GnRH

Gonadotropin-releasing hormone (GnRH) is a neurohormone consisting of ten amino acids which is produced by the arcuate nuclei of the hypothalamus. It is integral for starting the reproductive hormone cascade.

GnRH is secreted in the hypothalamus which is part of the brain. The hypothalamus is part of the 'Hypothalamus - Pituitary - Gonad' axis which regulates the reproductive system in men and women. Secretion of GnRH by the hypothalamus is delivered through a direct pathway between the hypothalamus and pituitary. GnRH stimulates the synthesis and secretion of two gonadotrophins namely, lutenizing hormone (LH) and follicle stimulating hormone (FSH) by the anterior pituitary gland. Controlled by internal and external factors, GnRH acts in a negative feedback loop. For instance, if there is excess FSH, LH or testosterone, then these hormones will inhibit GnRH production.

Lifestyles can also affect GnRH secretion. Lack of exercise, poor diet, opiad drugs and excessive stress can negatively affect GnRH production. What is so striking in GnRH is that under normal circumstances, GnRH is released at intervals of 90 to 120 minutes. Hence, in patients with GnRH deficiency, the releasing hormone should be administered in pulses. Constant administration of GnRH also suppresses gonadotropin secretion especially in children in puberty stage and in men with prostate cancer.

Why is GnRH treatment used?

This hormone is produced by the hypothalamus and it stimulates the pituitary gland to produce LH and FSH. Lack of GnRH in the hypothalamus can halt testosterone production in the testicles of men. In women, abnormal GnRH levels can be responsible for ovulatory disorders.

This is commonly used when Clomid treatment has not stimulated egg follicles to develop on the ovaries. GnRH works effectively to replace the natural GnRH in women and men who do not produce enough of it. Failure of release of GnRH can result in deficiency that can be partial or complete.

In a woman who is not ovulating because of lack of stimulation from hypothalamus.

In a man who is not producing sperm because his hypothalamus is not stimulating the hormones that trigger sperm production.

The use of GnRH can result in multiple pregnancies.

Some studies report that the pregnancy rate after treatment with GnRH is about 20%.

Side effects

Some side effects include:

• Breathing trouble
  
• Swelling of face, lips, tongue and throat
  
• Itching and redness at the site of the intravenous catheter
  
• Infection at the site of the IV catheter
  
• Ovarian hyper stimulation syndrome - GnRH poses less risk of this syndrome than does human menopausal Gonadotropin and other treatments for ovulation.

The small pump that is used for GnRH may bother some people and treatment requires daily monitoring by a doctor.

Although clinicians and scientists have observed the findings of olfactory disturbances and reproductive dysfunction, the syndrome comprising complete GnRH deficiency and lack of olfactory senses is named Kallmann Syndrome after the American geneticist Kallmann who identified this disorder in 1944.

Treatment

The choice of therapy depends upon the patient's desire to achieve one or more of the following options:

• Secondary sexual characteristics
  
• Fertility
  
• Bone and muscle mass

In males, treatment is decided to provide androgen replacement. The patient's age, potential adverse effects of therapy, patient's desire for fertility are considered. In the prepubertal male, GnRH stimulates penile growth, body and facial hair growth, bone and muscle development and voice changes. Androgens also stimulate growth hormone production, contributing to the adolescent growth spurt. Male androgen deficiency can result in social ridicule and therefore starting androgen therapy around age 14-15 is prudent.

Oral, injectable and transdermal and implantable pellets formulation are available for treatment of males with Kallmann syndrome. Oral androgen preparations should not be used due to their toxic effects on the liver and adverse effects on lipids. Injectable long-acting testosterone are low-cost, relatively safe and effective. The disadvantages include intramuscular injection and non physiologic pattern of testosterone over the dosing interval. There could be wide swings in libido in some men.

Transdermal patches and gel preparation of testosterone are currently available - adverse effect with these formulations include skin reactions at the application. In females as in males, treatment depends upon age and fertility desires. Estrogen replacement is a must to prevent osteoporosis.

Oral preparations, transdermal patches, vaginal cream and rings are available for standard hormone replacement therapy. Transdermally administered 17 beta estradiol has been shown as an effective regimen for preventing bone loss in normal menopausal women.

Women with intact uterus receive a cyclical progestin to accompany estradiol treatment. Optimal hormone therapy depends upon whether the patient has primary or secondary amenorrhea. Gradual dose escalation results in optimal breast development and allows time for young woman to adjust psychologically to her physical maturation.

Endorphin

Endorphins are brain chemicals made by the endocrine system. Endorphins are called anti stress proteins. The pituitary gland and hypothalamus produce endorphins when the body is in pain, excited or exercising. They work much like opiods in that they cause a sense of well-being and reduce pain and stress. They are natural painkillers. Endorphins also play a role in modulating appetite, enhancing immune response and euphoric feeling.

The polypeptide chain of the endorphin is made up of 3 to 39 amino acids. Structurally endorphins are similar to morphine and hence the term endogenous morphine was coined. However, these endorphins have similar prototypes called enkephalins and dynorphins. Endorphins facilitate the mechanism of pain reduction in the body. These protein molecules play analgesic role in cohesion with receptors called opioids in the brain cord causing pain relief. Endorphins are also called as natural analgesics and they have a very significant effect on the nervous system.

Endorphins are released by the nervous system hence; they are also called neuropeptides. Endorphins also possess neuro transmitter functionality. The prototypes of endorphins have smaller structure however, dynorphin facilitates potent sedation which is stronger than the effect of endorphin. The action of endorphins has very high significance in important situations during childbirth.

The bodies of living organisms have a unique mechanism of pain management to which the production of endorphins contribute in a major way. The series of events that occur in the body proactively triggers the brain to produce endorphins in order to effectively subside the pain and stress produced. However, fear is the only form of human expression that has a tendency to inhibit the endorphin production from the brain.

The external pain generated is transmitted to the brain and spinal cord in a series of sensory and motor responses. This triggers the release of endorphins from the brain, immediately to reduce the pain. In addition, endorphins are associated with inducing the production of various hormones such as the growth hormone, luteinizing hormone, follicle stimulating hormone and thyrotropin. Endorphins reduce muscle wasting and depression. Endorphins effectively facilitate the process of hydration. Endorphins are also known to enhance the control of cravings, addictive behaviors and frustrated behavior patterns. Endorphins play a vital role promoting the delay of aging process and also enhancing the immune system.

Cataplexy

Cataplexy is muscle weakness accompanied by typically triggered emotions such as laughing, crying or terror. These emotions are exhibited in full conscious awareness. The term cataplexy is derived from Greek 'Kata' meaning down, and 'plexis' meaning stroke. Cataplexy affects about 70% of those with narcolepsy. It is caused by autoimmune destruction of the neurotransmitter hypocretin which regulates arousal and wakefulness. Cataplexy without Narcolepsy (neurological disorder with symptoms of excessive daytime sleepiness, uncontrollable sleep and cataplexy) is rare and the cause is unknown.

Cataplexy Symptoms

Cataplexy manifests itself as muscular weakness. It can range from slackening of facial muscle to complete muscle paralysis with postural collapse. Severe attacks may result in inability to stand or move. Attacks are often brief and last from few seconds to about 30 minutes. This typically involves dropping the jaw, neck weakness and buckling of knees. The cataplectic attack is slow and progressive, so much so, the patient is usually able to avoid injury as they notice the feeling before the attack begins. As they are fully conscious during attacks, even extreme ones, they are aware of what is happening around them. Speech is slurred and vision may be impaired, it could be double vision or inability to focus, but hearing and awareness remain normal.

Cataplexy attacks

The hypothalamus region in the brain regulates basic functions of hormone release, emotions and sleep. During cataplexy, the neurochemical hypocretin is significantly reduced. Hypocretin is a primary chemical in regulating sleep as well as states of arousal and its deficiency can lead to decreased levels of histamine and epinephrine, chemicals that promote wakefulness, arousal and alertness.

Since cataplexy attacks are self-limiting, they resolve without the need for medical intervention. For instance, if the person is reclining comfortably, he/she may transition into sleepiness, hypnagogic hallucinations or a sleep onset period.

Cataplexy worsens with fatigue, and is different from narcoleptic sleep attacks. It is usually triggered by strong emotional reactions such as laughter, surprise, awe, embarrassment or by sudden physical effort, when a person is caught off guard. Such attacks could also occur spontaneously without any identifiable emotional trigger.

Cataplexy - Causes

Most have cataplexy with narcolepsy. Cataplexy is the most dramatic symptom of narcolepsy. And most cataplectic attacks are brought on by strong or extreme emotional feelings such as anger, stress, anxiety, depression and joy. Laughter and other positive emotions are the most common triggers of cataplexy. While the cause of cataplexy without narcolepsy is unknown, secondary cataplexy is linked to reduced levels of the chemical hypocretin, a neurotransmitter in the brain.

Secondary cataplexy is also associated with specific lesions located primarily in the lateral and posterior hypothalamus. Other conditions causing cataplexy include ischemic events, multiple sclerosis, head injury, Paraneoplastic syndromes and infections such as encephalitis. Cataplexy may occur transiently or permanently due to lesions of the hypothalamus caused by surgery especially in difficult tumor resections.

Recent ongoing research has found a clear association of Narcolepsy with an allele of the HLA gene family which provides instructions for the making a group of related proteins known as the Human Leukocyte Antigen (HLA) complex. This allele strongly increases the susceptibility for cataplexy. But 41% of patients without the explicit symptoms of cataplexy are carriers.

Diagnosis

Diagnosis of cataplexy is usually made by symptoms presentation. Excessive daytime sleepiness, sleep onset paralysis, hallucinations are some symptoms strongly evidencing cataplexy. A multiple sleep latency test is often conducted in order to quantify daytime sleepiness.

Treatment

There is no cure for cataplexy but is treated with medications to manage symptoms. There are no behavioral treatments. Those with narcolepsy often try to avoid thoughts and situations that they know are likely to evoke strong emotions as they know that these emotions are likely to trigger cataplectic attacks. Regardless of whether a person has narcolepsy or not, the doctor prescribes a selective serotonin and norepinephrine re uptake inhibitor to alleviate symptoms of cataplexy. Sodium oxybate is another effective drug for cataplexy.

However taking Xyrem and other sleep medications which are narcotic pain relievers or alcohol can lead to difficulty in breathing, coma and even can be fatal. In case of high blood pressure, diabetes, or other health problems, it is recommended to take medications only after consultations with the doctor.

Complications

Cataplexy is not a life threatening condition, unless engaging in potentially dangerous activities while experiencing an attack such as operating heavy machinery or driving motor vehicle. Sleep disturbances and sexual dysfunction can be caused by narcolepsy of which cataplexy is a primary symptom. As cataplexy is sudden, brief loss of voluntary muscle tone can be triggered by strong emotions such as laughter.

Cataplexy can occur during the waking hours and attacks can sometimes be rarely visible such as drooping of eyelids or severe total body collapse. As cataplexy is a neurological problem, chances are it can be misdiagnosed as a seizure disorder. As there is no cure for cataplexy, it has to be managed with medications and modifications of potential triggers.