Reversible Hypogonadotropic Hypogonadism

Michael Scally MD

Doctor of Medicine
10+ Year Member
Laitinen EM, Tommiska J, Sane T, Vaaralahti K, Toppari J, Raivio T. Reversible Congenital Hypogonadotropic Hypogonadism in Patients with CHD7, FGFR1 or GNRHR Mutations. PLoS One 2012;7(6):e39450. PLoS ONE: Reversible Congenital Hypogonadotropic Hypogonadism in Patients with CHD7, FGFR1 or GNRHR Mutations

BACKGROUND: Congenital hypogonadotropic hypogonadism (HH) is a rare cause for delayed or absent puberty. These patients may recover from HH spontaneously in adulthood. To date, it is not possible to predict who will undergo HH reversal later in life. Herein we investigated whether Finnish patients with reversal of congenital hypogonadotropic hypogonadism (HH) have common phenotypic or genotypic features.

METHODS AND FINDINGS: Thirty-two male HH patients with anosmia/hyposmia (Kallmann Syndrome, KS; n = 26) or normal sense of smell (nHH; n = 6) were enrolled (age range, 18-61 yrs). The patients were clinically examined, and reversal of HH was assessed after treatment withdrawal. KAL1, FGFR1, FGF8, PROK2, PROKR2, CHD7, WDR11, GNRHR, GNRH1, KISS1R, KISS1, TAC3, TACR3, and LHbeta were screened for mutations. Six HH patients (2 KS, 4 nHH) were verified to have reversal of HH. In the majority of cases, reversal occurred early in adulthood (median age, 23 yrs; range, 21-39 yrs). All had spontaneous testicular growth while on testosterone replacement therapy (TRT). One nHH subject was restarted on TRT due to a decline in serum T. Two reversal variants had a same GNRHR mutation (R262Q), which was accompanied by another GNRHR mutation (R139H or del309F). In addition, both of the KS patients had a mutation in CHD7 (p.Q51X) or FGFR1 (c.91+2T>A).

CONCLUSIONS: Considerable proportion of patients with HH (8% of KS probands) may recover in early adulthood. Spontaneous testicular enlargement during TRT was highly suggestive for reversal of HH. Those with the GNRHR mutation R262Q accompanied by another GNRHR mutation may be prone to reversal, although even patients with a truncating mutation in CHD7 or a splice-site mutation in FGFR1 can recover. We recommend that all adolescents and young adults with congenital HH should be informed on the possibility of reversal.
 
[Open Access] Reversible Hypogonadotropic Hypogonadism

Congenital hypogonadotropic hypogonadism (CHH) is characterized by lack of puberty and infertility.

Traditionally, it has been considered a life-long condition yet cases of reversibility have been described wherein patients spontaneously recover function of the reproductive axis following treatment.

Reversibility occurs in both male and female CHH cases and appears to be more common (approximately 10-15%) than previously thought.

These reversal patients span a range of GnRH deficiency from mild to severe and many reversal patients harbor mutations in genes underlying CHH.

However, to date there are no clear factors for predicting reversible CHH.

Importantly, recovery of reproductive axis function may not be permanent.

Thus, CHH is not always life-long and the incidence of reversal warrants periodic treatment withdrawal with close monitoring and follow-up.

Reversible CHH highlights the importance of environmental (epigenetic) factors such as sex steroid treatment on the reproductive axis in modifying the phenotype.

This review provides an overview and an update on what is known about this phenomenon.

Dwyer AA, Raivio T, Pitteloud N. MANAGEMENT OF ENDOCRINE DISEASE: Reversible hypogonadotropic hypogonadism. European Journal of Endocrinology. http://www.eje-online.org/content/early/2016/01/20/EJE-15-1033.abstract (MANAGEMENT OF ENDOCRINE DISEASE: Reversible hypogonadotropic hypogonadism)
 
Mao J-F, Xu H-L, Duan J, et al. Reversal of idiopathic hypogonadotropic hypogonadism: a cohort study in Chinese patients. Asian Journal of Andrology 2015;17(3):497-502. Reversal of idiopathic hypogonadotropic hypogonadism: a cohort study in Chinese patients

Although idiopathic hypogonadotropic hypogonadism (IHH) has traditionally been viewed as a life-long disease caused by a deficiency of gonadotropin-releasing hormone neurons, a portion of patients may gradually regain normal reproductive axis function during hormonal replacement therapy. The predictive factors for potential IHH reversal are largely unknown. The aim of our study was to investigate the incidence and clinical features of IHH male patients who had reversed reproductive axis function. In this retrospective cohort study, male IHH patients were classified into a reversal group (n = 18) and a nonreversal group (n = 336). Concentration of gonadotropins and testosterone, as well as testicle sizes and sperm counts, were determined. Of 354 IHH patients, 18 (5.1%) acquired normal reproductive function during treatment. The median age for reversal was 24 years old (range 21–34 years). Compared with the nonreversal group, the reversible group had higher basal luteinizing hormone (LH) (1.0 ± 0.7 IU l-1 vs 0.4 ± 0.4 IU l−1, P < 0.05) and stimulated LH (28.3 ± 22.6 IU l−1 vs 1.9 ± 1.1 IU l−1, P < 0.01) levels, as well as larger testicle size (5.1 ± 2.6 ml vs 1.5 ± 0.3 ml, P < 0.01), at the initial visit. In summary, larger testicle size and higher stimulated LH concentrations are favorite parameters for reversal. Our finding suggests that reversible patients may retain partially active reproductive axis function at initial diagnosis.
 
Mao J-F, Xu H-L, Duan J, et al. Reversal of idiopathic hypogonadotropic hypogonadism: a cohort study in Chinese patients. Asian Journal of Andrology 2015;17(3):497-502. Reversal of idiopathic hypogonadotropic hypogonadism: a cohort study in Chinese patients

Although idiopathic hypogonadotropic hypogonadism (IHH) has traditionally been viewed as a life-long disease caused by a deficiency of gonadotropin-releasing hormone neurons, a portion of patients may gradually regain normal reproductive axis function during hormonal replacement therapy. The predictive factors for potential IHH reversal are largely unknown. The aim of our study was to investigate the incidence and clinical features of IHH male patients who had reversed reproductive axis function. In this retrospective cohort study, male IHH patients were classified into a reversal group (n = 18) and a nonreversal group (n = 336). Concentration of gonadotropins and testosterone, as well as testicle sizes and sperm counts, were determined. Of 354 IHH patients, 18 (5.1%) acquired normal reproductive function during treatment. The median age for reversal was 24 years old (range 21–34 years). Compared with the nonreversal group, the reversible group had higher basal luteinizing hormone (LH) (1.0 ± 0.7 IU l-1 vs 0.4 ± 0.4 IU l−1, P < 0.05) and stimulated LH (28.3 ± 22.6 IU l−1 vs 1.9 ± 1.1 IU l−1, P < 0.01) levels, as well as larger testicle size (5.1 ± 2.6 ml vs 1.5 ± 0.3 ml, P < 0.01), at the initial visit. In summary, larger testicle size and higher stimulated LH concentrations are favorite parameters for reversal. Our finding suggests that reversible patients may retain partially active reproductive axis function at initial diagnosis.

Dwyer A, Raivio PT. Comment on reversal of hypogonadotropic hypogonadism in a Chinese cohort. Asian Journal of Andrology 2015;17(3):508-. Comment on reversal of hypogonadotropic hypogonadism in a Chinese cohort

The reversal of congenital hypogonadotropic hypogonadism (CHH) is a relatively recent phenomenon that has gained increasing attention over the past 10 years. Yet to date, only one prospective study has been conducted estimating that 10% (95% confidence interval [CI]: 2%–18%) of cases undergo reversal.1 Other retrospective studies have reported rates in the range of 5%–8%2,3 and a recent study showed 44/308 (14%, 95% CI: 11%–19%) CHH patients underwent reversal.4 Moreover, a time-to-event analysis in this large cohort revealed a lifetime reversal incidence of 22%. The article by Mao and colleagues presented in this issue is a meaningful contribution to our understanding of reversal as it examines the largest retrospective cohort to date.5 Interestingly, they report the rate of reversal as 5% (95% CI: 3%–8%) in this Chinese cohort. It is difficult to reconcile the discrepancies in rates of reversibility and direct comparisons are hampered by the variable definitions employed. Using a novel definition for reversal (i.e, either endogenous testosterone (T) >270 ng dl−1, serum T gradually increasing above 150 ng dl−1 with increased testicular volume, or normal spontaneous sperm production/normal erectile function/ejaculation), Mao and colleagues posit that testicular size and triptorelin-stimulated LH levels are reliable predictive factors for reversal. However, these cannot be considered as hard and fast rules for predicting reversal as the groups intersect - akin to the overlap observed between CHH patients and those with delayed puberty. Indeed, the fact that approximately half (44%, 95% CI: 25%–66%) of the reversal patients in the study by Mao et al.5 were diagnosed between 17 and 19 years of age, underscores the challenge in differentiating CHH from extreme normal variants of puberty.

This study further lends credence the recently reported observations that reversals may relapse.4,6 The notion that reversal may not be lasting highlights the vulnerability of the reproductive axis among CHH patients. While the mechanism(s) for relapse are unclear, it seems plausible that environmental, metabolic or psychiatric stressors could contribute. The factors that Mao and colleagues identify as significantly different in cases of reversal, were not informative for identifying those cases that relapsed back to a hypogonadal state. Notably, reversal has been reported in probands harboring mutations in genes underlying CHH.1,3,4,6 Unfortunately, comprehensive genetic screening on the Chinese cohort is not available.

The reversal phenomenon is fascinating for its glimpse into the plasticity of the neuroendocrine control of reproduction. Future directions will almost certainly include investigation of specific genetic signatures and novel biomarkers for predicting reversal (and relapse). Yet CHH is a rare condition and to fully elucidate the biology of reversible CHH, it will be important to harmonize definitions of what constitutes a reversal, carefully phenotype patients and chart the natural history of their CHH. In this way, this unique human disease model may offer further insights into the control of human reproduction and provide opportunities to translate discoveries into enhanced approaches to improve the care and quality of life for these patients.
 
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