The 3 Men Who Lacked Estrogen Receptors Who Did Not Stop Growing

Me: These articles that are posted below are on the 3 male subjects that have been found to issues with their estrogen receptors causing them to have unfused growth plates and grow to extraordinary heights. I feel that this article is one of those posts that the reader should pay more attention to because it can give clues to ideas that can work. The exact location of this gene mutation was at the estrogen receptor or for cytochrome P-450 aromatase. There was a single G →A mutation at base pair (bp) 1094 in exon 9 of the P-450 aromatase gene, resulting in a glutamine instead of an arginine at position 365. For the other subject, his genetic mutation was a variant banding pattern in exon 2. Direct sequencing of exon 2 revealed a cytosine-to-thymine transition at codon 157 of both alleles, resulting in a premature stop codon. For the last subjects, who were brother and sister, their genetic mutation was at  only a single human gene encoding aromatase P450 (CYP19) has been isolated; tissue-specific regulation is controlled in part by alternative promoters in a tissue-specific manner. they report a novel mutation in the CYP19 gene.


Edited by: Thomas W. Durso ‘MAJOR IMPORTANCE’: Eric Smith evaluated a man shown to be estrogen-resistant. E.P. Smith, J. Boyd, G.R. Frank, H. Takahashi, R.M. Cohen, B. Specker, T.C. Williams, D.B. Lubahn, K.S. Korach, “Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man,” New England Journal of Medicine, 331:1056-61, 1994. (Cited in more than 50 publications as of August 1996) Comments by Eric P. Smith, Cincinnati Children’s Hospital Medical Center, University o

October 14, 1996

Edited by: Thomas W. Durso

Estrogen is generally thought to have important effects only on women. But with the publication of this paper, describing the first reported case of estrogen resistance in a human male, researchers demonstrated the importance of the hormone in men.E.P. Smith, J. Boyd, G.R. Frank, H. Takahashi, R.M. Cohen, B. Specker, T.C. Williams, D.B. Lubahn, K.S. Korach, “Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man,” New England Journal of Medicine331:10

The subject of this paper, a 28-year-old man who stood at 6 feet, 8 inches, was experiencing secondary-to-continued growth well into his third decade, and displayed delayed bone-age maturation comparable to a 15- year-old boy. Ultimately, the man was evaluated by pediatric endocrinologist Eric P. Smith, an associate professor of pediatrics at Cincinnati Children’s Hospital Medical Center, which is affiliated with the University of Cincinnati College of Medicine.

Despite the man’s age and height, further testing revealed that he had a bone-mineral mass similar to a “severely osteoporotic elderly woman,” according to Smith. Levels of testosterone and androgen, a pair of male hormones, were normal, but estrogen levels were elevated, which suggested resistance to estrogen.

To test the hypothesis of estrogen resistance, Smith treated the man with estrogen skin patches, raising the hormone level tenfold, for six months. “There was no measurable response to the treatment,” Smith recalls. “A normal individual would develop substantial breast enlargement, among many other physical and biomedical changes. We were quite surprised, because his lack of response suggested severe estrogen resistance, a condition that was thought to be embryonically lethal. Indeed, this was considered to be the explanation for why no cases of loss-of-function estrogen receptor mutations had been reported in the medical literature.”

But Smith was aware of a study in which researchers had successfully bred and sustained mice with mutated estrogen-receptor genes (D.B. Lubahn, Proceedings of the National Academy of Sciences90:11162-6, 1993). He sent samples of the man’s DNA to Kenneth S. Korach, chief of the Laboratory of Reproductive and Developmental Toxicology at the National Institute of Environmental Health Sciences in Research Triangle Park, N.C. Evaluation of the DNA revealed a mutation in the gene encoding the estrogen receptor.The implications of the case are significant, say the researchers. “Here’s the first reported mutation of this gene resulting in a living individual who is hormonally insensitive to estrogen,” Korach states.

The paper demonstrated, “dramatically and unequivocally,” according to Korach, that estrogen is the principal hormone involved in the final fusion of the epiphyses, the plates at the end of bones whose closure is necessary for bones to stop lengthening. In addition, the researchers say, estrogen must now be considered important in males for normal accretion of bone-mineral mass, with major implications for the common clinical condition of osteoporosis.

“Whether you have patients who don’t make estrogen or make estrogen but can’t use it through the receptors,” Korach declares, “you still have the same effect on the skeleton.”

Smith points to estrogen’s involvement in many different processes, such as growth and bone density, and the implications for males as the reasons the paper has been highly cited.

“From my point of view as a pediatric endocrinologist, the major importance is on growth implications,” he says. “We see a lot of children who have growth disorders, and their degree of bone maturation is a major component of their evaluation. Any advance in the understanding of the primary determinants of how growth plates mature and fuse will be useful in the evaluation of childhood growth disorders. Potentially, final height could be augmented by manipulating the androgen/estrogen milieu.”

Korach also attributes interest in the paper to “the uniqueness and novelty of the findings.” He notes that it was the first clinical description of this gene mutation, which debunked the long-held notion that it was a lethal mutation. “Now it turns out you can have mutation in this gene and it does not result in lethality, but produces significant phenotype.”

In addition, Korach points out correlations between the man’s case and the male mice. For example, the estrogen-receptor gene mutation in the mice resulted in male infertility, and Korach speculates that human males may evolve similar impairments related to decreased estrogen action. The man profiled in this paper had a low-normal sperm count with decreased movement at the time of the initial analysis, and Korach explains that the condition in the mice appears progressive.

“It told us for the first time there’s a critical role for estrogen in male fertility, and effects on the male reproductive tract were a real surprise,” he adds. “From the past we thought it was something that was androgen- or testosterone-related. Now we see the lack of a functional estrogen receptor and lack of estrogen action has been associated with male infertility. It ties estrogen exposure to the male, and it’s as important there as it is to the female. We hope it will allow us to make people aware that this mutation can exist in the human population.”

Effect of Testosterone and Estradiol in a Man with Aromatase Deficiency

Cesare Carani, M.D., Kenan Qin, Ph.D., Manuela Simoni, M.D., Ph.D., Marco Faustini-Fustini, M.D., Stefania Serpente, M.D., Jeff Boyd, Ph.D., Kenneth S. Korach, Ph.D., and Evan R. Simpson, Ph.D.

N Engl J Med 1997; 337:91-95  July 10, 1997  DOI: 10.1056/NEJM199707103370204

Recent reports of disruptive mutations of the genes for the estrogen receptor or for cytochrome P-450 aromatase1-6 have shed new light on the role of estrogen. In females the lack of estrogen due to aromatase deficiency leads to pseudohermaphroditism and progressive virilization at puberty, whereas in males pubertal development is normal. In members of both sexes epiphyseal closure is delayed, resulting in a eunuchoid habitus, and osteopenia is present.6 These findings suggest a crucial role of estrogen in skeletal maturation.1-6 We describe the responses to androgen and estrogen in a man with a novel, homozygous inactivating mutation of the P-450 aromatase gene.


The proband, the second of 10 siblings, was born after an uncomplicated pregnancy. His parents were first cousins (Figure 1FIGURE 1Pedigree of a Man with Aromatase Deficiency.). The patient’s early growth and pubertal development were normal, although his testicular volume remained subnormal. At 18 years of age he was 170 cm tall (25th percentile), and he continued to grow thereafter. At the age of 28 years, x-ray films of the right arm obtained after an injury revealed unfused epiphyses and osteopenia. At the age of 29 years, he married a woman who did not conceive despite regular unprotected intercourse. Semen analysis one year later7 revealed a sperm count of 1 million per milliliter (normal, >20 million) with 100 percent immotile spermatozoa. The patient was treated with 150 IU of human menopausal gonadotropin and 1000 IU of human chorionic gonadotropin intramuscularly three times weekly for four months, with no change in the sperm count.
In 1988, at the age of 31, the patient was evaluated because of a four-year history of persistent linear growth, infertility, and moderate skeletal pain, especially in the knee, that limited his ability to walk. He weighed 96.5 kg and was 187 cm tall (97th percentile). His arm span was 204 cm, and the ratio of the upper segment to the lower segment was 0.85. Physical examination revealed bilateral genu valgum. The patient’s blood pressure was normal. He had normal optic fundi and no gynecomastia, acromegaly, goiter, or acanthosis nigricans. The volume of each testis was 8 ml. His penis size and pattern of pubic hair were normal. His sexual identity and psychosexual orientation as assessed by questionnaire8 were heterosexual, and his libido was normal. He had spontaneous erections sufficient for intercourse.

The patient had normal concentrations of serum testosterone, undetectable concentrations of estradiol, slightly elevated concentrations of follicle-stimulating hormone, and concentrations of luteinizing hormone at the upper limit of the normal range (Table 1TABLE 1Biochemical Values before and after Six Months of Treatment with Testosterone Enanthate or Transdermal Estradiol in a Man with Aromatase Deficiency.). After he received an intravenous bolus dose of 100 μg of gonadotropin-releasing hormone (GnRH), his serum concentration of luteinizing hormone rose from 6 to 18 IU per liter after 60 minutes (when the peak response occurs), and the concentration of serum follicle-stimulating hormone rose from 14 to 19 IU per liter. The serum concentrations of dehydroepiandrosterone sulfate, 17-hydroxyprogesterone, androstenedione, parathyroid hormone, free thyroxine, and thyrotropin were normal. The serum concentration of growth hormone rose from 0.8 to 6.2 ng per milliliter after the administration of levodopa. The serum concentration of insulin-like growth factor I was 332 ng per milliliter (normal range at the age of 25 to 35 years, 193 to 575). The serum concentrations of total cholesterol and triglycerides were high, and the serum concentration of high-density lipoprotein (HDL) cholesterol was low (Table 1).

X-ray films of the left wrist and hand revealed open metacarpal and phalangeal epiphyses; the bone age was 14.8 years (Figure 2AFIGURE 2X-Ray Films of the Left Hand of the Proband. and Figure 2B). X-ray films of the tibias, knees, and pelvis showed diffuse bone demineralization and lack of epiphyseal fusion. A bone biopsy of the iliac crest after labeling with tetracycline revealed several slightly widened areas of osteoid seams lined by active osteoblasts.

A semen analysis7 revealed a sperm count of less than 1 million per milliliter, with 100 percent immotile spermatozoa. A testicular biopsy showed hypospermatogenesis and germ-cell arrest, mainly at the level of primary spermatocytes. The karyotype was 46,XY.

In an attempt to arrest his persistent linear growth and stimulate epiphyseal closure, the patient, after giving informed consent, was treated with 250 mg of testosterone enanthate intramuscularly every 10 days for 6 months. There were no clinical, behavioral, hormonal, or metabolic changes, except for a small decrease in the serum concentration of HDL cholesterol (Table 1). His bone age did not change, and moderate bone pain persisted. He interrupted the treatment spontaneously in 1989 because of its ineffectiveness and because he believed it was rendering him irretrievably infertile.

In 1995 the patient was 190 cm tall (above the 97th percentile), and his bone age and biochemical values had not changed appreciably (Table 1). The results of an oral glucose-tolerance test were normal. The similarity between his phenotype and that of a man with a mutated estrogen-receptor gene1 prompted us to analyze the patient’s DNA for a mutation in that gene or in the P-450 aromatase gene. As expected from the low serum estradiol levels, the estrogen-receptor gene was normal, but there was a single G →A mutation at base pair (bp) 1094 in exon 9 of the P-450 aromatase gene, resulting in a glutamine instead of an arginine at position 365 (Figure 3FIGURE 3Nucleotide Sequence of a Region of Exon 9 of the P-450 Aromatase Gene in the Patient, a Normal Subject, and the Patient’s Parents.). This mutation abolishes a site cleaved by the restriction enzyme Acc651; restriction analysis, used to determine the carrier status of other family members, showed that both parents were heterozygous for the mutation. Expression studies in COS-1 cells showed that the aromatase activity of the mutant protein was 0.4 percent of that of the wild-type protein in the presence of the same amount of total cellular protein, as measured by a Western blot assay corrected for the efficiency of transfection.

After giving informed consent and with the approval of the local university review board, the patient was treated with 50 μg of transdermal estradiol twice weekly. His bone pain improved after four months and resolved completely after six months. His serum concentrations of luteinizing hormone, follicle–stimulating hormone, and testosterone decreased, that of HDL cholesterol increased, and that of low-density lipoprotein (LDL) cholesterol decreased (Table 1). His fasting concentrations of serum insulin and blood glucose were normal. The serum concentrations of alkaline phosphatase and osteocalcin increased, as did the urinary excretion of pyridinoline, indicating active bone remodeling (Table 1). The bone mineral density of the lumbar spine was 0.93 g per square centimeter before treatment (normal range 9 for adolescents in Tanner stage 5, 0.96 to 1.31) and was 1.05 and 1.17 g per square centimeter after four and seven months of treatment, respectively. Epiphyseal closure was documented after nine months of therapy, with a bone age greater than 16 years (Figure 2A andFigure 2B). The treatment did not induce gynecomastia, hyperprolactinemia, or sexual dysfunction. Testicular volume and the results of semen analysis did not change. At this writing the patient is being treated with 25 μg of transdermal estradiol twice weekly.


Biochemical Measurements

Blood samples were obtained by venipuncture after an overnight fast. Serum luteinizing hormone, follicle-stimulating hormone, and growth hormone were measured by an immunofluorimetric assay (Delfia kits, Pharmacia, Milan, Italy) according to the instructions of the manufacturer. All the other hormones were measured by commercially available radioimmunoassays.

Molecular Analysis of the Genes for the Estrogen Receptor and P-450 Aromatase

Genomic DNA was prepared from blood samples obtained from the patient, his parents, two of his brothers, one of his nephews, and a normal unrelated man.4 Single-strand conformation analysis of the estrogen-receptor gene was performed as previously reported.1 To determine the complete sequence of the exons and the intron–exon junctions, each exon of the P-450 aromatase gene, including the 5′ untranslated exons and their respective 5′ flanking regions, was amplified as previously described.10 Both strands were sequenced to exclude artifacts. The complete sequence of each exon, including the 5′ and 3′ splice junctions, was compared with the published sequence.11

Exon 9 of the genomic DNA from the normal subject, the proband, and the family members was amplified and digested with Acc651 (Promega, Madison, Wis.), according to the specifications of the manufacturer, and subjected to electrophoresis in a 2 percent agarose gel. The digested fragments were visualized by staining with ethidium bromide.

P-450 aromatase complementary DNA (cDNA) was prepared from wild-type pCMV5arom.11 The wild-type, mutant (R365Q), and vector-only constructs were transfected into COS-1 cells by lipofectamine (BRL, Grand Island, N.Y.). Aromatase activity was determined by the production of tritiated water from [1β-3H]androstenedione.12 Incubations were conducted in triplicate 48 hours after transfection. Western blot analysis was performed as previously described.10


We studied the effects of estrogen therapy in a man with a loss-of-function mutation of the aromatase gene. Our first conclusion is that estrogen therapy had a large effect on the patient’s skeletal growth and bone maturation, whereas androgen therapy did not. The dichotomy between the histologic picture of active bone formation and normal biochemical measures of bone metabolism suggests that testosterone exerted an active effect on osteoblasts, albeit an inefficient one. With estrogen treatment spinal bone mineral density increased, and complete epiphyseal closure was achieved after nine months. The increases in bone mineral density, serum levels of alkaline phosphatase and osteocalcin, and urinary excretion of pyridinoline were similar to those that occur during normal skeletal maturation during puberty.13,14 By contrast, testosterone had no effect on skeletal maturation. Therefore, the eunuchoid skeleton may result mainly from a deficiency of estrogen, rather than a deficiency of androgen. The lack of eunuchoid skeletal development in patients with complete androgen insensitivity supports this view.15 Conversely, patients of either sex who have a complete deficiency of 17α-hydroxylase or a combined deficiency of 17α-hydroxylase and 17,20-lyase have tall stature, retardation of bone age, osteoporosis, and a eunuchoid skeleton16 — a phenotype classically related to the poor production of sex steroids, which can now be explained by a deficiency of estrogen. As is consistent with these findings, estrogen seems required for epiphyseal fusion, an event that takes longer in patients with hypogonadism, who produce insufficient androgens for aromatization. Such fusion never takes place in men with estrogen deficiency or estrogen resistance.

Estrogen treatment induced substantial decreases in the ratio of serum LDL cholesterol to serum HDL cholesterol and in serum triglycerides in our patient (Table 1). Although this effect may depend at least in part on reduced concentrations of serum testosterone, it is clear that the abnormal lipid profile in an aromatase-deficient subject can be modified with estrogen treatment.17

Our patient did not have insulin resistance, unlike previously described patients with aromatase deficiency or estrogen insensitivity.1,4 This finding raises the possibility that insulin resistance is an unrelated phenomenon. His serum concentrations of luteinizing hormone and follicle-stimulating hormone were normal or slightly elevated and responded normally to GnRH stimulation. However, estrogen treatment caused complete suppression of serum gonadotropins whereas androgen treatment did not. In contrast, serum gonadotropins are hyperresponsive to GnRH in female patients with aromatase deficiency,3 because there is a complete absence of steroid feedback. These results indicate that the mechanism of sex-steroid–gonadotropin feedback in male patients is mainly mediated by testosterone, but that some testosterone must be converted to estrogen.17-22 This conclusion is supported by a report that the concomitant administration of testosterone and an aromatase inhibitor prevents testosterone-induced suppression of gonadotropin,20 whereas dihydrotestosterone has no effect.21

Unlike the other two men with estrogen deficiency or resistance described to date, our patient had small testicles and severe oligozoospermia. Azoospermia and infertility were also reported in one of his brothers (Subject IV-5), who had a normal P-450 aromatase gene. Therefore, spermatogenic damage may also be a primary event in the proband, independent of estrogen deficiency. Mouse germ cells express aromatase,23 and mice in which the estrogen-receptor gene is knocked out have reduced testicular volume and are infertile, indicating that estrogen is necessary for fertility in that species.24 In adult men, aromatase is located in Leydig cells, but its function is unknown. 25 The ineffectiveness of estrogen therapy in inducing spermatogenesis in our patient argues against estrogen-dependent spermatogenic damage.

In conclusion, we describe a therapeutic response to estrogen therapy, but not to androgen therapy, in a man with aromatase deficiency. When to initiate treatment, at what doses, and for how long all remain uncertain.

Supported in part by a grant from the Italian Research Council, by a grant (FY96-0428) from the March of Dimes, by a grant (R37-A908174) from the Public Health Service, by a training grant (5-T32-HD07190) from the Public Health Service (to Dr. Qin), by a grant (130/15-1) from the Deutsche Forschungsgemeinschaft (to Dr. Simoni), and by a grant from Ares Serono, Geneva, through the European Academy of Andrology (to Dr. Carani).

We are indebted to Dr. M.G. Ferrari for DNA preparation, to Dr. P. Ballanti and Dr. A. Maiorana for histologic analysis, to Dr. V. Spina for radiologic evaluation, and to Dr. P. Beck-Peccoz for his helpful suggestions.


N Engl J Med. 1994 Oct 20;331(16):1056-61.

Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man.

Smith EP, Boyd J, Frank GR, Takahashi H, Cohen RM, Specker B, Williams TC, Lubahn DB, Korach KS.


Department of Pediatrics, Children’s Hospital Medical Center, University of Cincinnati College of Medicine, OH 45229.

Erratum in

  • N Engl J Med 1995 Jan 12;332(2):131.



Mutations in the estrogen-receptor gene have been thought to be lethal. A 28-year-old man whose estrogen resistance was caused by a disruptive mutation in the estrogen-receptor gene underwent studies of pituitary-gonadal function and bone density and received transdermal estrogen for six months. Estrogen-receptor DNA, extracted from lymphocytes, was evaluated by analysis of single-strand-conformation polymorphisms and by direct sequencing.


The patient was tall (204 cm [80.3 in.]) and had incomplete epiphyseal closure, with a history of continued linear growth into adulthood despite otherwise normal pubertal development. He was normally masculinized and had bilateral axillary acanthosis nigricans. Serum estradiol and estrone concentrations were elevated, and serum testosterone concentrations were normal. Serum follicle-stimulating hormone 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 per square centimeter, 3.1 SD below the mean for age-matched normal women; 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 revealed a variant banding pattern in exon 2. Direct sequencing of exon 2 revealed a cytosine-to-thymine transition at codon 157 of both alleles, resulting in a premature stop codon. The patient’s parents were heterozygous carriers of this mutation, and pedigree analysis revealed consanguinity.


Disruption of the estrogen receptor in humans need not be lethal. Estrogen is important for bone maturation and mineralization in men as well as women.


J Clin Endocrinol Metab. 1995 Dec;80(12):3689-98.

Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens.

Morishima A, Grumbach MM, Simpson ER, Fisher C, Qin K.


Department of Pediatrics, Columbia University College of Physicians and Surgeons, New York, New York, USA.


The aromatase enzyme complex catalyzes the conversion of androgens to estrogens in a wide variety of tissues, including the ovary, testis, placenta, brain, and adipose tissue. Only a single human gene encoding aromatase P450 (CYP19) has been isolated; tissue-specific regulation is controlled in part by alternative promoters in a tissue-specific manner. We report a novel mutation in the CYP19 gene in a sister and brother. The 28-yr-old XX proband, followed since infancy, exhibited the cardinal features of the aromatase deficiency syndrome as recently defined. She had nonadrenal female pseudohermaphrodism at birth and underwent repair of the external genitalia, including a clitorectomy. At the age of puberty, she developed progressive signs of virilization, pubertal failure with no signs of estrogen action, hypergonadotropic hypogonadism, polycystic ovaries on pelvic sonography, and tall stature. The basal concentrations of plasma testosterone, androstenedione, and 17-hydroxyprogesterone were elevated, whereas plasma estradiol was low. Cyst fluid from the polycystic ovaries had a strikingly abnormal ratio of androstenedione and testosterone to estradiol and estrone. Hormone replacement therapy led to breast development, menses, resolution of ovarian cysts, and suppression of the elevated FSH and LH values. Her adult height is 177.6 cm (+2.5 SD). Her only sibling, an XY male, was studied at 24 yr of age. During both pregnancies, the mother exhibited signs of progressive virilization that regressed postpartum. The height of the brother was 204 cm (+3.7 SD) with eunuchoid skeletal proportions, and the weight was 135.1 kg (+2.1 SD). He was sexually fully mature and had macroorchidism. The plasma concentrations of testosterone (2015 ng/dL), 5 alpha-dihydrotestosterone (125 ng/dL), and androstenedione (335 ng/dL) were elevated; estradiol and estrone levels were less than 7 pg/mL. Plasma FSH and LH concentrations were more than 3 times the mean value. Plasma PRL was low; serum insulin-like growth factor I and GH-binding protein were normal. The bone age was 14 yr at a chronological age of 24 3/12 yr. Striking osteopenia was noted at the wrist. Bone mineral densitometric indexes of the lumbar spine (cancellous bone) and distal radius (cortical bone) were consistent with osteoporosis; the distal radius was -4.7 SD below the mean value for age- and sex-matched normal men; indexes of bone turnover were increased. Hyperinsulinemia, increased serum total and low density lipoprotein cholesterol, and triglycerides and decreased high density lipoprotein cholesterol were detected.(ABSTRACT TRUNCATED AT 400 WORDS)

PMID: 8530621    [PubMed – indexed for MEDLINE]


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