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The hypothalamic–pituitary–gonadal axis in normal individuals. LH and FSH lead to the production of sex hormones (testosterone). The sex hormones (testosterone) then down regulate the entire axis. In HH patients, this axis does not function properly.

Hypogonadotropic hypogonadism (HH), also known as secondary or central hypogonadism, as well as gonadotropin-releasing hormone deficiency or gonadotropin deficiency (GD), is a condition which is characterized by hypogonadism due to an impaired secretion of gonadotropins, including follicle-stimulating hormone (FSH) and luteinizing hormone (LH), by the pituitary gland in the brain, and in turn decreased gonadotropin levels and a resultant lack of sex steroid production.^[1]

Causes

Impaired function of the testis or ovary is characteristic of hypogonadism. There are two types of hypogonadism. It can be caused by a disorder in the testes or ovary (hypergonadotropic) or impaired function of the hypothalamus and pituitary gland (hypogonadotropic).

The type of hypogonadism is based on the cause. It can be classified as either primary or secondary. Primary hypogonadism, also called isolated hypergonadotropic hypogonadism, is responsible for only a small subset of cases. It is characterized by an otherwise normal function and anatomy of the hypothalamus and anterior pituitary. In primary hypogonadism, the hypothalamus and anterior pituitary are unaffected. However, males have low testosterone production and high follicle stimulating hormone (FSH) and luteinizing hormone (LH).

Secondary hypogonadism, also known as acquired or syndromic hypogonadotropic hypogonadism (HH), is far more common than primary hypogonadism, and is responsible for most cases of the condition. Secondary HH is characterized by a disorder of the hypothalamus and pituitary gland that leads to low/ absent GnRH secretion.

Secondary HH can either be congenital or acquired. A sense of smell can be used as a diagnostic tool to differentiate between the two main types of HH. Patients without a sense of smell have congenital HH which is referred to as Anosmic HH. An example of Anosmic HH is Kallmann syndrome.  

Acquired HH is more common and is due to conditions that affect the hypothalamic-pituitary axis. It has a multitude of different causes, including brain or pituitary tumors, pituitary apoplexy, head trauma, ingestion of certain drugs, and certain systemic diseases and syndromes.^[1] Acquired HH can be caused by extreme exercise, excessive alcohol and illicit drug intake.

Low GnRH Secretion

Gonadotropin releasing hormone (GnRH) neurons are part of the hypothalamic-pituitary- gonadal (HPG) axis. The neurons regulate sexual development and reproductive function. They converge at the median eminence and secrete GnRH into the hypothalamic portal vessels. The portal system transports hormones to the anterior pituitary gland. GnRH functions as a 10 amino acid polypeptide (decapeptide). GnRH binds and activates GnRH receptors on pituitary gonadotropes (cells of the anterior pituitary). This causes the gonadotropes to synthesize and release LH and FSH. These hormones are necessary for proper gonadal function. LH acts on Leydig cells in the testis to produce testosterone. LH also acts on the Theca cells in the ovaries to produce estrogen. FSH allows for the maturation of germ cells in both males and females.

When GnRH secretion is altered, it leads to impaired reproductive maturation and function. Improper GnRH secretion leads to HH. The altered secretion can be due to defects in GnRH synthesis, release or receptor interaction. It can also be caused by issues in GnRH neuron development.  

Clinical Diagnosis

Clinical characteristics are low serum androgen and pituitary hormone levels. There is also a lack/ delay in puberty and sexual maturation. HH can only be diagnosed after the age of eighteen because it is difficult to differentiate between HH and delayed puberty. Both conditions are associated with low gonadotropin and testosterone levels. A magnetic resonance imaging (MRI) can be used to show the potential absence of the olfactory bulb that leads to congenital HH.  

Treatment

Treatment of HH may consist of administration of either a GnRH agonist or a gonadotropin formulation in the case of primary HH and treatment of the root cause (e.g., a tumor) of the symptoms in the case of secondary HH.

The final response to gonadotropin varies on the patient. Treatment allows patients to undergo spermatogenesis. Spontaneous conception can occur within 6-9 months of the treatment. However, if conception does not occur within 20 months, other routes of therapy should be considered. Some patients use assisted reproductive technology to achieve pregnancy.

Alternatively, hormone replacement therapy with androgens and estrogens in males and females, respectively, may be employed.

Treatment Controversy  

Testosterone replacement therapy in older men is a controversial issue. Since testosterone has been on the market, only a few large-scale, placebo-controlled studies have been conducted on the therapy. Some physicians argue that exogenous testosterone causes older men to be susceptible to prostate cancer and cardiovascular disease. Many men do not fall under the specific category of either primary or secondary hypogonadism. Many patients have a mixed type of testosterone deficiency. Hence, the use of excess testosterone could lead these patients to be at risk. Currently, there are ongoing debates to change the therapy model to incorporate men who neither have primary or secondary hypogonadism.