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Cited by 41Hypothalamic control of reproductive hormonesHormonal and reproductive studiesMenstrual Health and Disorders

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

Open access
Dwyer, Andrew A, Chavan, Niraj R, Lewkowitz-Shpuntoff, Hilana, Plummer, Lacey, Hayes, Frances J, Seminara, Stephanie B, Crowley, William F, Pitteloud, Nelly +1 more·2019·The Journal of Clinical Endocrinology & Metabolism
DOI 10.1210/jc.2018-02697PMC PMC6594303
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Abstract

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.

Verified 2026-10-11 · 1 reference not checked yet

AI snapshot

Written from the paper’s full text.

TL;DR

This retrospective study describes functional hypogonadotropic hypogonadism (FHH) in 10 men whose hypogonadism was associated with excessive exercise or weight loss, compared with 18 healthy controls. The findings suggest a reversible reproductive-axis suppression marked by reduced LH pulse amplitude, sometimes with sleep-entrained or apulsatile LH secretion, and rare variants in CHD7 or NSMF in two men.

Key findings

  • Men with FHH had lower BMI (20.3 ± 2.2 vs 24.1 ± 2.2 kg/m², P < 0.001), lower testosterone and LH, and lower mean LH pulse amplitude (4.0 ± 2.0 vs 7.7 ± 2.9 IU/L, P = 0.001), while LH pulse frequency, FSH, and available sperm counts did not differ significantly.
  • LH pulse patterns varied: six men had a normal pattern, three had nocturnal sleep-entrained pulses resembling early puberty, and one had no detectable LH pulses.
  • Five men with follow-up recovered normal testosterone and symptom improvement after reducing exercise or gaining weight; for example, one rower’s testosterone rose from 145 ng/dL to 361 ng/dL after weight gain, with a later mean of 442 ng/dL.
  • Rare heterozygous missense variants were found in CHD7 (n = 1) and NSMF (n = 1); two men with a family history of hypothalamic amenorrhea had no rare variants in the screened genes.

Methods

  • Retrospective single-center study at Massachusetts General Hospital (1986–2016) including 10 men aged 18–35 with hypogonadal symptoms, morning testosterone <300 ng/dL, low gonadotropins, and either >10 hours/week exercise or >10% weight loss, plus 18 age-matched healthy controls.
  • Participants underwent overnight frequent blood sampling every 10 minutes for 12 hours for LH pulse analysis, pooled hormone measurements, semen analysis when possible (n = 3), DXA body composition/bone density in a subset, and Sanger sequencing of 14 genes linked to isolated GnRH deficiency.
  • Group comparisons used t tests or Mann-Whitney U tests, with P < 0.05 considered significant; rare-variant burden testing was not performed because of the small cohort.

Limitations

  • The paper states that the small retrospective single-center design, with cases and controls drawn from separately recruited cohorts, limits assessment of FHH prevalence and requires replication.
  • The paper also notes that sex steroids were not measured by liquid chromatography–mass spectrometry, that a 300 ng/dL testosterone threshold was used rather than higher thresholds used elsewhere, and that gonadal, inhibin B, and bone density data were incomplete.
  • The text makes evident additional constraints: only three men provided semen samples, only four had inhibin B measured, follow-up was available for five men, and neuroendocrine testing often occurred after lifestyle changes had begun, which may have affected the observed LH pulse patterns.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1210/jc.2018-02697

Cites

69 of 70 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

9 of 45 cited sources checked · 7 supported · 0 flagged · accuracy not yet measured

  • Findingcitation

    A small subset of men with FHH exhibited a sleep-entrained pulse pattern characteristic of early puberty.

    “A small subset of men with FHH exhibited a sleep-entrained pulse pattern characteristic of early puberty (Figs.123) (46), and this”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [46] Boyar, 1974, Human puberty. Simultaneous augmented secretion of luteinizing hormone and testosterone during sleep, J Clin Invest source

      The Discussion (page unavailable) describes sleep-synchronized pulsatile LH secretion as characteristic of puberty, supporting the comparison to an early-pubertal pattern. But the Methods describe healthy pubertal boys and normal young men, and the paper does not report a subset of men with FHH exhibiting that pattern. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
  • Premisecitation

    A few case reports have depicted men exhibiting functional hypogonadotropic hypogonadism (FHH) in the setting of extreme exercise or energy imbalance.

    “To date, a few case reports have depicted men exhibiting functional hypogonadotropic hypogonadism (FHH), that is, clinical hypogonadism evidenced by low serum T and hypogonadal symptoms in the setting of extreme exercise or energy imbalance (25,26), analogous to young women presenting with HA.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [25] Burge, 1997, Idiopathic hypogonadotropic hypogonadism in a male runner is reversed by clomiphene citrate, Fertil Steril source
    • cites [26] Shemesh, 2011, Reversible nutritional hypogonadism in a 22-year-old man, Am J Med source
  • Premisecitation

    CHD7 rare variants have previously been associated with milder reproductive phenotypes such as self-limiting delayed puberty and reversal of hypogonadotropic hypogonadism.

    “CHD7 rare variants have previously been associated with milder reproductive phenotypes such as self-limiting delayed puberty (58) and reversal of hypogonadotropic hypogonadism (59).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [58] Dauber, 2010, Delayed puberty due to a novel mutation in CHD7 causing CHARGE syndrome, Pediatrics source
    • cites [59] Laitinen, 2012, Reversible congenital hypogonadotropic hypogonadism in patients with CHD7, FGFR1 or GNRHR mutations, PLoS One source
  • Findingown data

    Six men with FHH had weight loss of ≥10% of their body weight.

    “Similarly, 6 men had weight loss of $10% of their body weight (Table 2).”
    Quote in the paperNot a substantial claim
  • Findingown data

    Patient 7 harbors a heterozygous rare missense variant in CHD7 predicted to be damaging by three in silico prediction algorithms.

    “Patient 7 harbors a heterozygous rare missense variant in CHD7 predicted to be damaging by three in silico prediction algorithms without associated features of CHARGE syndrome.”
    Quote in the paperNot a substantial claim
  • Classified as probably not a substantial claim. 15
  • May combine two claims. 27

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    A genetic contribution to HA has been described, with mutations in genes affecting GnRH neuronal integrity identified in some women with HA.

    “Furthermore, a genetic contribution to HA has been described, with mutations in genes affecting GnRH neuronal integrity identified in some women with HA (5).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [5] Caronia, 2011, A genetic basis for functional hypothalamic amenorrhea, N Engl J Med source

  • May combine two claims.

    Premisecitation

    Men with adult-onset hypogonadotropic hypogonadism lack identifiable triggers, display apulsatile LH secretion, and do not recover.

    “Indeed, men with adultonset hypogonadotropic hypogonadism lack identifiable triggers (i.e., exercise or weight loss), display apulstatile LH secretion, and do not recover (48).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [48] Dwyer, 2010, The long-term clinical follow-up and natural history of men with adult-onset idiopathic hypogonadotropic hypogonadism, J Clin Endocrinol Metab source

      The Abstract reports little evidence for functional triggers such as extreme exercise or malnutrition, and the Discussion reports no spontaneous recovery in the 10 men followed; it does not rule out eventual recovery in others. The Neuroendocrine studies section contradicts the blanket description of apulsatile LH secretion: five men had some pulsatile secretion at follow-up, while five were apulsatile. Page numbers were not provided in our copy. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Leptin administration could not only restore but also prevent starvation-induced inhibition of the HPG axis.

    “Furthermore, leptin administration could not only restore but also prevent starvationinduced inhibition of the HPG axis (53).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [53] Chan, 2003, The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men, J Clin Invest source

  • May combine two claims.

    Premisecitation

    Both NSMF and CHD7 encode proteins known to play a critical developmental role in the GnRH network and have been implicated in patients with pubertal failure (Kallmann syndrome or idiopathic hypogonadotropic hypogonadism).

    “Both NSMF (57) and CHD7 (37) encode proteins that are known to play a critical developmental role in the GnRH network and have been implicated in patients with pubertal failure (Kallmann syndrome or idiopathic hypogonadotropic hypogonadism) (36).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [57] Quaynor, 2015, NELF knockout is associated with impaired pubertal development and subfertility, Mol Cell Endocrinol source
    • cites [37] Balasubramanian, 2014, Functionally compromised CHD7 alleles in patients with isolated GnRH deficiency, Proc Natl Acad Sci USA source
    • cites [36] Stamou, 2016, Discovering genes essential to the hypothalamic regulation of human reproduction using a human disease model: adjusting to life in the “-omics” era, Endocr Rev source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Genetic variants in genes related to GnRH neuronal ontogeny are enriched in patients with HA.

    “It has been previously shown that genetic variants in genes related to GnRH neuronal ontogeny are enriched in patients with HA (5).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [5] Caronia, 2011, A genetic basis for functional hypothalamic amenorrhea, N Engl J Med source

  • May combine two claims.

    Findingown data

    Men with FHH exhibited normal adult male testicular volumes, not different from controls.

    “The men with FHH exhibited normal adult male testicular volumes, which were not different from controls (median 21.5 vs 25 mL, P 5 0.175).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Men with FHH had normal LH pulse frequency, not different from controls.

    “LH pulse frequency did not differ between the FHH group and controls (3.8 6 1.7 vs 5.0 6 1.9, P 5 0.109)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Men with FHH had normal serum FSH levels, not different from controls.

    “Men with FHH had similar serum FSH levels but significantly lower LH levels”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Findingown data

    A total of 10 men met the inclusion criteria for FHH and underwent detailed neuroendocrine profiling.

    “A total of 10 men met the inclusion criteria for FHH and underwent detailed neuroendocrine profiling.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Overall, LH pulse frequency did not differ between the FHH group and control group, whereas mean pulse amplitude was lower in the FHH group.

    “Overall, LH pulse frequency did not differ between the FHH group and control group, whereas mean pulse amplitude was lower in the FHH group (Table 1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The men with FHH were otherwise healthy and had undergone complete pubertal development.

    “The men (18 to 33 years old) were otherwise healthy, had undergone complete pubertal development (mean TV, 21.6 6 2.6 mL, median 21.5 mL), and had other possible causes of hypogonadism ruled out.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    We assessed bone mineral density (BMD) in six men with FHH, all of whom had normal BMD at the hip.

    “We assessed bone mineral density (BMD) in six men with FHH, all of whom had normal BMD at the hip.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Five men with FHH who decreased exercise and gained weight had normalized serum testosterone levels and symptom resolution.

    “After decreased exercise and weight gain, five men with men had normalized serum testosterone levels, and symptoms resolved.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    Subject 1 underwent only 8 hours of sampling and had recovered HPG axis function at the time of the neuroendocrine evaluation (normal serum T levels).

    “Subject 1 underwent only 8 hours of sampling and had recovered HPG axis function at the time of the neuroendocrine evaluation (normal serum T levels).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Both patients with FHH harboring genetic variants had normal timing of puberty, normal smell testing, and presented only with FHH.

    “Both patients with FHH harboring genetic variants had normal timing of puberty, with normal smell testing, and presented only with FHH.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Patient 5 exhibited nocturnal sleep-entrained LH pulses and hypogonadal serum T (225 ng/dL, 7.8 nmol/L).

    “(A) Patient 5 exhibited nocturnal sleep-entrained LH pulses and hypogonadal serum T (225 ng/dL, 7.8 nmol/L).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Findingnone given

    Men with FHH can recover HPG axis function with removal of the energy deficit.

    “Much like women with HA, men with FHH can recover HPG axis function with removal of the energy deficit.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    Despite hypogonadism, seminiferous tubular function remains intact, with normal testicular volume and normal sperm counts.

    “Despite hypogonadism, seminiferous tubular function remains intact, with normal testicular volume and normal sperm counts.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Subject 6 displayed sleep-entrained pulses.

    “(B) Subject 6 displayed sleep-entrained pulses (hatched bar depicts sleep period).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    After weight gain, repeat frequent sampling in Patient 5 showed normal LH pulse frequency and amplitude with normal serum T (442 ng/dL, 15.3 nmol/L).

    “(B) After weight gain, repeat frequent sampling showed normal LH pulse frequency and amplitude with normal serum T (442 ng/dL, 15.3 nmol/L).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    FHH is a rare, reversible form of male GnRH deficiency.

    “FHH is a rare, reversible form of male GnRH deficiency.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    A limited number of studies have shown reduced serum testosterone levels in response to exercise, yet T levels typically remain within the normal range.

    “However, a limited number of studies have shown reduced serum testosterone (T) levels in response to exercise, yet T levels typically remain within the normal range (6)(7)(8)(9)(10)(11)(12)(13).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites (6)(7)(8)(9)(10)(11)(12)(13)

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    In women, suppressed HPG axis function and HA often appear as part of the female athlete triad.

    “In women, suppressed HPG axis function and HA often appear as part of the female athlete triad (energy imbalance, amenorrhea, and osteoporosis).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Male FHH is a phenotypic equivalent parallel to women with HA and expands the spectrum of GnRH deficiency disorders in men to include FHH as a distinct hypogonadotropic state.

    “These observations indicate that male FHH is a phenotypic equivalent parallel to women with HA and expand the spectrum of GnRH deficiency disorders in men to include FHH as a distinct hypogonadotropic state.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    HIV-related hypogonadism may also share some pathophysiologic features with FHH.

    “Similarly, HIV-related hypogonadism may also share some pathophysiologic features with FHH (e.g., undernutrition, weight loss).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Hypogonadotropism in men is also known to occur in the context of acute starvation and critical illness.

    “Hypogonadotropism in men is also known to occur in the context of acute starvation (19,50) and critical illness (51).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [19] Friedl, 2000, Endocrine markers of semistarvation in healthy lean men in a multistressor environment, J Appl Physiol (1985) source
    • cites [50] Spratt, 1992, Both hyper- and hypogonadotropic hypogonadism occur transiently in acute illness: bio- and immunoactive gonadotropins, J Clin Endocrinol Metab source
    • cites [51] Woolf, 1985, Transient hypogonadotropic hypogonadism caused by critical illness, J Clin Endocrinol Metab source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The research activities were approved by the Partners HealthCare Human Research Committee.

    “The research activities of the hypogonadal subjects and control subjects were all approved by the Partners HealthCare Human Research Committee.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    HA is typically reversible when the relative energy deficit is corrected.

    “and is typically reversible when the relative energy deficit is corrected (2).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] Santoro, 1986, Hypogonadotropic disorders in men and women: diagnosis and therapy with pulsatile gonadotropin-releasing hormone, Endocr Rev source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In this acute model, refeeding rapidly returned T levels to the normal range.

    “In this acute model, refeeding rapidly returned T levels to the normal range.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    A preserved GnRH-induced LH pulse frequency with a diminished pulse amplitude is the neuroendocrine signature for FHH, and this discordant pulse frequency-amplitude pattern differentiates men with FHH from controls.

    “Cumulatively, these data suggest that a preserved GnRH-induced LH pulse frequency with a diminished pulse amplitude is the neuroendocrine signature for FHH, and this discordant pulse frequencyamplitude pattern differentiates men with FHH from the controls who exhibit robust pulse amplitude and normal frequency (Figs.123) (42).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42] Dwyer AA , ChavanNR, Lewkowitz-ShpuntoffH, PlummerL, HayesFJ, SeminaraSB, CrowleyWF, PitteloudN, BalasubramanianR. Data from: Functional hypogonadotropic hypogonadism in men: underlying neuroendocrine mechanisms and natural history. figshare. Deposited 2018. https://dx.doi.org/10.6084/m9.figshare.7464773.v3.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationcitation

    A cohort of 10 men with FHH secondary to exercise or weight loss was studied via detailed neuroendocrine studies that show pathophysiologic neuroendocrine defects similar to those previously reported in women with HA.

    “A cohort of 10 men with FHH secondary to exercise or weight loss was studied via detailed neuroendocrine studies that show pathophysiologic neuroendocrine defects similar to those previously reported in women with HA (2,3,44,45).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [2] Santoro, 1986, Hypogonadotropic disorders in men and women: diagnosis and therapy with pulsatile gonadotropin-releasing hormone, Endocr Rev source
    • cites [3] Perkins, 1999, Neuroendocrine abnormalities in hypothalamic amenorrhea: spectrum, stability, and response to neurotransmitter modulation, J Clin Endocrinol Metab

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [44] Santoro, 1986, Intravenous administration of pulsatile gonadotropin-releasing hormone in hypothalamic amenorrhea: effects of dosage, J Clin Endocrinol Metab source
    • cites [45] Gordon, 2010, Clinical practice. Functional hypothalamic amenorrhea, N Engl J Med source

  • May combine two claims.

    Premisecitation

    In contrast to FHH, patients with HIV also exhibit SHBG abnormalities and some may also display primary gonadal deficits.

    “However, in contrast to FHH, patients with HIV also exhibit SHBG abnormalities and some may also display primary gonadal deficits (52).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [52] Rochira, 2014, Hypogonadism in the HIV-infected man, Endocrinol Metab Clin North Am source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    All subjects provided written informed consent.

    “All subjects provided written informed consent before the initiation of study procedures.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A previous study demonstrated that acute starvation and high demands of physical exertion during training exercises can induce T levels that fall well below the normal range.

    “A previous study from Freidl et al. (19) demonstrated that acute starvation and high demands of physical exertion during training exercises can induce T levels that fall well below the normal range.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] Friedl, 2000, Endocrine markers of semistarvation in healthy lean men in a multistressor environment, J Appl Physiol (1985) source

  • May combine two claims.

    Premisecitation

    Pulsatile GnRH treatment can rescue the HA phenotype, and pulsatile GnRH can avert fasting-induced hypogonadotropism in men.

    “It has been previously shown that pulsatile GnRH treatment can rescue the HA phenotype (2, 44), and likewise, pulsatile GnRH can avert fasting-induced hypogonadotropism in men (49).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [2] Santoro, 1986, Hypogonadotropic disorders in men and women: diagnosis and therapy with pulsatile gonadotropin-releasing hormone, Endocr Rev source
    • cites [44] Santoro, 1986, Intravenous administration of pulsatile gonadotropin-releasing hormone in hypothalamic amenorrhea: effects of dosage, J Clin Endocrinol Metab source
    • cites [49] Aloi, 1997, Pulsatile intravenous gonadotropin-releasing hormone administration averts fasting-induced hypogonadotropism and hypoandrogenemia in healthy, normal weight men, J Clin Endocrinol Metab

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationown data

    FHH and HA co-occurred in related family members in two FHH pedigrees, suggesting shared pathogenic mechanisms.

    “Indeed, FHH and HA co-occurred in related family members in two FHH pedigrees, suggesting shared pathogenic mechanisms.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    The study included detailed clinical evaluation of subjects with FHH, overnight neuroendocrine profiling, and longitudinal follow-up.

    “Relative strengths of this study include the detailed clinical evaluation of subjects with FHH, overnight neuroendocrine profiling, and longitudinal follow-up.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    A recent study identified T levels <12 nmol/L in eight of nine distance runners, of whom three displayed osteopenia.

    “Similarly, a recent study by Hooper et al. (55) identified T levels ,12 nmol/L (,346 ng/dL) in eight of nine distance runners, of whom three displayed osteopenia.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [55] Hooper, 2017, The presence of symptoms of testosterone deficiency in the exercise-hypogonadal male condition and the role of nutrition, Eur J Appl Physiol source

  • May combine two claims.

    Study design and conductown data

    There was no misclassification of diagnosis with the <300 ng/dL threshold used in this study because all subjects with FHH showed unequivocally low total serum T levels <200 ng/dL at presentation.

    “because all subjects with FHH showed unequivocally low total serum T levels ,200 ng/dL at presentation (Table 1), there was no misclassification of diagnosis with the ,300 ng/dL threshold used in this study.”
    Quote in the paperSubstantial claim
39 of 39

  • The paper relies on this without support.

    In silico prediction programs correctly predict that the identified NSMF and CHD7 variants are deleterious.

    “Both variants were predicted to be deleterious by in silico prediction programs.”
1 of 1

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Preconception care is essential for better pregnancy outcomes.

    “preconception care is essential for improved pregnancy outcomes.1542,1543”

    From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [1542]

    The Clinical and biochemical assessment and Discussion passages address male hypogonadism and reproductive function, not preconception care or pregnancy outcomes. Searches for preconception care, prenatal care, and improved pregnancy outcomes found no passage supporting the claim. Page numbers were not available in our copy. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

  • Good glycemic control is the best way to protect current and future fertility.

    “appropriate glycemic control is the best way to safeguard current and future fertility”

    From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [1542]

    The Discussion addresses sperm counts and uncertainty about whether spermatogenesis is preserved in men with functional hypogonadotropic hypogonadism, but it does not address glycemic control. Searches for glycemic control, diabetes, glucose, insulin, and hyperglycemia found no passage linking blood-sugar control to current or future fertility. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Subject 2 has conflicting testosterone values at presentation

    Minor

    The narrative gives subject 2's initial testosterone as 119 ng/dL, whereas Table 1 lists 191 ng/dL in his presenting-testosterone column.

1 of 1

Cited works that were retracted

Works this paper cites that were later retracted, from the retraction notices publishers deposit. Major when the notice came out before this paper was published.

  • Cites a retracted work: 10.1210/er.2015-1045

    Info

    The cited work was retracted; the date of the notice is not on record.

    Cited work 10.1210/er.2015-1045 · retraction date not known · this paper published 2019-03-11

1 of 1

Cites

1 retracted

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6 of the 76 references couldn’t be matched to a known paper.

Cited by

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Related

Authors
Dwyer, A. A., Chavan, N. R., Lewkowitz-Shpuntoff, H., Plummer, L., Hayes, F. J., Seminara, S. B., Crowley, W. F., Pitteloud, N., & Balasubramanian, R.
Affiliations
  • Boston College (US)
  • University of Kentucky (US)
  • Harvard University (US)
  • Centre Hospitalier Universitaire Vaudois (CH)
Corresponding author
Balasubramanian, Ravikumar
ORCID
Venue
The Journal of Clinical Endocrinology & Metabolism
Publisher
The Endocrine Society
Published
2019-03-11
Volume
104
Issue
8
Pages
3403-3414
ISSN
  • 0021-972X (ISSN-L)
  • 1945-7197
DOI
10.1210/jc.2018-02697
PMC
PMC6594303
OpenAlex
W2921284185
Cited by
41
References
76
Citations by year
2025: 5 · 2024: 5 · 2023: 5 · 2022: 3 · 2021: 8 · 2020: 11 · 2019: 2
FWCI
5.35
Type
journal article
Language
en
Open access
Locations
  • The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
  • IRIS (submittedVersion)
  • SERVAL (Université de Lausanne) (submittedVersion)
Funders
Eunice Kennedy Shriver National Institute of Child Health and Human Development (K23 HD077043, R01 HD096324, P50 HD028138, R01HD043341)
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Menstrual Health and Disorders
Keywords
male hypogonadism, GnRH deficiency, hypothalamic amenorrhea, excessive exercise, weight loss, testosterone, CHD7, natural history (disease)
MeSH terms
Adolescent, Humans, Hypogonadism, Luteinizing Hormone, Gonadotropin-Releasing Hormone, Male, Neurosecretory Systems, Retrospective Studies

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-11.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-11.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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