Table 5.
Effects of loss of aromatase or ESR1 in men
| Original and Related Case Reports | Type of Mutation, Subject Age | Reproductive Effects | Skeletal Effects | Metabolic Effects |
|---|---|---|---|---|
| Aromatase mutation | ||||
| Morishima et al. 1995 (469), Bilezikian et al. 1998 (66) | Single point mutation, 27 yr | Virilization of mother; normal sexual and pubertal development; elevated T, LH, and FSH; low E2 levels; macro-orchidism; no semen analysis; heterosexual orientation and behavior | Tall stature, osteopenia, osteoporosis, younger bone age (14 yr), low bone mass and mineral density, unfused epiphyses | Hyperinsulinism, normal glucose, dyslipidemia, BMI 32.5 |
| Carani et al. 1997, 1999 (107, 108), Rochira et al. 2000 (588) | Single point mutation, 0.4% aromatase activity, 31 yr | Normal sexual and pubertal development, normal T, slightly elevated FSH, upper normal LH and undetectable E2, micro-orchidism, infertility, oligospermia with immotile spermatozoa. Hypospermatogenesis and germ cell arrest, heterosexual orientation and behavior | Tall stature and bilateral genu valgum, bone pain, open metacarpal and phalangeal epiphyses, and younger bone age (14.8 yr) | Normal insulin and glucose, dyslipidemia, BMI 27.6 |
| Deladoey et al. 1999 (173) | Base pair deletion in CYP19 gene causing truncated, inactive protein, infant | Normal sexual differentiation; maternal virilization; normal serum-free T and high androstenedione at birth, which decreased by 1 month; normal testes descent | ||
| Herrmann et al. 2002, 2005 (286, 287) | Frameshift mutation resulting in premature stop codon and truncated aromatase protein, 27 yr | Maternal virilization, normal sexual and pubertal development, high T and FSH, normal LH, low E2, normal testicular volume, oligospermia, reduced sperm motility, normal sperm morphology and vitality, heterosexual orientation and behavior | Tall stature, low bone mass and mineral density, increased linear bone growth, genu valgum, kyphoscoliosis, and pectus carniatus | Normal plasma glucose and insulin dyslipidemia, BMI 30.9 |
| Maffei et al. 2004 (433), Carrani et al. 2005 (106), Rochira et al. 2007 (590) | Point mutation resulting in truncated aromatase protein, 29 yr | History of bilateral cryptorchidism, normal sexual and pubertal development, normal LH and T but increased FSH and low E2, micro-orchid testes in inguinal canal, abnormal seminiferous tubules with Sertoli cell-only tubules, atrophy and degenerated epithelium, heterosexual orientation and behavior | Tall stature, persistent linear growth and diffuse bone pain, genu valgum, unfused metacarpal and phalangeal bones and younger bone age (15 yr), osteoporosis, low BMD | Upper normal insulin levels, normal glucose, normal total cholesterol, acanthosis nigricans, BMI 25.4 |
| Bouillon et al. 2004 (82) | Frame-shift mutation causing truncated, inactive enzyme, 17 yr | Congenital hearing problem, high serum T, upper normal range of LH and FSH, undetectable E2 levels, normal testicular volume, sexual and pubertal development | Tall stature, open epiphyses and younger bone age (12 yr), low BMD and bone size | BMI 27.7 |
| Maffei et al. 2007 (434) | Two point mutations, 25 yr | Normal sexual and pubertal development, normal LH and T, FSH slightly elevated, undetectable E2, normal testicular volume, hypospermia, heterosexual orientation and behavior | Tall stature, genu valgum, continuing linear growth, diffuse bone pain, younger bone age (15.3 yr), unfused epiphyses, low BMD, osteoporosis, osteopenia | Obesity, hyperinsulinemia, insulin resistance, dyslipidemia, acanthosis nigricans, nonalcoholic fatty liver disease, hepatomegaly, BMI 35.9 |
| Lanfranco et al. 2008 (386) | Compound heterozygous mutation resulting in truncated, inactive aromatase protein, 26 yr | History of right cryptorchidism, normal sexual and pubertal development, slightly elevated FSH, normal LH and T, undetectable E2, normal testicular volume and sperm concentration with slightly reduced motility, normal sexual behavior, heterosexual orientation | Tall stature, genu valgum, unfused epiphyses, osteopenia, low BMD, younger bone age (15.5 yr) | Increased fasting insulin, insulin resistance, dyslipidemia, fatty liver, impaired liver function, acanthosis nigricans, BMI 29.3 |
| Baykan et al. 2013 (47) | Point mutation, 27 yr proband and younger brother | High LH and FSH, normal testosterone, undetectable E2, ambiguous genitalia, normal testicular volume and sperm count, slightly reduced sperm motility | Tall stature, unfused epiphyses, linear bone growth, bone pain, recurrent bone fractures, osteopenia, osteoporosis, younger bone age (15 yr) | High total cholesterol and triglycerides, low HDL, hepatosteatosis, BMI 25.7 |
| Bouchoucha et al. 2014 (81) | Point mutation resulting in reduced aromatase activity, 1–6 yr | Hypospadias and bilateral cryptorchidism, normal hormonal profiles | ||
| Chen et al. 2015 (130) | Compound heterozygous point mutations resulting in decreased aromatase activity, 24 yr | Normal LH, FSH, and T; undetectable E2; normal sexual and pubertal development, sexual behavior, and orientation; normal testes size, sperm count, and viability | Tall stature, genu valgum, unfused epiphyses, osteopenia, younger bone age (16-18 yr), low BMD | Hyperinsulinemia, impaired glucose tolerance, steatohepatitis, dyslipidemia, acanthosis nigricans, BMI 26.5 |
| Miedlich et al. 2016 (464) | Point mutation resulting in truncated inactive protein, 25 yr | Virilization of mother during pregnancy, normal FSH and LH, high-normal T levels, undetectable E2, normal pubertal development, testis size, sexual behavior and libido | Tall stature, bone abnormalities | Normal insulin, glucose, and lipidemia; moderate acanthosis nigricans |
| Estrogen receptor 1 mutation | ||||
| Smith et al. 1994 (647) | Point mutation resulting in truncated protein, 28 yr | Normal sexual and pubertal development; elevated E2, LH, and FSH; normal T; normal testes size, sperm count, sexual behavior, and orientation; reduced sperm vitality | Tall stature, genu valgum, bone abnormalities, younger bone age (15 yr) | Impaired glucose tolerance and insulin resistance, acanthosis nigricans, BMI 30.5 |
| Bernard et al. 2017 (57) | Point mutation in ligand binding domain with reduced transcriptional activity, 18 yr | Elevated FSH, LH, and E2; low to normal serum T; low serum inhibin B and AMH; unilateral right cryptorchidism; hypoplastic left testis; normal pubertal development | Low bone age (11 yr) | BMI 23.7 |