Pulsatile Gonadotropin-releasing Hormone Therapy Research Articles

Pulsatile gonadotropin-releasing hormone therapy: comparison of efficacy between functional hypothalamic amenorrhea and congenital hypogonadotropic hypogonadism

ObjectiveTo compare the ongoing pregnancy rate per initiated cycle between patients with functional hypothalamic amenorrhea and patients with congenital hypogonadotropic hypogonadism treated with pulsatile GnRH administration. DesignRetrospective monocentric cohort study conducted at the University Hospital of Lille from 2004 to 2022. Patient(s)141 patients diagnosed with central supra-pituitary amenorrhea during infertility evaluation and subsequently treated with pulsatile GnRH therapy. 111 and 30 patients were diagnosed with functional hypothalamic amenorrhea or congenital hypogonadotropic hypogonadism, respectively. Exposure(s)Pulsatile GnRH administration Main outcome measure(s)Ongoing pregnancy rate per initiated cycle. Result(s)Ongoing pregnancy rates per initiated cycle were comparable between groups: 21.5% in the functional hypothalamic amenorrhea group versus 22% in the congenital hypogonadotropic hypogonadism group; p=0.537. Comparison of baseline characteristics showed a more pronounced FSH deficiency in patients with congenital hypogonadotropic hypogonadism than in those with functional hypothalamic amenorrhea: 2.55 [0.6 - 4.92] versus 4.80 [3.90 - 5.70] UI/L; p<0.001. Within the congenital hypogonadotropic hypogonadism group, basal FSH level was positively associated with the occurrence of ongoing pregnancies (OR= 1.57; CI95%: 1.11;2.22; p=0.010). In the congenital hypogonadotropic hypogonadism group the duration of treatment was higher than in the functional hypothalamic amenorrhea group: 23.59 (±8.02) versus 18.16 (±7.66) days, p<0.001. ConclusionBaseline FSH is lower in patients with congenital hypogonadotropic hypogonadism than in patients with functional hypothalamic amenorrhea. The lower the FSH, the lower the chance of pregnancy in patients with congenital hypogonadotropic hypogonadism. These patients also require more days of GnRH administration. However, the rate of ongoing pregnancies is comparable between the two groups.

Pulsatile gonadotropin releasing hormone therapy for spermatogenesis in congenital hypogonadotropic hypogonadism patients who had poor response to combined gonadotropin therapy.

Both pulsatile gonadotropin-releasing hormone (GnRH) and combined gonadotropin therapy are effective to induce spermatogenesis in men with congenital hypogonadotropic hypogonadism (CHH). This study aimed to evaluate the effect of pulsatile GnRH therapy on spermatogenesis in male patients with CHH who had poor response to combined gonadotropin therapy. Patients who had poor response to combined gonadotropin therapy ≥ 6 months were recruited and shifted to pulsatile GnRH therapy. The rate of successful spermatogenesis, the median time to achieve spermatogenesis, serum gonadotropins, testosterone, and testicular volume were used for data analysis. A total of 28 CHH patients who had poor response to combined gonadotropin (HCG/HMG) therapy for 12.5 (6.0, 17.75) months were recruited and switched to pulsatile GnRH therapy for 10.0 (7.25, 16.0) months. Sperm was detected in 17/28 patients (60.7%). The mean time for the appearance of sperm in semen was 12.0 (7.5, 17.5) months. Compared to those who could not achieve spermatogenesis during pulsatile GnRH therapy, the successful group had a higher level of LH60min (4.32 vs. 1.10 IU/L, P = 0.043) and FSH60min (4.28 vs. 1.90 IU/L, P = 0.021). Testicular size increased during pulsatile GnRH therapy, compared to previous HCG/ HMG therapy (P < 0.05). For CHH patients with prior poor response to one year of HCG/ HMG therapy, switching to pulsatile GnRH therapy may induce spermatogenesis.

Unlocking cognition with pulsatile GnRH in Down Syndrome: implications for Alzheimer’s disease

AbstractBackgroundThere is currently no viable treatment for the cognitive and olfactory deficits of Trisomy 21 and Alzheimer’s disease.MethodPhysiological characterization and epigenetic, cellular, chemogenetic, and pharmacological interventions in male and female Ts65Dn mice (P9‐P360), a mouse model of Down syndrome, and 12‐month‐old THY::TAU22 male mice, a mouse model of Alzheimer’s disease, and their wild‐type littermates. Seven men with Down syndrome (20‐50 years of age) were enrolled in an open‐label pilot study to assess the effect of 6‐month pulsatile GnRH therapy on cognitive and olfactory function.ResultWe show in Ts65Dn mice that olfactory and cognitive neurological symptoms are closely related to a post‐pubertal decrease in hypothalamic and extra‐hypothalamic expression of a master molecule controlling reproduction ‐ gonadotropin‐releasing hormone (GnRH) ‐ and appear to be linked to an imbalance in a microRNA‐gene network known to regulate the maturation of GnRH neurons as well as to an alteration in hippocampal synaptic transmission. Restoring physiological GnRH levels abolishes olfactory and cognitive deficits in Ts65Dn and THY::TAU22 mice, while pulsatile GnRH treatment improves cognition and brain connectivity in adult T21 patients.ConclusionWe have discovered that GnRH plays a crucial role in olfaction and cognition, and pulsatile GnRH treatment holds promise for improving cognitive deficits in patients with Down syndrome. Such treatment could potentially also be beneficial for mobilizing cognitive reserve in pathological brain aging such as that found in Alzheimer’s disease.

Pulsatile Gonadotropin-Releasing Hormone Therapy Is Associated With Better Spermatogenic Outcomes than Gonadotropin Therapy in Patients With Pituitary Stalk Interruption Syndrome

ObjectiveTo compare the effects of combined gonadotropin and pulsatile gonadotropin-releasing hormone (GnRH) therapy on spermatogenesis in patients with pituitary stalk interruption syndrome (PSIS). MethodsMale patients with PSIS (N = 119) were retrospectively studied. Patients received pulsatile GnRH therapy (N = 59) were divided into response and poor-response groups based on luteinizing hormone (LH) levels after 1-month treatment with a cutoff value of 1 or 2 IU/L. Participants with gonadotropin therapy were divided into human menopausal gonadotropin (hMG)/human chorionic gonadotropin (hCG) group (N = 60), and patients with pulsatile GnRH therapy were classified into GnRH group (N = 28) with treatment duration ≥6 months. ResultsThe overall success rates of spermatogenesis for hMG/hCG and GnRH therapy were 51.67% (31/60) vs 33.90% (20/59), respectively. GnRH group required a shorter period to induce spermatogenesis (8 vs 15 months, P = .019). hMG/hCG group had higher median total testosterone than GnRH group [2.16, interquartile range(IQR) 1.06-4.89 vs 1.31, IQR 0.21-2.26 ng/mL, P = .004]. GnRH therapy had a beneficial effect on spermatogenesis compared to hMG/hCG therapy (hazard ratio 1.97, 95% confidence interval 1.08-3.57, P = .026). In patients with pulsatile GnRH therapy, compared with the poor-response group, the response group had a higher successful spermatogenesis rate (5.00% vs 48.72%, P = .002) and higher median basal total testosterone (0.00, IQR 0.00-0.03 vs 0.04, IQR 0.00-0.16 ng/mL, P = .026) with LH = 1 IU/L as the cutoff value after 1-month pulsatile GnRH therapy. ConclusionsPulsatile GnRH therapy was superior to hMG/hCG therapy for spermatogenesis in patients with PSIS. Earlier spermatogenesis and higher concentrations of sperm could be obtained in the GnRH group if patients received therapy over 6 months.

A role for GnRH in olfaction and cognition: Implications for veterinary medicine.

Pulsatile secretion of gonadotropin-releasing hormone (GnRH) is essential for the activation and maintenance of the function of the hypothalamic-pituitary-gonadal (HPG) axis, which controls the onset of puberty and fertility. Two provocative recent studies suggest that, in addition to control reproduction, the neurons in the brain that produce GnRH are also involved in the control postnatal brain maturation, odour discrimination and adult cognition. Long-acting GnRH antagonists and agonists are commonly used to control fertility and behaviour in veterinary medicine, primarily in males. This review puts into perspective the potential risks of these androgen deprivation therapies and immunization on olfactory and cognitive performances and well-aging in domestic animals, including pets. We will also discuss the results reporting beneficial effects of pharmacological interventions restoring physiological GnRH levels on olfactory and cognitive alterations in preclinical models of Alzheimer's disease, which shares many pathophysiological and behavioural hallmarks with canine cognitive dysfunction. These novel findings raise the intriguing possibility that pulsatile GnRH therapy holds therapeutic potential for the management of this behavioural syndrome affecting older dogs.

New Horizons: Gonadotropin-Releasing Hormone and Cognition.

Pulsatile secretion of gonadotropin-releasing hormone (GnRH) is essential for activating and maintaining the function of the hypothalamic-pituitary-gonadal axis, which controls the onset of puberty and fertility. Two recent studies suggest that, in addition to controlling reproduction, the neurons in the brain that produce GnRH are also involved in the control of postnatal brain maturation, odor discrimination, and adult cognition. This review will summarize the development and establishment of the GnRH system, with particular attention to the importance of its first postnatal activation, a phenomenon known as minipuberty, for later reproductive and nonreproductive functions. In addition, we will discuss the beneficial effects of restoring physiological (ie, pulsatile) GnRH levels on olfactory and cognitive alterations in preclinical Down syndrome and Alzheimer disease models, as well as the potential risks associated with long-term continuous (ie, nonphysiological) GnRH administration in certain disorders. Finally, this review addresses the intriguing possibility that pulsatile GnRH therapy may hold therapeutic potential for the management of some neurodevelopmental cognitive disorders and pathological aging in elderly people.

Clinical and genetic characteristics of 42 Chinese paediatric patients with X-linked adrenal hypoplasia congenita

BackgroundX-linked adrenal hypoplasia congenita (AHC) is a rare disorder characterized by primary adrenal insufficiency (PAI) and hypogonadotropic hypogonadism (HH), with limited clinical and genetic characterization.MethodsThe clinical, biochemical, genetic, therapeutic, and follow-up data of 42 patients diagnosed with X-linked AHC were retrospectively analysed.ResultsHyperpigmentation (38/42, 90%), vomiting/diarrhoea (20/42, 48%), failure to thrive (13/42, 31%), and convulsions (7/42, 17%) were the most common symptoms of X-linked AHC at onset. Increased adrenocorticotropic hormone (ACTH) (42/42, 100%) and decreased cortisol (37/42, 88%) were the most common laboratory findings, followed by hyponatremia (32/42, 76%) and hyperkalaemia (29/42, 69%). Thirty-one patients presented with PAI within the first year of life, and 11 presented after three years of age. Three of the thirteen patients over the age of 14 exhibited spontaneous pubertal development, and ten of them experienced delayed puberty due to HH. Six patients receiving human chorionic gonadotropin (hCG) therapy exhibited a slight increase in testicular size and had rising testosterone levels (both P < 0.05). The testicular volumes of the three patients with pulsatile gonadotropin-releasing hormone (GnRH) therapy were larger than those of the six patients undergoing hCG therapy (P < 0.05), and they also exhibited some growth in terms of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone. Of the 42 patients, three had an Xp21 deletion, and 39 had an isolated DAX1 defect. Most patients (9/10) with entire DAX1 deletion accounting for 23.8% (10/42) of the total variants had early onset age of less than one year.ConclusionsThis study details the clinical features and genetic spectra of X-linked AHC. Patients with X-linked AHC show a bimodal distribution of the age of onset, with approximately 70% presenting within the first year of life. Pulsatile GnRH may be recommended for HH when hCG therapy is not satisfactory, although it is difficult to achieve normal testicular volume. The combination of clinical features and molecular tests provides information for an accurate diagnosis.

GNRHR-related central hypogonadism with spontaneous recovery – case report

BackgroundCongenital hypogonadotropic hypogonadism (CHH) is a clinically and genetically heterogeneous disease characterized by absent or incomplete puberty and infertility. Clinical characteristics are secondary to insufficient gonadotropin secretion, caused by deficient gonadotropin-releasing hormone (GnRH) production, secretion, or action. Loss-of-function variants of the gonadotropin-releasing hormone receptor (GNRHR) are associated with CHH without anosmia. CHH was previously considered a permanent condition, but in the past two decades, cases of spontaneous recovery of CHH have been reported. The reversal of hypogonadism in CHH is currently unpredictable, and can happen unnoticed.Case presentationThe male proband was diagnosed with CHH due to compound heterozygosity for two previously reported pathogenic missense variants in the GNRHR gene, NM_000406.2:c.416G > A (NP_000397.1:p.Arg139His) and c.785G > A (p.Arg262Gln) at 16 years of age. In addition to arrested partial puberty, he had a low testosterone level, gonadotropins in the range of early puberty, and a normal inhibin B level. A therapy with increasing doses of intramuscular testosterone undecanoate was received for 2.5 years, while there was no change in testicular volume. At the age of 19 years, testosterone supplementation was interrupted. During the next two years, he had spontaneous pubertal development to achieve a testicular volume of 20 mL, with normal adult levels of gonadotropins and testosterone.ConclusionsGenetic diagnostics can help discriminate congenital hypogonadotropic hypogonadism, deserving therapeutic intervention, from the self-limited constitutional delay of growth and puberty (CDGP). Patients with GNRHR associated hypogonadism can experience spontaneous recovery of the hypothalamic-pituitary–gonadal axis. Spontaneous testis enlargement in patients with central hypogonadism not taking gonadotropins or pulsatile GnRH therapy can indicate recovery of hypogonadism.

GnRH replacement rescues cognition in Down syndrome.

At the present time, no viable treatment exists for cognitive and olfactory deficits in Down syndrome (DS). We show in a DS model (Ts65Dn mice) that these progressive nonreproductive neurological symptoms closely parallel a postpubertal decrease in hypothalamic as well as extrahypothalamic expression of a master molecule that controls reproduction-gonadotropin-releasing hormone (GnRH)-and appear related to an imbalance in a microRNA-gene network known to regulate GnRH neuron maturation together with altered hippocampal synaptic transmission. Epigenetic, cellular, chemogenetic, and pharmacological interventions that restore physiological GnRH levels abolish olfactory and cognitive defects in Ts65Dn mice, whereas pulsatile GnRH therapy improves cognition and brain connectivity in adult DS patients. GnRH thus plays a crucial role in olfaction and cognition, and pulsatile GnRH therapy holds promise to improve cognitive deficits in DS.

Efficacy of Pulsatile Gonadotropin-Releasing Hormone Therapy in Male Patients: Comparison between Pituitary Stalk Interruption Syndrome and Congenital Hypogonadotropic Hypogonadism

ObjectivePulsatile gonadotropin-releasing hormone (GnRH), widely used to induce spermatogenesis in congenital hypogonadotropic hypogonadism (CHH) patients, can restore the pituitary-testis axis function in men with pituitary stalk interruption syndrome (PSIS). This retrospective study aimed to compare the differences in the long-term efficacy of pulsatile GnRH therapy on PSIS and CHH. MethodsPatients with PSIS (n = 25) or CHH (n = 64) who received pulsatile GnRH therapy for ≥3 months were included in this retrospective study. The rate of successful spermatogenesis, the median time to achieve spermatogenesis, serum gonadotropins, total testosterone, and testicular size were compared. ResultsBaseline characteristics were comparable except for the lower basal testosterone, triptorelin-stimulated peak luteinizing hormone (LH), and follicle-stimulating hormone in patients with PSIS. With similar duration of treatment and a significantly higher GnRH dose (P < .001), small increments in LH (2.82 [1.4, 4.55] vs 5.89 [3.88, 8.02] IU/L; P < .001), total testosterone (0.38 [0, 1.34] vs 2.34 [1.34, 3.66] ng/mL; P < .001), and testicular volume (5.3 ± 4.5 vs 8.8 ± 4.8 mL, P < .05) were observed. However, spermatogenesis rate (52.0% vs 70.3%, P > .05), median time of sperm appearance (14 vs 11 months, P > .05), sperm concentration, and progressive motility were comparable. Basal testicular volume (hazard ratio, 1.13; 95% CI, 1.01-1.27) and peak LH levels (hazard ratio, 1.11; 95% CI, 1.0-1.23) were predictors for early sperm appearance. ConclusionsPulsatile GnRH therapy can improve gonad function and induce spermatogenesis in men with PSIS. However, its efficacy may be inferior to that in CHH.

Efficacy and safety of pulsatile gonadotropin-releasing hormone therapy in patients with congenital hypogonadotropic hypogonadism: a multicentre clinical study.

BackgroundPulsatile gonadotropin-releasing hormone (GnRH) therapy may restore function of the hypothalamus-pituitary-gonad axis and induce spermatogenesis in male patients with congenital hypogonadotropic hypogonadism (CHH). The study sought to test the reliability of a newly developed Innopump® hormone pump, and to confirm the efficacy and safety of pulsatile GnRH therapy (by Innopump® hormone pump) in CHH patients.MethodsFrom November 2017 to November 2018, 28 male patients with CHH were treated with pulsatile GnRH at Peking Union Medical College Hospital, Beijing Chaoyang Hospital, and Shandong Provincial Hospital. A prospective, self-controlled, 7-day clinical trial was conducted. The primary outcome measures were the efficacy and safety of pulsatile GnRH therapy (which was administered via the Innopump® hormone pump). The secondary outcome measures included total serum testosterone, luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels.ResultsAll of the patients participated the clinical study. For 7 days, a dosage prescribed by doctors was accurately administered by the Innopump® hormone pump, and recorded by the pump. During the treatment, LH and FSH levels gradually increased to 2.66±1.74 and 5.05±3.03 IU/L, respectively. Upper respiratory tract infection in 1 patient and slight nausea in another patient were reported, which were confirmed to be unrelated to the pulsatile GnRH therapy.ConclusionsThe Innopump® hormone pump was found to be reliable in drug administration, and to have an accurate alarming system. It effectively and safely treated patients with CHH. Pulsatile GnRH therapy may produce a physiological pattern of GnRH secretion, and re-establish pituitary-gonad axis function by increasing gonadotropin levels.

Increased Bone Mineral Density in Male Patients With Idiopathic Hypogonadotropic Hypogonadism Who Undergo Sex Hormone Therapy: Findings From Cross-Sectional and Longitudinal Studies

ObjectiveThis retrospective observational study assessed the long-term impact of pulsatile gonadotropin-releasing hormone, combined gonadotropin, or testosterone replacement therapy on total hip, femoral, and lumbar bone mineral density (BMD) and Z-scores in adult men with idiopathic hypogonadotropic hypogonadism (IHH). MethodsIn the cross-sectional study, 69 patients were allocated to untreated (n = 42) and treated (n = 27) groups. The untreated group included IHH patients without hormone therapy history, while the treated group included age- and body mass index-matched patients who had received hormone therapy for at least 5 years. The longitudinal study included 53 IHH patients, and their hip and lumbar BMDs were measured several times during hormone therapy. We then evaluated the changes in their BMD. ResultsOur cross-sectional study showed that the treated group had a significantly higher BMD and Z-score for total hip, femoral neck, and lumbar spine (P < 0.001 for all) than the untreated group, and the average bone mass even reached the age-matched normal range. The prevalence of low BMD was 80.95% and 11.11% in untreated and treated groups, respectively. In the longitudinal study (N = 53), the total hip, femoral neck, and lumbar spine BMD gradually increased during treatment. The lumbar spine showed a greater increment in BMD compared with the total hip and femoral neck (P < 0.05). ConclusionSex hormone therapy improved hip and lumbar spine BMD and Z-scores in patients with IHH. The lumbar spine showed a greater improvement in BMD compared with the total hip and femoral neck.

The efficacy of pulsatile gonadotropin-releasing hormone therapy in male patients with hypogonadism caused by hypopituitarism

To evaluate the efficacy of pulsatile gonadotropin-releasing hormone (GnRH) therapy in patients with hypogonadism caused by hypopituitarism so as to guide clinical treatment. Clinical manifestations, laboratory examinations, and imaging features were collected from 22 patients with hypopituitarism that led to hypogonadism who were treated with pulsatile GnRH. Data were analyzed and the patients were followed up. The average age at which patients began to use pulsatile GnRH was 22.8±3.7 years old. The duration of pulsatile GnRH administration ranged from 3 to 60 months, with an average of 20.5±12.1 months. The dosage of GnRH administered was 10-12 µg/90 minutes. Patients were followed up for 26-81 months, with an average of 50.5±17.3 months. After pulsatile GnRH treatment, the clinical manifestations and hormone levels of these patients improved to varying degrees. The luteinizing hormone (LH) and testosterone (T) levels of 7 patients increased to the normal range, sperm could be detected in seminal fluid samples of 5 patients, and 2 patients successfully reproduced. Within the good-response group, 71.4% of patients achieved spermatogenesis within an average of 13 months of treatment. In patients who had poor response to gonadotropin therapy prior to pulsatile GnRH therapy, 25% achieved spermatogenesis, and 37.5% reached the normal range of LH and T. The levels of LH after pulsatile GnRH treatment was positively correlated with the peak levels of LH and testicular volume prior to treatment (P<0.01). Pulsatile GnRH therapy can improve gonadal function in most patients with hypogonadism caused by hypopituitarism. Patients were able to achieve spermatogenesis, especially in patients who were poor-responders to gonadotropin treatment. Patients with greater basal testicular volume may respond better to pulsatile GnRH treatment. The GnRH stimulation test not only helps to evaluate the reserve function of pituitary GnRH cells at a certain time but may also serve as a prognostic factor. The results of this study form a basis for guiding clinical therapeutic choices.

Clinical Characteristics and Spermatogenesis in Patients with Congenital Hypogonadotropic Hypogonadism Caused by FGFR1 Mutations.

Objective The aim of this study was to investigate the clinical characteristics of patients diagnosed with congenital hypogonadotropic hypogonadism (CHH) caused by FGFR1 (fibroblast growth factor receptor 1) gene mutations and to evaluate the effect of gonadotropin or pulsatile gonadotropin-releasing hormone (GnRH) therapy on spermatogenesis. Methods A retrospective study was conducted on CHH patients admitted to Peking Union Medical College Hospital from January 2012 to March 2020. Clinical features and laboratory results were recorded. Testicular volume and sperm count responding to gonadotropin and pulsatile GnRH therapy were compared between the FGFR1 mutation group and the mutation-negative group. Results (1) FGFR1 mutation group included 14 patients who received sperm-induction therapy, and the mutation-negative group enrolled 25 CHH patients. (2) The incidence of cryptorchidism was 50.0% (7/14) and 12.0% (3/25) in the FGFR1 group and the mutation-negative group, respectively (p=0.019). The baseline testicular volume of the FGFR1 mutation group was smaller than that of the mutation-negative group, 1.6 (0.5–2.0) mL vs. 2 (1.75–4) mL (p=0.033). The baseline luteinizing hormone (LH), Follicle-stimulating hormone (FSH), and testosterone levels were similar between the two groups. (3) Using the Kaplan–Meier and log-rank tests for the analysis of spermatogenesis, it was found that there was no significant difference in the first sperm appearance between the FGFR1 mutation group and the mutation-negative group (χ2 = 1.974, p=0.160). The median time of spermatogenesis in the FGFR1 mutation group was longer than that in the mutation-negative group, 16 months vs. 10 months, respectively. The cumulative spermatogenesis success rate at 12 months in the FGFR1 mutation group (35.71%) was lower than that in the mutation-negative group (68.75%) (p=0.047). The sperm concentration in the mutation-negative group was more easily achieved for different thresholds compared with that in the FGFR1 mutation group, but no significant difference was observed (p > 0.05) between the two groups. The last follow-up examination showed that the testicular volume was 7.00 (4.75–12.00) mL and 10.56 ± 4.82 mL (p=0.098), the ejaculate volume of sperm was 2.20 (1.40–2.26) mL and 3.06 ± 1.42 mL (p=0.175), and the sperm concentration was 7.19 (1.00–9.91) million/mL and 18.80 (4.58–53.62) million/mL (p=0.038) in the FGFR1 mutation and mutation-negative groups, respectively, while the sperm motility (A%, A + B%, and A + B + C%) was similar for the two groups (p=0.839, 0.909, and 0.759, respectively). The testosterone level during treatment was 366.02 ± 167.03 ng/dL and 362.27 ± 212.86 ng/dL in the FGFR1 mutation and mutation-negative groups, respectively (p=0.956). Conclusion Patients with FGFR1 mutations have a higher prevalence of cryptorchidism and smaller testicular volume. Although patients with FGFR1 mutations have a similar rate of success for spermatogenesis compared to that of the mutation-negative patients, a longer treatment period was required and a lower sperm concentration was achieved.

Spermatogenesis of Male Patients with Congenital Hypogonadotropic Hypogonadism Receiving Pulsatile Gonadotropin-Releasing Hormone Therapy Versus Gonadotropin Therapy: A Systematic Review and Meta-Analysis.

PurposePulsatile gonadotropin-releasing hormone (GnRH) therapy and gonadotropin therapy (GT) were widely used for male patients with congenital hypogonadotropic hypogonadism (CHH), but their efficacy was not well compared before. We conducted this meta-analysis to compare the efficacy of restoring fertility using these two therapies.Materials and MethodsPubMed, Web of Science, and Scopus were systematically searched for comparative studies evaluating the efficiency of GnRH therapy and GT for male patients with CHH. For continuous outcomes, the weighted mean difference (WMD) was used to measure the difference, whereas the risk ratio with 95% confidence interval was calculated for binary variables.ResultsOverall, eight articles from seven studies with 420 patients enrolled were included in the analysis. Patients from the two different groups were determined to be comparable in age, proportion with Kallmann syndrome, percentage of cryptorchidism and pretreatment hormones (follicular-stimulating hormone, luteinizing hormone, and testosterone). GnRH therapy was related to a larger testicular volume (standardized mean difference=−1.43; p=0.01) and earlier spermatogenesis (WMD=−5.30 months; p=0.004) compared to GT. However, the difference in the rate of positive sperm detection (p=0.08), sperm concentration (p=0.37), and pregnancy rate (p=0.11) were not significant. Allergic reactions mostly occurred during GnRH therapy, while GT was related to a higher incidence of gynecomastia and acne.ConclusionsCompared to GT, GnRH was related to earlier spermatogenesis and less estradiol-related adverse reactions, although there were no significant differences in spermatogenesis rate, sperm concentration, and pregnancy rate. High-quality randomized controlled trials are needed for future research.

Prevalence of lifetime eating disorders in infertile women seeking pregnancy with pulsatile gonadotropin-releasing hormone therapy.

Relationships between weight and fertility are well known. The aim of this study is to assess the prevalence of lifetime eating disorder (ED) in a sample of infertile women seeking a specific infertility treatment, pulsatile gonadotropin-releasing hormone (pGnRH) treatment, and to compare it to the prevalence of lifetime ED in a sample of infertile women seeking other types of assisted reproductive technology (ART) treatments. Non-randomized, observational study including infertile female patients. Two-group design including consecutive women treated with GnRH pump (pGnRH) or with other types of ART. Multi-centric infertility centers, France METHODS: Twenty one consecutive women treated with pGnRH treatment were compared to 21 consecutive women receiving other types of infertility treatment. Diagnosis of ED was based on DSM-IV and the Composite International Diagnostic Interview (CIDI). Twenty patients (95.2%) from the sample of women treated with pulsatile GnRH treatment and 5 patients (23.8%) from the patients receiving other types of infertility treatment met the criteria of lifetime ED diagnosis (p < 0.000). This study highlights the fact that the prevalence of ED is considerably higher in women receiving GnRH pulsatile treatment, when compared to women receiving other kinds of infertility treatment. In our study population ED were under-diagnosed, particularly in women receiving pulsatile GnRH treatment. Fertility clinicians should use reliable diagnostic tools to identify promptly ED in women presenting with hypothalamic amenorrhea and difficulties in conceiving. Level III: Evidence obtained from well-designed cohort or case-control analytic studies.

Congenital Hypogonadotropic Hypogonadism with Anosmia and Gorlin Features Caused by a PTCH1 Mutation Reveals a New Candidate Gene for Kallmann Syndrome

Background: Two loci (CHD7 and SOX10) underlying Kallmann syndrome (KS) were discovered through clinical and genetic analysis of CHARGE and Waardenburg syndromes, conditions that include congenital anosmia caused by olfactory bulb (CA/OBs) defects and congenital hypogonadotropic hypogonadism (CHH). We hypothesized that other candidate genes for KS could be discovered by analyzing rare syndromes presenting with these signs. Study Design, Size, Duration: We first investigated a family with Gorlin-Goltz syndrome (GGS) in which affected members exhibited clinical signs suggesting KS. Participants/Materials, Methods: Proband and family members underwent detailed clinical assessment. The proband received detailed neuroendocrine evaluation. Genetic analyses included sequencing the PTCH1 gene at diagnosis, followed by exome analyses of causative or candidate KS/CHH genes, in order to exclude contribution to the phenotypes of additional mutations. Exome analyses in additional 124 patients with KS/CHH probands with no additional GGS signs. Results: The proband exhibited CA, absent OBs on magnetic resonance imaging, and had CHH with unilateral cryptorchidism, consistent with KS. Pulsatile Gonadotropin-releasing hormone (GnRH) therapy normalized serum gonadotropins and increased testosterone levels, supporting GnRH deficiency. Genetic studies revealed 3 affected family members harbor a novel mutation of PTCH1 (c.838G> T; p.Glu280*). This unreported nonsense deleterious mutation results in either a putative truncated Ptch1 protein or in an absence of translated Ptch1 protein related to nonsense mediated messenger RNA decay. This heterozygous mutation cosegregates in the pedigree with GGS and CA with OBs aplasia/hypoplasia and with CHH in the proband suggesting a genetic linkage and an autosomal dominant mode of inheritance. No pathogenic rare variants in other KS/CHH genes cosegregated with these phenotypes. In additional 124 KS/CHH patients, 3 additional heterozygous, rare missense variants were found and predicted in silico to be damaging: p.Ser1203Arg, p.Arg1192Ser, and p.Ile108Met. Conclusion: This family suggests that the 2 main signs of KS can be included in GGS associated with PTCH1 mutations. Our data combined with mice models suggest that PTCH1 could be a novel candidate gene for KS/CHH and reinforce the role of the Hedgehog signaling pathway in pathophysiology of KS and GnRH neuron migration.

Type A insulin resistance syndrome misdiagnosed as polycystic ovary syndrome: a case report

BackgroundType A insulin resistance syndrome, one type of the hereditary insulin resistance syndromes, is a rare disorder. Patients with type A insulin resistance syndrome are nonobese and demonstrate severe hyperinsulinemia, hyperandrogenism, and acanthosis nigricans. The clinical features are more severe in affected females than in males, and they mostly become apparent at the age of puberty. In many cases, when severe insulin resistance is covered up by other signs or symptoms of type A insulin resistance syndrome, patients are often easily misdiagnosed with other diseases, such as polycystic ovary syndrome.Case presentationOur patient was a 27-year-old Han Chinese woman who sought treatment because of a menstrual disorder and hirsutism. Tests showed that her levels of insulin and testosterone were elevated, and gynecological color Doppler ultrasound suggested multiple cystic changes in the bilateral ovaries. After a diagnosis of polycystic ovary syndrome was made, pulsatile gonadotropin-releasing hormone therapy and metformin were administered, but the patient’s symptoms did not improve in 1 year of follow-up. Considering that the previous diagnosis might have been incorrect, venous blood samples were collected from the patient and her relatives for genetic analysis. Subsequently, using Illumina sequencing, it was found that the proband, her father, and two brothers all had the c.3601C>T heterozygous missense mutation in exon 20 of the insulin receptor gene. The diagnosis was corrected to type A insulin resistance syndrome, and the patient’s treatment was modified.ConclusionWe report a case of a young woman with type A insulin resistance syndrome that was misdiagnosed as polycystic ovary syndrome. We discuss the causes, clinical features, diagnosis, and treatment of type A insulin resistance syndrome to improve the recognition of the disease and reduce its misdiagnosis. Female patients with high androgen levels and severe hyperinsulinemia should be considered for the possibility of hereditary insulin resistance syndromes (such as type A insulin resistance syndrome). Gene sequencing helps in making an early diagnosis and developing a targeted treatment strategy.

Efficacy and safety of pulsatile gonadotropin-releasing hormone therapy among patients with idiopathic and functional hypothalamic amenorrhea: a systematic review of the literature and a meta-analysis

To systematically review and appraise the existing evidence in relation to the efficacy and safety of pulsatile gonadotropin-releasing hormone (pGnRH) for the treatment of women with hypothalamic amenorrhea (HA). Systematic review and meta-analysis. Not applicable. A total of 35 studies (three randomized and 32 observational) encompassing 1,002 women with HA. None. Primary outcomes: ovulation rate (OvR), pregnancy per ovulatory cycle rate (POR), and live birth per ovulatory cycle rate (LBOR). multiple gestation (MG), ovarian hyperstimulation syndrome (OHSS), and superficial thrombophlebitis (ST) rates. The summary measures were expressed as proportions and 95% confidence intervals (CI). Pulsatile GnRH treatment appears to achieve high OvRs. A trend toward high PORs and LBORs among women with HA is demonstrated. SC pGnRH achieves comparable OvR compared with IV pGnRH. The incidence of OHSS is low and of mild severity. Treatment with pGnRH is associated with low but slightly higher MG rates compared with the general population. IV administered pGnRH is rarely associated with ST. The high OvRs leading to a high rate of singleton pregnancies and the low likelihood of OHSS render the pGnRH treatment modality both effective and safe for the treatment of women with HA of either primary or secondary origin.

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

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.