In this report, we describe an 18-year-old woman who had presented with persistently elevated serum estrogen levels, mildly elevated gonadotropin levels, and intermittent pelvic pain secondary to multicystic ovaries. She had had no breast development after 5 months of receiving oral estrogen — 3 months at standard doses and 2 months with an increased dose of micronized estradiol. We subsequently identified a homozygous ESR1 missense mutation in a highly conserved Gln residue within the ligand-binding domain of estrogen receptor α. In vitro analysis indicated that the mutant ESR1 did not affect nuclear localization but markedly impaired estrogen signaling except during the administration of very high doses of estradiol, when estrogen signaling was minimal.
Untreated, the patient had a plasma estradiol level that was 10 times the normal value, similar to that of the α-ERKO mouse. Her normal serum levels of sex-hormone–binding globulin, corticosteroid-binding globulin, thyroxine-binding globulin, prolactin, and triglycerides, which are known to be increased by estrogen, provide further evidence of estrogen resistance. In the male patient with an ESR1
mutation who was reported previously, 3
normal levels of corticosteroid-binding globulin and thyroxine-binding globulin were also found. In contrast, the male patient had an elevated baseline level of sex-hormone–binding globulin, which did not rise after the administration of exogenous estrogen.
Estrogen resistance has been associated with hyperinsulinemia, which was diagnosed in the male patient with the ESR1
but not in our female patient. The male patient’s hyperinsulinemia may have been related to obesity, since he had a body-mass index of 30.5, as compared with 16.6 in our patient. However, both sexes of α-ERKO mice have hyperinsulinemia after the administration of oral glucose, as well as increased fat.21
Our patient had normal levels of fasting glucose, insulin, and glycated hemoglobin and a normal HOMA-IR, indicating no impaired glucose tolerance. However, since her glucose dropped during an oral glucose-tolerance test, she will require follow-up for insulin resistance. Her body weight and fat were normal, but it is unknown whether she will be at increased risk for obesity or diabetes in the future.
Current evidence indicates that in women, both negative and positive feedback in the hypothalamus and pituitary are mediated by estrogen receptor α rather than by estrogen receptor β.11
The male patient with estrogen resistance had a mildly increased serum estradiol level, but levels of both follicle-stimulating hormone and luteinizing hormone were markedly elevated, at approximately 30 mIU per milliliter (normal range, <15 and <20, respectively). This finding was similar to those in male α-ERKO mice.12
In contrast, our patient had only mildly elevated gonadotropin levels. Female α-ERKO mice have a luteinizing hormone level that is eight times the normal value and normal serum levels of follicle-stimulating hormone; the latter is probably due to an increase in inhibin A levels by a factor of 5 in such mice.12
Inhibin A levels in our patient were markedly elevated, which probably contributed to the mild elevation in the level of follicle-stimulating hormone. Since men do not produce inhibin A, follicle-stimulating hormone levels were not suppressed in the estrogen-resistant male patient. Serum testosterone levels in our patient ranged from 38 to 88 ng per deciliter, which is only slightly above the normal range; however, the levels were higher than those in women with complete estrogen deficiency caused by mutations in follicle-stimulating hormone beta (FSHB
We speculate that testosterone may have partially suppressed the patient’s luteinizing hormone levels and contributed to facial acne, since this androgen effect was unopposed by estrogen in our patient. In addition, late follicular or early luteal levels of progesterone could have suppressed luteinizing hormone in our patient, but actions associated with estrogen receptor β or other atypical actions cannot be excluded.
Our patient’s presenting symptom was intermittent bilateral pelvic pain caused by hemorrhagic ovarian cysts, a condition that was probably caused by mildly elevated levels of gonadotropins (follicle-stimulating hormone, 6.7 to 19.1 mIU per milliliter; luteinizing hormone, 5.8 to 13.2 mIU per milliliter). With impaired estrogen-mediated negative feedback, the persistent, mildly elevated gonadotropin levels could stimulate and maintain multiple ovarian cysts producing estradiol and progesterone. In addition, the administration of norethindrone was temporally associated with reductions in ovarian volume and number of cysts, which suggests that negative feedback mediated by progesterone receptor was intact. During this treatment, there were slight reductions in serum gonadotropin levels and a substantial reduction in the serum estradiol level. Although levothyroxine administration may decrease the size of ovarian cysts,23
the patient’s cysts persisted, despite adequate thyroid replacement, which argues against hypothyroidism as a contributory factor. Women with a deficiency in aromatase, which converts androgens to estrogens, show sexual ambiguity at birth, but ovarian cysts, clitoromegaly, and hypergonadotropic hypogonadism develop at puberty.24
However, in such patients, the response to estrogen is normal.
Estrogen resistance would be predicted to affect bone metabolism. Our patient had a lowerthan-expected bone mass for her age on the basis of DXA scanning. Levels of both osteocalcin and C-telopeptide were elevated, suggesting increased bone turnover. However, she had not yet achieved peak bone age and was still growing (on the basis of open epiphyses); thus, high markers of bone turnover could simply reflect ongoing bone growth. Long-term consequences of estrogen resistance could include osteoporosis,25
but this will require follow-up.
In conclusion, our patient with an ESR1
mutation showed clinical signs of complete estrogen insensitivity, the counterpart to complete androgen insensitivity in 46,XY males.1–3
However, we cannot exclude the possibility that some residual estrogen sensitivity could be present in some tissues. The prevalence of ESR1
mutations in humans is unknown but they are probably rare. It remains to be seen whether milder ESR1
mutations could cause an incomplete estrogen-deficient state similar to the partial androgen resistance caused by mild mutations in the gene encoding androgen receptor.2
The presence of biallelic mutations suggested that the patient’s estrogen resistance was autosomal recessive, especially since microarray analysis revealed a region of homozygosity consistent with a parental history of second-degree relation.20
Nineteen years after the description of an estrogen-resistant state in a man, we provide evidence that ESR1
mutations in women are not lethal but confer a profoundly estrogen-resistant state.