Responsiveness to a Physiological Regimen of GnRH Therapy and Relation to Genotype in Women With Isolated Hypogonadotropic Hypogonadism

Abel, Brent S.; Shaw, Natalie D.; Brown, Jenifer M; Adams, Judith; Alati, Teresa; Pitteloud, Nelly; Seminara, Stephanie B.; Plummer, Lacey; Pignatelli, Duarte; Crowley, William F.; Welt, Corrine K.; Hall, Janet E.

doi:10.1210/jc.2012-3294

Cited by 23 publications

(11 citation statements)

References 64 publications

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“… 11 A pituitary resistance to pulsatile GnRH therapy also manifested in 30% of female CHH patients. 12 The current data are consistent with these other studies and show that 11% of CHH patients had a poor pituitary response even when the dosage of GnRH was adjusted to as high as 190 ng kg −1 per pulse.…”

Section: Discussionsupporting

confidence: 91%

Predictive factors for pituitary response to pulsatile GnRH therapy in patients with congenital hypogonadotropic hypogonadism

et al. 2018

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Pulsatile gonadotropin-releasing hormone (GnRH) may induce spermatogenesis in most patients with congenital hypogonadotropic hypogonadism (CHH) by stimulating gonadotropin production, while the predictors for a pituitary response to pulsatile GnRH therapy were rarely investigated. Therefore, the aim of our study is to investigate predictors of the pituitary response to pulsatile GnRH therapy. This retrospective cohort study included 82 CHH patients who received subcutaneous pulsatile GnRH therapy for at least 1 month. Patients were categorized into poor or normal luteinizing hormone (LH) response subgroups according to their LH level (LH <2 IU l−1 or LH ≥2 IU l−1) 1 month into pulsatile GnRH therapy. Gonadotropin and testosterone levels, testicular size, and sperm count were compared between the two subgroups before and after GnRH therapy. Among all patients, LH increased from 0.4 ± 0.5 IU l−1 to 7.5 ± 4.4 IU l−1 and follicle-stimulating hormone (FSH) increased from 1.1 ± 0.9 IU l−1 to 8.8 ± 5.3 IU l−1. A Cox regression analysis showed that basal testosterone level (β = 0.252, P = 0.029) and triptorelin-stimulated FSH60min (β = 0.518, P = 0.01) were two favorable predictors for pituitary response to GnRH therapy. Nine patients (9/82, 11.0%) with low LH response to GnRH therapy were classified into the poor LH response subgroup. After pulsatile GnRH therapy, total serum testosterone level was 39 ± 28 ng dl−1 versus 248 ± 158 ng dl−1 (P = 0.001), and testicular size was 4.0 ± 3.1 ml versus 7.9 ± 4.5 ml (P = 0.005) in the poor and normal LH response subgroups, respectively. It is concluded that higher levels of triptorelin-stimulated FSH60minand basal total serum testosterone are favorable predictors of pituitary LH response to GnRH therapy.

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Section: Discussionsupporting

confidence: 91%

Predictive factors for pituitary response to pulsatile GnRH therapy in patients with congenital hypogonadotropic hypogonadism

et al. 2018

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“…221 The goal of ovulation induction therapy in female patients with CHH is to obtain a single ovulation and to avoid multiple pregnancies. Ovulation can be achieved either with pulsatile GnRH therapy [222][223][224] or, alternatively, with FSH treatment followed by hCG or LH to trigger ovulation. 225 One caveat is that most women with CHH do not secrete endogenous LH and, thus, require a complement of LH to stimulate local production of androgen substrates by theca cells, which facilitates sufficient secretion of estradiol by the dominant follicle.…”

Section: Induction Of Female Sexual Characteristicsmentioning

confidence: 99%

“…229 Typically, subcutaneous FSH doses of 75-150 IU per day are sufficient. [223][224][225]229 The usual time required to obtain a dominant mature follicle (>18 mm) is ~12 days. [223][224][225]229 The starting dose of FSH is often increased or decreased depending on the ovarian response, as assessed by repeated serum estradiol measurements or by counting maturing follicles (using ultrasonography) performed approximately every 3-4 days.…”

Section: Induction Of Female Sexual Characteristicsmentioning

confidence: 99%

European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment

et al. 2015

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| Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder caused by the deficient production, secretion or action of gonadotropin-releasing hormone (GnRH), which is the master hormone regulating the reproductive axis. CHH is clinically and genetically heterogeneous, with >25 different causal genes identified to date. Clinically, the disorder is characterized by an absence of puberty and infertility. The association of CHH with a defective sense of smell (anosmia or hyposmia), which is found in ~50% of patients with CHH is termed Kallmann syndrome and results from incomplete embryonic migration of GnRHsynthesizing neurons. CHH can be challenging to diagnose, particularly when attempting to differentiate it from constitutional delay of puberty. A timely diagnosis and treatment to induce puberty can be beneficial for sexual, bone and metabolic health, and might help minimize some of the psychological effects of CHH. In most cases, fertility can be induced using specialized treatment regimens and several predictors of outcome have been identified. Patients typically require lifelong treatment, yet ~10-20% of patients exhibit a spontaneous recovery of reproductive function. This Consensus Statement summarizes approaches for the diagnosis and treatment of CHH and discusses important unanswered questions in the field.

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“…Ovulation induction can be achieved either with pulsatile GnRH therapy (2,9,33) or, alternatively, with FSH and LH administration followed by hCG or LH to trigger ovulation (2,3,(7)(8)(9). Thus, in contrast to many other primary causes of infertility with gonadal involvement (e.g.…”

Section: Chh/ks Is a Treatable Form Of Infertilitymentioning

confidence: 99%

GENETICS IN ENDOCRINOLOGY: Genetic counseling for congenital hypogonadotropic hypogonadism and Kallmann syndrome: new challenges in the era of oligogenism and next-generation sequencing

Maione

Dwyer

Francou

et al. 2018

European Journal of Endocrinology

131

166

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Congenital hypogonadotropic hypogonadism (CHH) and Kallmann syndrome (KS) are rare, related diseases that prevent normal pubertal development and cause infertility in affected men and women.However, the infertility carries a good prognosis as increasing numbers of patients with CHH/KS are now able to have children through medically assisted procreation.These are genetic diseases that can be transmitted to patients' offspring. Importantly patients and their families should be informed of this risk and given genetic counseling. CHH and KS are phenotypically and genetically heterogeneous diseases in which the risk of transmission largely depends on the gene(s) responsible(s). Inheritance may be classically Mendelian yet more complex, oligogenic modes of transmission have also been described. The prevalence of oligogenicity has risen dramatically since the advent of massively parallel next-generation sequencing (NGS) in which tens, hundreds or thousands of genes are sequenced at the same time. NGS is medically and economically more efficient and more rapid than traditional Sanger sequencing, and is increasingly being used in medical practice. Thus it seems plausible that oligogenic forms of CHH/KS will be increasingly identified making genetic counseling even more complex. In this context, the main challenge will be to differentiate true oligogenism from situations when several rare variants that do not have a clear phenotypic effect are identified by chance. This review aims to summarize the genetics of CHH/KS and to discuss the challenges of oligogenic transmission but also its role in incomplete penetrance and variable expresivity in a perspective of genetic counseling.

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Responsiveness to a Physiological Regimen of GnRH Therapy and Relation to Genotype in Women With Isolated Hypogonadotropic Hypogonadism

Cited by 23 publications

References 64 publications

Predictive factors for pituitary response to pulsatile GnRH therapy in patients with congenital hypogonadotropic hypogonadism

Predictive factors for pituitary response to pulsatile GnRH therapy in patients with congenital hypogonadotropic hypogonadism

European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment

GENETICS IN ENDOCRINOLOGY: Genetic counseling for congenital hypogonadotropic hypogonadism and Kallmann syndrome: new challenges in the era of oligogenism and next-generation sequencing

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