Hypogonadotropic hypogonadism

Despite the genetic basis for hypogonadotropic hypogonadism remaining largely unknown, there are two known subtypes of HH, congenital HH (CHH) and acquired HH (AHH). or the complete/partial failure of puberty due to incorrect cell dysfunction resulting in insufficient secretion of the pituitary gonadotropin. CHH is divided into 2 subtypes depending on the condition of the olfactory system, anosmic HH (Kallman syndrome) and normosmic HH. AHH is an acquired form of the disease often occurring after sexual maturation and is not related to genetic defects. AHH can also be developed through drug and alcohol use and encephalic trauma. AHH, in a clinical setting, can be shown through a lack/delay/stop of maturation as it relates to pubertal. 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. ==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 and migrate into the central nervous system (CNS) during embryonic development. Congenital hypogonadotropic hypogonadism, CHH, is a genetically, as well as clinically, heterogenous disorder stemming from over 25 causal genes identified to date, with cases reported as being X-linked, recessive and autosomally inherited. Acquired hypogonadotropic hypogonadism (AHH) is a postnatal onset of a GnRH releasing disorder and/or pituitary gonadotroph cell disorder. 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. There is evidence to suggest indirect inhibition of GnRH neurons mediated by other neurotransmitters such as dopamine, opioid, neuropeptide Y and γ-aminobutyric acid. 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. 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. 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. Breast development is variable and pubic hair may or may not be present. CHH can be diagnosed in the male neonate with cryptorchidism (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, 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 (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-caused AHH, dopamine agonists are used to improve GnRH secretion. Dopamine binds to D2 receptors on lactotrophs 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 within GnRH releasing cells. ==See also==