Episodic Luteinizing Hormone Secretion in Man PULSE ANALYSIS, CLINICAL INTERPRETATION, PHYSIOLOGIC MECHANISMS

Santen, Richard J.; Bardin, C. Wayne

doi:10.1172/jci107454

Cited by 708 publications

(232 citation statements)

References 31 publications

(42 reference statements)

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“…Positive controls created by PCR-directed mutagenesis (16,17) were included on each gel to optimize the TGGE gel conditions and check the sensitivity.…”

Section: Methodsmentioning

confidence: 99%

“…Thirty-seven patients were admitted to the General Clinical Research Center of the Massachusetts General Hospital for overnight blood sampling (q 10 min), for 12-24 h, to assess LH levels. The presence of LH pulses was determined by a modification of the method of Santen and Bardin (16,17), as previously described. Individuals were considered as having apulsatile LH secretion if they had 1 peak or less in 24 h, and low amplitude LH secretion if the mean amplitude was less than 2 sds of mean LH amplitude of 10.2 Ϯ 1.8 IU/L, as identified in 20 normal men (10).…”

Section: Methodsmentioning

confidence: 99%

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The Importance of Autosomal Genes in Kallmann Syndrome: Genotype-Phenotype Correlations and Neuroendocrine Characteristics

Oliveira¹

2001

Journal of Clinical Endocrinology & Metabolism

121

120

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Kallmann syndrome (KS) consists of congenital, isolated, idiopathic hypogonadotropic hypogonadism (IHH) and anosmia. The gene responsible for the X-linked form of KS, KAL, encodes a protein, anosmin, that plays a key role in the migration of GnRH neurons and olfactory nerves to the hypothalamus. In addition to X-linked pedigrees, autosomal dominant and recessive kindreds with KS have been reported. The relative importance of these autosomal vs. X-linked genes in producing KS, and the frequency of KAL mutations, are currently unknown because these are rare disorders and large series are unusual.We examined 101 individuals with IHH (Ϯ anosmia) and their families to determine their modes of inheritance, incidence of mutations in the coding sequence of KAL, genotype-phenotype correlations, and [in a subset (n ϭ 38)] their neuroendocrine phenotype.Of the 101 patients, 59 had true KS (IHH ϩ anosmia/hyposmia); whereas, in the remaining 42, no anosmia was evident in the patients or their families. Of the 59 KS patients, 21 were familial, whereas 38 were sporadic cases. Mutations in the coding sequence of KAL were identified in only 3 of 21 familial cases (14%) and 4 of 38 (11%) of the sporadic cases. Of the X-linked cases confirmed by mutational analysis, only 1 of 3 pedigrees appeared X-linked by inspection whereas the other 2 contained only affected brothers. Female members of known KAL mutation families (n ϭ 3) exhibited no reproductive phenotype and were not anosmic, whereas families with anosmic women (n ϭ 3) were not found to carry mutations in KAL. Mutations were uniformly absent in nonanosmic IHH probands (n ϭ 42), as well as in families with both anosmic and nonanosmic members (n ϭ 2). Overall, 4 novel mutations were identified (C172R, R191ϫ, R457ϫ, and delC@L600).With respect to neuroendocrine phenotype, KS men with documented KAL mutations (n ϭ 8) had completely apulsatile LH secretion, whereas those with autosomal modes of inheritance demonstrated a more variable spectrum with evidence of enfeebled (but present) GnRH-induced LH pulses.Our conclusions are: 1) Confirmed mutations in the coding sequence of the KAL gene occur in the minority of KS cases, i.e. only 14% of familial and 11% of sporadic cases; 2) The majority of familial (and presumably sporadic) cases of KS are caused by defects in at least two autosomal genes that are currently unknown; 3) Obligate female carriers in families with KAL mutations have no discernible phenotype; 4) KAL mutations are uniformly absent in patients with either normosmic IHH or in families with both anosmic and nonanosmic individuals; and 5) Patients with KAL mutations have apulsatile LH secretion consistent with a complete absence of GnRH migration of GnRH cells into the hypothalamus, whereas evidence of present (but enfeebled) GnRH-induced LH pulses may be present in autosomal KS cases. Taken together, these findings suggest that autosomal genes account for the majority of familial cases of KS, and that unique neuroendocrine phenotypes consistent with some GnRH n...

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“…Positive controls created by PCR-directed mutagenesis (16,17) were included on each gel to optimize the TGGE gel conditions and check the sensitivity.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

The Importance of Autosomal Genes in Kallmann Syndrome: Genotype-Phenotype Correlations and Neuroendocrine Characteristics

Oliveira¹

2001

Journal of Clinical Endocrinology & Metabolism

121

120

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“…It is of interest that pulses with similar features are also observed during the luteal phase of the menstrual cycle in normal women when progesterone levels are high (14,36). Since androgens and progestins exert many similar hormonal effects in rodents (37), the possibility that T and progesterone produce high amplitude, low frequency pulses by a similar mechanism deserves further study.…”

Section: Pulsatile Lh Releasementioning

confidence: 99%

“…Serum LH levels were measured by a double-antibody radioimmunoassay system similar to that previously described (14). Human chorionic gonadotrophin, lot no.…”

Section: Hormone Assaysmentioning

confidence: 99%

“…Interpretation of the significance of these observations requires an understanding of the physiologic mechanisms which initiate LH pulses and modulate pulse amplitude. A large number of studies sin rodents and primates suggest that spontaneous LU pulses reflect the periodic secretion of LU-RU from the hypothalamus in response to firing of a-adrenergically mediated CNS neurons (14,(28)(29)(30)(31). If this consideration 15 correct, LU pulse amplitude could be modulated either by (a) the amount of endogenous LU-RU released to initiate each spontaneous LU pulse or (b) by the responsiveness of the pituitary to a given quantity of LU-RU.…”

Section: Pulsatile Lh Releasementioning

confidence: 99%

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Is Aromatization of Testosterone to Estradiol Required for Inhibition of Luteinizing Hormone Secretion in Men?

SANrEN¹

1976

Obstetrical & Gynecological Survey

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A B S T R A C T A variety of studies in man and animalsdemonstrate that testosterone (T) is aromatized to estradiol (E) in the hypothalamus and limbic system. These observations suggested the possibility that conversion to E is an absolute requirement for the biologic activity of T on the hypothalamic-pituitary axis. Since this hypothesis implies a common mechanism of action of these two steroids, the demonstration of divergent effects of T and E on luteinizing hormone (LH) secretion would exclude this possibility. To test this hypothesis, the actions of T and E on three separate aspects of LH release (mean LH, pulsatile LH secretion, and responsiveness to LHreleasing hormone [LH-RH]) were contrasted. T and E, infused at two times their respective production rates into normal men, reduced mean LH levels similarly during 6 h of steroid infusion and for 6 h thereafter. However, these steroids exerted different effects on pulsatile secretion. E reduced the amplitude of spontaneous LH pulses from pre-and postinfusion control levels of 75+14 and 68±5.6% (SEM) to 39±5.7%. In contrast, T increased pulse amplitude to 96+14% and decreased pulse frequency from basal levels of 3.4+0.31 to 1.8± 0.31 pulses/6 h.The site of suppressive action was determined by administering 25 lAg of LH-RH to the same men during T and E infusions and during three additional control periods without steroid administration. LH-RH produced similar 170-190% increments in serum LH during the three control periods and during T infusion. In contrast, E markedly blunted (76±31%, P <0.005) the LH response to LH-RH. Under the conditions of acute steroid infusion at doses (utilized in these experiments) pro- ducing similar inhibition of mean LH, E but not T acted directly on the pituitary to diminish LH-RH responsiveness.As further support that androgens can act without conversion to estrogens, the effects of a nonaromatizable androgen, dihydrotestosterone (DHT), on mean LH levels were studied. DHT, infused at the same rate as T, suppressed mean LH to a similar but somewhat greater extent than T. Since T and E produced divergent effects on LH secretion and a nonaromatizable androgen, DHT, suppressed mean LH, aromatization is not a necessary prerequisite for the action of androgens on the hypothalamic-pituitary axis.

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Empty Sella Syndrome

Santen²

1975

Arch Intern Med

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Episodic Luteinizing Hormone Secretion in Man PULSE ANALYSIS, CLINICAL INTERPRETATION, PHYSIOLOGIC MECHANISMS

Cited by 708 publications

References 31 publications

The Importance of Autosomal Genes in Kallmann Syndrome: Genotype-Phenotype Correlations and Neuroendocrine Characteristics

The Importance of Autosomal Genes in Kallmann Syndrome: Genotype-Phenotype Correlations and Neuroendocrine Characteristics

Is Aromatization of Testosterone to Estradiol Required for Inhibition of Luteinizing Hormone Secretion in Men?

Empty Sella Syndrome

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