Hypogonadotropic hypogonadism

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Hypogonadotropic hypogonadism
Other namesSecondary hypogonadism

Hypogonadotropic hypogonadism (HH), is due to problems with either the hypothalamus or pituitary gland affecting the hypothalamic-pituitary-gonadal axis (HPG axis). [1] Hypothalamic disorders result from a deficiency in the release of gonadotropic releasing hormone (GnRH), while pituitary gland disorders are due to a deficiency in the release of gonadotropins from the anterior pituitary. [1] 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, into the hypophyseal portal system acting on gonadotrophs in the anterior pituitary. [1] 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 in the male testes and theca cells in the female. FSH acts on Sertoli cells in the male and follicular cells in the female. Combined this causes the secretion of gonadal sex steroids and the initiation of folliculogenesis and spermatogenesis. The production of sex steroids forms a negative feedback loop acting on both the anterior pituitary and hypothalamus causing a pulsatile secretion of GnRH. [1] GnRH neurons lack sex steroid receptors and mediators such as kisspeptin stimulate GnRH neurons for pulsatile secretion of GnRH. [2]

Contents

Types

Despite the genetic basis for hypogonadotropic hypogonadism remaining largely unknown [3] , there are two known subtypes of HH, congenital HH (CHH) and acquired HH (AHH). [4] CHH is either due to genetic abnormalities resulting in non-functional gonadotrophin-releasing hormone (GnRH) secreting neurons [5] or the complete/partial failure of pubertal, puberty [6] due to incorrect cell dysfunction resulting in insufficient secretion of the pituitary gonadotropin. [7] CHH is divided into 2 subtypes depending on the condition of the olfactory system, anosmic HH (Kallman syndrome) and normosmic HH. [8] AHH is an acquired form of the disease often occurring after sexual maturation and is not related to genetic defects. [4] AHH can also be developed through drug and alcohol use and encephalic trauma. [8] AHH, in a clinical setting, can be shown through a lack/delay/stop of maturation as it relates to pubertal. [8] Although therapy, and or treatment, is mostly up to the patient depending on their fertility desire, it is often treated by testosterone supplements for males, and estrogen supplements for females. [8]

Pathogenesis

CHH is a type of HH resulting from the abnormal migration of GnRH neurons during embryonic development. [9] GnRH neurons are derived from the olfactory placode and migrate into the central nervous system (CNS) during embryonic development. [9] Embryonic migration can be affected by several gene mutations including but not limited to, KAL1, fibroblast growth factor (FGF8), sex determining region Y-Box 10 (SOX10), GNRHR, GNRH1 and KISS1R. [4] Kallmann syndrome results in a loss of smell (anosmia) and is associated with KAL1 mutations. The KAL1 gene encodes anosmin-1, an extracellular adhesion molecule that plays a role in GnRH neuronal migration and adhesion. [4] 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. [8] 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. [2] Inactivating mutations of KISS1 or KISS1R causes normosmic CHH in humans. [2] 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. [10]

Congenital hypogonadotropic hypogonadism, CHH, is a genetically, as well as clinically, heterogenous disorder stemming from over 25 causal genes identified to date, [11] with cases reported as being X-linked, recessive and autosomally inherited. [12]

Acquired hypogonadotropic hypogonadism (AHH) is a postnatal onset of a GnRH releasing disorder and/or pituitary gonadotroph cell disorder. [4] There are many causes of AHH, mostly due to structural lesions or functional abnormalities involving the HPG axis such as sarcoidosis, lymphocytic hypophysitis, pituitary adenomas, craniopharyngiomas and other CNS tumours. Most of these patients have multiple pituitary hormone deficiencies. [12] Hyperprolactinaemia is the most common cause of AHH. It is a well-established cause of infertility in both male and female mammals. [13] Prolactin 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. [13] 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, opioid, neuropeptide Y and γ-aminobutyric acid. [13] Drug usage of glucocorticoids and opioid analgesics in high dosages can lead to the inhibition of GnRH synthesis. [14] Opioid receptors reside in the hypothalamus and when bound to opioids they decrease the normal pulsatile secretion of GnRH and therefore result in HH. [14] 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. [14]

Diagnosis

The clinical presentation of HH depend on the time of onset as well as the severity of the defect. [12] Diagnostic tests to measure GnRH levels are difficult. This is because GnRH, when confined within hypophyseal portal system, has a short half-life of 2–4 minutes. [8] GnRH levels are thus checked indirectly via blood testing. [15] These blood tests measure the levels of hormones such as prolactin, estradiol, testosterone, TSH, but specifically LH and FSH levels which will be totally or partially absent in HH. [15] 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. [16] 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. [12]

In men with CHH, serum levels of inhibin B are typically very low as inhibin B is a marker of Sertoli cell number. [4] For females, CHH is most commonly revealed by primary amenorrhea. Breast development is variable and pubic hair may or may not be present. [16] CHH can be diagnosed in the male neonate with cryptorchidism (maldescended testes) and a micropenis as signs of GnRH deficiency. [4] There are no clear signs of CHH in female neonates. [4] 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. [12] Testing anterior pituitary function is helpful to identify if the HH is due to hyperprolactinemia. [16]

Management

The goal for HH therapy is to induce pubertal development, sexual function, fertility, bone health, and psychological wellbeing. [4] 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, as well as improving sexual function. [12] 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. [12]

Gonadotropin therapy involves the use of human chorionic gonadotropin (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. [1] 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. [1]

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.[ citation needed ]

For hyperprolactinaemia-caused AHH, dopamine agonists are used to improve GnRH secretion. Dopamine binds to D2 receptors on lactotrophs within the anterior pituitary. [13] This results in the inhibition of secretion of prolactin resulting in less direct and indirect inhibition of GnRH secretion.[ citation needed ]

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 within GnRH releasing cells. [8]

See also

Related Research Articles

<span class="mw-page-title-main">Luteinizing hormone</span> Gonadotropin secreted by the adenohypophysis

Luteinizing hormone is a hormone produced by gonadotropic cells in the anterior pituitary gland. The production of LH is regulated by gonadotropin-releasing hormone (GnRH) from the hypothalamus. In females, an acute rise of LH known as an LH surge, triggers ovulation and development of the corpus luteum. In males, where LH had also been called interstitial cell–stimulating hormone (ICSH), it stimulates Leydig cell production of testosterone. It acts synergistically with follicle-stimulating hormone (FSH).

<span class="mw-page-title-main">Follicle-stimulating hormone</span> Gonadotropin that regulates the development of reproductive processes

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, and reproductive processes of the body. FSH and luteinizing hormone (LH) work together in the reproductive system.

<span class="mw-page-title-main">Gonadotropin-releasing hormone</span> Mammalian protein found in Homo sapiens

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 from GnRH neurons within the hypothalamus. The peptide belongs to gonadotropin-releasing hormone family. It constitutes the initial step in the hypothalamic–pituitary–gonadal axis.

Delayed puberty is when a person lacks or has incomplete development of specific sexual characteristics past the usual age of onset of puberty. The person may have no physical or hormonal signs that puberty has begun. In the United States, girls are considered to have delayed puberty if they lack breast development by age 13 or have not started menstruating by age 15. Boys are considered to have delayed puberty if they lack enlargement of the testicles by age 14. Delayed puberty affects about 2% of adolescents.

Anovulation is when the ovaries do not release an oocyte during a menstrual cycle. Therefore, ovulation does not take place. However, a woman who does not ovulate at each menstrual cycle is not necessarily going through menopause. Chronic anovulation is a common cause of infertility.

Hypogonadism means diminished functional activity of the gonads—the testicles or the ovaries—that may result in diminished production of sex hormones. Low androgen levels are referred to as hypoandrogenism and low estrogen as hypoestrogenism. These are responsible for the observed signs and symptoms in both males and females.

Gonadarche refers to the earliest gonadal changes of puberty. In response to pituitary gonadotropins, the ovaries in females and the testes in males begin to grow and increase the production of the sex steroids, especially estradiol and testosterone. The ovary and testis have receptors, follicle cells and leydig cells, respectively, where gonadotropins bind to stimulate the maturation of the gonads and secretion of estrogen and testosterone. Certain disorders can result in changes to timing or nature of these processes.

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 hypogonadotropic hypogonadism, Kallmann syndrome has the additional symptom of a total lack of sense of smell (anosmia) or a reduced sense of smell. If left untreated, people will have poorly defined secondary sexual characteristics, show signs of hypogonadism, almost invariably are infertile and are at increased risk of developing osteoporosis. A range of other physical symptoms affecting the face, hands and skeletal system can also occur.

<span class="mw-page-title-main">Hypothalamic–pituitary–gonadal axis</span> Concept of regarding the hypothalamus, pituitary gland and gonadal glands as a single entity

The hypothalamic–pituitary–gonadal axis refers to the hypothalamus, pituitary gland, and gonadal glands as if these individual endocrine glands were a single entity. Because these glands often act in concert, physiologists and endocrinologists find it convenient and descriptive to speak of them as a single system.

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 (HH) due to deficiency in or insensitivity to gonadotropin-releasing hormone (GnRH) where the function and anatomy of the anterior pituitary is otherwise normal and secondary causes of HH are not present.

<span class="mw-page-title-main">Gonadotropin-releasing hormone agonist</span> Drug class affecting sex hormones

A gonadotropin-releasing hormone agonist is a type of medication which affects gonadotropins and sex hormones. They are used for a variety of indications including in fertility medicine and to lower sex hormone levels in the treatment of hormone-sensitive cancers such as prostate cancer and breast cancer, certain gynecological disorders like heavy periods and endometriosis, high testosterone levels in women, early puberty in children, as a part of transgender hormone therapy, and to delay puberty in transgender youth among other uses. It is also used in the suppression of spontaneous ovulation as part of controlled ovarian hyperstimulation, an essential component in IVF. GnRH agonists are given by injections into fat, as implants placed into fat, and as nasal sprays.

Functional hypothalamic amenorrhea (FHA) is a form of amenorrhea and chronic anovulation and is one of the most common types of secondary amenorrhea. It is classified as hypogonadotropic hypogonadism. It was previously known as "juvenile hypothalamosis syndrome," prior to the discovery that sexually mature females are equally affected. FHA has multiple risk factors, with links to stress-related, weight-related, and exercise-related factors. FHA is caused by stress-induced suppression of the hypothalamic-pituitary-ovarian (HPO) axis, which results in inhibition of gonadotropin-releasing hormone (GnRH) secretion, and gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Severe and potentially prolonged hypoestrogenism is perhaps the most dangerous hormonal pathology associated with the disease, because consequences of this disturbance can influence bone health, cardiovascular health, mental health, and metabolic functioning in both the short and long-term. Because many of the symptoms overlap with those of organic hypothalamic, pituitary, or gonadal disease and therefore must be ruled out, FHA is a diagnosis of exclusion; "functional" is used to indicate a behavioral cause, in which no anatomical or organic disease is identified, and is reversible with correction of the underlying cause. Diagnostic workup includes a detailed history and physical, laboratory studies, such as a pregnancy test, and serum levels of FSH and LH, prolactin, and thyroid-stimulating hormone (TSH), and imaging. Additional tests may be indicated in order to distinguish FHA from organic hypothalamic or pituitary disorders. Patients present with a broad range of symptoms related to severe hypoestrogenism as well as hypercortisolemia, low serum insulin levels, low serum insulin-like growth factor 1 (IGF-1), and low total triiodothyronine (T3). Treatment is primarily managing the primary cause of the FHA with behavioral modifications. While hormonal-based therapies are potential treatment to restore menses, weight gain and behavioral modifications can have an even more potent impact on reversing neuroendocrine abnormalities, preventing further bone loss, and re-establishing menses, making this the recommended line of treatment. If this fails to work, secondary treatment is aimed at treating the effects of hypoestrogenism, hypercortisolism, and hypothyroidism.

Hypothalamic–pituitary hormones are hormones that are produced by the hypothalamus and pituitary gland. Although the organs in which they are produced are relatively small, the effects of these hormones cascade throughout the body. They can be classified as a hypothalamic–pituitary axis of which the adrenal, gonadal, thyroid, somatotropic, and prolactin axes are branches.

Hypergonadotropic hypogonadism (HH), also known as primary or peripheral/gonadal hypogonadism or primary gonadal failure, is a condition which is characterized by hypogonadism which is due to an impaired response of the gonads to the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), and in turn a lack of sex steroid production. As compensation and the lack of negative feedback, gonadotropin levels are elevated. Individuals with HH have an intact and functioning hypothalamus and pituitary glands so they are still able to produce FSH and LH. HH may present as either congenital or acquired, but the majority of cases are of the former nature. HH can be treated with hormone replacement therapy.

An antigonadotropin is a drug which suppresses the activity and/or downstream effects of one or both of the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). This results in an inhibition of the hypothalamic-pituitary-gonadal (HPG) axis, and thus a decrease in the levels of the androgen, estrogen, and progestogen sex steroids in the body. Antigonadotropins also inhibit ovulation in women and spermatogenesis in men. They are used for a variety of purposes, including for the hormonal birth control, treatment of hormonally-sensitive cancers, to delay precocious puberty and puberty in transgender youth, as a form of chemical castration to reduce the sex drives of individuals with hypersexuality or pedophilia, and to treat estrogen-associated conditions in women such as menorrhagia and endometriosis, among others. High-dose antigonadotropin therapy has been referred to as medical castration.

Gonadotropin-releasing hormone (GnRH) insensitivity also known as Isolated gonadotropin-releasing hormone (GnRH)deficiency (IGD) is a rare autosomal recessive genetic and endocrine syndrome which is characterized by inactivating mutations of the gonadotropin-releasing hormone receptor (GnRHR) and thus an insensitivity of the receptor to gonadotropin-releasing hormone (GnRH), resulting in a partial or complete loss of the ability of the gonads to synthesize the sex hormones. The condition manifests itself as isolated hypogonadotropic hypogonadism (IHH), presenting with symptoms such as delayed, reduced, or absent puberty, low or complete lack of libido, and infertility, and is the predominant cause of IHH when it does not present alongside anosmia.

<span class="mw-page-title-main">GnRH neuron</span> Cell type

GnRH neurons, or gonadotropin-releasing hormone expressing neurons, are the cells in the hypothalamic infundibular nucleus in the brain that control the release of reproductive hormones from the pituitary. These brain cells control reproduction by secreting GnRH into the hypophyseal portal capillary bloodstream, so are sometimes referred to as "sex neurons". This small capillary network carries GnRH to the anterior pituitary, causing release of luteinizing hormone (LH) and follicle stimulating hormone (FSH) into the wider bloodstream. When GnRH neurons change their pattern of release from the juvenile to the adult pattern of GnRH secretion, puberty is initiated. Failure of GnRH neurons to form the proper connections, or failure to successfully stimulate the pituitary with GnRH, means that puberty is not initiated. These disruptions to the GnRH system cause reproductive disorders like hypogonadotropic hypogonadism or Kallmann Syndrome.

Kisspeptin, neurokinin B, and dynorphin (KNDy) neurons are neurons in the hypothalamus of the brain that are central to the hormonal control of reproduction.

Mini-puberty is a transient hormonal activation of the hypothalamic-pituitary-gonadal (HPG) axis that occurs in infants shortly after birth. This period is characterized by a surge in the secretion of gonadotropins and sex steroids, similar to but less intense than the hormonal changes that occur in puberty during adolescence. Mini-puberty plays a crucial role in the early development of the reproductive system and the establishment of secondary sexual characteristics.

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