Reversible Isolated Hypogonadotropic Hypogonadism due to ...

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Reversible Isolated Hypogonadotropic Hypogonadism due to Mutations in the Neurokinin B Regulation of Gonadotropin-Releasing Hormone Release Allen W. Root Division of Pediatric Endocrinology, Diabetes and Metabolism, University of South Florida College of Medicine, Tampa, Florida 33612; and All Children’s Hospital, St. Petersburg, Florida 33701

n this commentary, congenital isolated hypogonadotropic hypogonadism (IHH) is defined as absent, incomplete, or arrested isosexual development when both chronological and bone ages are at least 18 yr, together with low concentrations of gonadotropins and sex hormones in the absence of systemic disease, syndromic malformations, nutritional deprivation, and other functional or anatomic pituitary abnormalities. To date, the identified forms of IHH are primarily due to inactivating mutations in the genes whose products control: 1) the differentiation and development (NROB1 or DAX1, CHD7, FGFR1, FGF8); 2) the subsequent migration of neurons that synthesize and secrete GnRH from their embryological site of origin in the nasal (olfactory) placode to their network in the hypothalamic arcuate nucleus (infundibulum); 3) the synthesis, release, and action of GnRH; and 4) the synthesis and secretion of the gonadotropins (LH, FSH) (Table 1) (1, 2). The migration of GnRH-synthesizing nerve cells requires the coordinated activity of the products encoded by KAL1, FGFR1, FGF8, NELF, PROK2, PROKR2, and likely many other factors yet to be identified. Inasmuch as loss-of-function mutations in these genes are often associated with abnormalities of olfaction (anosmia, hyposmia), they constitute the defined forms of Kallmann syndrome. Disrupted expression of factors (LEP, LEPR, KISS1R) that regulate the synthesis of GnRH (GNRH1), its storage in the median eminence, its release into the hypophyseal-portal vasculature, its action upon the pituitary gonadotrope (GHAHR), or the expression and synthesis of the gonadotropins (LH␤, FSH␤, PCSK1) themselves also leads to IHH (3). To the list of modulators of GnRH synthesis and secretion have recently been added the products of TAC3

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(tachykinin 3 or neurokinin B) and TACR3 (the G proteincoupled receptor for tachykinin 3) (4, 5). Gianetti et al. (6) have now genotyped TAC3 and TACR3 in 345 patients (247 males) with IHH and have identified both nonsense and missense nonsynonymous and synonymous mutations in TACR3 in 19 patients (four females) (5.5%) as well as a frameshift mutation in TAC3 in one woman (0.3%). In nine subjects, the TACR3 mutation was biallelic and in eight of nine homozygotic, whereas in 10 patients the mutations in TACR3 were monoallelic. Both recessive and dominant modes of IHH transmission were present in patients with mutations in TACR3. Patients with heterozygous mutations in TACR3 were clinically similar to the subjects with homozygous mutations. In none of the patients with heterozygous mutations in TACR3 were mutations in other examined IHH genes identified, suggesting that digenic transmission of IHH was less likely in these subjects (7). Functional characterization of several of the missense mutations in TACR3 revealed that the DNA base changes inactivated the product except for two monoallelic mutations (Gly18Asp and Ile249Val) in which in vitro bioactivity was normal, leaving unexplained the mechanism by which these mutations resulted in IHH in their carriers. Clinically, 14 of 15 males with IHH due to mutations in TACR3 had phallic lengths that were less than 10.5 cm and were classified as micropenis. As anticipated, at diagnosis of IHH, most affected males had very small testes, but in some patients testicular volumes were a bit larger than prepubertal, a size increase attributable to endogenous mechanisms. After discontinuation of sex hormone replacement therapy, testicular volume and/or gonadotropin and/or testosterone secretion increased spontaneously in five males, two of whom reported

ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2010 by The Endocrine Society doi: 10.1210/jc.2010-0733 Received March 26, 2010. Accepted April 21, 2010.

Abbreviations: CDGD, Constitutional delay in growth and sexual development; IHH, isolated hypogonadotropic hypogonadism.

For article see page 2857

J Clin Endocrinol Metab, June 2010, 95(6):2625–2629

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Vide supra Nasal embryonic LHRH factor neurons and axonal outgrowth

FGF8 NELF

KISS1 receptor

Prokineticin 2

PROK2

Transmits kisspeptin signals to release GnRH, expressed on cell bodies and axons of GnRH neurons

Guidance factor for olfactory & GnRH neurons & axonal outgrowth

Chemoattractant for neuronal progenitors; transmits signals from suprachiasmatic circadian clock

Transmits PROK2 signals

Extracellular matrix component that promotes neuronal branching and guides migration of GnRH and olfactory neurons

Growth factor essential for differentiation and migration of olfactory & GnRH neurons

Hypogonadotropism (AR)

19p13.3

9q34.3

3p21.1

*Kallmann 4 (AD, AR)

Kallmann syndrome (Digenic)

20p13

Xp22.3

10q24

604161

608137

607002

244200

308700

600483

136350

608892

300473

OMIM

(Continued)

8p11.2-p11.1

8q12.1

Xp21.3-p21.2

Chromosome locus

*Kallmann 3 (AD, AR, digenic) (reversible)

*Kallmann 1 (XL) - hypogonadotropism, hyposmia/anosmia, midline cranial anomalies, unilateral renal agenesis, synkinesia; (reversible)

Adrenal failure, hypogonadotropism in males *Kallmann 5 (AD) - allelic variation of CHARGE association (coloboma, choanal atresia, cleft lip. . .) *Kallmann 2 (AD, digenic ) - variable severity of hypogonadotropism, cleft lip or palate, synkinesia; (reversible) *Kallmann 6 (AD, AR, digenic) - cleft lip or palate, synkinesia

Phenotype

Reversible Hypogonadotropism and Neurokinin B

Impaired regulation of GnRH synthesis and secretion KISS1R

Vide supra Prokineticin-2 receptor

FGFR1 PROKR2

Anosmin-1

Fibroblast growth factor 8

FGF8

Impaired migration of GnRH synthesizing neurons KAL1

Fibroblast growth factor receptor-1

Orphan nuclear receptor; inhibitor of transcription Essential for DNA unwinding & genesis of olfactory & GnRH neurons Transmits FGF8 signals

Dosage-sensitive sex reversal-adrenal hypoplasia congenita (DAX1) Chromodomain helicase DNA-binding protein-7

FGFR1

Function

Product

Root

CHD7

Gene Impaired development of GnRH synthesizing neurons NR0B1

TABLE 1. Genetic bases of congenital IHH

2626 J Clin Endocrinol Metab, June 2010, 95(6):2625–2629

Receptor for TAC3

TACR3

Proprotein convertase subtilisin/ kexin-type 1

PCSK1

Essential for ovarian follicle formation, testicular Sertoli cell proliferation, spermatogenesis Serine endoprotease

Stimulates Leydig cell synthesis & secretion of testosterone

Stimulates secretion of pituitary LH & FSH Receptor for GnRH

Transmits signals of neurokinin B, expressed on axons of GnRH neurons

Function Regulates food intake & energy expenditure Transmits leptin satiety signals Stimulates GnRH release

XL - X-linked transmission, AD - Autosomal dominant transmission, AR - Autosomal recessive transmission.

* Kallmann syndrome - Hypogonadotropism and hyposmia or anosmia.

␤-subunit of FSH

␤-subunit of LH

GnRH receptor

FSH␤

Impaired synthesis of the gonadotropins LH␤

GNRHR

Gonadotropin releasing hormone

Leptin receptor Neurokinin B

LEPR TAC3

Impaired synthesis and action of GnRH GNRH1

Leptin

Product

LEP

Gene

TABLE 1. Continued

Hypogonadism (AR) - obesity, variably impaired processing of several prohormones including those of LH & FSH as well as proinsulin & proopiomelanocortin, hormone levels either low or immunologically measurable with low bioactivity

Hypogonadism (AR) - heterozygous males may be infertile, heterozygous females may be normal, LH levels either low or immunologically measurable with low bioactivity Hypogonadotropism (AR) FSH levels low by immunoassay & bioassay

Hypogonadotropism (AR, digenic) fertile eunuch syndrome (reversible)

Hypogonadotropism (AR)

Obesity, hypogonadotropism (AR) Hypogonadotropism (AD, AR) (reversible) Hypogonadotropism (AD, AR) (reversible)

Phenotype Obesity, hypogonadotropism (AR)

136530

162150

15q15-q21

152780

138850

152760

162332

601007 162330

OMIM 164160

11p13

19q13.32

4q21.2

8p21-p11.2

4q25

1p31 12q13-q21

Chromosome locus 7q31.2

J Clin Endocrinol Metab, June 2010, 95(6):2625–2629 jcem.endojournals.org 2627

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Reversible Hypogonadotropism and Neurokinin B

fertility. Each of the four women with mutations in TACR3 recovered reproductive function when estrogens were discontinued, but none conceived. In the pedigrees of patients with IHH due to mutations in TACR3 were family members with histories of constitutional delay in growth and sexual development (CDGD). In the one woman with IHH attributed to a mutation in TAC3 as well as in three of her similarly affected sisters, reproductive function recovered spontaneously after discontinuing estrogen therapy, and two even conceived. In this family, one of the affected sisters reportedly was anosmic. Gianetti et al. (6) concluded that loss-of-function mutations in TAC3/TACR3 impaired maturation of the hypothalamic-pituitary-gonadal axis in utero and during adolescence, but that reproductive function might recover in some older subjects. Tachykinins are neuropeptides that serve as neurotransmitters/neuromodulators in the central and peripheral nervous systems and are also present in nonneuronal cells (e.g. endothelial, Leydig, immune, and genitourinary cells) (8). They share the common carboxyl-terminal sequence -Phe-X-Gly-Leu-Met-NH2; the amino-terminal sequence of amino acids determines receptor specificity of the tachykinins. There are six mammalian tachykinins, four of which are derived by alternative splicing of TAC1 (chromosome 7q21-q22; OMIM 162320): tachykinin 1 (substance P), neurokinin A (substance K), neuropeptide K, and neuropeptide ␥. The latter two peptides serve as neurotransmitters as well as precursors for neurokinin A. Neurokinin B is encoded by TAC3, and hemokinin-1 is encoded by TAC4 (chromosome 17q21; OMIM 607833). Neurokinin B is a decapeptide derived from a 121-amino acid precursor protein (preprotachykinin-B) that is expressed in the central nervous system, spinal cord, uterus, and placenta. There are three tachykinin G protein-coupled receptors that signal through the phosphoinositide and MAPK pathways and are encoded by TACR1 (chromosome 2p11; OMIM 162323), TACR2 (chromosome 10q11-q21; OMIM 162321), and TACR3. Although substance P, neurokinin A, and neurokinin B are recognized by each of the tachykinin receptors, TACR1 preferentially binds substance P, TACR2 primarily binds neurokinin A but also recognizes neuropeptide K and neuropeptide ␥, and TACR3 binds most avidly to neurokinin B. TACR3 is expressed in the central nervous system, placenta, uterus, skeletal muscle, lung, liver, and intestinal tract. In the rat, Tacr3 is also expressed in portal and mesenteric veins. Substance P is essential for recognition of pain (nociception) and initiation of the inflammatory response that leads to wound healing (8). Neurokinin B may be of pathophysiological significance in preeclampsia. It has been suggested that neurokinin B and TACR3 may be components of a system that regulates gonadotropin secretion because


the expression of the genes encoding both peptides is down-regulated by estrogen (8, 9). In addition to other sites within the central nervous system, neurokinin B is synthesized by a subset of infundibular (arcuate nucleus) neurons distinct from those that generate GnRH (10). These neurons also express genes encoding estrogen receptor ␣, kisspeptin, and dynorphin (an inhibitor of GnRH release) as well as TACR3 (11, 12). Axons from neurokinin B-synthesizing neurons are intermingled and juxtaposed to GnRH-transporting nerve fibers in the median eminence, and these GnRH fibers express TACR3, suggesting that neurokinin B may influence GnRH release into the pituitary portal vascular system by nonsynaptic transmission (10, 13). Kisspeptin regulates the secretion of GnRH by signaling through its G protein-coupled receptor, KISS1R, expressed on the membrane of GnRH-synthesizing neuronal cells (11). Interestingly, in the median eminence, axons expressing Kiss1 also contact GnRHcontaining fibers, and in vitro kisspeptin directly releases GnRH from explants of the medial basal hypothalamus of wild-type but not of Kiss1r null mice (14). Neurokinin B might modulate not only the release of GnRH but also the synthesis and/or release of kisspeptin in the arcuate nucleus through an autocrine, paracrine, or intracrine mechanism. Functionally, estrogen receptor ␣, neurokinin B, and kisspeptin appear to form an interactive unit that regulates the pulsatile secretion of GnRH and secondarily that of the gonadotropins, perhaps directs the pace of pubertal progression, and mediates the negative feedback effects of estrogen (11). The fact that inactivation of the TAC3/TACR3 pathway impedes sexual maturation demonstrates its critical importance for this process. The fact that the obstruction to pubertal progression due to impaired function of the TAC3/TACR3 unit is reversible in some patients suggests that a secondary track (perhaps through an alternative tachykinin or tachykinin receptor) that circumvents this barrier may develop and demonstrates the operational versatility and plasticity of the reproductive endocrine system. Usually, IHH is an irreversible and lifelong situation. However, spontaneous recovery has been reported in patients with IHH, primarily in males. Raivio et al. (15) described 15 men with IHH, four of whom had anosmia (Kallmann syndrome), in whom spontaneous activation of the reproductive endocrine system occurred after discontinuation of hormone replacement therapy. One of 13 men studied had a loss-of-function mutation in GNRHR, and two had inactivating mutations in FGFR1; in this study, no patients were found with mutations in the other genes analyzed (KAL1, KISS1R). However, patients with reversible IHH due to mutations in KAL1 or PROK2R have been reported (16, 17). To this list of genes associated


with reversible IHH can now be added TACR3 and TAC3, and in patients with either defect, reversibility of IHH can occur not only in males with IHH but also in affected females. Testicular enlargement during androgen administration is a subtle biomarker of activation of endogenous hypothalamic-pituitary-gonadal function in men with IHH, as it is in boys with CDGD during short-term treatment with testosterone (15, 18). In the families of many patients with IHH are subjects with CDGD—the two entities being differentiated clinically by the absence of micropenis and cryptorchidism (in males) and by endogenous initiation of sexual maturation by age 18 yr in the latter group. The co-occurrence of CDGD and IHH in the same pedigree and at times with the same genetic mutation (e.g. KAL1, FGFR1, TACR3) suggests that these aberrations of pubertal timing are varying clinical manifestations of a broad phenotypic expression of disordered regulation of GnRH pulse generation that might be circumvented by treatment with androgen or estrogen (15, 19). In patients with IHH due to deleterious mutations in the TAC3/TACR3 unit, pulsatile infusions of GnRH would be expected to stimulate pituitary-gonadal maturation (20, 21). It will also be of interest to determine whether administration of kisspeptin could circumvent the blockade imposed by mutations in the TAC3/TACR3 system, in both experimental models and clinical situations (11). Such studies would provide information concerning the relative hierarchy of these neuropeptides in the regulation of GnRH secretion and are eagerly anticipated.

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Acknowledgments Address all correspondence and requests for reprints to: Dr. Allen W. Root, All Childrens Hospital, Division of Pediatric Endocrinology, Diabetes, and Metabolism, 801 6th Street South, Box 6900, St. Petersburg, Florida 33701. E-mail: [email protected]. Disclosure Summary: The author has nothing to declare.

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