Year: 2012
Type: dissertation
Study design: Observational Study
Abstract: Congenital hypogonadotropic hypogonadism (HH) is a rare explanation for absent or delayed puberty. HH is caused by a lack or reduced number of gonadotropin-releasing hormone (GnRH) neurons, or disrupted secretion or action of GnRH. If HH appears with defects in sense of smell, the condition is termed Kallmann syndrome (KS). Clinical and genetic features of KS and congenital HH with normal sense of smell (normosmic HH; nHH) are heterogeneous, and the disease phenotype may even differ within the same family. Severity of HH may vary from cryptorchidism and micropenis in infant boys and absent pubertal development to reversal of HH later in life. This study aimed to characterize the clinical and genetic features of patients with KS or nHH, as well as the features of those who had recovered from HH later in life, and to estimate the frequency of KS in Finland. We also investigated the long-term associations of treatment of HH on bone health. In addition, we investigated the role of HH genes in the etiology of isolated cryptorchidism. Patients previously diagnosed with congenital HH were enrolled at all five university hospitals in Finland. Participants underwent detailed clinical examination and dual energy x-ray absorptiometry (DXA) scan for bone mineral density (BMD) assessment. Serum reproductive hormones and bone turnover markers were measured. In addition, recovery of HH was assessed after treatment withdrawal. Subjects with congenital HH (KS or nHH) were screened for mutation(s) in genes involved in development and/or migration of GnRH neurons: KAL1 (KS patients only), FGFR1, FGF8, PROK2, PROKR2, CHD7, and WDR11. Normosmic subjects were also screened for mutation(s) in the additional genes regulating secretion and/or action of GnRH: GNRHR, GNRH1, TAC3, TACR3, KISS1, and KISS1R. Furthermore, FGFR1, PROK2, PROKR2, GNRHR, TAC3, and TACR3 were screened in 54 boys and men from 46 families with isolated cryptorchidism, but no other features of HH. The minimal incidence estimate of KS in Finland between 1976 and 1987 was 1:48 000, with a clear difference between boys (1:30 000) and girls (1:125 000) (p=0.02). The reproductive phenotype of 35 KS patients (29 men) and 10 nHH patients (6 men) ranged from severe HH to reversal of HH later in life (n=6, all men). Twenty-six patients underwent DXA scan, and BMDs of all measured sites were lower in subjects who had had long (>5 years) treatment pauses or low-dose testosterone treatment (n=9) as compared to subjects without such a history (n=17; all p-values<0.05). Altogether, mutational analysis revealed mutation(s) in 19 of 45 index cases: three KS men had a mutation in KAL1, six women (5 KS and 1 nHH) and five KS men (one with reversal of HH) had an FGFR1 mutation, one KS man with HH reversal harbored a CHD7 mutation, and two normosmic men both with reversal, and one pair of sisters all had compound heterozygous mutations in GNRHR. No other mutations in screened genes were found. Two of the 46 index cases with isolated cryptorchidism were heterozygous carriers of a single GNRHR mutation, also present in male controls at a similar frequency (3/120; p=0.62). In conclusion, KS is a rare condition, with a minimal incidence estimate of 1:48 000 in Finland. Approximately 40% of the cases attained a molecular genetic cause for the condition; particularly, Finnish KS women frequently harbored a mutation in FGFR1. A considerable proportion of male patients with HH may recover in early adulthood. We therefore recommend that all adolescents and young adults with congenital HH should be informed on the possibility of reversal. However, HH patients may still require life-long follow-up to avoid inadequate hormone treatment, long treatment pauses, and further morbidity. Finally, isolated cryptorchidism is not commonly caused by defects in genes involved in congenital HH.
Source: Työväentutkimus Vuosikirja
Author: Eeva‐Maria Laitinen
Language: English
Subfield: Reproductive Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W1551012874