Isolated hypogonadotropic hypogonadism (IHH), also called idiopathic or congenital hypogonadotropic hypogonadism (CHH), as well as isolated or congenital gonadotropin-releasing hormone deficiency (IGD), is a condition which results in a small subset of cases of

hypogonadotropic hypogonadism Hypogonadotropic hypogonadism (HH), is due to problems with either the hypothalamus or pituitary gland affecting the hypothalamic-pituitary-gonadal axis (HPG axis). Hypothalamic disorders result from a deficiency in the release of gonadotropic r ...

(HH) due to deficiency in or insensitivity to

gonadotropin-releasing hormone Gonadotropin-releasing hormone (GnRH) is a releasing hormone responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. GnRH is a tropic peptide hormone synthesized and released ...

(GnRH) where the function and anatomy of the

anterior pituitary A major organ of the endocrine system, the anterior pituitary (also called the adenohypophysis or pars anterior) is the glandular, anterior lobe that together with the posterior lobe (posterior pituitary, or the neurohypophysis) makes up the p ...

is otherwise normal and secondary causes of HH are not present.

Presentation

Congenital hypogonadotropic hypogonadism presents as

hypogonadism Hypogonadism means diminished functional activity of the gonads—the testes or the ovaries—that may result in diminished production of sex hormones. Low androgen (e.g., testosterone) levels are referred to as hypoandrogenism and low estrogen ...

, e.g., reduced or absent puberty,Young J. Approach to the male patient with congenital hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2012 Mar;97(3):707-18. doi: 10.1210/jc.2011-1664. low

libido Libido (; colloquial: sex drive) is a person's overall sexual drive or desire for sexual activity. Libido is influenced by biological, psychological, and social factors. Biologically, the sex hormones and associated neurotransmitters that act up ...

infertility Infertility is the inability of a person, animal or plant to reproduce by natural means. It is usually not the natural state of a healthy adult, except notably among certain eusocial species (mostly haplodiploid insects). It is the normal state ...

, etc. due to an impaired release of the

gonadotropin Gonadotropins are glycoprotein hormones secreted by gonadotropic cells of the anterior pituitary of vertebrates. This family includes the mammalian hormones follicle-stimulating hormone (FSH) and luteinizing hormone (LH), the placental/ chorioni ...

follicle-stimulating hormone Follicle-stimulating hormone (FSH) is a gonadotropin, a glycoprotein polypeptide hormone. FSH is synthesized and secreted by the gonadotropic cells of the anterior pituitary gland and regulates the development, growth, pubertal maturation, an ...

(FSH) and

luteinizing hormone Luteinizing hormone (LH, also known as luteinising hormone, lutropin and sometimes lutrophin) is a hormone produced by gonadotropic cells in the anterior pituitary gland. The production of LH is regulated by gonadotropin-releasing hormone (GnRH) ...

(LH), and a resultant lack of

sex steroid Sex hormones, also known as sex steroids, gonadocorticoids and gonadal steroids, are steroid hormones that interact with vertebrate steroid hormone receptors. The sex hormones include the androgens, estrogens, and progestogens. Their effects are ...

and peptides production by the

gonad A gonad, sex gland, or reproductive gland is a mixed gland that produces the gametes and sex hormones of an organism. Female reproductive cells are egg cells, and male reproductive cells are sperm. The male gonad, the testicle, produces sper ...

s.Giton F, Trabado S, Maione L, et al . Sex steroids, precursors, and metabolite deficiencies in men with isolated hypogonadotropic hypogonadism and panhypopituitarism: a GCMS-based comparative study. J Clin Endocrinol Metab. 2015 Feb;100(2):E292-6. doi: 10.1210/jc.2014-2658. Epub 2014 Nov 13. Trabado S, Maione L, Bry-Gauillard H, et al. Insulin-like peptide 3 (INSL3) in men with congenital hypogonadotropic hypogonadism/Kallmann syndrome and effects of different modalities of hormonal treatment: a single-center study of 281 patients. J Clin Endocrinol Metab. 2014 Feb;99(2):E268-75. doi: 10.1210/jc.2013-2288. Epub 2013 Nov 15. In

Kallmann syndrome Kallmann syndrome (KS) is a genetic disorder that prevents a person from starting or fully completing puberty. Kallmann syndrome is a form of a group of conditions termed hypogonadotropic hypogonadism. To distinguish it from other forms of hypog ...

, a variable non-reproductive phenotype occurs with

anosmia Anosmia, also known as smell blindness, is the loss of the ability to detect one or more smells. Anosmia may be temporary or permanent. It differs from hyposmia, which is a decreased sensitivity to some or all smells. Anosmia can be due to a num ...

(loss of the sense of

smell Smell may refer to; * Odor, airborne molecules perceived as a scent or aroma * Sense of smell, the scent also known scientifically as olfaction * "Smells" (''Bottom''), an episode of ''Bottom'' * The Smell, a music venue in Los Angeles, Californ ...

) including sensorineural deafness, coloboma, bimanual synkinesis, craniofacial abnormalities, and/or renal agenesis.Hernan Valdes-Socin, Matilde Rubio Almanza, Mariana Tomé Fernández-Ladreda, et al. Reproduction, smell, and neurodevelopmental disorders: genetic defects in different hypogonadotropic hypogonadal syndromes. Frontiers in Endocrinology 2014, 5: 109. review

Causes

IHH is divided into two syndromes: IHH with olfactory alterations or anosmia,

and IHH with normal smell (normosmic IHH). Kallmann syndrome is responsible for approximately 50% of all cases of the condition. It is associated with mutations in ''

KAL1 Anosmin-1 is a secreted, EM associated glycoprotein found in humans and other organisms responsible for normal development, which is expressed in the brain, spinal cord and kidney. Absence or damage to the protein results in Kallmann syndrome in ...

'', ''

FGFR1 Fibroblast growth factor receptor 1 (FGFR1), also known as basic fibroblast growth factor receptor 1, fms-related tyrosine kinase-2 / Pfeiffer syndrome, and CD331, is a receptor tyrosine kinase whose ligands are specific members of the fibroblast ...

FGF8 Fibroblast growth factor 8 (FGF-8) is a protein that in humans is encoded by the ''FGF8'' gene. Function The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and ...

'', ''

FGF17 Fibroblast growth factor 17 is a protein that in humans is encoded by the ''FGF17'' gene. The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell survival acti ...

'', ''

IL17RD Interleukin 17 receptor D is a protein that in humans is encoded by the IL17RD gene. Function This gene encodes a membrane protein belonging to the interleukin-17 receptor (IL-17R) protein family. The encoded protein is a component of the int ...

'', ''

PROKR2 Prokineticin receptor 2 (PKR2), is a dimeric G protein-coupled receptor encoded by the PROKR2 gene in humans. Function Prokineticins are secreted proteins that can promote angiogenesis and induce strong gastrointestinal smooth muscle contracti ...

'', '' NELF'', ''

CHD7 Chromodomain-helicase-DNA-binding protein 7 also known as ATP-dependent helicase CHD7 is an enzyme that in humans is encoded by the ''CHD7'' gene. CHD7 is an ATP-dependent chromatin remodeler homologous to the Drosophila trithorax-group protei ...

''(which positively regulates GnRH secretion), HS6ST1, ''

FLRT3 Leucine-rich repeat transmembrane protein FLRT3 is a protein that in humans is encoded by the ''FLRT3'' gene. FLRT1, FLRT2 and FLRT3 are members of the fibronectin leucine rich transmembrane protein (FLRT) family. They may function in cell adhe ...

'', ''

SPRY4 Protein sprouty homolog 4 is a protein that in humans is encoded by the ''SPRY4'' gene. Function SPRY4 is an inhibitor of the receptor-transduced mitogen-activated protein kinase (MAPK) signaling pathway. It is positioned upstream of RAS (see ...

'',

DUSP6 Dual specificity phosphatase 6 (DUSP6) is an enzyme that in humans is encoded by the ''DUSP6'' gene. Function The protein encoded by this gene is a member of the dual specificity protein phosphatase subfamily. These phosphatases inactivate the ...

, ''

SEMA3A Semaphorin-3A is a protein that in humans is encoded by the ''SEMA3A'' gene. Function The ''SEMA3A'' gene is a member of the semaphorin family and encodes a protein with an Ig-like C2-type (immunoglobulin-like) domain, a PSI domain and a Sema ...

'', and ''

WDR11 (gene) WD repeat-containing protein 11 (WDR11) also known as bromodomain and WD repeat-containing protein 2 (BRWD2) is a protein that in humans is encoded by the WDR11 gene. Function This gene encodes a member of the WD repeat protein family. WD repe ...

'', genes which are related to defects in neuronal migration. Gene defects associated with IHH and normal smell include ''PROKR2, FGFR1, FGF8, CHD7, DUSP6,'' and ''WDR11'', as in KS, but in addition also mutations in ''

KISS1R The KiSS1-derived peptide receptor (also known as GPR54 or the Kisspeptin receptor) is a G protein-coupled receptor which binds the peptide hormone kisspeptin (metastin). Kisspeptin is encoded by the metastasis suppressor gene KISS1, which is exp ...

'', ''

TACR3 Tachykinin receptor 3, also known as TACR3, is a protein which in humans is encoded by the ''TACR3'' gene. Function This gene belongs to a family of genes that function as receptors for tachykinins. Receptor affinities are specified by variat ...

'',

GNRH1 Gonadotropin-releasing hormone (GnRH) is a releasing hormone responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. GnRH is a tropic peptide hormone synthesized and released f ...

GNRHR Gonadotropin-releasing hormone receptor is a protein that in humans is encoded by the ''GNRHR'' gene. This gene encodes the receptor for type 1 gonadotropin-releasing hormone. This receptor is a member of the seven-transmembrane, G-protein couple ...

, LEP/

LEPR Leptin receptor, also known as LEP-R or OB-R, is a type I cytokine receptor, a protein that in humans is encoded by the ''LEPR'' gene. LEP-R functions as a receptor for the fat cell-specific hormone leptin. LEP-R has also been designated as CD295 ...

HESX1 Homeobox expressed in ES cells 1, also known as homeobox protein ANF, is a homeobox protein that in humans is encoded by the ''HESX1'' gene. Expression of HEX1 and HESX1 marks the anterior visceral endoderm of the embryo. The AVE is an extra-emb ...

, FSHB, and LHB. GnRH insensitivity is the second most common cause of IHH, responsible for up to 20% of cases.A minority of less than 5-10% is due to inactivating

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...

s in genes which positively regulate GnRH secretion such as ''CHD7'', ''KISS1R'', and ''TACR3''. The causes of about 25% of all IHH cases are still unknown.

Genetics

Treatment

References

External links

{{Medical resources , ICD10 = E23.0 , ICD9 = , ICDO = , OMIM = 146110 , DiseasesDB = , MedlinePlus = , eMedicineSubj = , eMedicineTopic = , MeSH = , GeneReviewsNBK = , GeneReviewsName = , Orphanet = 432 Endocrine gonad disorders Gonadotropin-releasing hormone and gonadotropins

Presentation

Causes

Genetics

Treatment

See also

References

External links