Hypogonadotropic hypogonadism (HH), is due to problems with either 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 ...

pituitary gland In vertebrate anatomy, the pituitary gland, or hypophysis, is an endocrine gland, about the size of a chickpea and weighing, on average, in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain. The ...

affecting the hypothalamic-pituitary-gonadal axis (HPG axis). Hypothalamic disorders result from a deficiency in the release of gonadotropic releasing hormone (

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 released f ...

), while pituitary gland disorders are due to a deficiency in the release of

gonadotropins 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/chorio ...

from 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 ...

. GnRH is the central regulator in reproductive function and sexual development via the HPG axis. GnRH is released by GnRH neurons, which are hypothalamic

neuroendocrine cells Neuroendocrine cells are cells that receive neuronal input (through neurotransmitters released by nerve cells or neurosecretory cells) and, as a consequence of this input, release messenger molecules (hormones) into the blood. In this way they bri ...

, into the hypophyseal portal system acting on gonadotrophs in the anterior pituitary. The release of gonadotropins, LH and FSH, act on the gonads for the development and maintenance of proper adult reproductive physiology. LH acts on

Leydig cells Leydig cells, also known as interstitial cells of the testes and interstitial cells of Leydig, are found adjacent to the seminiferous tubules in the testicle and produce testosterone in the presence of luteinizing hormone (LH). They are polyhedral ...

in the male testes and

theca cells In biology, a theca (plural thecae) is a sheath or a covering. Botany In botany, the theca is related to plant's flower anatomy. The theca of an angiosperm consists of a pair of microsporangia that are adjacent to each other and share a commo ...

in the female. FSH acts on

Sertoli cells Sertoli cells are a type of sustentacular "nurse" cell found in human testes which contribute to the process of spermatogenesis (the production of sperm) as a structural component of the seminiferous tubules. They are activated by follicle-stimula ...

in the male and follicular cells in the female. Combined this causes the secretion of gonadal sex steroids and the initiation of

folliculogenesis :''Although the process is similar in many animals, this article will deal exclusively with human folliculogenesis.'' In biology, folliculogenesis is the maturation of the ovarian follicle, a densely packed shell of somatic cells that contains an ...

and

spermatogenesis Spermatogenesis is the process by which haploid spermatozoa develop from germ cells in the seminiferous tubules of the testis. This process starts with the mitotic division of the stem cells located close to the basement membrane of the tubule ...

. The production of sex steroids forms a negative feedback loop acting on both the anterior pituitary and hypothalamus causing a pulsatile secretion of GnRH. GnRH neurons lack sex steroid receptors and mediators such as

kisspeptin Kisspeptins (including kisspeptin-54 (KP-54), formerly known as metastin) are proteins encoded by the ''KISS1'' gene in humans. Kisspeptins are ligands of the G-protein coupled receptor, GPR54. ''Kiss1'' was originally identified as a human me ...

stimulate GnRH neurons for pulsatile secretion of GnRH.

Types

There are two subtypes of HH, congenital HH (CHH) and acquired HH (AHH). CHH is due to genetic abnormalities resulting in non-functional GnRH secreting neurons or gonadotropic cell dysfunction in the anterior pituitary. CHH is divided into 2 subtypes depending on the condition of the olfactory system, anosmic HH (

Kallman 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 ...

) and normosmic HH. AHH is an acquired form of the disease often occurring after sexual maturation and is not related to genetic defects.

Pathogenesis

CHH is a type of HH resulting from the abnormal migration of GnRH neurons during embryonic development. GnRH neurons are derived from the

olfactory placode The nasal placode (or olfactory placode) gives rise to the olfactory epithelium of the nose. Two nasal placodes arise as thickened ectoderm from the frontonasal process. They give rise to the nose, the philtrum of the upper lip, and the primary pal ...

and migrate into the central nervous system (CNS) during embryonic development. Embryonic migration can be affected by several gene mutations including but not limited to,

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 ...

, fibroblast growth factor (

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 ...

), sex determining region Y-Box 10 (

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 ...

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 '' ...

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 releas ...

and

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 ex ...

. Kallmann syndrome results in a loss of smell (anosmia) and is associated with KAL1 mutations. The KAL1 gene encodes

anosmin-1 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 ...

, an extracellular adhesion molecule that plays a role in GnRH neuronal migration and adhesion. Mutated KAL1 genes leads to ill GnRH neuronal migration as well as olfactory neuron disorder causing anosmia and non-functional GnRH releasing neurons. Mutations of KAL1 are mostly nucleotide insertion or deletion causing frame shifts in the translation of anosmin-1 resulting in a faulty protein. Inactivating mutations in the genes encoding GNRH1 or its receptor will result in the failure of the HPG axis and give rise to normosmic CHH. Inactivating mutations of KISS1 or KISS1R causes normosmic CHH in humans. This is because KISS1 is the mediator for the feedback loop in the HPG axis allowing low levels of sex steroid to stimulate GnRH secretion from the hypothalamus. CHH is a genetically heterogenous disorder with cases reported as being X-linked, recessive and autosomally inherited. The prevalence has been estimated to be 1/4000 to 1/10000 in males and 2 to 5 times less frequent in females. The prevalence difference between male and females is unknown, and is likely to be underreported for females. Acquired hypogonadotropic hypogonadism (AHH) is a postnatal onset of a GnRH releasing disorder and/or pituitary gonadotroph cell disorder. There are many causes of AHH, mostly due to structural or functional abnormalities involving the HPG axis such as

sarcoidosis Sarcoidosis (also known as ''Besnier-Boeck-Schaumann disease'') is a disease involving abnormal collections of inflammatory cells that form lumps known as granulomata. The disease usually begins in the lungs, skin, or lymph nodes. Less commonly af ...

lymphocytic hypophysitis Autoimmune hypophysitis is defined as inflammation of the pituitary gland due to autoimmunity. Signs and symptoms Autoimmune hypophysitis can lead to deficiencies in one or more pituitary hormones, causing central diabetes insipidus if the poster ...

pituitary adenomas Pituitary adenomas are tumors that occur in the pituitary gland. Most pituitary tumors are benign, approximately 35% are invasive and just 0.1% to 0.2% are carcinomas.craniopharyngiomas 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 ...

and other CNS tumours. Most of these patients have multiple pituitary hormone deficiencies.

Hyperprolactinaemia 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 ...

is the most common cause of AHH. It is a well-established cause of infertility in both male and female mammals.

Prolactin Prolactin (PRL), also known as lactotropin, is a protein best known for its role in enabling mammals to produce milk. It is influential in over 300 separate processes in various vertebrates, including humans. Prolactin is secreted from the pit ...

inhibits GnRH neurons and therefore inhibits the subsequent release of LH, FSH and sex steroids. The mechanism of prolactin induced inhibition of GnRH release is poorly understood. It is suspected that the prolactin receptor is expressed on a small subset of GnRH neurons in mice and thus has a direct inhibitory effect on GnRH release. There is evidence to suggest indirect inhibition of GnRH neurons mediated by other neurotransmitters such as

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...

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 us ...

neuropeptide Y Neuropeptide Y (NPY) is a 36 amino-acid neuropeptide that is involved in various physiological and homeostatic processes in both the central and peripheral nervous systems. NPY has been identified as the most abundant peptide present in the ma ...

and γ-aminobutyric acid. Drug usage of glucocorticoids and opioid analgesics in high dosages can lead to the inhibition of GnRH synthesis. Opioid receptors reside in the hypothalamus and when bound to opioids they decrease the normal pulsatile secretion of GnRH and therefore result in HH. Chronic treatment with supraphysiological doses of glucocorticoids results in a marked decrease in testosterone without an increase of LH levels, suggestive of a central mechanism of induced HH.

Diagnosis

The clinical presentation of HH depend on the time of onset as well as the severity of the defect. Diagnostic tests to measure GnRH levels are difficult. This is because GnRH is confined within hypophyseal portal system and has a short half-life of 2–4 minutes. GnRH levels are thus checked indirectly via LH and FSH levels which will be totally or partially absent in HH. Exogenous GnRH can be used as a diagnostic tool. If the patient has hypothalamic GnRH deficiency, LH and FSH will gradually appear in response to the exogenous GnRH but in pituitary cases of HH, a minimal response will be generated. Typically, CHH is diagnosed in adolescence due to a lack of pubertal development, but it can be possible to diagnose in male neonates. Clinical presentations of CHH involve an absence of puberty by 18 years of age, poorly developed secondary sexual characteristics, or infertility. In men with CHH, serum levels of inhibin B are typically very low as inhibin B is a marker of Sertoli cell number. For females, CHH is most commonly revealed by

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 ...

. Breast development is variable and pubic hair may or may not be present. CHH can be diagnosed in the male neonate with

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 ...

(maldescended testes) and a micropenis as signs of GnRH deficiency. There are no clear signs of CHH in female neonates. Another clinical sign of CHH, more specifically Kallmann syndrome, is a lack of a sense of smell due to the altered migration of GnRH neurons on the olfactory placode. Kallmann syndrome can also be shown through MRI imaging with irregular morphology or aplasia of the olfactory bulb and olfactory sulci. Anterior pituitary function must be normal for all other axes in CHH as it is an isolated disorder. Testing anterior pituitary function is helpful to identify if the HH is due to hyperprolactinemia.

Management

The goal for HH therapy is to induce pubertal development, sexual function, fertility, bone health, and psychological wellbeing. Testosterone therapy for males and estradiol therapy for females is used to improve genital development, develop secondary sexual characteristics, allow for the growth and closure of the

epiphyseal plate The epiphyseal plate (or epiphysial plate, physis, or growth plate) is a hyaline cartilage plate in the metaphysis at each end of a long bone. It is the part of a long bone where new bone growth takes place; that is, the whole bone is alive, wi ...

, as well as improving sexual function. This therapy does not restore fertility as gonadotropins are required for spermatogenesis and folliculogenesis. If fertility is desired, pulsatile GnRH therapy or gonadotropin therapy is necessary. Gonadotropin therapy involves the use of

human chorionic gonadotropin Human chorionic gonadotropin (hCG) is a hormone for the maternal recognition of pregnancy produced by trophoblast cells that are surrounding a growing embryo (syncytiotrophoblast initially), which eventually forms the placenta after implantation ...

(hCG) and FSH. In the male, hCG stimulates Leydig cells to produce testosterone so that plasma and testicular levels increase. With the increased levels of testosterone, sexual activity, libido and overall wellbeing should improve. Administration of FSH is required to induce spermatogenesis by acting on Sertoli cells. FSH is required for maintaining the production of high numbers of good quality sperm. Gonadotropin therapy in HH men usually is able to generate enough sperm for fertility to occur, however sperm count is still lower than normal. In the female, the goal for gonadotropin therapy is to obtain ovulation. This is obtained with FSH treatment followed by hCG or LH to trigger ovulation. FSH will stimulate granulosa cells for follicular maturation while LH will act on luteal cells to produce steroids aiding follicular maturation and preparing the endometrium for pregnancy. For

hyperprolactinaemia 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 ...

-caused AHH, dopamine agonists are used to improve GnRH secretion.

Dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...

binds to

D2 receptors Dopamine receptor D2, also known as D2R, is a protein that, in humans, is encoded by the ''DRD2'' gene. After work from Paul Greengard's lab had suggested that dopamine receptors were the site of action of antipsychotic drugs, several groups, in ...

lactotrophs A lactotropic cell (also known as prolactin cell, epsilon acidophil, lactotrope, lactotroph, mammatroph, mammotroph) is a cell in the anterior pituitary which produces prolactin in response to hormonal signals including dopamine which is inhibitor ...

within the anterior pituitary. This results in the inhibition of secretion of prolactin resulting in less direct and indirect inhibition of GnRH secretion. In up to 10–20% of cases, patients can exhibit sustained fertility and steroid production after therapy, resulting in hypogonadotropic hypogonadism reversal. The mechanism for this reversal is unknown but there is believed to be some

neuronal plasticity Neuroplasticity, also known as neural plasticity, or brain plasticity, is the ability of neural networks in the brain to change through growth and reorganization. It is when the brain is rewired to function in some way that differs from how it p ...

within GnRH releasing cells.

References

External links