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A Window of Opportunity: The Diagnosis of Gonadotropin Deficiency in the Male Infant¹

Department of Pediatrics, University of California, San Francisco, San Francisco, California 94143-0434

Address all correspondence and requests for reprints to: Melvin M. Grumbach, Department of Pediatrics, S-672, University of California, San Francisco, San Francisco, California 94143-0434. E-mail: grumbac{at}itsa.ucsf.edu.

	Abstract

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A common cause of micropenis is congenital hypogonadotropic hypogonadism, whether isolated or associated with multiple pituitary hormone deficiencies. The postnatal surge in FSH, LH, and testosterone in the male infant as a consequence of the continued function of the fetal GnRH pulse generator provides a 6-month window of opportunity to establish the diagnosis of hypogonadotropic hypogonadism and alert the clinician to the possibility of its association with multiple pituitary hormone deficiencies. When ACTH or GH deficiency or both deficiencies are present, hypoglycemia and cortisol deficiency can lead to neonatal and infantile death or increased morbidity. Establishing the diagnosis of hypogonadotropic hypogonadism in infancy preempts the uncertainties and delays in distinguishing constitutional delay in puberty from hypogonadotropic hypogonadism. Accordingly, hormone replacement therapy can be initiated at the normal age of pubertal onset.

The ontogenesis of infantile testicular function, including the possible significance of the infantile surge in gonadotropins and testosterone, is reviewed. The molecular basis for certain developmental disorders associated with hypogonadotropic hypogonadism and micropenis is considered and the management and treatment of congenital hypopituitarism discussed.

	Introduction

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IN RECENT YEARS remarkable advances have occurred in the following areas:

1) In our knowledge of the complex developmental endocrinology and neuroendocrinology of the fetus and infant.

2) In new technology that has yielded dramatic advances in imaging techniques and new diagnostic modalities including more sensitive, specific immunoassays for gonadotropin, sex steroids, anti-Müllerian hormone/Müllerian inhibitory substance (AMH/MIS), and inhibin B (and A).

3) In the clinical diagnosis of isolated hypogonadotropic hypogonadism (IHH) including the recognition of its phenotypic and etiologic heterogeneity.

4) Continued progress in establishing a specific genetic etiology and molecular pathogenesis for this heterogeneous syndrome, IHH, and neonatal multiple pituitary hormone deficiencies, including critical insights gained from mouse models (targeted mutagenesis, expression of transgenes).

In childhood, FSH, LH, and sex steroid secretion, although present, are low. However, in boys there is a window of opportunity from birth to about 6 months of age (and in girls to 2 yr of age) to establish the diagnosis of hypogonadotropic hypogonadism (reviewed in Refs. 1 , 2).

In the human being, the fetal hypothalamic GnRH pulse generator has developed and is well functional by the end of the first trimester.

In childhood FSH, LH, and sex steroid secretion are low.

Plasma FSH and LH low in umbilical cord blood (inhibitory effect of high circulating placental derived estrogens on hypothalamus and pituitary gonadotropes). BUT

In the male infant: serum FSH, LH, and testosterone levels increase during second week, reach a maximum at 4–10 wks, and decline by about age 6 months to low levels.

In the female infant: increase in serum FSH and LH (and inconstantly E2) for 2–3 yrs.

Striking features of the ontogeny of the GnRH pulse generator (3) are: 1) its development and function in the fetus and the continued function of the oscillator in infancy, the developmental phase; 2) the gradual dampening of its activity during late infancy (earlier in boys than girls) leading to its virtual but not absolute quiescence during childhood and as a consequence the low secretion of FSH and LH by the pituitary gland and sex steroids by the gonads, the prepubertal juvenile pause; 3) the gradual disinhibition and reactivation of the GnRH pulse generator mainly at night during late childhood leading to the increased amplitude of the GnRH pulses, which are reflected in the progressively increased and changing pattern of circulating LH pulses with the approach of and during puberty, the pubertal phase, including the augmented plasma LH response to iv GnRH administration; and finally 4) the attainment of the adult or fully mature phase.

In both the male and female, the concentration of plasma FSH and LH is low in umbilical cord blood owing to the inhibitory effect of the high circulating levels of placenta-derived estrogens on both the GnRH pulse generator and pituitary gonadotropes (3, 4, 5). Within a few minutes after birth, in the male neonate, a brief surge in LH secretion (about 10-fold greater concentration than in cord blood) is followed by an increase in the serum concentration of testosterone, which persists for about 12 h (6, 7). In the female neonate, this increase in LH does not occur. FSH levels during the first neonatal days are low in both sexes. After the fall in circulating placentally derived steroids (especially estrogens) during the first few days after birth, the subsequent disinhibition of the neonatal GnRH pulse generator-pituitary gonadotropin apparatus leads to reactivation of the sex steroid inhibited pituitary gonadotropin-gonadal system at 1–2 wk of age (8); the increase in FSH and LH secretion evokes increased secretion of gonadal sex steroids (9).

This transient surge in the hypothalamic GnRH pulse generator-pituitary gonadotropin-gonadal apparatus, sometimes called the minipuberty of early infancy, is associated with a pubertal concentration of circulating LH (higher in the male) and FSH (higher in the female) in the male and female infant, but the amplitude and duration of this reactivation differ in the two sexes (see bulleted list on previous page). In the male infant, serum FSH and LH levels increase during the second postnatal week, reach a maximum at 4–10 wk and decline by about age 6 months to the low levels that are present until the onset of puberty. In the female, the increase in FSH and LH (and inconstantly estradiol) persists for 2–3 yr, but the values are highly variable and inconstant (10).

In the male infant, the concentration of serum testosterone follows the pattern of LH secretion, reaching a peak at about 3 months of age with a subsequent decline to prepubertal values by 6–9 months of age (3, 9, 10). Soon after birth Leydig cell numbers increase to reach a peak at about 3 months of age, followed by striking regression and apoptosis of the fetal (and infantile) Leydig cell (11, 12, 13). Inhibin B, a glycoprotein member of TGFß superfamily, is secreted by the Sertoli cells in prepubertal boys; it is an indicator of Sertoli cell function (but in prepubertal boys not germ cell function or number) and an important regulator of FSH secretion. Present in cord blood, circulating inhibin B increases soon after birth and reaching a peak at 4–12 months of age (to greater values than in the adult male), decreasing to a nadir from 3 to 9 yr of age and increasing again with the onset of puberty (10). Its profile reflects the continued wave of Sertoli cell proliferation (which begins in the fetus) during infancy, which continues at a low level during the juvenile pause and increases again with the onset of puberty and persists until late puberty when terminal differentiation of Sertoli cells occur (14). In hypogonadotropic hypogonadism, the plasma concentration of inhibin B remains low (15, 16).

AMH/MIS, the earliest Sertoli cell hormone secretion in the human fetus and like the inhibins, a glycoprotein member of the TGFß family, is present in cord blood from males but not females, rises rapidly in concentration in boys during the first month, reaching a peak level at about 6 months of age, and then slowly declines during childhood, falling to low levels in puberty (17, 18); the latter related to increased testosterone secretion. Its secretion is mainly constitutive.

Both inhibin B and AMH/MIS assays are useful for determining the presence and function of Sertoli cells in male infants and prepubertal boys. They replace the human chorionic gonadotropin (hCG) stimulation test in the group of initial laboratory tests used as a marker for the presence of testes in bilateral cryptorchidism. [In the rare persistent müllerian duct syndrome due to a mutation in the gene encoding AMH, AMH levels (but not inhibin B) are low despite intact testes.]

In sum, the neonatal-midinfancy surge in pulsatile gonadotropin secretion is attributable to an increase in GnRH pulse amplitude and is associated with the following:

Increase in testicular volume (by direct measurement) due to increase in seminiferous tubule length (6-fold increase in yr 1) (13, 19).

Rapid expansion of Sertoli cell population (makes up 85–95% of seminiferous tubular cell mass) (14).

High concentration of circulating inhibin B (low in hypogonadotropic hypogonadism).

Sertoli cell number, including postnatal proliferation, is a determinant of spermatogenic function (reviewed in Ref. 20).

The total number of germ cells increases up to about 100 d (21), indicating mitotic activity [and the transformation of gonocytes into Ad (dark) spermatogonia (the stem cell for spermatogenesis] and subsequently decreases mainly by apoptosis (22).

The suggestion is that the transient postnatal to midinfancy function of the GnRH pulse generator in the male infant is related to future spermatogenic function and fertility (20, 23, 24). The postnatal surge apparently is not essential for masculine-typical psychosexual development (25); the brain in congenital hypogonadotropic hypogonadism including Kallmann syndrome is masculinized by testosterone therapy at puberty despite the lack of an infantile surge in gonadotropins and testosterone. Of interest, an LH and testosterone surge is absent in the complete androgen insensitivity syndrome (26, 27). Parenthetically, in the McCune-Albright syndrome, an activating mutation in the Gs gene primarily expressed in the Sertoli cell can cause macroorchidism due to Sertoli cell proliferation and hyperfunction with increased concentration of serum inhibin B and AMH but without increased testosterone levels due to Leydig cell hyperplasia, elevated gonadotropins, or signs of puberty (28).

	Clinical Aspects

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A cardinal feature of IHH is the presence of a micropenis with or without associated cryptorchidism (25, 29) (cryptorchidism can be associated with either hypogonadotropic hypogonadism or hypergonadotropic hypogonadism). Micropenis is defined as a morphologically normal penis, with a penile urethra, the stretched length of which measured along the dorsal surface from pubis to tip of glans is more than –2.5 SD below the mean value for age: the mean value at birth is 3.5 ± 0.4 cm (SD). A stretched penile length of less than 2.5 cm in term infants is by definition a micropenis (see Ref. 25).

There are many causes of micropenis including hypogonadotropic hypogonadism, primary hypogonadism (hypergonadotropic forms), genetic defects in the LH receptor, testosterone biosynthesis or androgen action (these latter causes represent less severe mutations and loss of function than the severe or more complete forms of these genetically determined disorders), and structural anomalies, mainly developmental field defects (25).

The focus of this discussion is on hypogonadotropic hypogonadism in the male infant.

When presented with an infant with micropenis with or without cryptorchidism, it is essential to determine promptly whether the cause is isolated hypogonadotropic hypogonadism or hypogonadotropic hypogonadism associated with other pituitary hormone deficiencies (neonatal or congenital hypopituitarism). If the latter is associated with GH deficiency and/or ACTH deficiency as it commonly is, the infant is at high risk for death due to hypoglycemia or cortisol deficiency (29, 30, 31). Recurrent, severe, and persistent hypoglycemia and its manifestations (apneic spells, seizures, jitteriness, flaccidity, and temperature instability) may be due to either GH or ACTH deficiency or both deficiencies. Neonatal hypoglycemia occurred in virtually all [31 of 34 with congenital hypopituitarism (1) and 16 of 44 with septooptic dysplasia] full-term infants with neonatal hypopituitarism in our clinic.

A prompt diagnosis is critical to reduce morbidity and mortality and is greatly facilitated by the ready availability of determinations of plasma thyroxine or free thyroxine; plasma cortisol, serum electrolytes (and careful measurement of fluid intake and output to alert the physician to diabetes insipidus); serum-conjugated bilirubin; and, of course, plasma glucose. Simultaneously, a blood sample should be obtained for plasma GH, IGF binding protein-3 (32, 33), TSH, ACTH, prolactin (PRL), FSH, LH, testosterone, and inhibin B or AMH/MIS. The concentration of plasma PRL in the infant can distinguish between defects involving the hypothalamus from those at the level of the pituitary, e.g. pituitary aplasia or hypoplasia, Prophet of Pit-1 (PROP1), PIT1, or LIM class of homeodomain protein-3 (LHX3) mutations. Plasma PRL is high (150 ng/dl) in umbilical vein blood of normal newborns and remains relatively high for 2–3 months after birth. In infants with hypothalamic hypopituitarism (including anencephaly) in whom the normally inhibitory hypothalamic dopaminergic system is disrupted, plasma PRL is abnormally elevated and hyperresponsive to the iv administration of TRH. In contrast, in those primary pituitary abnormalities noted above, circulating PRL is low (1, 3, 29). In addition, the diagnosis is strongly supported by the presence of prolonged conjugated hyperbilirubinemia (29, 30, 34) owing to cholestasis and giant cell hepatitis (35); pendular nystagmus; breech delivery, especially in the male fetus, is more prevalent in hypothalamic hypopituitarism [but not in pituitary aplasia (36)]; perinatal hypoxia-ischemia; optic nerve hypoplasia; midline facial malformations such as cleft lip and/or palate; facial asymmetry; and evidence of excessive urination and dehydration consistent with central diabetes insipidus. In affected males, micropenis, a frequent clinical marker, facilitates the diagnosis. Growth retardation usually is not a major clinical feature for the first 2 months of life (31, 37, 38). Notably, congenital hypopituitarism when associated with fetal ACTH deficiency is a cause of low maternal serum and urine estriol values (39).

The infantile GnRH-gonadotropin spurt affords the clinician the opportunity to nail down the diagnosis of hypogonadotropic hypogonadism by using this brief window (see bulleted list on first page) of normally increased FSH, LH, testosterone, and inhibin B values to make the diagnosis. By establishing the diagnosis of hypogonadotropic hypogonadism in the male infant, the timing of hormone replacement therapy at the age of puberty can be optimized and the uncertainties and delay in making a definitive diagnosis avoided. This stands in sharp contrast to the possibility of a delay in final diagnosis of hypogonadotropic hypogonadism until the age of 20 yr, i.e., if the window of opportunity in infancy is missed.

The diagnosis of isolated hypogonadotropic hypogonadism in the male newborn (after excluding congenital hypopituitarism) raised by the presence of micropenis (with or without cryptorchidism) is supported by detecting low levels of plasma LH, FSH, testosterone, and inhibin B as well as the absence of, or very low, amplitude LH pulses. Furthermore, the iv administration of GnRH either fails to elicit an augmented LH response or results in a blunted rise in plasma LH (1, 3, 4, 29).

Cranial magnetic resonance imaging, with special attention to the hypothalamic pituitary region, is exceedingly useful for identifying the pituitary stalk dysplasia syndrome with or without an ectopic neurohypophysis or a posterior pituitary bright spot (absent in central diabetes insipidus), septooptic dysplasia and other midline defects, optic nerve hypoplasia, holoprosencephaly, and pituitary aplasia (reviewed in Refs. 1 , 40, 41, 42, 43, 44). With special coronal sections, the olfactory bulbs and sulci can be assessed to obtain evidence of aplasia or hypoplasia of the olfactory bulbs and sulci in infants and boys with isolated hypogonadotropic hypogonadism in whom Kallmann syndrome should be considered (45).

Genetic defects and hypogonadotropic hypogonadism in the infant

The detection of single-gene mutations that result in hypogonadotropic hypogonadism in the human being and mouse and the development of genetically engineered animal models have provided useful clinical insights and diagnostic applications and have given us extraordinary insight into the complexity of the developmental and molecular biology of the hypothalamus and pituitary gland (Table 1).

Our current knowledge of the genetics of hypogonadotropic hypogonadism can be conveniently separated into mutations associated with multiple pituitary hormone deficiencies, including gonadotropin deficiency (e.g. PROP1, HESX1, LHX3, PHF6) and isolated hypogonadotropic hypogonadism [e.g. KAL1, FGFR1 (KAL2), GNHR, GPR54 (KiSS1-derived peptide receptor), SNRPN (Prader-Willi), LEP, LEPR, DAX1] that can be associated with micropenis and evidence of hypogonadotropic hypogonadism in the male infant (Table 1).

Management and treatment

In infants with neonatal (congenital) hypopituitarism, after testing for pituitary hormone deficiencies, appropriate hormonal replacement therapy is initiated expeditiously (1, 29, 30, 40).

Infants with micropenis, whether owing to congenital hypopituitarism or isolated hypothalamic hypogonadism, require testosterone therapy to increase the length of the penis. Testosterone can be administered im, locally by a testosterone lotion, salve, or gel, transdermally by a testosterone patch or suppository.

We prefer to administer a long-acting testosterone ester (e.g. testosterone enanthate) im 25 mg every 4 wk for three doses. If a satisfactory increase in penile length (>0.9 cm) has not occurred by the end of the third month, another three-injection course can be given (25, 46). We have not found it necessary to repeat the treatment during infancy in hypogonadotropic hypogonadism. Intramuscular long-acting testosterone ester preparations provide a convenient, safe, reliable approach; compliance has been excellent.

Some clinicians have used injections of hCG; this approach requires more injections and is more costly. The penile growth 5 d after a 3-d course has been used mainly to assess androgen responsiveness.

Dihydrotestosterone preparations, either parenteral or local, have been used by some, but this steroid is not readily available, and it is more expensive. Because we are not dealing here with infants with 5-reductase-2 deficiency, dihydrotestosterone therapy is unnecessary.

It has been proposed that male infants with hypothalamic hypogonadism be given a course of recombinant human FSH and human LH (16). Even though FSH treatment can increase testicular size, presumably by increasing the number of Sertoli cells (as also reflected in an increase in plasma inhibin B levels), we lack evidence of the importance of this approach in ensuring future fertility. Recombinant human LH with its short half-life is less effective than hCG.

In summary, the detection of congenital hypopituitarism in the male or female neonate and infant and appropriate hormone replacement therapy reduces the risk of morbidity (29), especially involving the central nervous system (47) with consequent cognitive and neurodevelopmental disabilities, as well as the liver (35), can reduce mortality dramatically and ensure normal growth (48). In the affected male infant, the presence of micropenis is an important clinical sign of possible hypogonadotropic hypogonadism, either isolated or associated with multiple pituitary hormone deficiencies. Furthermore, the recognition of the cause of the micropenis, the normalization of penile size evoked by testosterone therapy in infancy, and the favorable prognosis for pubertal development and fertility with hormonal treatment are sources of relief and reassurance for the parents. Establishing the diagnosis of hypogonadotropic hypogonadism in the male infant greatly facilitates the initiation of hormone replacement therapy at the usual age of onset of puberty

	Footnotes

 
This work was supported by the National Center for Research Resources Grant 5 M01 RR-01271 from the U.S. Public Health Service.

These studies were carried out in part at the Pediatric Clinical Research Center, University of California, San Francisco.

First Published Online February 22, 2005

¹ In memory of Judson J. Van Wyk, pioneer pediatric endocrinologist, iconic mentor, inspiring pediatrician-scientist, and uncommonly faithful friend for more than half a century.

Abbreviations: AMH, Anti-Müllerian hormone; GPR54, G protein-coupled receptor 54; IHH, isolated hypogonadotropic hypogonadism; hCG, human chorionic gonadotropin; KAL, Kallmann syndrome; LHX3, LIM class of homeodomain protein-3; MIS, Müllerian inhibitory substance; PRL, prolactin; PROP1, Prophet of Pit-1.

Received December 15, 2004.

Accepted February 11, 2005.

	References

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1. Grumbach MM, Gluckman PD 1994 The human fetal hypothalamus and pituitary gland: the maturation of neuroendocrine mechanisms controlling the secretion of fetal pituitary growth hormone, prolactin, gonadotropin, adrenocorticotropin-related peptides, and thyrotropin. In: Tulchinsky D, Little AB, eds. Maternal-fetal endocrinology. 2nd ed. Philadelphia: WB Saunders; 193–261
2. Grumbach MM, Styne DM 2003 Puberty: ontogeny, neuroendocrinology, physiology, and disorders. In: Larsen PR, Kronenberg HM, Melmed S, Polonsky KS, eds. Williams textbook of endocrinology. 10th ed. Philadelphia: WB Saunders; 1115–1286
3. Grumbach MM, Kaplan SL 1990 The neuroendocrinology of human puberty: An ontogenetic perspective. In: Grumbach MM, Sizonenko PC, Aubert ML, eds. Control of the onset of puberty. Baltimore: Williams, Wilkins; 1–62
4. Kaplan SL, Grumbach MM, Aubert ML 1976 The ontogenesis of pituitary hormones and hypothalamic factors in the human fetus: maturation of central nervous system regulation of anterior pituitary function. In: Greep R, ed. Recent progress in hormone research. New York: Academic Press; 32:161–243
5. Massa G, de Zegher F, Vanderschueren-Lodeweyckx M 1992 Serum levels of immunoreactive inhibin, FSH, and LH in human infants at preterm and term birth. Biol Neonate 61:150–155[CrossRef][Medline]
6. Corbier P, Dehennin L, Castanier M, Mebazaa A, Edwards DA, Roffi J 1990 Sex differences in serum luteinizing hormone and testosterone in the human neonate during the first few hours after birth. J Clin Endocrinol Metab 71:1344–1348[Abstract]
7. de Zegher F, Devlieger H, Veldhuis JD 1992 Pulsatile and sexually dimorphic secretion of luteinizing hormone in the human infant on the day of birth. Pediatr Res 32:605–607[Medline]
8. Schmidt H, Schwarz HP 2000 Serum concentrations of LH and FSH in the healthy newborn. Eur J Endocrinol 143:213–215[Abstract]
9. Forest MG 1990 Pituitary gonadotropins and sex steroid secretion during the first two years of life. In: Grumbach MM, Sizonenko PC, Aubert ML, eds. Control of the onset of puberty. Baltimore: Williams and Wilkins; 451–477
10. Andersson AM, Toppari J, Haavisto AM, Petersen JH, Simell T, Simell O, Skakkebaek NE 1998 Longitudinal reproductive hormone profiles in infants: peak of inhibin B levels in infant boys exceeds levels in adult men. J Clin Endocrinol Metab 83:675–681[Abstract/Free Full Text]
11. Nistal M, Paniagua R, Regadera J, Santamaria L, Amat P 1986 A quantitative morphological study of human Leydig cells from birth to adulthood. Cell Tissue Res 246:229–236[CrossRef][Medline]
12. Lejeune H, Habert R, Saez JM 1998 Origin, proliferation and differentiation of Leydig cells. J Mol Endocrinol 20:1–25[CrossRef][Medline]
13. Chemes HE 2001 Infancy is not a quiescent period of testicular development. Int J Androl 24:2–7[CrossRef][Medline]
14. Cortes D, Müller J, Skakkebaek NE 1987 Proliferation of Sertoli cells during development of the human testis assessed by stereological methods. Int J Androl 10:589–596[Medline]
15. Nachtigall LB, Boepple PA, Seminara SB, Khoury RH, Sluss PM, Lecain AE, Crowley Jr WF 1996 Inhibin B secretion in males with gonadotropin-releasing hormone (GnRH) deficiency before and during long-term GnRH replacement: relationship to spontaneous puberty, testicular volume, and prior treatment—a clinical research center study. J Clin Endocrinol Metab 81:3520–3525[Abstract]
16. Main KM, Schmidt IM, Toppari J, Skakkebaek NE 2002 Early postnatal treatment of hypogonadotropic hypogonadism with recombinant human FSH and LH. Eur J Endocrinol 146:75–79[Abstract]
17. Rey RA, Belville C, Nihoul-Fékéte C, Michel-Calemard L, Forest MG, Lahlou N, Jaubert F, Mowszowicz I, David M, Saka N, Bouvattier C, Bertrand AM, Lecointre C, Soskin S, Cabrol S, Crosnier H, Leger J, Lortat-Jacob S, Nicolino M, Rabl W, Toledo SP, Bas F, Gompel A, Czernichow P, Josso N, et al 1999 Evaluation of gonadal function in 107 intersex patients by means of serum antimullerian hormone measurement. J Clin Endocrinol Metab 84:627–631[Abstract/Free Full Text]
18. Lee MM, Misra M, Donahoe PK, MacLaughlin DT 2003 MIS/AMH in the assessment of cryptorchidism and intersex conditions. Mol Cell Endocrinol 211:91–98[CrossRef][Medline]
19. Müller J, Skakkebaek NE 1983 Quantification of germ cells and seminiferous tubules by stereological examination of testicles from 50 boys who suffered from sudden death. Int J Androl 6:143–156[Medline]
20. Sharpe RM, McKinnell C, Kivlin C, Fisher JS 2003 Proliferation and functional maturation of Sertoli cells, and their relevance to disorders of testis function in adulthood. Reproduction 125:769–784[Abstract]
21. Müller J, Skakkebaek NE 1984 Fluctuations in the number of germ cells during the late foetal and early postnatal periods in boys. Acta Endocrinol (Copenh) 105:271–274[Medline]
22. Berensztein EB, Sciara MI, Rivarola MA, Belgorosky A 2002 Apoptosis and proliferation of human testicular somatic and germ cells during prepuberty: high rate of testicular growth in newborns mediated by decreased apoptosis. J Clin Endocrinol Metab 87:5113–5118[Abstract/Free Full Text]
23. Pitteloud N, Hayes FJ, Dwyer A, Boepple PA, Lee H, Crowley Jr WF 2002 Predictors of outcome of long-term GnRH therapy in men with idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab 87:4128–4136[Abstract/Free Full Text]
24. Sharpe RM, Fraser HM, Brougham MF, McKinnell C, Morris KD, Kelnar CJ, Wallace WH, Walker M 2003 Role of the neonatal period of pituitary-testicular activity in germ cell proliferation and differentiation in the primate testis. Hum Reprod 18:2110–2117[Abstract/Free Full Text]
25. Bin-Abbas B, Conte FA, Grumbach MM, Kaplan SL 1999 Congenital hypogonadotropic hypogonadism and micropenis: effect of testosterone treatment on adult penile size. Why sex reversal is not indicated. J Pediatr 134:579–583[CrossRef][Medline]
26. Bouvattier C, Carel JC, Lecointre C, David A, Sultan C, Bertrand AM, Morel Y, Chaussain JL 2002 Postnatal changes of T, LH, and FSH in 46,XY infants with mutations in the AR gene. J Clin Endocrinol Metab 87:29–32[Abstract/Free Full Text]
27. Quigley CA 2002 The postnatal gonadotropin and sex steroid surge-insights from the androgen insensitivity syndrome. J Clin Endocrinol Metab 87:24–28 (Editorial)[Abstract/Free Full Text]
28. Coutant R, Lumbroso S, Rey R, Lahlou N, Venara M, Rouleau S, Sultan C, Limal JM 2001 Macroorchidism due to autonomous hyperfunction of Sertoli cells and G(s) gene mutation: an unusual expression of McCune-Albright syndrome in a prepubertal boy. J Clin Endocrinol Metab 86:1778–1781[Abstract/Free Full Text]
29. Lovinger RD, Kaplan SL, Grumbach MM 1975 Congenital hypopituitarism associated with neonatal hypoglycemia and microphallus: four cases secondary to hypothalamic hormone deficiencies. J Pediatr 87:1171–1181[CrossRef][Medline]
30. Kaplan SL, Grumbach MM 1980 Pathophysiology of GH deficiency and other disorders of GH metabolism. In: La Cauza C, Root AW, eds. Problems in pediatric endocrinology, Serono Symposia. Vol 32. London: Academic Press; 45–55
31. Goodman HG, Grumbach MM, Kaplan SL 1968 Growth and growth hormone. II. A comparison of isolated growth-hormone deficiency and multiple pituitary-hormone deficiencies in 35 patients with idiopathic hypopituitary dwarfism. N Engl J Med 278:57–68
32. Giudice LC, de Zegher F, Gargosky SE, Dsupin BA, de las Fuentes L, Crystal RA, Hintz RL, Rosenfeld RG 1995 Insulin-like growth factors and their binding proteins in the term and preterm human fetus and neonate with normal and extremes of intrauterine growth. J Clin Endocrinol Metab 80:1548–1555[Abstract/Free Full Text]
33. Bhala A, Harris MC, Zirin S, Corcoran L, Cohen P 1998 Insulin-like growth factor axis parameters in sick hospitalized neonates. J Pediatr Endocrinol Metab 11:451–459[Medline]
34. Kaufman FR, Costin G, Thomas DW, Sinatra FR, Roe TF, Neustein HB 1984 Neonatal cholestasis and hypopituitarism. Arch Dis Child 59:787–789[Abstract]
35. Spray CH, Mckiernan P, Waldron KE, Shaw N, Kirk J, Kelly DA 2000 Investigation and outcome of neonatal hepatitis in infants with hypopituitarism. Acta Paediatr 89:951–954[Medline]
36. de Zegher F, Kaplan SL, Grumbach MM, Van den Berghe G, Francois I, Vanhole C, Devlieger H 1995 The foetal pituitary, postmaturity and breech presentation. Acta Paediatr 84:1100–1102[Medline]
37. Wit JM, van Unen H 1992 Growth of infants with neonatal growth hormone deficiency. Arch Dis Child 67:920–924[Abstract]
38. Pena-Almazan S, Buchlis J, Miller S, Shine B, MacGillivray M 2001 Linear growth characteristics of congenitally GH-deficient infants from birth to one year of age. J Clin Endocrinol Metab 86:5691–5694[Abstract/Free Full Text]
39. Malpuech G, Vanlieferinghen P, Dechelotte P, Gaulme J, Labbe A, Guiot F 1988 Isolated familial adrenocorticotropin deficiency: prenatal diagnosis by maternal plasma estriol assay. Am J Med Genet 29:125–130[CrossRef][Medline]
40. Reiter EO, Rosenfeld RG 2003 Normal and aberrant growth. In: Larsen PR, Kronenberg HM, Melmed S, Polonsky KS, eds. Williams textbook of endocrinology, 10th ed. Philadelphia: WB Saunders; 1003–1114
41. Maghnie M, Salati B, Bianchi S, Rallo M, Tinelli C, Autelli M, Aimaretti G, Ghigo E 2001 Relationship between the morphological evaluation of the pituitary and the growth hormone (GH) response to GH-releasing hormone plus arginine in children and adults with congenital hypopituitarism. J Clin Endocrinol Metab 86:1574–1579[Abstract/Free Full Text]
42. Maghnie M, Ghirardello S, Genovese E 2004 Magnetic resonance imaging of the hypothalamus-pituitary unit in children suspected of hypopituitarism: who, how and when to investigate. J Endocrinol Invest 27:496–509[Medline]
43. Birkebaek NH, Patel L, Wright NB, Grigg JR, Sinha S, Hall CM, Price DA, Lloyd IC, Clayton PE 2003 Endocrine status in patients with optic nerve hypoplasia: relationship to midline central nervous system abnormalities and appearance of the hypothalamic-pituitary axis on magnetic resonance imaging. J Clin Endocrinol Metab 88:5281–5286[Abstract/Free Full Text]
44. Osorio MG, Marui S, Jorge AA, Latronico AC, Lo LS, Leite CC, Estefan V, Mendonca BB, Arnhold IJ 2002 Pituitary magnetic resonance imaging and function in patients with growth hormone deficiency with and without mutations in GHRH-R, GH-1, or PROP-1 genes. J Clin Endocrinol Metab 87:5076–5084[Abstract/Free Full Text]
45. Truwit CL, Barkovich AJ, Grumbach MM, Martini JJ 1993 MR imaging of Kallmann syndrome, a genetic disorder of neuronal migration affecting the olfactory and genital systems. Am J Neuroradiol 14:827–838[Abstract]
46. Burstein S, Grumbach MM, Kaplan SL 1979 Early determination of androgen-responsiveness is important in the management of microphallus. Lancet 2:983–986[Medline]
47. Brown K, Rodgers J, Johnstone H, Adams W, Clarke M, Gibson M, Cheetham T 2004 Abnormal cognitive function in treated congenital hypopituitarism. Arch Dis Child 89:827–830[Abstract/Free Full Text]
48. Grumbach MM, Bin-Abbas BS, Kaplan SL 1998 The growth hormone cascade: progress and long-term results of growth hormone treatment in growth hormone deficiency. Horm Res 49(Suppl 2):41–57
49. Mody S, Brown MR, Parks JS 2002 The spectrum of hypopituitarism caused by PROP1 mutations. Best Pract Res Clin Endocrinol Metab 16:421–431[CrossRef][Medline]
50. Dattani MT, Robinson IC 2002 HESX1 and septo-optic dysplasia. Rev Endocr Metab Disord 3:289–300[CrossRef][Medline]
51. Tajima T, Hattorri T, Nakajima T, Okuhara K, Sato K, Abe S, Nakae J, Fujieda K 2003 Sporadic heterozygous frameshift mutation of HESX1 causing pituitary and optic nerve hypoplasia and combined pituitary hormone deficiency in a Japanese patient. J Clin Endocrinol Metab 88:45–50[Abstract/Free Full Text]
52. Netchine I, Sobrier ML, Krude H, Schnabel D, Maghnie M, Marcos E, Duriez B, Cacheux V, Moers A, Goossens M, Gruters A, Amselem S 2000 Mutations in LHX3 result in a new syndrome revealed by combined pituitary hormone deficiency. Nat Genet 25:182–186[CrossRef][Medline]
53. Lower KM, Turner G, Kerr BA, Mathews KD, Shaw MA, Gedeon AK, Schelley S, Hoyme HE, White SM, Delatycki MB, Lampe AK, Clayton-Smith J, Stewart H, van Ravenswaay CM, de Vries BB, Cox B, Grompe M, Ross S, Thomas P, Mulley JC, Gecz J 2002 Mutations in PHF6 are associated with Borjeson-Forssman-Lehmann syndrome. Nat Genet 32:661–665[CrossRef][Medline]
54. Franco B, Guioli S, Pragliola A, Incerti B, Bardoni B, Tonlorenzi R, Carrozzo R, Maestrini E, Pieretti M, Taillon-Miller P, et al 1991 A gene deleted in Kallmann‘s syndrome shares homology with neural cell adhesion and axonal path-finding molecules. Nature 353:529–536[CrossRef][Medline]
55. Seminara SB, Hayes FJ, Crowley Jr WF 1998 Gonadotropin-releasing hormone deficiency in the human (idiopathic hypogonadotropic hypogonadism and Kallmann’s syndrome): pathophysiological and genetic considerations. Endocr Rev 19:521–539[Abstract/Free Full Text]
56. Hardelin JP, Julliard AK, Moniot B, Soussi-Yanicostas N, Verney C, Schwanzel-Fukuda M, Ayer-Le Lievre C, Petit C 1999 Anosmin-1 is a regionally restricted component of basement membranes and interstitial matrices during organogenesis: implications for the developmental anomalies of X chromosome-linked Kallmann syndrome. Dev Dyn 215:26–44[CrossRef][Medline]
57. Dode C, Levilliers J, Dupont JM, De Paepe A, Le Du N, Soussi-Yanicostas N, Coimbra RS, Delmaghani S, Compain-Nouaille S, Baverel F, Pecheux C, Le Tessier D, Cruaud C, Delpech M, Speleman F, Vermeulen S, Amalfitano A, Bachelot Y, Bouchard P, Cabrol S, Carel JC, Delemarre-van de Waal H, Goulet-Salmon B, Kottler ML, Richard O, Sanchez-Franco F, Saura R, Young J, Petit C, Hardelin JP 2003 Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome. Nat Genet 33:463–465[CrossRef][Medline]
58. Sato N, Katsumata N, Kagami M, Hasegawa T, Hori N, Kawakita S, Minowada S, Shimotsuka A, Shishiba Y, Yokozawa M, Yasuda T, Nagasaki K, Hasegawa D, Hasegawa Y, Tachibana K, Naiki Y, Horikawa R, Tanaka T, Ogata T 2004 Clinical assessment and mutation analysis of Kallmann syndrome 1 (KAL1) and fibroblast growth factor receptor 1 (FGFR1, or KAL2) in five families and 18 sporadic patients. J Clin Endocrinol Metab 89:1079–1088[Abstract/Free Full Text]
59. de Roux N, Young J, Misrahi M, Genet R, Chanson P, Schaison G, Milgrom E 1997 A family with hypogonadotropic hypogonadism and mutations in the gonadotropin-releasing hormone receptor. N Engl J Med 337:1597–1602[Free Full Text]
60. Layman LC, Cohen DP, Jin M, Xie J, Li Z, Reindollar RH, Bolbolan S, Bick DP, Sherins RR, Duck LW, Musgrove LC, Sellers JC, Neill JD 1998 Mutations in gonadotropin-releasing hormone receptor gene cause hypogonadotropic hypogonadism. Nat Genet 18:14–15[CrossRef][Medline]
61. Caron P, Chauvin S, Christin-Maitre S, Bennet A, Lahlou N, Counis R, Bouchard P, Kottler ML 1999 Resistance of hypogonadic patients with mutated GnRH receptor genes to pulsatile GnRH administration. J Clin Endocrinol Metab 84:990–996[Abstract/Free Full Text]
62. Millar RP, Lu ZL, Pawson AJ, Flanagan CA, Morgan K, Maudsley SR 2004 Gonadotropin-releasing hormone receptors. Endocr Rev 25:235–275[Abstract/Free Full Text]
63. de Roux N, Genin E, Carel JC, Matsuda F, Chaussain JL, Milgrom E 2003 Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci USA 100:10972–10976[Abstract/Free Full Text]
64. Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno Jr JS, Shagoury JK, Bo-Abbas Y, Kuohung W, Schwinof KM, Hendrick AG, Zahn D, Dixon J, Kaiser UB, Slaugenhaupt SA, Gusella JF, O’Rahilly S, Carlton MB, Crowley Jr WF, Aparicio SA, Colledge WH 2003 The GPR54 gene as a regulator of puberty. N Engl J Med 349:1614–1627[Abstract/Free Full Text]
65. Nicholls RD, Knepper JL 2001 Genome organization, function, and imprinting in Prader-Willi and Angelman syndromes. Annu Rev Genomics Hum Genet 2:153–175[CrossRef][Medline]
66. Ozcelik T, Leff S, Robinson W, Donlon T, Lalande M, Sanjines E, Schinzel A, Francke U 1992 Small nuclear ribonucleoprotein polypeptide N (SNRPN), an expressed gene in the Prader-Willi syndrome critical region. Nat Genet 2:265–269[CrossRef][Medline]
67. Buiting K, Gross S, Lich C, Gillessen-Kaesbach G, el-Maarri O, Horsthemke B 2003 Epimutations in Prader-Willi and Angelman syndromes: a molecular study of 136 patients with an imprinting defect. Am J Hum Genet 72:571–577[CrossRef][Medline]
68. Goldstone AP 2004 Prader-Willi syndrome: advances in genetics, pathophysiology and treatment. Trends Endocrinol Metab 15:12–20[CrossRef][Medline]
69. Montague CT, Farooqi IS, Whitehead JP, Soos MA, Rau H, Wareham NJ, Sewter CP, Digby JE, Mohammed SN, Hurst JA, Cheetham CH, Earley AR, Barnett AH, Prins JB, O’Rahilly S 1997 Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 387:903–908[CrossRef][Medline]
70. Ozata M, Ozdemir IC, Licinio J 1999 Human leptin deficiency caused by a missense mutation: multiple endocrine defects, decreased sympathetic tone, and immune system dysfunction indicate new targets for leptin action, greater central than peripheral resistance to the effects of leptin, and spontaneous correction of leptin-mediated defects. J Clin Endocrinol Metab 84:3686–3695; erratum in: J Clin Endocrinol Metab 2000;85:416[Abstract/Free Full Text]
71. Farooqi IS, O’Rahilly S 2004 Monogenic human obesity syndromes. Recent Prog Horm Res 59:409–424[Abstract/Free Full Text]
72. Clement K, Vaisse C, Lahlou N, Cabrol S, Pelloux V, Cassuto D, Gourmelen M, Dina C, Chambaz J, Lacorte JM, Basdevant A, Bougneres P, Lebouc Y, Froguel P, Guy-Grand B 1998 A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 392:398–401[CrossRef][Medline]
73. Zanaria E, Muscatelli F, Bardoni B, Strom TM, Guioli S, Guo W, Lalli E, Moser C, Walker AP, McCabe ER, et al 1994 An unusual member of the nuclear hormone receptor superfamily responsible for X-linked adrenal hypoplasia congenita. Nature 372:635–641[CrossRef][Medline]
74. Muscatelli F, Strom TM, Walker AP, Zanaria E, Recan D, Meindl A, Bardoni B, Guioli S, Zehetner G, Rabl W, et al 1994 Mutations in the DAX-1 gene give rise to both X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism. Nature 372:672–676[CrossRef][Medline]
75. Achermann JC, Meeks JJ, Jameson JL 2001 Phenotypic spectrum of mutations in DAX-1 and SF-1. Mol Cell Endocrinol 185:17–25[CrossRef][Medline]

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