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The spectrum of abnormal patterns of gonadotropin-releasing hormone secretion in men with idiopathic hypogonadotropic hypogonadism: clinical and laboratory correlations
Abstract
Several lines of evidence indicate that hypothalamic-pituitary-gonadal activity varies among men with idiopathic hypogonadotropic hypogonadism (IHH). To test the hypothesis that a spectrum of abnormalities of GnRH secretion underlies the syndrome of IHH, we characterized the patterns of GnRH-induced gonadotropin secretion during periods of frequent sampling in 50 consecutive men with IHH and contrasted them with those in 20 normal men. The largest group of IHH patients (n = 42) had no detectable LH or FSH pulsations and could be categorized into 2 subsets according to the presence or absence of evidence of spontaneous puberty. The most severely affected subset (n = 32), who recalled no history of puberty, had testes with a mean volume of 3.3 +/- 0.5 (+/- SEM) ml, with a prepubertal appearance on biopsy, and often were anosmic (n = 17). The second subset of apulsatile IHH men (n = 10) had histories of partial or complete spontaneous sexual development with subsequent isolated loss of sexual function, testes with a mean volume of 13.3 +/- 1.9 ml (P less than 0.01 compared to the first subset), a pubertal or adult appearance of the testes on biopsy, and an intact sense of smell. In a second group of IHH patients (n = 3), LH was secreted predominantly in a nighttime pattern similar to that of normal children during early puberty. These men were aged 18-24 yr, had a mean testicular volume of 10.5 +/- 2.3 ml, pubertal changes on testicular biopsy, and an intact sense of smell. A third group of IHH men (n = 4) had LH pulses of abnormally low amplitude. Only one patient in this group had a history of spontaneous sexual development. The mean testicular volume of these patients was 5.6 +/- 1.9 ml, and the testes appeared prepubertal (n = 3) or pubertal (n = 1) on biopsy. In addition to these groups, another patient had apparent LH pulsations and nearly normal amplitude, but the LH was bioinactive and appeared to consist chiefly of alpha-subunit. Testing of other anterior pituitary hormone functions did not distinguish IHH men from normal men. However, those IHH patients with some evidence of endogenous GnRH secretion had higher basal and stimulated serum PRL levels than IHH men without such evidence (P less than 0.05), suggesting an influence of GnRH on PRL secretion.
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“LH pulses were identified using a modification of the Santen and Bardin criteria (28, 29).”
From Kisspeptin Overcomes GnRH Neuronal Suppression Secondary to Hyperprolactinemia in Humans (2022) · cites this paper as [28]
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“hand is the small group defined by GnRH deficiency who may or may not have associated hyposmia, including patients with variants of Kallmann syndrome (93–99) and partial forms of GnRH deficiency such as fertile eunuch syndrome (125) and delayed puberty (41,126).”
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“It must be emphasized however, that although the total responders mimic the IHH group in their response to GnRH infusion, patients with IHH have a purely functional GnRH de®ciency without any evidence of pituitary disease (Spratt et al., 1987).”
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“For example, patients with IDIOPATHIC HYPOGONADOTROPIC HYPOGONADISM (IHH) demonstrate a complete or partial absence of GnRH secretion and failure to initiate puberty”
Neuroendocrine Control of Human Reproduction in the Male
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“All of these patterns are insufficient to sustain folliculogenesis and consequently, the patient is rendered amenorrheic. 4 Fig. 4. Spectrum of GnRH abnormalities in 4 women with hypothalamic amenorrhea. x = Detected LH pulsations. Note the predominance of LH pulsations during sleeping hours (open bars) [reproduced fr…”
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“…is both a clinical and genetic heterogeneous disorder that constitutes one of the most common causes of hereditary hypogonadism (Spitz et al., 1974; Spratt et al., 1987; Chaussain et al., 1988; Dean et al., 1990; Waldstreicher et al., 1996; Georgopoulos et al., 1997; Seminara et al., 1998; de Roux…”
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Richards, M., Plummer, L., Chan, Y.-M., Lippincott, M. F., Quinton, R., Kumanov, P., & Seminara, S. B. (2016) · Journal of Medical Genetics · doi:10.1136/jmedgenet-2016-104064 · Cited by 51
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“Some patients exhibit complete absence of LH pulsatility; others exhibit LH pulses but with low amplitude and/or frequency, demonstrating that their ability to secrete and respond to GnRH is still intact despite being markedly impaired; and yet others exhibit normal LH pulses at night but not during the day, similar t…”
BackgroundResultKisspeptin Overcomes GnRH Neuronal Suppression Secondary to Hyperprolactinemia in Humans
Hoskova, K., Kayton Bryant, N., Chen, M. E., Nachtigall, L. B., Lippincott, M. F., Balasubramanian, R., & Seminara, S. B. (2022) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgac166 · Cited by 39
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“Thus, the pituitary responsiveness to low doses of GnRHcan be analyzed without interference from endogenous GnRHsecretion (14, 15, 20, 21).”
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“Most patients with IHH have a lack of GnRH-induced LH pulsations (2).”
BackgroundThree‐dimensional properties of GnRH neuroterminals in the median eminence of young and old rats
Yin, W., Mendenhall, J. M., Monita, M. M., & Gore, A. C. (2009) · The Journal of Comparative Neurology · doi:10.1002/cne.22156 · Cited by 31
“The biological pattern of GnRH release is essential for normal reproductive function (Crowley et al., 1985; Spratt et al., 1987), but the mechanisms for the coordination of GnRH pulses remain controversial.”
BackgroundEndocrine Evaluation of Testicular Function
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Evaluation of gonadotropin-replacement therapy in male patients with hypogonadotropic hypogonadism
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The genetic basis of infertility in men
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Diseases of the Hypothalamus and the Pituitary Gland
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Self-citationTestis morphology in patients with idiopathic hypogonadotropic hypogonadism
Kumar, P. A., Pitteloud, N., Andrews, P. A. M., Dwyer, A. A., Hayes, F. J., Crowley, W. F., & Dym, M. (2006) · Human Reproduction · doi:10.1093/humrep/dei444 · Cited by 23
“This is confirmed by a nearly uniform response to physiological regimens of exogenous GnRH-replacement therapy (Hoffman and Crowley, 1982; Spratt et al., 1987).”
BackgroundSelf-citationDivergent responses to kisspeptin in children with delayed puberty
Chan, Y.-M., Lippincott, M. F., Kusa, T. O., & Seminara, S. B. (2018) · JCI Insight · doi:10.1172/jci.insight.99109 · Cited by 22
“Though patients with IHH classically present with complete absence of reproductive endocrine activity, as described above, some individuals with IHH have evidence of partial neuroendocrine activity (9, 15, 16, 19).”
Episodic Activation of the Rat GnRH Promoter: Role of the Homeoprotein Oct-1
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“and the varied clinical and biochemical presentations of IHH [”
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“These gonadotropin episodes are needed for the continued function of various reproductive tissues (Crowley et al., 1985; Spratt et al., 1987).”
BackgroundLandy, H., Boepple, P. A., Mansfield, M. J., Charpie, P. M., Schoenfeld, D., Link, K., Romero, G., Crawford, J. D., Crigler, J. F., Blizzard, R. M., et al. (1990) · Pediatric Research · doi:10.1203/00006450-199009000-00011 · Cited by 17
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“At the time of diagnosis, patients may display various pulse patterns including present, albeit attenuated LH pulses [28].”
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Reproductive Phenotypes and Genotypes in Men With IHH
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“These gonadotropin pulses are required for maintaining the function of gonadal and accessory sex tissues [”
BackgroundYang, F., Sun, H., Yang, Y., Wang, Y., Dai, S., Lin, Z., Shen, Y., & Liu, H. (2023) · Clinical Genetics · doi:10.1111/cge.14300 · Cited by 7
“IHH is diagnosed in men and women over the age of 18 who lack sexual maturation or menstruation and have hypogonadotropic hypogonadism (T < 100 ng/dl in men, and Estradiol<20 pg/ml in women).(18) In our study, the hormonal status of those two patients met the criteria for diagnosis of IHH (Table S1).”
Background
Metadata
- Authors
- SPRATT, D. I., CARR, D. B., MERRIAM, G. R., SCULLY, R. E., RAO, P. N., & CROWLEY, W. F.
- Affiliations
- Massachusetts General Hospital (US)
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 1987-02
- Volume
- 64
- Issue
- 2
- Pages
- 283-291
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2030071125
- Cited by
- 153
- References
- 33
- Citations by year
- 2026: 1 · 2023: 3 · 2022: 5 · 2020: 2 · 2019: 5 · 2018: 2 · 2017: 5 · 2016: 4 · 2015: 3 · 2014: 2 · 2013: 2 · 2012: 3
- FWCI
- 7.86
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Center for Research Resources (RR-1066)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD15788, R01HD015788, U54HD029164, P30HD028138, U54HD028138)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
- Keywords
- idiopathic hypogonadotropic hypogonadism, LH pulsatility, hypothalamic-pituitary-gonadal axis, testicular volume, anosmia, spontaneous puberty, LH alpha subunit, LH bioactivity, LH pulse amplitude, LH pulse frequency
- MeSH terms
- Adolescent, Adult, Follicle Stimulating Hormone, Humans, Hypogonadism, Luteinizing Hormone, Gonadotropin-Releasing Hormone, Male, Middle Aged, Pituitary Gland, Anterior, Testis
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