Publications by authors named "Stephanie B Seminara"

86 Publications

Phenotypic continuum between Waardenburg syndrome and idiopathic hypogonadotropic hypogonadism in humans with SOX10 variants.

Genet Med 2021 Jan 13. Epub 2021 Jan 13.

Harvard Reproductive Sciences Center, The Reproductive Endocrine Unit and The Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.

Purpose: SOX10 variants previously implicated in Waardenburg syndrome (WS) have now been linked to Kallmann syndrome (KS), the anosmic form of idiopathic hypogonadotropic hypogonadism (IHH). We investigated whether SOX10-associated WS and IHH represent elements of a phenotypic continuum within a unifying disorder or if they represent phenotypically distinct allelic disorders.

Methods: Exome sequencing from 1,309 IHH subjects (KS: 632; normosmic idiopathic hypogonadotropic hypogonadism [nIIHH]: 677) were reviewed for SOX10 rare sequence variants (RSVs). The genotypic and phenotypic spectrum of SOX10-related IHH (this study and literature) and SOX10-related WS cases (literature) were reviewed and compared with SOX10-RSV spectrum in gnomAD population.

Results: Thirty-seven SOX10-associated IHH cases were identified as follows: current study: 16 KS; 4 nIHH; literature: 16 KS; 1 nIHH. Twenty-three IHH cases (62%; all KS), had ≥1 known WS-associated feature(s). Moreover, five previously reported SOX10-associated WS cases showed IHH-related features. Four SOX10 missense RSVs showed allelic overlap between IHH-ascertained and WS-ascertained cases. The SOX10-HMG domain showed an enrichment of RSVs in disease states versus gnomAD.

Conclusion: SOX10 variants contribute to both anosmic (KS) and normosmic (nIHH) forms of IHH. IHH and WS represent SOX10-associated developmental defects that lie along a unifying phenotypic continuum. The SOX10-HMG domain is critical for the pathogenesis of SOX10-related human disorders.
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http://dx.doi.org/10.1038/s41436-020-01051-3DOI Listing
January 2021

Evaluating co-created patient-facing materials to increase understanding of genetic test results.

J Genet Couns 2020 Oct 24. Epub 2020 Oct 24.

Harvard Reproductive Endocrine Sciences Center and Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.

Patients often have difficulty understanding genetic test reports. Technical language and jargon can impede comprehension and limit patients using results to act on findings. One potential way to improve patient understanding of genetic test reports is to provide patient-facing materials. This study aimed to examine understandability and actionability of co-created patient-facing materials for genetic test results in a research context. We combined interprofessional perspectives and patient engagement to co-create patient-facing materials for patients undergoing research genetic testing for congenital hypogonadotropic hypogonadism (Kallmann syndrome). The iterative development process was guided by principles of health literacy and human-centered design (i.e., design thinking). Readability was assessed using eight validated algorithms. Patients and parents evaluated materials using a web-based survey. The gold standard Patient Education Materials Assessment Tool for print materials (PEMAT-P) was employed to measure understandability (content, style, use of numbers, organization, design, use of visual aids) and actionability. PEMAT-P scores >80% were considered high quality. Results were analyzed descriptively and correlations performed to identify relationships between education/health literacy and PEMAT-P ratings. A consensus score of eight algorithms indicated the materials were an 8 -9th grade reading level. Our findings are consistent with the U.S. Department of Health and Human Services 'average difficulty' classification (i.e., 7th-9th grade). In total, 61 patients/parents evaluated the materials. 'Visual Aids' received the lowest mean PEMAT-P rating (89%). All other parameters scored 90%-97%. PEMAT-P scores did not differ according to educational attainment (less than college vs. college or more, p = 0.28). Participants with adequate health literacy were more likely to approve of the 'organization' of information (p < 0.05). Respondents with low health literacy had more favorable views of 'visual aids' (p < 0.01). Involving patients in a co-creation process can produce high-quality patient-facing materials that are easier to understand.
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http://dx.doi.org/10.1002/jgc4.1348DOI Listing
October 2020

Kisspeptin deficiency leads to abnormal adrenal glands and excess steroid hormone secretion.

Hum Mol Genet 2020 Dec;29(20):3443-3450

Section on Endocrinology and Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), Bethesda, MD 20892, USA.

Knockout mice for the kisspeptin receptor, Kiss1r (Kiss1r-/-) and its ligand kisspeptin, Kiss1 (Kiss1-/-) replicate the phenotype of isolated hypogonadotropic hypogonadism (IHH) associated with variants of these genes in humans. A recent report suggests that kisspeptin may be involved in human fetal adrenocortical development and function. Herein, we characterized the adrenal function and morphology in Kiss1-/- mice that do not go through normal puberty. Two fetal markers were expressed in eosinophilic cells potentially derived from the X-zone that should disappear at puberty in male mice and during the first pregnancy in female animals. Although the hypercorticosteronism observed in Kiss1-/- females corrected overtime, hyperaldosteronism persisted at 14 months and correlated with the overexpression of Star. To determine if KISS1 and KISS1R genes are involved in the development of primary aldosteronism (PA) and hypercortisolism [Cushing's syndrome (CS)] in humans, we sequenced these 2 genes in 65 patients with PA and/or CS. Interestingly, a patient with CS presented with a germline KISS1 variant (p.H90D, rs201073751). We also found three rare variants in the KISS1R gene in three patients with PA: p.C95W (rs141767649), p.A189T (rs73507527) and p.R229R (rs115335009). The two missense variants have been previously associated with IHH. Our findings suggest that KISS1 may play a role in adrenal function in mice and possibly adrenocortical steroid hormone secretion in humans, beyond its recently described role in human fetal adrenocortical development.
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http://dx.doi.org/10.1093/hmg/ddaa215DOI Listing
December 2020

Increased Burden of Rare Sequence Variants in GnRH-Associated Genes in Women with Hypothalamic Amenorrhea.

J Clin Endocrinol Metab 2020 Sep 1. Epub 2020 Sep 1.

National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC.

Context: Functional hypothalamic amenorrhea (HA) is a common, acquired form of hypogonadotropic hypogonadism that occurs in the setting of energy deficits and/or stress. Variability in individual susceptibility to these stressors, HA heritability, and previous identification of several rare sequence variants (RSVs) in genes associated with the rare disorder, isolated hypogonadotropic hypogonadism (IHH), in individuals with HA suggest a possible genetic contribution to HA susceptibility.

Objective: We sought to determine whether the burden of RSVs in IHH-related genes is greater in women with HA than controls.

Design: We compared patients with HA to control women.

Setting: The study was conducted at secondary referral centers.

Patients And Other Participants: Women with HA (n=106) and control women (ClinSeq study; n=468).

Interventions: We performed exome sequencing in all patients and controls.

Main Outcome Measure(s): The frequency of RSVs in 53 IHH-associated genes was determined using rare variant burden and association tests.

Results: RSVs were overrepresented in women with HA compared with controls (P = 0.007). Seventy-eight heterozygous RSVs in 33 genes were identified in 58 women with HA (36.8% of alleles) compared to 255 RSVs in 41 genes among 200 control women (27.2%).

Conclusions: Women with HA are enriched for RSVs in genes that cause IHH suggesting that variation in genes associated with GnRH neuronal ontogeny and function may be a major determinant of individual susceptibility to developing HA in the face of diet, exercise and/or stress.
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http://dx.doi.org/10.1210/clinem/dgaa609DOI Listing
September 2020

Tachykinin signaling is required for the induction of the preovulatory LH surge and normal LH pulses.

Neuroendocrinology 2020 Jun 8. Epub 2020 Jun 8.

Tachykinins (NKA, NKB and Substance P) are important components of the neuroendocrine control of reproduction by directly stimulating Kiss1 neurons to control GnRH pulsatility, essential for reproduction. Despite this role of tachykinins for successful reproduction, knockout mice for Tac1 (NKA/SP) and Tac2 (NKB) genes are fertile, resembling the phenotype of human patients bearing NKB signaling mutations, who often reverse their hypogonadal phenotype. This suggests the existence of compensatory mechanisms among the different tachykinin ligand-receptor systems, to maintain reproduction in the absence of one of them. In order to test this hypothesis, we generated complete tachykinin deficient mice (Tac1/Tac2KO). Male mice displayed delayed puberty onset and decreased LH pulsatility (frequency and amplitude of LH pulses) but preserved fertility. However, females did not show signs of puberty onset (first estrus) within 45 days after vaginal opening, displayed low frequency (but normal amplitude) of LH pulses and 80% of them remained infertile. Further evaluation identified a complete absence of the preovulatory LH surge in Tac1/Tac2KO females as well as in WT females treated with NKB or SP receptor antagonists. These data confirmed a fundamental role for tachykinins in the timing of puberty onset and LH pulsatility and uncovered a role of tachykinin signaling in the facilitation of the preovulatory LH surge. Overall, these findings indicate that tachykinin signaling plays a dominant role in the control of ovulation, with potential implications as pathogenic mechanism and therapeutic target to improve reproductive outcomes in women with ovulation impairments.
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http://dx.doi.org/10.1159/000509222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722126PMC
June 2020

Hypogonadotropic hypogonadism due to variants in : expanding the phenotypic and genotypic spectrum of Martsolf syndrome.

Cold Spring Harb Mol Case Stud 2020 06 12;6(3). Epub 2020 Jun 12.

Harvard Reproductive Endocrine Sciences Center, Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

Biallelic pathogenic variants in cause Warburg Micro syndrome (WARBM) and Martsolf syndrome (MS), two rare, phenotypically overlapping disorders characterized by congenital cataracts, intellectual disability, and hypogonadism. Although the initial report documented hypergonadotropic hypogonadism (implying a gonadal defect), an adolescent girl with WARBM/MS was subsequently reported to have hypogonadotropic hypogonadism (implying a central defect in either the hypothalamus or anterior pituitary). However, in adult MS, hypogonadotropism has not been convincingly demonstrated. Additionally, the correlation between the pathogenic severity of variants in and the phenotypic severity also remains unclear. Here we present a clinical report of a woman with congenital cataracts, apparent intellectual disability, and pubertal failure who underwent exome sequencing (ES) to determine a precise molecular diagnosis. Reproductive phenotypes reported previously in individuals with MS and the genotypic spectrum of previous variants were also reviewed. The ES identified pathogenic compound heterozygous variants (c.387-2A > G; p.(Arg428Glu)) combined with her phenotypic features, which enabled a unifying molecular diagnosis of MS. Reproductive evaluation confirmed a normosmic idiopathic hypogonadotropic hypogonadism. Review of the allelic spectrum in WARBM/MS suggests that although variants resulting in complete abrogation of RAB3GAP2 protein function cause severe WARBM, variants associated with partially preserved RAB3GAP2 function cause milder MS. This report expands the genotypic and phenotypic spectrum of MS and demonstrates hypogonadotropic hypogonadism as a key pathophysiologic abnormality in MS. Genotype-phenotype associations of previously reported variants indicate that variants that fully abolish RAB3GAP2 function result in WARBM, whereas MS is associated with variants of lesser severity with residual RAB3GAP2 function.
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http://dx.doi.org/10.1101/mcs.a005033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7304352PMC
June 2020

DLG2 variants in patients with pubertal disorders.

Genet Med 2020 Aug 28;22(8):1329-1337. Epub 2020 Apr 28.

Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.

Purpose: Impaired function of gonadotropin-releasing hormone (GnRH) neurons can cause a phenotypic spectrum ranging from delayed puberty to isolated hypogonadotropic hypogonadism (IHH). We sought to identify a new genetic etiology for these conditions.

Methods: Exome sequencing was performed in an extended family with autosomal dominant, markedly delayed puberty. The effects of the variant were studied in a GnRH neuronal cell line. Variants in the same gene were sought in a large cohort of individuals with IHH.

Results: We identified a rare missense variant (F900V) in DLG2 (which encodes PSD-93) that cosegregated with the delayed puberty. The variant decreased GnRH expression in vitro. PSD-93 is an anchoring protein of NMDA receptors, a type of glutamate receptor that has been implicated in the control of puberty in laboratory animals. The F900V variant impaired the interaction between PSD-93 and a known binding partner, Fyn, which phosphorylates NMDA receptors. Variants in DLG2 that also decreased GnRH expression were identified in three unrelated families with IHH.

Conclusion: The findings indicate that variants in DLG2/PSD-93 cause autosomal dominant delayed puberty and may also contribute to IHH. The findings also suggest that the pathogenesis involves impaired NMDA receptor signaling and consequently decreased GnRH secretion.
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http://dx.doi.org/10.1038/s41436-020-0803-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510947PMC
August 2020

Using Kisspeptin to Predict Pubertal Outcomes for Youth With Pubertal Delay.

J Clin Endocrinol Metab 2020 08;105(8)

Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.

Context: The management of youth with delayed puberty is hampered by difficulty in predicting who will eventually progress through puberty and who will fail to attain adult reproductive endocrine function. The neuropeptide kisspeptin, which stimulates gonadotropin-releasing hormone (GnRH) release, can be used to probe the integrity of the reproductive endocrine axis.

Objective: We sought to determine whether responses to kisspeptin can predict outcomes for individuals with pubertal delay.

Design, Setting, And Participants: We conducted a longitudinal cohort study in an academic medical center of 16 children (3 girls and 13 boys) with delayed or stalled puberty.

Intervention And Outcome Measures: Children who had undergone kisspeptin- and GnRH-stimulation tests were followed every 6 months for clinical evidence of progression through puberty. Inhibin B was measured in boys. A subset of participants underwent exome sequencing.

Results: All participants who had responded to kisspeptin with a rise in luteinizing hormone (LH) of 0.8 mIU/mL or greater subsequently progressed through puberty (n = 8). In contrast, all participants who had exhibited LH responses to kisspeptin ≤ 0.4 mIU/mL reached age 18 years without developing physical signs of puberty (n = 8). Thus, responses to kisspeptin accurately predicted later pubertal outcomes (P = .0002). Moreover, the kisspeptin-stimulation test outperformed GnRH-stimulated LH, inhibin B, and genetic testing in predicting pubertal outcomes.

Conclusion: The kisspeptin-stimulation can assess future reproductive endocrine potential in prepubertal children and is a promising novel tool for predicting pubertal outcomes for children with delayed puberty.
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http://dx.doi.org/10.1210/clinem/dgaa162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7282711PMC
August 2020

Insight Into the Ontogeny of GnRH Neurons From Patients Born Without a Nose.

J Clin Endocrinol Metab 2020 05;105(5)

Clinical Research Branch, National Institute of Environmental Health Sciences, Durham, North Carolina.

Context: The reproductive axis is controlled by a network of gonadotropin-releasing hormone (GnRH) neurons born in the primitive nose that migrate to the hypothalamus alongside axons of the olfactory system. The observation that congenital anosmia (inability to smell) is often associated with GnRH deficiency in humans led to the prevailing view that GnRH neurons depend on olfactory structures to reach the brain, but this hypothesis has not been confirmed.

Objective: The objective of this work is to determine the potential for normal reproductive function in the setting of completely absent internal and external olfactory structures.

Methods: We conducted comprehensive phenotyping studies in 11 patients with congenital arhinia. These studies were augmented by review of medical records and study questionnaires in another 40 international patients.

Results: All male patients demonstrated clinical and/or biochemical signs of GnRH deficiency, and the 5 men studied in person had no luteinizing hormone (LH) pulses, suggesting absent GnRH activity. The 6 women studied in person also had apulsatile LH profiles, yet 3 had spontaneous breast development and 2 women (studied from afar) had normal breast development and menstrual cycles, suggesting a fully intact reproductive axis. Administration of pulsatile GnRH to 2 GnRH-deficient patients revealed normal pituitary responsiveness but gonadal failure in the male patient.

Conclusions: Patients with arhinia teach us that the GnRH neuron, a key gatekeeper of the reproductive axis, is associated with but may not depend on olfactory structures for normal migration and function, and more broadly, illustrate the power of extreme human phenotypes in answering fundamental questions about human embryology.
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http://dx.doi.org/10.1210/clinem/dgaa065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108682PMC
May 2020

Role of Kisspeptin and NKB in Puberty in Nonhuman Primates: Sex Differences.

Semin Reprod Med 2019 03 17;37(2):47-55. Epub 2019 Dec 17.

Wisconsin National Primate Research Center, University of Wisconsin, Madison, Wisconsin.

To understand the roles of kisspeptin and neurokinin B (NKB) in puberty and sex differences in their involvement, we conducted a series of experiments measuring the release of gonadotropin-releasing hormone (GnRH) and kisspeptin in the median eminence of the hypothalamus in male and female monkeys throughout sexual development. Results indicate that kisspeptin-10 and the NKB agonist, senktide, stimulated GnRH release in males and females at the prepubertal and pubertal stages, but females are much more sensitive to kisspeptin signaling than males. Moreover, throughout the progress of puberty, major remodeling of kisspeptin and NKB signaling pathways for the regulation of GnRH release takes place. In females during puberty, reciprocal pathways (i.e., kisspeptin signaling mediated through NKB neurons and NKB signaling mediated through kisspeptin neurons) are established, to provide powerful and flexible mechanisms for GnRH neurosecretory activity necessary for complex female reproductive function in adulthood. By contrast, during puberty in males, reciprocal pathways are consolidated to a simpler kisspeptin-dominant signaling pathway. Nevertheless, in primates, both kisspeptin and NKB signaling are contributing factors for the pubertal increase in GnRH release, rather than initiating puberty.
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http://dx.doi.org/10.1055/s-0039-3400253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055930PMC
March 2019

Functional Hypogonadotropic Hypogonadism in Men: Underlying Neuroendocrine Mechanisms and Natural History.

J Clin Endocrinol Metab 2019 08;104(8):3403-3414

Harvard Reproductive Endocrine Sciences Center and Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.

Context: After completion of puberty a subset of men experience functional hypogonadotropic hypogonadism (FHH) secondary to excessive exercise or weight loss. This phenomenon is akin to hypothalamic amenorrhea (HA) in women, yet little is known about FHH in men.

Objective: To investigate the neuroendocrine mechanisms, genetics, and natural history underlying FHH.

Design: Retrospective study in an academic medical center.

Participants: Healthy postpubertal men presenting with symptoms of hypogonadism in the setting of excessive exercise (>10 hours/week) or weight loss (>10% of body weight). Healthy age-matched men served as controls.

Interventions: Clinical assessment, biochemical and neuroendocrine profiling, body composition, semen analysis, and genetic evaluation of genes known to cause isolated GnRH deficiency.

Main Outcome Measures: Reproductive hormone levels, endogenous GnRH-induced LH pulse patterns, and rare genetic variants.

Results: Ten men with FHH were compared with 18 age-matched controls. Patients had significantly lower body mass index, testosterone, LH, and mean LH pulse amplitudes yet normal LH pulse frequency, serum FSH, and sperm counts. Some patients exhibited nocturnal, sleep-entrained LH pulses characteristic of early puberty, and one FHH subject showed a completely apulsatile LH secretion. After decreased exercise and weight gain, five men with men had normalized serum testosterone levels, and symptoms resolved. Rare missense variants in NSMF (n = 1) and CHD7 (n = 1) were identified in two men with FHH.

Conclusions: FHH is a rare, reversible form of male GnRH deficiency. LH pulse patterns in male FHH are similar to those observed in women with HA. This study expands the spectrum of GnRH deficiency disorders in men.
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http://dx.doi.org/10.1210/jc.2018-02697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594303PMC
August 2019

Paediatric and adult-onset male hypogonadism.

Nat Rev Dis Primers 2019 May 30;5(1):38. Epub 2019 May 30.

Sexual Medicine and Andrology Unit Department of Experimental Clinical and Biomedical Sciences 'Mario Serio', University of Florence, Florence, Italy.

The hypothalamic-pituitary-gonadal axis is of relevance in many processes related to the development, maturation and ageing of the male. Through this axis, a cascade of coordinated activities is carried out leading to sustained testicular endocrine function, with gonadal testosterone production, as well as exocrine function, with spermatogenesis. Conditions impairing the hypothalamic-pituitary-gonadal axis during paediatric or pubertal life may result in delayed puberty. Late-onset hypogonadism is a clinical condition in the ageing male combining low concentrations of circulating testosterone and specific symptoms associated with impaired hormone production. Testosterone therapy for congenital forms of hypogonadism must be lifelong, whereas testosterone treatment of late-onset hypogonadism remains a matter of debate because of unclear indications for replacement, uncertain efficacy and potential risks. This Primer focuses on a reappraisal of the physiological role of testosterone, with emphasis on the critical interpretation of the hypogonadal conditions throughout the lifespan of the male individual, with the exception of hypogonadal states resulting from congenital disorders of sex development.
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http://dx.doi.org/10.1038/s41572-019-0087-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944317PMC
May 2019

Role of Kisspeptin and Neurokinin B Signaling in Male Rhesus Monkey Puberty.

Endocrinology 2018 08;159(8):3048-3060

Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin.

Despite the well-established concept that an increase in pulsatile GnRH release triggers puberty, the precise signaling mechanism responsible for the pubertal increase in GnRH release remains unclear. A recent study indicates that developmental changes in the network formation between kisspeptin and neurokinin B (NKB) signaling greatly contribute to the pubertal increase in GnRH release in female monkeys. It is, however, unknown whether similar developmental changes in the kisspeptin and NKB network are involved in male puberty. In the current study, we first characterized the pubertal stages in male rhesus monkeys by assessing physiological and hormonal changes during sexual development. Subsequently, we examined the role of the kisspeptin and NKB signaling network in the pubertal increase in GnRH release. Results suggest that while collaborative kisspeptin and NKB signaling to GnRH neurons was active before puberty onset, after initiation of puberty the role of NKB signaling in GnRH neurons diminished and kisspeptin signaling assumed the primary stimulatory role in the regulation of GnRH release in male monkeys. These findings in males differ from those seen in females.
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http://dx.doi.org/10.1210/en.2018-00443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456982PMC
August 2018

Role of Kisspeptin and Neurokinin B in Puberty in Female Non-Human Primates.

Front Endocrinol (Lausanne) 2018 6;9:148. Epub 2018 Apr 6.

Wisconsin National Primate Research Center, University of Wisconsin, Madison, WI, United States.

In human patients, loss-of-function mutations in the genes encoding kisspeptin () and neurokinin B ( and their receptors ( and , respectively) result in an abnormal timing of puberty or the absence of puberty. To understand the neuroendocrine mechanism of puberty, we investigated the contribution of kisspeptin and NKB signaling to the pubertal increase in GnRH release using rhesus monkeys as a model. Direct measurements of GnRH and kisspeptin in the median eminence of the hypothalamus with infusion of agonists and antagonists for kisspeptin and NKB reveal that kisspeptin and NKB signaling stimulate GnRH release independently or collaboratively by forming kisspeptin and NKB neuronal networks depending on the developmental age. For example, while in prepubertal females, kisspeptin and NKB signaling independently stimulate GnRH release, in pubertal females, the formation of a collaborative kisspeptin and NKB network further accelerates the pubertal increase in GnRH release. It is speculated that the collaborative mechanism between kisspeptin and NKB signaling to GnRH neurons is necessary for the complex reproductive function in females.
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http://dx.doi.org/10.3389/fendo.2018.00148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5897421PMC
April 2018

Divergent responses to kisspeptin in children with delayed puberty.

JCI Insight 2018 04 19;3(8). Epub 2018 Apr 19.

Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.

Background: The neuropeptide kisspeptin stimulates luteinizing hormone (LH) secretion in healthy adults but not in adults with idiopathic hypogonadotropic hypogonadism. We hypothesized that, in children presenting with delayed or stalled puberty, kisspeptin would elicit LH secretion in those children found on detailed nighttime neuroendocrine profiling to have evidence of emerging reproductive endocrine function.

Methods: Eleven boys and four girls were admitted overnight to assess LH secretion at baseline, after a single intravenous bolus of kisspeptin, and after a single intravenous bolus of gonadotropin-releasing hormone (GnRH). Subjects then received exogenous pulsatile GnRH for 6 days and returned for a second visit to measure responses to kisspeptin and GnRH after this pituitary "priming." Responses to kisspeptin and GnRH were also measured in 5 healthy men.

Results: Of the 15 children with delayed/stalled puberty, 6 exhibited at least one spontaneous LH pulse overnight; all of these subjects had clear responses to kisspeptin, as did one additional subject. Seven subjects had no response to kisspeptin, and one subject exhibited an intermediate response. In the children who responded to kisspeptin, the responses had features comparable to those of adult men.

Conclusion: In this first report of kisspeptin administration to pediatric subjects to our knowledge, children with delayed/stalled puberty showed a wide range of responses, with some showing a robust response and others showing little to no response. Further follow-up will determine whether responses to kisspeptin predict future pubertal entry for children with delayed puberty.

Trial Registration: ClinicalTrials.gov NCT01438034 and NCT01952782.

Funding: NIH Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01 HD043341, R01 HD090071, P50 HD028138), NIH National Center for Advancing Translational (UL1 TR001102), NIH National Institute of Diabetes and Digestive and Kidney Diseases (T32 DK007028), the Massachusetts General Hospital Executive Committee on Research Fund for Medical Discovery, Harvard Catalyst, Doris Duke Charitable Foundation (award 2013110), Charles H. Hood Foundation, Robert and Laura Reynolds MGH Research Scholar Program, and Harvard University. These funding sources had no role in the design of this study and did not have any role in conducting the study, analyses, interpretation of the data, or the decision to submit results.
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http://dx.doi.org/10.1172/jci.insight.99109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5931121PMC
April 2018

Different Cerebellar Ataxia Phenotypes Associated with Mutations of the PNPLA6 Gene in Brazilian Patients with Recessive Ataxias.

Cerebellum 2018 Jun;17(3):380-385

Morton and Gloria Shulman Movement Disorders Centre and the Edmond J. Safra Program in Parkinson's Disease, Toronto Western Hospital, University Health Network, Toronto, ON, Canada.

Autosomal recessive cerebellar ataxias (ARCAs) represent a heterogeneous group of inherited disorders. The association of early-onset cerebellar ataxia with hypogonadotropic hypogonadism is related to two syndromes, known as Gordon Holmes syndrome (GHS-ataxia and pyramidal signs with hypogonadotropic hypogonadism) and Boucher-Neuhäuser syndrome (BNS-ataxia with chorioretinal dystrophy). Mutations in the PNPLA6 gene have been identified as the cause of hereditary spastic paraplegia and complex forms of ataxia associated with retinal and endocrine manifestations. We reported two Brazilian patients with sporadic, progressive cerebellar ataxia, associated with hypogonadotropic hypogonadism, in whom the GHS and BNS were confirmed by the demonstration of compound heterozygote mutations in the PNPLA6 gene. Genetic analysis of the patient 1 revealed compound heterozygous mutations, one allele in exon 34 and the other allele in exon 29. Genetic exam of the patient 2 also demonstrated compound heterozygous mutations. Three were novel mutations. The missense mutation c.3373G> A, found in the BNS patient, was previously related to Oliver-McFarlane syndrome. These different mutations in this gene suggest a complex phenotype associated disease spectrum.
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http://dx.doi.org/10.1007/s12311-017-0909-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5970027PMC
June 2018

Kisspeptin and Neurokinin B Signaling Network Underlies the Pubertal Increase in GnRH Release in Female Rhesus Monkeys.

Endocrinology 2017 10;158(10):3269-3280

Wisconsin National Primate Research Center, Madison, Wisconsin 53715.

Loss-of-function or inactivating mutations in the genes coding for kisspeptin and its receptor (KISS1R) or neurokinin B (NKB) and the NKB receptor (NK3R) in humans result in a delay in or the absence of puberty. However, precise mechanisms of kisspeptin and NKB signaling in the regulation of the pubertal increase in gonadotropin-releasing hormone (GnRH) release in primates are unknown. In this study, we conducted a series of experiments infusing agonists and antagonists of kisspeptin and NKB into the stalk-median eminence, where GnRH, kisspeptin, and NKB neuroterminal fibers are concentrated, and measuring GnRH release in prepubertal and pubertal female rhesus monkeys. Results indicate that (1) similar to those previously reported for GnRH stimulation by the KISS1R agonist (i.e., human kisspeptin-10), the NK3R agonist senktide stimulated GnRH release in a dose-responsive manner in both prepubertal and pubertal monkeys; (2) the senktide-induced GnRH release was blocked in the presence of the KISS1R antagonist peptide 234 in pubertal but not prepubertal monkeys; and (3) the kisspeptin-induced GnRH release was blocked in the presence of the NK3R antagonist SB222200 in the pubertal but not prepubertal monkeys. These results are interpreted to mean that although, in prepubertal female monkeys, kisspeptin and NKB signaling to GnRH release is independent, in pubertal female monkeys, a reciprocal signaling mechanism between kisspeptin and NKB neurons is established. We speculate that this cooperative mechanism by the kisspeptin and NKB network underlies the pubertal increase in GnRH release in female monkeys.
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http://dx.doi.org/10.1210/en.2017-00500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5659687PMC
October 2017

Corrigendum: SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome.

Nat Genet 2017 05;49(6):969

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http://dx.doi.org/10.1038/ng0617-969cDOI Listing
May 2017

Continuous Kisspeptin Administration in Postmenopausal Women: Impact of Estradiol on Luteinizing Hormone Secretion.

J Clin Endocrinol Metab 2017 06;102(6):2091-2099

Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114.

Context: Kisspeptin stimulates the reproductive endocrine cascade in both men and women. Circulating sex steroids are thought to modulate the ability of kisspeptin to stimulate gonadotropin-releasing hormone (GnRH)-induced luteinizing hormone (LH) release.

Objective: To probe the effects of sex steroids on kisspeptin-stimulated GnRH-induced LH pulses.

Participants: Eight healthy postmenopausal women.

Intervention: Subjects underwent every-10-minute blood sampling to measure GnRH-induced LH secretion at baseline and in response to a continuous kisspeptin infusion (12.5 µg/kg/h) over 24 hours. A subset of the participants also received kisspeptin (0.313 µg/kg) and GnRH (75 ng/kg) intravenous boluses.

Results: Postmenopausal women are resistant to the stimulatory effect of continuous kisspeptin on LH secretion. Postmenopausal women receiving estradiol replacement therapy are also resistant to kisspeptin initially, but they demonstrate a significant increase in LH pulse amplitude in direct proportion to the circulating estradiol concentration and duration of kisspeptin administration.

Conclusions: Kisspeptin administration has complex effects on GnRH, and by extension, on LH secretion. The ability of kisspeptin to affect LH secretion can be modulated by the ambient sex-steroid milieu in a time- and dose-dependent manner.
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http://dx.doi.org/10.1210/jc.2016-3952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5470760PMC
June 2017

SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome.

Nat Genet 2017 Feb 9;49(2):238-248. Epub 2017 Jan 9.

Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.

Arhinia, or absence of the nose, is a rare malformation of unknown etiology that is often accompanied by ocular and reproductive defects. Sequencing of 40 people with arhinia revealed that 84% of probands harbor a missense mutation localized to a constrained region of SMCHD1 encompassing the ATPase domain. SMCHD1 mutations cause facioscapulohumeral muscular dystrophy type 2 (FSHD2) via a trans-acting loss-of-function epigenetic mechanism. We discovered shared mutations and comparable DNA hypomethylation patterning between these distinct disorders. CRISPR/Cas9-mediated alteration of smchd1 in zebrafish yielded arhinia-relevant phenotypes. Transcriptome and protein analyses in arhinia probands and controls showed no differences in SMCHD1 mRNA or protein abundance but revealed regulatory changes in genes and pathways associated with craniofacial patterning. Mutations in SMCHD1 thus contribute to distinct phenotypic spectra, from craniofacial malformation and reproductive disorders to muscular dystrophy, which we speculate to be consistent with oligogenic mechanisms resulting in pleiotropic outcomes.
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http://dx.doi.org/10.1038/ng.3743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5473428PMC
February 2017

Phenotypic spectrum of POLR3B mutations: isolated hypogonadotropic hypogonadism without neurological or dental anomalies.

J Med Genet 2017 01 10;54(1):19-25. Epub 2016 Aug 10.

Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.

Background: A constellation of neurodegenerative disorders exists (Gordon Holmes syndrome, 4H leucodystrophy, Boucher-Neuhauser syndrome) in which patients suffer from both neurological disease (typically manifested by ataxia) and reproductive failure (idiopathic hypogonadotropic hypogonadism (IHH)). POLR3B, which encodes the second largest subunit of RNA polymerase III (pol III), and POLR3A, which forms the pol III catalytic centre, are associated with 4H leucodystrophy.

Methods: Whole exome sequencing was performed on a large cohort of subjects with IHH (n=565). Detailed neuroendocrine studies were performed in some individuals within this cohort.

Results: Four individuals (two of them siblings) were identified with two rare nucleotide variants in POLR3B. On initial evaluation, all subjects were free of neurological disease. One patient underwent treatment with exogenous pulsatile gonadotropin-releasing hormone for 8 weeks which failed to result in normalisation of his sex steroid milieu due to pituitary resistance.

Conclusions: These findings suggest that the spectrum of phenotypes resulting from POLR3B mutations is wider than previously believed and that POLR3B can be associated exclusively with disorders characterised by abnormal gonadotropin secretion.
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http://dx.doi.org/10.1136/jmedgenet-2016-104064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5189673PMC
January 2017

Kisspeptin Responsiveness Signals Emergence of Reproductive Endocrine Activity: Implications for Human Puberty.

J Clin Endocrinol Metab 2016 08 23;101(8):3061-9. Epub 2016 May 23.

Harvard Reproductive Sciences Center and Reproductive Endocrine Unit (M.F.L., Y.-M.C., D.R.-M., S.B.S.), Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114; Division of Endocrinology (Y.-M.C.), Department of Medicine, Boston Children's Hospital, and Division of Sleep Medicine (J.P.B.), Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115; and Unit on Genetics of Puberty and Reproduction (A.D.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland 20892.

Context: Some patients with idiopathic hypogonadotropic hypogonadism (IHH) undergo spontaneous activation of their hypothalamic-pituitary-gonadal axis resulting in normalization of steroidogenesis and/or gametogenesis, a phenomenon termed reversal.

Objective: To assess the responsiveness of the GnRH neuronal network to exogenous kisspeptin administration in IHH patients who have undergone reversal.

Participants: Six men with congenital IHH and evidence for reversal.

Intervention: Subjects underwent q10 min blood sampling to measure GnRH-induced LH secretion at baseline and in response to iv boluses of kisspeptin (0.24-2.4 nmol/kg) and GnRH (75 ng/kg).

Results: Individuals with sustained reversal of their hypogonadotropism (spontaneous LH pulses) responded to exogenous kisspeptin with a GnRH-induced LH pulse. Individuals who had reversal but then subsequently suffered relapse of their IHH (loss of spontaneous LH pulsatility) did not respond to kisspeptin.

Conclusions: The ability of kisspeptin to stimulate a GnRH-induced LH pulse correlates with the presence of endogenous LH pulses. These data suggest that reversal of hypogonadotropism, and by extension sexual maturation, may be due to the acquisition of kisspeptin responsiveness.
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http://dx.doi.org/10.1210/jc.2016-1545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4971332PMC
August 2016

A shared genetic basis for self-limited delayed puberty and idiopathic hypogonadotropic hypogonadism.

J Clin Endocrinol Metab 2015 Apr 30;100(4):E646-54. Epub 2015 Jan 30.

Harvard Reproductive Sciences Center and Reproductive Endocrine Unit (J.Z., R.E.-Y.C., L.P., C.B., S.B.S., Y.-M.C.), Massachusetts General Hospital, Boston, Massachusetts 02114; Division of Endocrinology, Department of Medicine (M.H.G., J.N.H., Y.-M.C.), Boston Children's Hospital, Boston, Massachusetts 02115; Department of Genetics (M.H.G., J.N.H.), Harvard Medical School, Boston, Massachusetts 02115; Program in Medical and Population Genetics (M.H.G., J.N.H.), Broad Institute, Cambridge, Massachusetts 02142; Division of Endocrinology and Genetics and Genome Biology Program (M.R.P.), Hospital for Sick Children, Toronto, Canada M5G 1X8; and Institute of Medical Science and Departments of Pediatrics and Physiology (M.R.P.), University of Toronto, Toronto, Canada M5S 1A8.

Context: Delayed puberty (DP) is a common issue and, in the absence of an underlying condition, is typically self limited. Alhough DP seems to be heritable, no specific genetic cause for DP has yet been reported. In contrast, many genetic causes have been found for idiopathic hypogonadotropic hypogonadism (IHH), a rare disorder characterized by absent or stalled pubertal development.

Objective: The objective of this retrospective study, conducted at academic medical centers, was to determine whether variants in IHH genes contribute to the pathogenesis of DP.

Subjects And Outcome Measures: Potentially pathogenic variants in IHH genes were identified in two cohorts: 1) DP family members of an IHH proband previously found to have a variant in an IHH gene, with unaffected family members serving as controls, and 2) DP individuals with no family history of IHH, with ethnically matched control subjects drawn from the Exome Aggregation Consortium.

Results: In pedigrees with an IHH proband, the proband's variant was shared by 53% (10/19) of DP family members vs 12% (4/33) of unaffected family members (P = .003). In DP subjects with no family history of IHH, 14% (8/56) had potentially pathogenic variants in IHH genes vs 5.6% (1 907/33 855) of controls (P = .01). Potentially pathogenic variants were found in multiple DP subjects for the genes IL17RD and TAC3.

Conclusions: These findings suggest that variants in IHH genes can contribute to the pathogenesis of self-limited DP. Thus, at least in some cases, self-limited DP shares an underlying pathophysiology with IHH.
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http://dx.doi.org/10.1210/jc.2015-1080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4399304PMC
April 2015

Neurokinin B is critical for normal timing of sexual maturation but dispensable for adult reproductive function in female mice.

Endocrinology 2015 Apr 9;156(4):1386-97. Epub 2015 Jan 9.

Harvard Reproductive Sciences Center and Reproductive Endocrine Unit (C.T., S.N.A., K.C., Y.-M.C., S.S.), Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114; and Division of Endocrinology (Y.-M.C.), Department of Medicine, Boston Children's Hospital, Boston, Massachusetts 02115.

Humans carrying mutations in neurokinin B (NKB) or the NKB receptor fail to undergo puberty due to decreased secretion of GnRH. Despite this pubertal delay, many of these patients go on to achieve activation of their hypothalamic-pituitary-gonadal axis in adulthood, a phenomenon termed reversal, indicating that NKB signaling may play a more critical role for the timing of pubertal development than adult reproductive function. NKB receptor-deficient mice are hypogonadotropic but have no defects in the timing of sexual maturation. The current study has performed the first phenotypic evaluation of mice bearing mutations in Tac2, the gene encoding the NKB ligand, to determine whether they have impaired sexual development similar to their human counterparts. Male Tac2-/- mice showed no difference in the timing of sexual maturation or fertility compared with wild-type littermates and were fertile. In contrast, Tac2-/- females had profound delays in sexual maturation, with time to vaginal opening and first estrus occurring significantly later than controls, and initial abnormalities in estrous cycles. However, cycling recovered in adulthood and Tac2-/- females were fertile, although they produced fewer pups per litter. Thus, female Tac2-/- mice parallel humans harboring NKB pathway mutations, with delayed sexual maturation and activation of the reproductive cascade later in life. Moreover, direct comparison of NKB ligand and receptor-deficient females confirmed that only NKB ligand-deficient animals have delayed sexual maturation, suggesting that in the absence of the NKB receptor, NKB may regulate the timing of sexual maturation through other tachykinin receptors.
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http://dx.doi.org/10.1210/en.2014-1862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4399316PMC
April 2015

The integrated hypothalamic tachykinin-kisspeptin system as a central coordinator for reproduction.

Endocrinology 2015 Feb 25;156(2):627-37. Epub 2014 Nov 25.

Division of Endocrinology, Diabetes, and Hypertension (V.M.N., S.S., R.S.C., U.B.K.), Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115; Department of Physiology and Pharmacology (M.A.B., O.K.R.), Oregon Health and Science University, Portland, Oregon 97239; Department of Cell Biology, Physiology, and Immunology (S.L., L.P., M.T.-S.), University of Córdoba; Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición (S.L., L.P., M.T.-S.), Instituto de Salud Carlos III; and Instituto Maimónides de Investigaciones Biomédicas and Hospital Universitario Reina Sofia (S.L., L.P., M.T.-S.), 14004 Córdoba, Spain; Department of Obstetrics and Gynecology (S.S.), Pamukkale University School of Medicine, Denizli, 20020 Turkey; and Massachusetts General Hospital and Harvard Medical School (C.T., S.B.S.), Boston, Massachusetts 02114.

Tachykinins are comprised of the family of related peptides, substance P (SP), neurokinin A (NKA), and neurokinin B (NKB). NKB has emerged as regulator of kisspeptin release in the arcuate nucleus (ARC), whereas the roles of SP and NKA in reproduction remain unknown. This work explores the roles of SP and NKA in the central regulation of GnRH release. First, central infusion of specific agonists for the receptors of SP (neurokinin receptor 1, NK1R), NKA (NK2R) and NKB (NK3R) each induced gonadotropin release in adult male and ovariectomized, estradiol-replaced female mice, which was absent in Kiss1r(-/-) mice, indicating a kisspeptin-dependent action. The NK2R agonist, however, decreased LH release in ovariectomized-sham replaced females, as documented for NK3R agonists but in contrast to the NK1R agonist, which further increased LH release. Second, Tac1 (encoding SP and NKA) expression in the ARC and ventromedial nucleus was inhibited by circulating estradiol but did not colocalize with Kiss1 mRNA. Third, about half of isolated ARC Kiss1 neurons expressed Tacr1 (NK1R) and 100% Tacr3 (NK3R); for anteroventral-periventricular Kiss1 neurons and GnRH neurons, approximately one-fourth expressed Tacr1 and one-tenth Tacr3; Tacr2 (NK2R) expression was absent in all cases. Overall, these results identify a potent regulation of gonadotropin release by the SP/NK1R and NKA/NK2R systems in the presence of kisspeptin-Kiss1r signaling, indicating that they may, along with NKB/NK3R, control GnRH release, at least in part through actions on Kiss1 neurons.
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http://dx.doi.org/10.1210/en.2014-1651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4298326PMC
February 2015

Exogenous kisspeptin administration as a probe of GnRH neuronal function in patients with idiopathic hypogonadotropic hypogonadism.

J Clin Endocrinol Metab 2014 Dec;99(12):E2762-71

Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Department of Medicine (Y-M.C., M.F.L.,V.F.S., C.X.L., L.P., S.B.S.), Massachusetts General Hospital, Boston, Massachusetts 02114; Division of Endocrinology, Department of Medicine (Y-M.C.), Boston Children's Hospital, Boston, Massachusetts 02115; and Division of Sleep Medicine (J.P.B.), Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115.

Context: Idiopathic hypogonadotropic hypogonadism (IHH) results from defective synthesis, secretion, or action of GnRH. Kisspeptin is a potent stimulus for GnRH secretion.

Objective: We probed the functional capacity of the GnRH neuronal network in patients with IHH.

Participants: Eleven subjects with congenital IHH (9 men and 2 women) and one male subject who underwent reversal of IHH were studied. Six of the twelve subjects had an identified genetic cause of their IHH: KAL1 (n = 1), FGFR1 (n = 3), PROKR2 (n = 1), GNRHR (n = 1).

Intervention: Subjects underwent q10 min blood sampling to measure GnRH-induced LH secretion at baseline and in response to intravenous boluses of kisspeptin (0.24 nmol/kg) and GnRH (75 ng/kg) both pre- and post-six days of treatment with exogenous GnRH (25 ng/kg sc every 2 h).

Results: All subjects with abiding IHH failed to demonstrate a GnRH-induced LH response to exogenous kisspeptin. In contrast, the subject who achieved reversal of his hypogonadotropism demonstrated a robust response to kisspeptin.

Conclusions: The functional capacity of the GnRH neuronal network in IHH patients is impaired, as evidenced by their inability to respond to the same dose of kisspeptin that effects a robust GnRH-induced LH response in healthy men and luteal-phase women. This impairment is observed across a range of genotypes, suggesting that it reflects a fundamental property of GnRH neuronal networks that have not been properly engaged during pubertal development. In contrast, a patient who had experienced reversal of his hypogonadotropism responded to exogenous kisspeptin.
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http://dx.doi.org/10.1210/jc.2014-2233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4255107PMC
December 2014

Fatness and fertility: which direction?

J Clin Invest 2014 Jul 17;124(7):2853-4. Epub 2014 Jun 17.

Metabolic status has long been thought to determine reproductive status, with abnormal metabolic phenotypes altering reproductive cascades, such as the onset of puberty. In this issue of the JCI, Tolson and colleagues provide evidence that kisspeptin, a hormone that promotes sexual maturation, regulates metabolism. Female mice lacking the kisspeptin receptor (KISS1R) gained more weight than control animals, and this weight gain was caused not by increased food consumption, but by an overall decrease in energy and metabolism. While this study provides a direct link between the kisspeptin pathway and metabolic output, more work will need to be done to determine whether alterations in this pathway contribute to human obesity.
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http://dx.doi.org/10.1172/JCI76623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4071384PMC
July 2014

Implantation failure in female Kiss1-/- mice is independent of their hypogonadic state and can be partially rescued by leukemia inhibitory factor.

Endocrinology 2014 Aug 30;155(8):3065-78. Epub 2014 May 30.

The Children's Health Research Institute (M.C., M.P., A.E., C.G.-M., N.G.B., A.J.W., A.V.B.), Lawson Health Research Institute (M.C., M.P., A.E., C.G.-M., N.G.B., A.J.W., A.V.B.), and Department of Obstetrics and Gynaecology (M.C., M.P., A.J.W., A.V.B.), London, Ontario, Canada N6C 2V5; Harvard Reproductive Endocrine Sciences Center (Y.-M.C., C.C., S.B.S.), Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts 02114; Division of Endocrinology (Y.-M.C.), Department of Medicine, Boston Children's Hospital, Boston, Massachusetts 02115; Department of Obstetrics and Gynecology and Reproductive Sciences (R.R.), University of Vermont College of Medicine, Burlington, Vermont 05405; and Departments of Paediatrics (A.E., N.G.B.), Biochemistry (A.E., N.G.B.), Physiology and Pharmacology (M.N., M.B., A.J.W., A.V.B.), and Oncology (M.B.), The University of Western Ontario, London, Ontario, Canada N6A 5C1.

The hypothalamic kisspeptin signaling system is a major positive regulator of the reproductive neuroendocrine axis, and loss of Kiss1 in the mouse results in infertility, a condition generally attributed to its hypogonadotropic hypogonadism. We demonstrate that in Kiss1(-/-) female mice, acute replacement of gonadotropins and estradiol restores ovulation, mating, and fertilization; however, these mice are still unable to achieve pregnancy because embryos fail to implant. Progesterone treatment did not overcome this defect. Kiss1(+/-) embryos transferred to a wild-type female mouse can successfully implant, demonstrating the defect is due to maternal factors. Kisspeptin and its receptor are expressed in the mouse uterus, and we suggest that it is the absence of uterine kisspeptin signaling that underlies the implantation failure. This absence, however, does not prevent the closure of the uterine implantation chamber, proper alignment of the embryo, and the ability of the uterus to undergo decidualization. Instead, the loss of Kiss1 expression specifically disrupts embryo attachment to the uterus. We observed that on the day of implantation, leukemia inhibitory factor (Lif), a cytokine that is absolutely required for implantation in mice, is weakly expressed in Kiss1(-/-) uterine glands and that the administration of exogenous Lif to hormone-primed Kiss1(-/-) female mice is sufficient to partially rescue implantation. Taken together, our study reveals that uterine kisspeptin signaling regulates glandular Lif levels, thereby identifying a novel and critical role for kisspeptin in regulating embryo implantation in the mouse. This study provides compelling reasons to explore this role in other species, particularly livestock and humans.
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http://dx.doi.org/10.1210/en.2013-1916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4098000PMC
August 2014

Reversal and relapse of hypogonadotropic hypogonadism: resilience and fragility of the reproductive neuroendocrine system.

J Clin Endocrinol Metab 2014 Mar 1;99(3):861-70. Epub 2013 Jan 1.

Harvard Center for Reproductive Endocrine Sciences and Reproductive Endocrine Unit (V.F.S., Y.-M.C., M.F.L., R.B., L.P., A.D., N.P., F.J.H., J.E.H., K.A.M., P.A.B., S.B.S.), Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114; Division of Endocrinology (Y.-M.C.), Department of Medicine, Boston Children's Hospital, Boston, Massachusetts 02115; and Department of Endocrinology (R.Q.), Institute for Human Genetics, University of Newcastle-upon-Tyne, Newcastle-upon-Tyne NE1 3BZ, United Kingdom.

Context: A subset of patients diagnosed with idiopathic hypogonadotropic hypogonadism (IHH) later achieves activation of their hypothalamic-pituitary-gonadal axis with normalization of steroidogenesis and/or gametogenesis, a phenomenon termed reversal.

Objective: The objective of this study was to determine the natural history of reversal and to identify associated phenotypes and genotypes.

Design, Setting, And Subjects: This was a retrospective review of clinical, biochemical, and genetic features of patients with IHH evaluated at an academic medical center.

Main Outcome Measures: History of spontaneous fertility, regular menses, testicular growth, or normalization of serum sex steroids, LH secretory profiles, brain imaging findings, and sequences of 14 genes associated with IHH were reviewed.

Results: Of 308 patients with IHH, 44 underwent reversal. Time-to-event analysis estimated a lifetime incidence of reversal of 22%. There were no differences in the rates of cryptorchidism, micropenis, or partial pubertal development in patients with reversal vs IHH patients without reversal. Fifteen patients with reversal (30%) had Kallmann syndrome (IHH and anosmia); one had undetectable olfactory bulbs on a brain magnetic resonance imaging scan. Subjects with reversal were enriched for mutations affecting neurokinin B signaling compared with a cohort of IHH patients without reversal (10% vs 3%, P = .044), had comparable frequencies of mutations in FGFR1, PROKR2, and GNRHR, and had no mutations in KAL1. Five men did not sustain their reversal and again developed hypogonadotropism.

Conclusions: Reversal of IHH may be more widespread than previously appreciated and occurs across a broad range of genotypes and phenotypes. Enrichment for mutations that disrupt neurokinin B signaling in patients who reversed indicates that, despite the importance of this signaling pathway for normal pubertal timing, its function is dispensable later in life. The occurrence of reversal in a patient with no olfactory bulbs demonstrates that these structures are not essential for normal reproductive function. Patients with IHH require lifelong monitoring for reversal and, if reversal occurs, subsequent relapse also may occur.
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http://dx.doi.org/10.1210/jc.2013-2809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3942233PMC
March 2014

TACR3 mutations disrupt NK3R function through distinct mechanisms in GnRH-deficient patients.

FASEB J 2014 Apr 27;28(4):1924-37. Epub 2013 Dec 27.

1Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, 221 Longwood Ave., Boston, MA 02115, USA.

Neurokinin B (NKB) and its G-protein-coupled receptor, NK3R, have been implicated in the neuroendocrine control of GnRH release; however, little is known about the structure-function relationship of this ligand-receptor pair. Moreover, loss-of-function NK3R mutations cause GnRH deficiency in humans. Using missense mutations in NK3R we previously identified in patients with GnRH deficiency, we demonstrate that Y256H and Y315C NK3R mutations in the fifth and sixth transmembrane domains (TM5 and TM6), resulted in reduced whole-cell (79.3±7.2%) or plasma membrane (67.3±7.3%) levels, respectively, compared with wild-type (WT) NK3R, with near complete loss of inositol phosphate (IP) signaling, implicating these domains in receptor trafficking, processing, and/or stability. We further demonstrate in a FRET-based assay that R295S NK3R, in the third intracellular loop (IL3), bound NKB but impaired dissociation of Gq-protein subunits from the receptor compared with WT NK3R, which showed a 10.0 ± 1.3% reduction in FRET ratios following ligand binding, indicating activation of Gq-protein signaling. Interestingly, R295S NK3R, identified in the heterozygous state in a GnRH-deficient patient, also interfered with dissociation of G proteins and IP signaling from wild-type NK3R, indicative of dominant-negative effects. Collectively, our data illustrate roles for TM5 and TM6 in NK3R trafficking and ligand binding and for IL3 in NK3R signaling.
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http://dx.doi.org/10.1096/fj.13-240630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3963009PMC
April 2014