To the Editor,
An ongoing controversy exists on the presence of andropause in ageing men. Our previous findings show that some ageing men exhibit decreased circulating testosterone levels in combination with low or low–normal gonadotropin levels, a condition resembling adult-onset hypogonadotropic hypogonadism.
We recently described a patient with a homozygous p.R262Q mutation in the GNRHR gene coding for gonadotropin-releasing hormone receptor; he presented with fascinating temporal variation in his phenotype with periods of hypogonadotropic hypogonadism, reversal and relapse at a later age.
Biallelic GNRHRmutations are the most common genetic cause of normosmic congenital hypogonadotropic hypogonadism (CHH). However, we have detected carrier frequencies of GNRHR mutations of 2·1–4·8% at population level in different cohorts without CHH, but, at the same time, CHH is much rarer than would be expected based on Hardy–Weinberg's law (the 2% carrier frequency would produce the incidence of 1:9800; 4% would produce 1:2400).
This finding suggests that patients with biallelic GNRHR mutations can potentially present with a milder phenotype than CHH, especially if the mutation only partially disrupts the receptor function. We hypothesized that biallelic GNRHR mutations may be found among ageing men presenting with symptomatic androgen deficiency.
Of the 63 men defined as having late onset hypogonadism (LOH) in the European Male Ageing Study (EMAS), 57 gave written informed consent for their genetic material to be used in the study. LOH was defined as having the following: total testosterone <11 mmol\l and free testosterone <220 pmol\l and the presence of three sexual systems (low libido; poor morning erections and erectile dysfunction). Exons and exon–intron junctions of the GNRHR gene were PCR-amplified from their genomic DNA and Sanger-sequenced bidirectionally.
None of the males, irrespective of their phenotypic presentation, displayed biallelic GNRHR mutations. Two men carried heterozygous mutations in GNRHR: a known CHH causing mutation c.416G>A (p.R139H), and a novel missense change c.185A>G (p.K62R), which was predicted to be benign by PolyPhen2 (score 0·001, sensitivity: 0·99; specificity: 0·15), predicted to be a polymorphism by Mutation Taster (probability 0·99) and predicted tolerated by SIFT (score 0·95).
The p.R139H mutation has been reported with a frequency of 1/8600 in the European American population in the NHLBI Exome Sequencing Project (ESP) database, whereas the p.K62R mutation was not found in any database searched (ESP, 1000 Genomes, Exome Aggregation Consortium (ExAC)).
Carrier of the p.R139H mutation had BMI of 28 kg/m2 at the age of 65 years, mildly decreased circulating T (9 nm) and normal LH (8·4 IU/l) and FSH (4·4 IU/l) levels. Subject with the p.K62R variant had BMI of 30 kg/m2 at the age of 77 years and presented with frankly hypogonadal circulating T (1·5 nm) and elevated gonadotropin (FSH>41 IU/l and LH >20 IU/l). He has two children and his adult height is 158 cm, two clinical findings suggesting that hypergonadotropism was not due to Klinefelter syndrome.
Our results show that biallelic GNRHR mutations are not a frequent cause of age-related androgen decline in men. Although the GNRHR mutations in CHH families are generally recessive, and the heterozygous carriers asymptomatic, some heterozygous GNRHR mutations have been described to segregate with a phenotype of compromised hypothalamic–pituitary–gonadal (HPG) axis function, such as hypothalamic amenorrhoea and constitutional delay of growth and puberty.
In our study, only two subjects carried heterozygous missense changes, one of which is predicted to be benign. However, the p.R139H mutation has been previously implicated in severe CHH, both in homozygous and compound heterozygous biallelic state, and causes complete loss of receptor function. We cannot therefore completely exclude the possibility that the p.R139H mutation, even in heterozygous state, might have predisposed the carrier to age-related decrease in HPG axis function.
Tommiska J, Kansakoski J, Pitteloud N, Wu F, Raivio T. Gonadotropin-releasing hormone receptor mutations in ageing men. Clin Endocrinol (Oxf) 2016;84(1):150-1. Gonadotropin-releasing hormone receptor mutations in ageing men - Tommiska - 2015 - Clinical Endocrinology - Wiley Online Library
An ongoing controversy exists on the presence of andropause in ageing men. Our previous findings show that some ageing men exhibit decreased circulating testosterone levels in combination with low or low–normal gonadotropin levels, a condition resembling adult-onset hypogonadotropic hypogonadism.
We recently described a patient with a homozygous p.R262Q mutation in the GNRHR gene coding for gonadotropin-releasing hormone receptor; he presented with fascinating temporal variation in his phenotype with periods of hypogonadotropic hypogonadism, reversal and relapse at a later age.
Biallelic GNRHRmutations are the most common genetic cause of normosmic congenital hypogonadotropic hypogonadism (CHH). However, we have detected carrier frequencies of GNRHR mutations of 2·1–4·8% at population level in different cohorts without CHH, but, at the same time, CHH is much rarer than would be expected based on Hardy–Weinberg's law (the 2% carrier frequency would produce the incidence of 1:9800; 4% would produce 1:2400).
This finding suggests that patients with biallelic GNRHR mutations can potentially present with a milder phenotype than CHH, especially if the mutation only partially disrupts the receptor function. We hypothesized that biallelic GNRHR mutations may be found among ageing men presenting with symptomatic androgen deficiency.
Of the 63 men defined as having late onset hypogonadism (LOH) in the European Male Ageing Study (EMAS), 57 gave written informed consent for their genetic material to be used in the study. LOH was defined as having the following: total testosterone <11 mmol\l and free testosterone <220 pmol\l and the presence of three sexual systems (low libido; poor morning erections and erectile dysfunction). Exons and exon–intron junctions of the GNRHR gene were PCR-amplified from their genomic DNA and Sanger-sequenced bidirectionally.
None of the males, irrespective of their phenotypic presentation, displayed biallelic GNRHR mutations. Two men carried heterozygous mutations in GNRHR: a known CHH causing mutation c.416G>A (p.R139H), and a novel missense change c.185A>G (p.K62R), which was predicted to be benign by PolyPhen2 (score 0·001, sensitivity: 0·99; specificity: 0·15), predicted to be a polymorphism by Mutation Taster (probability 0·99) and predicted tolerated by SIFT (score 0·95).
The p.R139H mutation has been reported with a frequency of 1/8600 in the European American population in the NHLBI Exome Sequencing Project (ESP) database, whereas the p.K62R mutation was not found in any database searched (ESP, 1000 Genomes, Exome Aggregation Consortium (ExAC)).
Carrier of the p.R139H mutation had BMI of 28 kg/m2 at the age of 65 years, mildly decreased circulating T (9 nm) and normal LH (8·4 IU/l) and FSH (4·4 IU/l) levels. Subject with the p.K62R variant had BMI of 30 kg/m2 at the age of 77 years and presented with frankly hypogonadal circulating T (1·5 nm) and elevated gonadotropin (FSH>41 IU/l and LH >20 IU/l). He has two children and his adult height is 158 cm, two clinical findings suggesting that hypergonadotropism was not due to Klinefelter syndrome.
Our results show that biallelic GNRHR mutations are not a frequent cause of age-related androgen decline in men. Although the GNRHR mutations in CHH families are generally recessive, and the heterozygous carriers asymptomatic, some heterozygous GNRHR mutations have been described to segregate with a phenotype of compromised hypothalamic–pituitary–gonadal (HPG) axis function, such as hypothalamic amenorrhoea and constitutional delay of growth and puberty.
In our study, only two subjects carried heterozygous missense changes, one of which is predicted to be benign. However, the p.R139H mutation has been previously implicated in severe CHH, both in homozygous and compound heterozygous biallelic state, and causes complete loss of receptor function. We cannot therefore completely exclude the possibility that the p.R139H mutation, even in heterozygous state, might have predisposed the carrier to age-related decrease in HPG axis function.
Tommiska J, Kansakoski J, Pitteloud N, Wu F, Raivio T. Gonadotropin-releasing hormone receptor mutations in ageing men. Clin Endocrinol (Oxf) 2016;84(1):150-1. Gonadotropin-releasing hormone receptor mutations in ageing men - Tommiska - 2015 - Clinical Endocrinology - Wiley Online Library
