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 ...

(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 rele ...

(GnRH) where the function and anatomy of the

anterior pituitary The anterior pituitary (also called the adenohypophysis or pars anterior) is a major Organ (anatomy), organ of the endocrine system. The anterior pituitary is the glandular, Anatomical terms of location#Usage in human anatomy, anterior lobe that t ...

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 human gonad, gonads—the testicles or the ovary, ovaries—that may result in diminished biosynthesis, production of sex hormones. Low androgen (e.g., testosterone) levels are referred t ...

, 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 In psychology, libido (; ) is psychic drive or energy, usually conceived of as sexual in nature, but sometimes conceived of as including other forms of desire. The term ''libido'' was originally developed by Sigmund Freud, the pioneering origin ...

infertility In biology, infertility is the inability of a male and female organism to Sexual reproduction, reproduce. It is usually not the natural state of a healthy organism that has reached sexual maturity, so children who have not undergone puberty, whi ...

, etc. due to an impaired release of the

gonadotropin Gonadotropins are glycoprotein hormones secreted by gonadotropic cells of the anterior pituitary of vertebrates. They are central to the complex endocrine system that regulates normal growth, sexual development, and reproductive function. T ...

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, puberty, pubertal maturat ...

(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 (G ...

(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 a ...

and peptides production by the

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

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 hereditary, 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 fo ...

, a variable non-reproductive phenotype occurs with

anosmia Anosmia, also known as smell blindness, is the lack of 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 categorized int ...

(loss of the sense of smell) 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'', '' FGFR1/

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 belongs to the fibroblast growth factor (FGF) family. FGF proteins are multifunctional signaling molecul ...

'', '' FGF17'', '' IL17RD'', '' PROKR2'', '' NELF'', ''

CHD7 Chromodomain-helicase-DNA-binding protein 7 is an ATP-dependent 'chromatin' or 'nucleosome' remodeling factor that in humans is encoded by the ''CHD7'' gene. CHD7 is an ATP-dependent chromatin remodeler homologous to the Drosophila trithorax-g ...

''(which positively regulates GnRH secretion), HS6ST1, '' FLRT3'', ''

SPRY4 Protein sprouty homolog 4 is a protein that in humans is encoded by the ''SPRY4'' gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that ...

'',

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 th ...

, ''

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 S ...

'', and '' WDR11 (gene)'', 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 mutations in '' KISS1R'', '' TACR3'', GNRH1/ GNRHR, LEP/ LEPR,

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-em ...

, 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, ...

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