintain hemoglobin levels of 7-10 g/dL. Patients with coronary artery disease may need to be maintained at 10-12 g/dL if they are symptomatic at lower levels of hemoglobin. The benefits of this therapy are limited to 1 month because the life span of transfused red blood cells is limited to the average life span of collected cells. Also, each unit of transfused packed red cells introduces unwanted iron, which over time, accumulates in the patient. Although minimal, the risk of infection still is present (eg, human immunodeficiency virus [HIV], hepatitis C).

Bleeding/hemorrhage resulting from thrombocytopenia is a major problem and may be life threatening if it occurs intracranially. Platelet transfusions are effective for stopping acute bleeding. Unfortunately, the platelet life span is short; the effects may last 2-4 days. This treatment temporarily stops bleeding, but it is not a practical maintenance therapy. Development of alloantibodies can make the patient refractory to platelet transfusions.

 

Medication

Medication Summary

The approach to bone marrow failure depends on which mechanism is thought to predominate in the patient. If an immune mechanism is suspected, an immunosuppressive agent is used. Hematopoietic growth factors and androgens also have been tried in an effort to stimulate hematopoiesis.

As previously mentioned, androgens were used in the past for treatment of bone marrow failure, but most are masculinizing and poorly tolerated by females and children. Danazol is a nonmasculinizing androgen that may be useful. The response rate is limited to approximately 45%, and results may require 6-10 months of therapy.

Immunosuppressants

Class Summary

These are used to manipulate the bone marrow microenvironment and eliminate any immune-mediated bone marrow suppression. Intensive immunosuppression using a combination of ALG and cyclosporine has resulted in hematologic remission rates of 70-80% in patients with aplastic anemia.

Lymphocyte immune globulin (Atgam)

This agent, an antibody to T cells, is used as an immunosuppressive agent. Because it is extracted from horse serum, serum sickness may be induced when the drug is administered.

Cyclosporine A (Sandimmune, Neoral, Gengraf)

Cyclosporine A is a cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions, such as delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft versus host disease. For children and adults, the dosing should be based on ideal body weight.

Methylprednisolone (A-Methapred, Medrol, Solu-Medrol)

Methylprednisolone decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reversing increased capillary permeability.

Prednisone

Prednisone is used as an immunosuppressant in the treatment of autoimmune disorders. By reversing increased capillary permeability and suppressing polymorphonuclear leukocyte activity, it may decrease inflammation.

Androgens

Class Summary

These agents push the resting hematopoietic stem cells into cycle, making them more responsive to differentiation by hematopoietic growth factors. They also stimulate endogenous secretion of erythropoietin

Danocrine

Danocrine is an attenuated androgen that does not have adverse virilizing and masculinizing effects. It increases levels of the C4 component of the complement.