Gonadotropin-releasing hormone (GnRH) insensitivity also known as Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is a rare
autosomal recessive genetic and
endocrine syndrome
A syndrome is a set of medical signs and symptoms which are correlated with each other and often associated with a particular disease or disorder. The word derives from the Greek language, Greek σύνδρομον, meaning "concurrence". When a sy ...
which is characterized by inactivating
mutations of the
gonadotropin-releasing hormone receptor
The gonadotropin-releasing hormone receptor (GnRHR), also known as the luteinizing hormone releasing hormone receptor (LHRHR), is a member of the seven-transmembrane, G-protein coupled receptor (GPCR) family. It is the receptor of gonadotropin-r ...
(GnRHR) and thus an insensitivity of the receptor 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 release ...
(GnRH), resulting in a partial or complete loss of the ability of the
gonads to synthesize the
sex hormone
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 effect ...
s. The condition manifests itself as
isolated hypogonadotropic hypogonadism
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 subs ...
(IHH), presenting with symptoms such as
delayed, reduced, or absent puberty, low or complete lack of
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 u ...
, and
infertility, and is the predominant cause of IHH when it does not present alongside
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 nu ...
.
Signs and Symptoms
There is a relatively broad spectrum of clinical signs and symptoms that can occur in, ranging from complete absence of sexual development to partial completion of puberty that does not subsequently progress. Of note, the
X-linked
Sex linked describes the sex-specific patterns of inheritance and presentation when a gene mutation (allele) is present on a sex chromosome (allosome) rather than a non-sex chromosome (autosome). In humans, these are termed X-linked recessive, ...
form of
Kallmann syndrome (KS) form of GnRH insensitivity relating to mutations in the
ANOS1 gene has the most consistent severe phenotypic presentation (i.e., prepubertal testes size and complete absence of
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 release ...
nRHinduced
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) ...
Hpulsations during frequency sampling studies) of all of the genes associated with this condition.
GnRH insensitivity can present at any age, but the presenting signs and symptoms are a function of the age-related period of reproductive activity.
During the
neonatal
An infant or baby is the very young offspring of human beings. ''Infant'' (from the Latin word ''infans'', meaning 'unable to speak' or 'speechless') is a formal or specialised synonym for the common term ''baby''. The terms may also be used to ...
period, boys with the more severe cases of GnRH insensitivity can present with
microphallus
''Microphallus'' is a genus of parasitic trematodes (flukes) in the family Microphallidae. The Greek name means "tiny penis".
Hosts
They are parasitic on a variety of molluscs, crustaceans, birds, and mammals, some species having complex life ...
and/or
cryptorchidism
Cryptorchidism, also known as undescended testis, is the failure of one or both testes to descend into the scrotum. The word is from Greek () 'hidden' and () 'testicle'. It is the most common birth defect of the male genital tract. About 3% of ...
, presumably due to in
utero and/or
neonatal GnRH deficiency; approximately one-half of boys with microphallus have GnRH insensitivity as the underlying diagnosis. In comparison, newborn girls with GnRH insensitivity have no obvious abnormal reproductive tract findings that might provide clues to the diagnosis. However, in both sexes, other congenital nonreproductive features may be present (e.g., midline facial defects, skeletal abnormalities).
During childhood, since the
hypothalamic GnRH-pituitary-gonadal axis is quiescent, a diagnosis of GnRH insensitivity can generally be heralded only in the presence of
nonreproductive phenotypes (e.g., the lack of sense of smell in some patients
nosmiaor skeletal abnormalities, such as
cleft lip/cleft palate,
hearing deficits
Hearing loss is a partial or total inability to hear. Hearing loss may be present at birth or acquired at any time afterwards. Hearing loss may occur in one or both ears. In children, hearing problems can affect the ability to acquire spoken ...
, or
syndactyly
Syndactyly is a condition wherein two or more digits are fused together. It occurs normally in some mammals, such as the siamang and diprotodontia, but is an unusual condition in humans. The term is from Greek σύν, ''syn'' 'together' and δά ...
).
At puberty, patients of both sexes can present with a complete form of GnRH insensitivity that is characterized by a failure to initiate sexual maturation (e.g., lack of secondary sexual characteristics, primary
amenorrhea
Amenorrhea is the absence of a menstrual period in a woman of reproductive age. Physiological states of amenorrhoea are seen, most commonly, during pregnancy and lactation (breastfeeding). Outside the reproductive years, there is absence of menses ...
in girls, lack of
virilization
Virilization or masculinization is the biological development of adult male characteristics in young males or females. Most of the changes of virilization are produced by androgens.
Virilization is most commonly used in three medical and biology ...
in boys) and failure to establish a pubertal growth spurt.
Some patients present with partial forms of GnRH insensitivity and undergo some degree of pubertal development that subsequently ceases. For example, some males with GnRH insensitivity exhibit some testicular growth, while some females can have
thelarche
Thelarche, also known as breast budding, is the onset of secondary breast development, often representing the beginning of pubertal development. It is the stage at which male and female breasts differentiate due to variance in hormone levels; howe ...
and
menarche, but hypogonadotropic hypogonadism (HH) is demonstrable soon thereafter. Extremely rarely, a few have completely normal pubertal development and adulthood gonadal function, only to develop HH with prepubertal levels of testosterone but sometimes with normal testicular size as a clue to its acquired status, i.e., developing only after adult testicular development has been complete subsequently in adulthood, leading to
infertility and
sexual dysfunction
Sexual dysfunction is difficulty experienced by an individual or partners during any stage of normal sexual activity, including physical pleasure, desire, preference, arousal, or orgasm. The World Health Organization defines sexual dysfunction a ...
.
These patients are referred to as having the adult-onset or acquired form of GnRH insensitivity.
Causes
Congenital Causes
*
Genetic Mutations
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, mitos ...
** Kallmann syndrome
*** ANOS1 (formerly KAL1),
X-linked recessive
X-linked recessive inheritance is a mode of inheritance in which a mutation in a gene on the X chromosome causes the phenotype to be always expressed in males (who are necessarily homozygous for the gene mutation because they have one X and one Y ...
KS
***
SOX10
Transcription factor SOX-10 is a protein that in humans is encoded by the ''SOX10'' gene.
Function
This gene encodes a member of the SOX gene family, SOX (Testis-determining factor, SRY-related HMG-box) family of transcription factors involved ...
(SRY-box 10 gene),
autosomal dominant KS with
variable penetrance
Penetrance in genetics is the proportion of individuals carrying a particular variant (or allele) of a gene (the genotype) that also express an associated trait (the phenotype). In medical genetics, the penetrance of a disease-causing mutation is t ...
***
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 ...
, autosomal dominant KS with variable penetrance
***
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 Sem ...
, autosomal dominant KS with variable penetrance
***
FEZF1
FEZ family zinc finger 1 is a protein that in humans is encoded by the FEZF1 gene.
Clinical significance
FEZF1 is a gene that encodes for transcriptional repressors, and it has been shown to repress the transcription factor HES5. In the mouse ...
, autosomal recessive KS
***
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 ...
, autosomal dominant KS with variable penetrance
** Digenic and
Oligogenic Mutations
*** A
heterozygous
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
Mo ...
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 ...
mutation and heterozygous deletion in th
NSMF genein the anosmic pedigree
*** A compound heterozygous
GNRHR
Gonadotropin-releasing hormone receptor is a protein that in humans is encoded by the ''GNRHR'' gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning '' ...
mutation and heterozygous FGFR1 mutation in the normosmic pedigree
* GnRH deficiency associated with
mental retardation
Intellectual disability (ID), also known as general learning disability in the United Kingdom and formerly mental retardation, Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010). is a generalized neurodevelopmental disorder characterized by signifi ...
/
obesity
Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's ...
*
Congenital malformations
A birth defect, also known as a congenital disorder, is an abnormal condition that is present at birth regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities can r ...
often associated with craniofacial anomalies
*
Laurence-Moon-Biedl syndrome
*
Prader-Willi syndrome
Acquired Causes
*
Benign tumor
A benign tumor is a mass of cells (tumor) that does not invade neighboring tissue or metastasize (spread throughout the body). Compared to malignant (cancerous) tumors, benign tumors generally have a slower growth rate. Benign tumors have re ...
s and cysts
*
Craniopharyngioma
A craniopharyngioma is a rare type of brain tumor derived from pituitary gland embryonic tissue that occurs most commonly in children, but also affects adults. It may present at any age, even in the prenatal and neonatal periods, but peak incidence ...
s
*
Germinoma
A germinoma is a type of germ-cell tumor, which is not differentiated upon examination. It may be benign or malignant.
Cause
Germinomas are thought to originate from an error of development, when certain primordial germ cells fail to migrate pro ...
s,
meningiomas,
glioma
A glioma is a type of tumor that starts in the glial cells of the brain or the spine. Gliomas comprise about 30 percent of all brain tumors and central nervous system tumours, and 80 percent of all malignant brain tumours.
Signs and symptoms
...
s,
astrocytoma
Astrocytomas are a type of brain tumor. They originate in a particular kind of glial cells, star-shaped brain cells in the cerebrum called astrocytes. This type of tumor does not usually spread outside the brain and spinal cord and it does not usu ...
s
*
Metastatic tumors (breast, lung, prostate)
* Chronic systemic disease
*
Malnutrition
Malnutrition occurs when an organism gets too few or too many nutrients, resulting in health problems. Specifically, it is "a deficiency, excess, or imbalance of energy, protein and other nutrients" which adversely affects the body's tissues ...
,
anorexia nervosa
Anorexia nervosa, often referred to simply as anorexia, is an eating disorder characterized by low weight, food restriction, body image disturbance, fear of gaining weight, and an overpowering desire to be thin. ''Anorexia'' is a term of Gr ...
,
bulimia
Bulimia nervosa, also known as simply bulimia, is an eating disorder characterized by binge eating followed by purging or fasting, and excessive concern with body shape and weight. The aim of this activity is to expel the body of calories eaten ...
*
Hypothyroidism,
hyperprolactinemia
Hyperprolactinaemia is the presence of abnormally high levels of prolactin in the blood. Normal levels average to about 13 ng/mL in women, and 5 ng/mL in men, with an upper normal limit of serum prolactin levels being 15-25 ng/mL ...
,
diabetes mellitus
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...
,
Cushing's disease
Cushing's disease is one cause of Cushing's syndrome characterised by increased secretion of adrenocorticotropic hormone (ACTH) from the anterior pituitary (secondary hypercortisolism). This is most often as a result of a pituitary adenoma (spe ...
* Post-androgen abuse
* Infiltrative diseases
*
Hemochromatosis
Iron overload or hemochromatosis (also spelled ''haemochromatosis'' in British English) indicates increased total accumulation of iron in the body from any cause and resulting organ damage. The most important causes are hereditary haemochromatos ...
* Granulomatous diseases
Histiocytosis
In medicine, histiocytosis is an excessive number of histiocytes (tissue macrophages), and the term is also often used to refer to a group of rare diseases which share this sign as a characteristic. Occasionally and confusingly, the term "histioc ...
*
Head trauma
A head injury is any injury that results in trauma to the skull or brain. The terms ''traumatic brain injury'' and ''head injury'' are often used interchangeably in the medical literature. Because head injuries cover such a broad scope of inju ...
*
Pituitary apoplexy
Pituitary apoplexy is bleeding into or impaired blood supply of the pituitary gland. This usually occurs in the presence of a tumor of the pituitary, although in 80% of cases this has not been diagnosed previously. The most common initial sympto ...
* Drugs -
marijuana,
opioid
Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia. Other medical uses include suppression of diarrhea, replacement therapy for opioid use ...
s,
anabolic steroids
Pathophysiology
The genetic mechanisms of gonadotropin-releasing hormone (GnRH) insensitivity involve mutations in at least twenty-four genes regulating GnRH neuronal migration, secretion, and activity. So far, the mechanisms underlying gonadotropin deficiency, both in prepubertal and in adulthood onset forms, remain unknown in most of the cases.
The lack of endogenous hypothalamic gonadotropin-releasing hormone (GnRH) secretion/action in patients with GnRH insensitivity cannot be proven by direct assay of GnRH in the portal circulation but can be reasonably inferred by two findings:
* The lack of any endogenous GnRH-induced luteinizing hormone (LH) pulses during frequent
blood sampling
* Typically, most patients respond to exogenous GnRH when administered in a pulsatile regimen designed to mimic endogenous GnRH secretion (GnRH dose and frequency based upon a previous study of LH secretion in normal men) with robust gonadotropin secretion. This responsiveness demonstrates the intact anatomic and functional integrity of the gonadotrophs and the gonads in these patients.
Diagnosis
When suspected on the basis of the clinical presentation or physical findings, the diagnosis of GnRH insensitivity should be confirmed biochemically. The diagnosis requires the following findings:
* The demonstration of prepubertal
serum concentrations of
sex steroid hormones (serum testosterone less than 100 ng/dL
.5 nmol/Lin males or serum
estradiol
Estradiol (E2), also spelled oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of the estrous and menstrual female reproductive cycles. Estradiol is responsible for the development o ...
less than 20 pg/mL
3 pmol/Lin females).
* Inappropriately low or normal serum
luteinizing hormone (LH) and
follicle-stimulating hormone (FSH) concentrations (usually less than 4 to 5 international units/L) rather than the high concentrations expected with primary
gonadal failure.
* Otherwise normal
anterior pituitary function.
* Normal appearance of the
hypothalamus
The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamu ...
and pituitary region on
magnetic resonance imaging (MRI); when seeking this diagnosis, it is useful to request fine (1 mm) cuts through the
olfactory bulb
The olfactory bulb (Latin: ''bulbus olfactorius'') is a neural structure of the vertebrate forebrain involved in olfaction, the sense of smell. It sends olfactory information to be further processed in the amygdala, the orbitofrontal cortex ( ...
region of the MRI to define subtle abnormalities of the
olfactory system
The olfactory system, or sense of smell, is the sensory system used for smelling ( olfaction). Olfaction is one of the special senses, that have directly associated specific organs. Most mammals and reptiles have a main olfactory system and an ...
that may signal which
genetic tests
Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, o ...
to request first.
* Differential diagnosis — For patients fulfilling the above laboratory criteria, the main (and most difficult) differential diagnosis is with
constitutional delay
Constitutional delay of growth and puberty (CDGP) is a term describing a temporary delay in the skeletal growth and thus height of a child with no physical abnormalities causing the delay. Short stature may be the result of a growth pattern inher ...
of growth and puberty (CDGP).
* A definitive diagnosis of GnRH insensitivity in the absence of a family history or prior genetic testing is difficult to make until the patient reaches at least 18 years of age, unless other suggestive features are present (i.e., prior
microphallus
''Microphallus'' is a genus of parasitic trematodes (flukes) in the family Microphallidae. The Greek name means "tiny penis".
Hosts
They are parasitic on a variety of molluscs, crustaceans, birds, and mammals, some species having complex life ...
and/or cryptorchism, anosmia, renal agenesis, skeletal defects, etc.). CDGP is far more common than GnRH insensitivity, affecting approximately 3 percent of adolescents while the incidence of the Kallmann syndrome (KS) form of GnRH insensitivity is 1:48,000 with a clear difference between males (1:30,000) and females (1:125,000).
* No single test can reliably distinguish between GnRH insensitivity and CDGP until more widespread genetic testing becomes available, and therefore, one has to rely on an array of clinical clues as well as on the natural evolution over time. However, certain features may indicate a higher likelihood of GnRH insensitivity rather than CDGP:
* A family history of gonadotropin-releasing hormone (GnRH) deficiency, anosmia, and/or the presence of one or several associated congenital abnormalities suggests congenital nonreproductive abnormalities (e.g., cleft lip/palate, syndactyly) suggest KS form of GnRH deficiency.
* A history of "stalled" puberty rather than total absence of development, a family history of delayed puberty, or early evidence of breast or testicular development are useful indicators that puberty is likely to occur spontaneously (i.e., CDGP).
* The presence of pubic hair suggests GnRH insensitivity because normal
adrenarche
Adrenarche is an early stage in sexual maturation that happens in some higher primates and in humans, typically peaks at around 20 years of age, and is involved in the development of pubic hair, body odor, skin oiliness, axillary hair, sexual ...
still occurs; in comparison, both adrenarche and
gonadarche are delayed in CDGP, and therefore, pubic hair is usually absent.
* In females, functional hypogonadotropic hypogonadism (FHH) (or functional hypothalamic amenorrhea) is part of the differential diagnosis for GnRH insensitivity. The presence of predisposing factors like
excessive exercise,
weight loss
Weight loss, in the context of medicine, health, or physical fitness, refers to a reduction of the total body mass, by a mean loss of fluid, body fat ( adipose tissue), or lean mass (namely bone mineral deposits, muscle, tendon, and other co ...
, or psychological stress point towards the diagnosis of FHH rather than GnRH insensitivity.
* When GnRH deficiency presents after puberty,
other causes of
secondary 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 ...
(particularly tumors of the hypothalamic-pituitary axis) must be eliminated, as GnRH insensitivity is really a diagnosis of exclusion. These include:
* Tumors of the
hypothalamic-pituitary region that occasionally can be suspected by the presence of other neurologic symptoms (headaches, visual disturbances) or the demonstration of other defects or excess in anterior pituitary hormone secretion on initial biochemical screening. However, enlarging mass lesions in either the pituitary or the
central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...
decrease the secretion of
corticotropin (ACTH) or thyroid-stimulating hormone (TSH) less than that of gonadotropins or
growth hormone
Growth hormone (GH) or somatotropin, also known as human growth hormone (hGH or HGH) in its human form, is a peptide hormone that stimulates growth, cell reproduction, and cell regeneration in humans and other animals. It is thus important in h ...
.
* Similarly,
hemochromatosis
Iron overload or hemochromatosis (also spelled ''haemochromatosis'' in British English) indicates increased total accumulation of iron in the body from any cause and resulting organ damage. The most important causes are hereditary haemochromatos ...
should be eliminated by appropriate testing of serum iron, total
iron binding capacity, and
ferritin levels.
Approach to genetic testing — When the diagnosis of GnRH insensitivity is suspected, it is suggested that referral to a clinical geneticist for further evaluation and possible genetic testing be done. As many of the genes causing GnRH insensitivity have
pleotropic physiologic functions, genetic testing can aid assessment of both reproductive and nonreproductive clinical features. In addition, ascertaining the specific inheritance modes can aid genetic screening within the family to predict recurrence risk in siblings, family members or offspring of GnRH insensitivity patients. However, genetic testing in GnRH insensitivity is challenging, given the genetic and
allelic heterogeneity
Allelic heterogeneity is the phenomenon in which different mutations at the same locus lead to the same or very similar phenotypes. These allelic variations can arise as a result of natural selection processes, as a result of exogenous mutagens ...
, as well as complex
oligogenic inheritance
Oligogenic inheritance (Greek ὀλίγος – ''ὀligos'' = few, a little) describes a trait that is influenced by a few genes. Oligogenic inheritance represents an intermediate between monogenic inheritance in which a trait is determined by a ...
patterns. However, in the presence of either clear
Mendelian inheritance
Mendelian inheritance (also known as Mendelism) is a type of biological inheritance following the principles originally proposed by Gregor Mendel in 1865 and 1866, re-discovered in 1900 by Hugo de Vries and Carl Correns, and later popularize ...
patterns or specific phenotypic cues, targeted genetic testing or multigene panel testing may be performed. However, if such testing is done, variant interpretation and
genetic counseling should be performed in conjunction with a clinical genetics service. Alternatively, several research units have special interests in the genetics of GnRH insensitivity, and clinicians can consider referring these patients to such specialized centers. Genetic testing is now commercially available through several
Clinical Laboratory Improvement Amendments (CLIA) laboratories in the United States (
GeneDx, Athena Diagnostics, Fulgent Diagnostics).
Treatment
The choice of therapy for GnRH insensitivity depends upon the patient's age and desire to achieve one or more of the following goals:
* Induction of puberty and/or maintenance of sexual maturation
* Induction or restoration of fertility
Puberty induction and
sexual maturation
Sexual maturity is the capability of an organism to reproduce. In humans it might be considered synonymous with adulthood, but here puberty is the name for the process of biological sexual maturation, while adulthood is based on cultural definiti ...
Girls and women — Exogenous estrogens are used to start secondary sexual development in prepubertal girls and to build and sustain normal bone and
muscle mass. Initiation of treatment are based upon the patient's bone age, current height percentiles,
psychosexual needs, and predicted adult height. The shorter the predicted adult height, the later puberty should be induced. Inappropriate use of estrogens may result in rapid osseous maturation with resulting short stature and irregular
menstrual bleeding
The menstrual cycle is a series of natural changes in hormone production and the structures of the uterus and ovaries of the female reproductive system that make pregnancy possible. The ovarian cycle controls the production and release of eggs a ...
.
Initiation of puberty can begin with any type or route of exogenous estrogen, oral or
transdermal
Transdermal is a route of administration wherein active ingredients are delivered across the skin for systemic distribution. Examples include transdermal patches used for medicine delivery.
The drug is administered in the form of a patch or ointme ...
. Initiation of puberty with transdermal
17-beta estradiol, starting with low doses of approximately 0.08 to 0.12 mcg
estradiol
Estradiol (E2), also spelled oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of the estrous and menstrual female reproductive cycles. Estradiol is responsible for the development o ...
per kg/day body weight, is successful and commonly prescribed by
pediatricians
Pediatrics ( also spelled ''paediatrics'' or ''pædiatrics'') is the branch of medicine that involves the medical care of infants, children, adolescents, and young adults. In the United Kingdom, paediatrics covers many of their youth until the ...
.
The dose is then gradually increased over several years. Initial therapy consist of unopposed estrogen alone to maximize
breast growth, achieve appropriate skeletal maturation, and to induce uterine and endometrial proliferation. A
progestin eventually needs to be added to prevent
endometrial hyperplasia
Endometrial hyperplasia is a condition of excessive proliferation of the cells of the endometrium, or inner lining of the uterus.
Most cases of endometrial hyperplasia result from high levels of estrogens, combined with insufficient levels of t ...
, but adding it prematurely or administering combinations of estrogens and progestins (e.g.,
birth control pills) before completion of breast development should be avoided because it is likely to reduce ultimate breast size.
Once pubertal induction is completed, estrogen and progestin therapy are continued indefinitely. Doses and principles of therapy are similar to those for women with primary ovarian insufficiency.
Boys and men — In boys, puberty can be induced with testosterone, exogenous gonadotropins, or pulsatile gonadotropin-releasing hormone (GnRH) therapy. The latter two options also induce
spermatogenesis, which is not necessary for this age group. Testosterone therapy is suggested for pubertal induction in boys. The goals of therapy are to:
* Induce
virilization
Virilization or masculinization is the biological development of adult male characteristics in young males or females. Most of the changes of virilization are produced by androgens.
Virilization is most commonly used in three medical and biology ...
* Promote optimal skeletal maturation (with bone age monitoring)
* Maximize adult height
* Promote
psychosexual development
In Freudian psychology, psychosexual development is a central element of the psychoanalytic sexual drive theory. Freud believed that personality developed through a series of childhood stages in which pleasure seeking energies from the child b ...
* Build and sustain normal bone and
muscle mass
Oral testosterone preparations should not be used, because of
hepatic
The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it is ...
toxicity. The choices for testosterone replacement include
intramuscular injections of long-acting testosterone preparations or topical gels/solutions/patches. Serum testosterone levels should be monitored and dose adjusted.
Whichever form of testosterone replacement is chosen, providing psychological support is important because the patient will have a variety of new and often confusing symptoms, much like an adolescent undergoing puberty but more difficult because it will likely be at a later age.
Testosterone therapy
Androgen replacement therapy (ART), often referred to as testosterone replacement therapy (TRT) or hormone replacement therapy (HRT), is a form of hormone therapy in which androgens, often testosterone, are supplemented or replaced exogenously ...
should be initiated at a low dose and gradually increased to an adult dose over a few years.
Once pubertal induction is completed, testosterone therapy is continued indefinitely.
Prognosis
The prognosis is generally good, with the outcome for fertility depending on the severity of the sex hormone deficiency and the age of initiation of treatment. Rare cases of complete resolution have been described but the pathophysiology of the disease in these patients is not understood.
Epidemiology
Gonadotropin-releasing hormone (GnRH) insensitivity affects both sexes but has a significant male preponderance. A population-based, epidemiological study from Finland showed a minimal prevalence estimate of the Kallman syndrome (KS) form of Gonadotropin-releasing hormone (GnRH) insensitivity to be 1:48,000 with a clear difference between males (1:30,000) and females (1:125,000).
Research
The research of GnRH deficiency has been long studied over the past five decades. The classic studies from the 1970s identified that pulsatile release of GnRH from the hypothalamus is a prerequisite for physiologic gonadotrope function. Further theses studies demonstrated that the absence, decreased frequency, or decreased amplitude of pulsatile GnRH release results in the clinical syndrome of hypogonadotropic hypogonadism (HH).
Current research primarily aims to define the physiology of GnRH, as it is critical to understanding the clinical heterogeneity of GnRH insufficiency and its comparison to other conditions resulting in hypogonadotropic hypogonadism (HH). Some overall goals of current research have focused on investigating:
* The neuroendocrine control of reproduction and specifically the physiology and pathophysiology of GnRH secretion and action in humans
* Efficacy of genetic counseling and patient management
* The psychopathology, sexuality, and personality characteristics in patients with GnRH deficiency under hormonal replacement therapy
See also
*
GnRH
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 releas ...
and
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 ...
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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 ...
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Hypopituitarism
Hypopituitarism is the decreased (''hypo'') secretion of one or more of the eight hormones normally produced by the pituitary gland at the base of the brain. If there is decreased secretion of one specific pituitary hormone, the condition is know ...
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Inborn errors of steroid metabolism
An inborn error of steroid metabolism is an inborn error of metabolism due to defects in steroid metabolism. Types
A variety of conditions of abnormal steroidogenesis exist due to genetic mutations in the steroidogenic enzymes involved in the pr ...
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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 ...
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Leydig cell hypoplasia
Leydig cell hypoplasia (or aplasia) (LCH), also known as Leydig cell agenesis, is a rare autosomal recessive genetic disorder, genetic and endocrine disease, endocrine syndrome affecting an estimated 1 in 1,000,000 genetic males. It is characteriz ...
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Sex hormone
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 effect ...
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References
External links
{{Receptor deficiencies
Autosomal recessive disorders
Endocrine gonad disorders
Gonadotropin-releasing hormone and gonadotropins
Rare diseases
Syndromes