Estrogen Resistance Caused by a Mutation in the Estrogen-Receptor Gene in a Man
Eric P. Smith, Jeff Boyd, Graeme R. Frank, Hiroyuki Takahashi, Robert M. Cohen, Bonny Specker, Timothy C. Williams, Dennis B. Lubahn, and Kenneth S. Korach
Background and Methods Mutations in the estrogen-receptor genehave been thought to be lethal. A 28-year-old man whose estrogenresistance was caused by a disruptive mutation in the estrogen-receptorgene underwent studies of pituitary-gonadal function and bonedensity and received transdermal estrogen for six months. Estrogen-receptorDNA, extracted from lymphocytes, was evaluated by analysis ofsingle-strand-conformation polymorphisms and by direct sequencing.
Results The patient was tall (204 cm [80.3 in.]) and had incompleteepiphyseal closure, with a history of continued linear growthinto adulthood despite otherwise normal pubertal development.He was normally masculinized and had bilateral axillary acanthosisnigricans. Serum estradiol and estrone concentrations were elevated,and serum testosterone concentrations were normal. Serum follicle-stimulatinghormone and luteinizing hormone concentrations were increased.Glucose tolerance was impaired, and hyperinsulinemia was present.The bone mineral density of the lumbar spine was 0.745 g persquare centimeter, 3.1 SD below the mean for age-matched normalwomen; there was biochemical evidence of increased bone turnover.
The patient had no detectable response to estrogen administration,despite a 10-fold increase in the serum free estradiol concentration.Conformation analysis of his estrogen-receptor gene revealeda variant banding pattern in exon 2. Direct sequencing of exon2 revealed a cytosine-to-thymine transition at codon 157 ofboth alleles, resulting in a premature stop codon. The patient'sparents were heterozygous carriers of this mutation, and pedigreeanalysis revealed consanguinity.
Conclusions Disruption of the estrogen receptor in humans neednot be lethal. Estrogen is important for bone maturation andmineralization in men as well as women.
The actions of adrenal and gonadal steroids, thyroid hormone,and vitamin D are mediated by receptors encoded by a familyof related genes. Mutations of glucocorticoid, androgen, thyroidhormone, and vitamin D receptors leading to syndromes of hormoneresistance have been reported1,2,3,4. It has been thought thatmutation of the estrogen-receptor gene would be lethal, affectingembryo implantation in particular5. Recent insertional disruptionof the mouse estrogen-receptor gene6 and two case reports,7,8however, raise questions about the validity of the lethalityhypothesis and reveal intriguing phenotypes. In mice with disruptedestrogen-receptor genes, both sexes are viable. The affectedfemale mice have hypoplastic breasts and uteri, hyperemic cysticovaries without corpora lutea, infertility, and decreased skeletalmineralization; the male mice have decreased skeletal mineralizationand low sperm counts.
The first case report7 involving decreased estrogen synthesisdescribed a female patient with pseudohermaphroditism due toplacental aromatase deficiency, suggesting that, at least beginninglate in the first trimester, excess androgen with low or absentestrogen in the female fetus is compatible with life. The secondcase report8 described a karyotypically female patient withpseudohermaphroditism caused by a null mutation in the aromatasecytochrome P-450 gene. At puberty progressive virilization withoutbreast development or growth acceleration was noted. Estrogentreatment resulted in normal breast development, a pubertalgrowth spurt, and menarche, suggesting that androgen is relativelyineffective in stimulating pubertal growth.
In this report, we describe a man with estrogen resistance whohad osteoporosis, unfused epiphyses, and continuing linear growthin adulthood. He also had elevated serum estrogen concentrations,abnormal gonadotropin secretion, and no target-tissue responsesto estrogen therapy. Analysis of the estrogen-receptor generevealed a change in a single base pair in the second exon,generating a premature stop codon. These findings indicate thatestrogen-receptor mutations need not be lethal and that estrogenis important in the male, as it is in the female, for normalskeletal growth and development.
Case Report
A 28-year-old white man presented to an orthopedic surgeon withtall stature and a four-to-five-year history of progressivegenu valgum. Because radiologic evaluation revealed unfusedepiphyses, he was referred for further evaluation. His birthweight and early growth and development were within normal limits,and his stature was in the average range. He first noted pubicand axillary hair at 12 to 13 years of age and started shavingregularly at age 17 to 18 years of age but had no recollectionof associated growth acceleration. His height at the age of16 was approximately 178 cm (70 in.) according to informationprovided on his driver's license (Figure 1). His legs and feetcontinued to grow slowly after adolescence.
Figure 1. Growth Chart of a 28-Year-Old Man with Estrogen Resistance and Radiographs of the Left Hand and Wrist and Left Knee.
Anthropometric measurements made at the age of 28 years are also shown.
Review of the family history revealed four sisters who wereaverage in stature (160 to 165 cm [63 to 65 in.]). His motherwas 162 cm (64 in.) tall, and his father was 180 cm (71 in.).His mother was given a diagnosis of non-insulin-dependent diabetesmellitus at the age of 45 years. A paternal uncle had coloncancer, two maternal cousins had insulin-dependent diabetesmellitus (one of whom was given the diagnosis in infancy), anda niece had XO/XY mixed gonadal dysgenesis.
The patient had a history of Osgood-Schlatter disease, whichwas diagnosed when he was 20 years of age and was treated withrest. At the age of 24, a meniscal tear in the right knee requiredarthroscopic surgery and the results of a glucose-tolerancetest were reportedly slightly abnormal. There was no historyof polyuria, polydipsia, blurred vision, or nocturia. The patientdid not recall any change in facial structure, thickening oroiliness of the skin, excessive diaphoresis, skin tags, or changesin his voice. He did remember noticing increased pigment inthe skin of each axilla starting at the age of 23. Though unmarried,he reported no history of gender-identity disorder. He indicatedstrong heterosexual interests and had normal functioning, includingmorning erections and nocturnal emissions.
Physical examination revealed a tall, healthy-appearing manwith no acromegaloid features but with obvious genu valgum.His height was 204 cm (80.3 in.) (>95th percentile), weight127 kg (280 lb), heart rate 80 per minute, and blood pressure140/85 mm Hg. The upper segment of his body was 96 cm (37.7in.), and his lower segment was 109 cm (42.9 in.), yieldinga ratio of the upper segment to the lower segment of 0.88 (averagefor men, 0.96). His left middle finger measured 10 cm (3.9 in.)(97th percentile, 9 cm), left hand 23 cm (8.9 in.) (97th percentile,19.5 cm), and foot 33 cm (13 in.) (97th percentile, 29 cm).He had an arm span of 213 cm (83.8 in.). There was bilateralaxillary acanthosis nigricans and a 0.5-cm skin tag in the leftaxilla. The patient had a full beard with early temporal hairloss. There was no thyroid enlargement or gynecomastia. Theresults of cardiovascular, respiratory, and abdominal examinationswere normal. The patient had normal male genitalia with bilateraldescended testes, each with a volume of 20 to 25 ml, and a normal-sizedprostate gland.
Radiography of his left wrist and hand revealed a bone age of15 years9 (Figure 1). Knee films revealed open epiphyses (Figure 1);a review of radiographs from previous orthopedic evaluationsdemonstrated minimal evidence of epiphyseal maturation overa 10-year period and demineralized bones. The density of thelumbar spine, measured by dual-energy x-ray absorptiometry (Hologic,Waltham, Mass.), was 0.745 g per square centimeter (3.1 SD belowthe mean for age-matched normal women and more than 2 SD belowthe mean for 15-year-old boys [the patient's bone age]). Thekaryotype was 46,XY. Semen analysis revealed a sperm densityof 25 million per milliliter (normal, >20 million per milliliter),with a viability of 18 percent (normal, >50 percent). Theresults of initial laboratory tests are shown in Table 1. Theserum testosterone concentration was normal, and estradiol,estrone, follicle-stimulating hormone, and luteinizing hormoneconcentrations were high. A five-hour oral glucose-tolerancetest (75 g) revealed a fasting blood glucose concentration of135 mg per deciliter (7.6 mmol per liter), a peak response of224 mg per deciliter (12.5 mmol per liter) at three hours, anda concentration of 163 mg per deciliter (9.1 mmol per liter)at five hours. The respective serum insulin values were 50 microU per milliliter (300 pmol per liter), 114 micro U per milliliter(684 pmol per liter), and 93 micro U per milliliter (558 pmolper liter).
Table 1. Biochemical Measurements before and after Four and Six Months of Transdermal Ethinyl Estradiol Therapy in a Man with Estrogen Resistance.
On the basis of the hypothesis that primary estrogen resistancemight explain the elevated serum estrogen and abnormal serumgonadotropin concentrations, failure of epiphyseal fusion, andpossibly insulin resistance, the patient was treated with high-dosetransdermal ethinyl estradiol (Estraderm patch system, Ciba,Summit, N.J.) for six months. The starting dose was 2 100-µgpatches per week, with 100-µg increments each week untila maintenance dose of 14 100-µg patches per week was reached.The dose was based on clinical experience with men treated withhigh doses of estrogen for either prostate cancer or transsexualconversion10,11. This protocol was approved by the CincinnatiChildren's Hospital institutional review board, and the patientgave informed consent.
The serum hormone and metabolic measurements before and afterfour and six months of estrogen therapy are shown in Table 1.(All serial tests in Table 1 were performed at the Nichols Institute,San Juan Capistrano, Calif., and for each assay, results wereanalyzed simultaneously for purposes of comparison).
During estrogen therapy, the patient had no nausea, fluid retention,hypertension, unusual headaches, weight gain, gynecomastia,impotence, or mood alterations. In addition, there was no significantincrease in the serum concentration of any estrogen-dependentprotein (sex hormone-binding globulin, thyroxine-binding globulin,cortisol-binding globulin, or prolactin) or change in serumgonadotropin concentrations (Table 1). The results of testsof bone turnover were all consistent with active bone demineralizationand did not decrease. Finally, total bone mineral density andbone age did not change during estrogen administration.
Because of the patient's resistance to estrogen, peripheral-bloodlymphocyte DNA was obtained to study his estrogen-receptor geneby analysis of single-strand-conformation polymorphisms12. Exons1 through 813 were independently amplified by the polymerasechain reaction (PCR) and subjected to single-strand-conformationanalysis with DNA from several normal subjects as a control.All exons were wild type, with the exception of exon 2, whichhad a variant banding pattern suggestive of a homozygous mutation(Figure 2B). Direct sequencing of the exon 2 product revealedthe substitution of thymine for cytosine at codon 157 (Figure 2C),resulting in the replacement of an arginine codon (CGA)with a premature stop codon (TGA). The translated protein wouldtherefore be severely truncated, lacking the DNA-binding andhormone-binding domains (Figure 2A), and expected to be functionallyinert. Because the mutation was homozygous, the patient's parentswere interviewed to obtain a more detailed family history. Thefamily pedigree (Figure 3) demonstrates that his parents weresecond cousins. On the basis of slot blot analyses performedwith wild-type and mutant oligonucleotide probes (Figure 4A)and direct sequence analysis (Figure 4B), each parent, as wellas three of the patient's four sisters, proved to be heterozygousfor the mutation, a finding consistent with autosomal recessiveinheritance.
Panel A shows the location of the codon 157 mutation in the estrogen-receptor protein. The mutation occurs in the A/B domain that is upstream of both the DNA-binding and hormone-binding domains and would be expected to yield a severely truncated protein with no functional activity. Panel B shows the results of single-strand-conformation analysis of exon 2 of the estrogen-receptor gene. A homozygous sequence variant is present in the patient's DNA (lane 10) but not in DNA from nine normal subjects (lanes 1 through 9). In Panel C, sequence analysis of the exon 2 PCR product revealed that the patient had thymine substituted for cytosine at codon 157 (indicated by the asterisk).
Figure 3. Pedigree of a Man with Estrogen Resistance Demonstrating Consanguinity (Double Lines).
Sequence analysis of the estrogen-receptor gene was performed only in the proband, his parents, and his sisters. Squares denote male family members, circles female family members, the solid square the homozygous proband, half-solid symbols family members who were heterozygous for the estrogen-receptor mutation, the cross a stillbirth, and small circles spontaneous abortions.
Figure 4. Parental Origin of the Mutation of the Estrogen-Receptor Gene.
Panel A shows the results of DNA slot blotting after hybridization with radiolabeled oligonucleotide probes specific for the wild-type or mutant sequence of exon 2. The filter contained PCR-amplified exon 2 from DNA of the patient (slot 1), his father (slot 2), his mother (slot 6), and two normal subjects (slots 3 and 5). For slot blot analysis of parental DNA, the exon 2 products obtained by PCR were blotted and hybridized to radiolabeled oglionucleotide probes as described.14 The oglionucleotide sequences were as follows: 5'TTCAGATAATCGACGCCAGGG3' (wild type) and 5'TTCAGATAATTGACGCCAGGG3' (mutant). In Panel B, sequence analysis of the exon 2 PCR product indicated constitutional heterozygosity for the codon 157 mutation in both parents.
Methods
The coding region of the estrogen-receptor gene was amplifiedby PCR. Primer sequences for the eight coding exons of the genewere designed on the basis of information on the exon-intronjunction sequence13. The forward primer sequence for exon 2was 5'CCCAGGCCAAATTCAGATAA3', and the reverse primer sequencewas 5'CGTTTTCAACACACTATTAC3'. PCR was carried out with 35 cyclesconsisting of one minute at 94 °C, one minute at 55 °C,and one minute at 72 °C. The reaction mixtures were heatedat 94 °C for 90 seconds before the first cycle and at 72°C for 7 minutes after the last cycle. After amplification,a 4-microl aliquot of the product was diluted with denaturingbuffer, heated at 95 °C for five minutes, and cooled onice for five minutes; 3 to 4 microl of this solution was usedfor electrophoresis.
The gels used for single-strand-conformation analysis consistedof 0.5X MDE solution (AT Biochem, Malvern, Pa.) and 0.6X TBEbuffer (89 mM Tris, 89 mM borate, and 2 mM EDTA), and they wererun in 0.6X TBE buffer at 8 W for 16 hours at room temperature.For sequence analysis, both strands of the purified exon 2 productsobtained by PCR were subjected to cycle sequencing with a double-strandedDNA Cycle Sequencing System (Life Technologies, Gaithersburg,Md.) as specified by the manufacturer, except that [-33P]ATPwas used for primer labeling. Sequencing reaction samples wererun on a 6 percent polyacrylamide gel containing 8.3 M ureaat 70 W for two to four hours at room temperature and processedfor autoradiography according to standard procedures.
Discussion
The findings in this man with a naturally occurring disruptivemutation of the estrogen-receptor gene demonstrate that mutationsin this gene need not be lethal. The major phenotypic manifestationsof estrogen resistance that he demonstrated were tall staturewith evidence of continued slow linear growth, markedly delayedskeletal maturation, and osteoporosis. These abnormalities providecompelling evidence of the critical part played by estrogenin bone development and mineralization during puberty not onlyin girls but also in boys.
The pubertal growth spurt and epiphyseal maturation are consideredto be induced primarily by the actions of sex steroids, estrogenin the female and androgen in the male. The close associationof sex steroids and advancement of bone age is well demonstratedin precocious puberty, which is characterized by a prematureincrease in sex-steroid secretion, increased height velocity,accelerated epiphyseal maturation, and reduced final adult height15.Despite the normal timing of pubertal onset and normal serumandrogen concentrations, this adult with estrogen resistancehad a bone age of 15 years and a slow continued increase inheight during his third decade. His presentation is similarto that of a genetic female with pseudohermaphroditism causedby an aromatase-gene defect in whom androgen was present inthe absence of circulating estrogen, rather than estrogen resistance8,16.Despite virilization at puberty, the patient's bone age wasdelayed relative to her chronologic age, and she had no growthspurt16. However, unlike the results in this man with estrogeninsensitivity, her treatment with estrogen resulted in growthacceleration, advancement of bone age, and breast development.Finally, our patient's phenotype is consistent with that associatedwith two other conditions, testotoxicosis and androgen insensitivity.In testotoxicosis, in which there is autonomous production ofandrogen from the testes, therapy with an antiandrogen aloneis not sufficient to slow skeletal growth to a prepubertal rate;this is achieved by the addition of an aromatase inhibitor17.Patients with complete androgen insensitivity have a pubertalgrowth spurt that is normal for a genetic female in both magnitudeand timing18. This man's phenotype confirms what these earlierclinical observations suggested -- namely, that estrogen hasa critical role in pubertal growth and epiphyseal maturationin both sexes.
Although the importance of estrogen deficiency in the pathogenesisof osteoporosis in postmenopausal women is well known, manyclinical observations have supported the idea that androgenis important for the maintenance of bone mass in men. Men withhypogonadism have osteoporosis19,20; decreased serum testosteroneconcentrations in elderly men are a risk factor for fractures21;men with a history of constitutional delay of puberty have decreasedbone density as adults22; and androgenic steroids increase bonemass23. This man with estrogen resistance had a severely undermineralizedskeleton with biochemical evidence of increased bone resorption24,25despite normal serum androgen concentrations. These observationsindicate that androgen alone is not sufficient to promote skeletalmaturation and retain bone mass and that estrogen has a pivotalrole in the mineralization of the skeleton in males as wellas females.
The elevated serum estrogen concentrations in this man suggesta compensatory increase in aromatase activity in response toestrogen resistance, and increased aromatase activity couldaccount for the normal concentrations of androgen despite increasedsecretion of luteinizing hormone. In men, multiple tissues areinvolved in the aromatization of androgen to form estrogen,including the testes, liver, skin, and adipose tissue26,27.Testicular estrogen secretion is stimulated by luteinizing hormone,making the testis the most likely source of the elevated serumestrogen concentrations in this man. His elevated gonadotropinsecretion suggests that estrogen plays a part in the regulationof gonadotropin secretion in men.
The relation of insulin resistance, glucose intolerance, andacanthosis nigricans to estrogen resistance in the patient isintriguing. Isolated increases in estrogen improve glucose toleranceby enhancing either target-tissue responsiveness to insulinor insulin secretion28,29,30. Acanthosis nigricans is a cutaneousmarker of insulin resistance, especially when insulin resistanceis associated with relative hyperandrogenism31. In this man,loss of estrogen effect or an altered balance of androgen andestrogen action may well account for diminished insulin sensitivity,glucose intolerance, and acanthosis nigricans. The elevatedserum concentration of sex hormone-binding globulin, an estrogen-dependentprotein, is unexplained.
It is possible that mutations causing milder estrogen resistanceexist, and that compensatory hyperestrogenemia can overcomethe resistance and result in a normal phenotype. The absenceof lethality and the rather striking phenotype in either sexsuggest that previous cases would eventually have been appropriatelydiagnosed. It is possible that heterozygous women may have impairedfertility, thus reducing the incidence of the mutation in thepopulation and decreasing the prevalence of homozygous cases.Notably, the patient's mother had three spontaneous abortions.Regardless, this patient's diagnosis suggests that there arelikely to be other patients with phenotypic presentations ofvariable severity. Estrogen-receptor defects should be includedin the differential diagnosis of such apparently disparate entitiesas tall stature, unfused epiphyses, osteoporosis, abnormal gonadotropinsecretion, and infertility.
Supported in part by the Children's Hospital-University of CincinnatiClinical Research Center (under grant MO1 RR 08084) and by aclinical research grant (to Dr. Cohen) from the American DiabetesAssociation. Dr. Lubahn was a Pew Scholar.
We are indebted to Drs. Judson J. Van Wyk, Frank S. French,Robert M. Blizzard, Hartmut Malluche, Penelope Manasco, andPhilip S. Zeitler for helpful discussions of this case; to Dr.Richard Jolson, the orthopedic surgeon who first recognizedthe abnormal epiphyseal maturation; to Nichols Institute forperforming numerous assays before and during the estrogen therapy;to Dr. Nancy D. Leslie for lymphocyte transformation; to Ms.JoAnn Horn for technical assistance; and to Ms. Vicki Livengoodfor assistance in the preparation of the manuscript.
Source Information
From the Department of Pediatrics, Divisions of Endocrinology (E.P.S., G.R.F.) and Neonatology (B.S.), Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati; the Department of Internal Medicine, Division of Endocrinology, University of Cincinnati College of Medicine, Cincinnati (R.M.C., T.C.W.); the Departments of Pediatrics and Pathology, University of North Carolina School of Medicine at Chapel Hill, Chapel Hill (D.B.L.); and the Gynecologic Pathobiology Group, Laboratory of Molecular Carcinogenesis (J.B., H.T.), and Receptor Biology Section, Laboratory and Developmental Toxicology (K.S.K.), National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, N.C.
Address reprint requests to Dr. Smith at the Department of Pediatrics, Division of Endocrinology, Children's Hospital Medical Center, 3333 Burnett Ave., Cincinnati, OH 45229.
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A correction has been published: N Engl J Med 1995;332(2):131.
-33P]ATP was used for primer labeling. Sequencing reaction samples were run on a 6 percent polyacrylamide gel containing 8.3 M urea at 70 W for two to four hours at room temperature and processed for autoradiography according to standard procedures. 
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