Gonadotropin Releasing Hormone (GnRH) Function

Gonadotropin-releasing hormone (GnRH) stimulates the release of FSH and LH. It helps trigger puberty and keeps men and women fertile as adults. Read more below to learn about this important reproductive hormone.

What Is Gonadotropin-Releasing Hormone?

Gonadotropin-releasing hormone (GnRH) is a signaling hormone that stimulates the release of other hormones. More specifically, it triggers two hormones in the gonadotropin family: follicle-stimulating hormone (FSH) and luteinizing hormone (LH) [1].

The gonadotropins regulate the growth, development, and function of the reproductive organs. FSH and LH stimulate the production of eggs, sperm, and the sex steroids (estrogen, progesterone, and testosterone). They’re released from the pituitary [1, 2].

GnRH is, therefore, vital to sperm production in men and egg release (ovulation) in women. GnRH levels are very low before puberty; however, as puberty approaches, GnRH levels increase to prepare for sexual maturity [1].

Snapshot of GnRH Function

The mechanisms and end products of gonadotropin-releasing hormone are complicated and delicate. This post will describe and explain how it all works, but it may be useful to build a road map first:

• A protein interestingly named kisspeptin activates GnRH neurons in a region of the brain called the hypothalamus [3];
• GnRH is released from the hypothalamus and travels to receptors in the pituitary gland, tucked at the base of the brain [4];
• The pituitary gland releases hormones called gonadotropins: LH and FSH [4];
• LH and FSH travel to the testes or ovaries [5];
• The testes release testosterone and the ovaries release estrogen and progesterone [5];
• Testosterone, estrogen, and progesterone then inhibit GnRH, which stops GnRH levels from getting too high [5].

This whole cycle is part of the hypothalamic-pituitary-gonadal (HPG) axis. The HPG axis is so named because of the three major structures involved in the signaling loop: the hypothalamus, pituitary gland, and gonads (a word for both the testes and ovaries) [6].

GnRH and the HPG axis are important for starting puberty in late childhood and for maintaining fertility in adulthood. GnRH regulates a healthy menstrual cycle in women and promotes sperm production in men [7, 5, 8].

GnRH Function

Where Is GnRH produced?

GnRH is produced in the hypothalamus. Too little GnRH can lead to underdevelopment of the testes or ovaries, resulting in infertility. Treatments with GnRH and its analogs can be used in humans, as well as animals [1].

GnRH Pathway

As mentioned above, GnRH is part of a complex hormonal signaling pathway called the hypothalamic-pituitary-gonadal (HPG) axis [9]:

Kisspeptin

Around the turn of the century, researchers discovered that two genes called KISS1 and KISS1R were necessary for a child to begin adolescence. These genes code for a protein called kisspeptin and its receptor; together, they trigger GnRH neurons in the hypothalamus to start firing during puberty [3, 5].

During adulthood, kisspeptin continues to regulate GnRH release and, in turn, fertility [3, 5].

Did you know? Kisspeptin receptors were initially known under the code name “Harry Potter” by researchers at Paradigm Therapeutics. This biotech company has a tradition of naming its discoveries after orphans, which is how J.K. Rowling’s hero made it into the scientific community. With further investigation, these receptors were renamed to KISS1R [10].

GnRH receptor

Once GnRH is released from the hypothalamus, it travels to the pituitary gland. There, it binds to GnRH receptors on the surface of gonadotrope cells, which make and release the gonadotropins: LH and FSH [4].

GnRH and its receptors can also be found outside the hypothalamus and pituitary. For example, in the ovary and uterus, they help regulate ovulation and pregnancy. When this system fails or goes wrong, it may lead to reproductive diseases like endometriosis and polycystic ovarian syndrome [11].

LH and FSH

GnRH stimulates the pituitary to release both LH and FSH, but not in the same amounts at the same time. So, how does the pituitary gland “know” which hormone to release? The trick is that GnRH comes in pulses, the speed and rhythm of which tells the pituitary what to produce [12, 5].

When GnRH pulses are fast, the pituitary gland produces more LH relative to FSH. When GnRH pulses are slow, the pituitary gland produces more FSH relative to LH [12].

In the female reproductive system, GnRH pulses speed up dramatically in the middle of the menstrual cycle. This produces a huge spike in LH, which triggers the ovary to release an egg. This LH surge is one of the most reliable signals of fertility in women [5, 13].

The GnRH Family

This article, like most of the scientific literature, uses the name “gonadotropin-releasing hormone” or GnRH to refer to only one of at least two closely related hormones. This GnRH from the hypothalamus is, more specifically, GnRH1. To make things more complicated, GnRH1 is also sometimes referred to as luteinizing hormone releasing hormone (LHRH) [14, 15].

Many vertebrates, including humans, also have a second gene called GnRH2. In other species, GnRH2 seems to regulate food intake and sexual behavior; however, researchers haven’t yet determined whether it has the same function in humans [16, 17].

So, to recap:

• GnRH, GnRH1, and LHRH all refer to the same hormone.
• GnRH2 exists in humans, and it may or may not regulate appetite and sexual behavior.

Negative Feedback Control of GnRH

Just about every system and hormone in the body has a kind of off switch: a signal that tells it to slow down or ease up. Often, when a particular hormone increases, its own end result is the off switch. This is called a “negative feedback loop,” and it keeps the levels of hormones and neurotransmitters within a certain healthy range [18].

GnRH has multiple off switches. The first is GnRH itself: when neurons release this hormone, they also become less sensitive to stimulation. This may be why GnRH is released in short pulses rather than at a steady rate [18, 19].

Sex Steroids

The final downstream products of GnRH signaling are the sex steroids, testosterone and estrogen. These, in turn, put the brakes on GnRH production from the hypothalamus [20, 21, 5].

Progesterone is yet another GnRH off switch. In women, GnRH pulses become very quick right before an egg is released. These fast pulses trigger a huge spike in luteinizing hormone (LH), which in turn causes the ovary to release the egg. Once this happens, the ovary produces progesterone, which then blocks GnRH release [5].

Reduced Kisspeptin

Stress, calorie restriction, and high prolactin (as in a condition called hyperprolactinemia) can all decrease GnRH release as well. Kisspeptin, the compound that would normally signal the hypothalamus to make GnRH, decreases in response to these stimuli [5, 9].

GnRH Stimulation Test

The GnRH stimulation test is used to identify problems with puberty in adolescents. The patient receives an injection of GnRH, and the doctor or nurse then takes blood samples at various time points afterward. Each blood sample is then analyzed for luteinizing hormone (LH) and follicle stimulating hormone (FSH) [22, 23].

This test is used to diagnose central precocious puberty (CPP), constitutional delay of growth and puberty (CDP), and idiopathic hypogonadotropic hypogonadism (IHH). These diagnoses are useful for doctors to tell whether a child needs some sort of treatment, or whether they will grow out of certain ailments or abnormalities [22, 23].

Deficiency of Gonadotropins

Hypopituitarism

Hypopituitarism describes a decrease or loss of any one of the hormones produced by the pituitary gland. These include the gonadotropins LH and FSH [24].

Causes of hypopituitarism include tumors, diabetes, sickle cell disease, aneurysm, radiation, and surgical damage. Hypopituitarism can also be genetic. LH and FSH deficiency, specifically, can be caused by a loss of GnRH receptors in the part of the pituitary gland that makes the gonadotropins [24].

A deficiency of LH and FSH causes a loss of libido and sexual function. In men, it can also cause loss of bone and muscle mass, blood cells, and hair. In women, it can cause osteoporosis, atherosclerosis, and irregular or absent periods [24].

Isolated GnRH Deficiency

Isolated GnRH deficiency (IGD) is an inherited disorder that causes very low GnRH. It is assumed to be genetic, as 40% of cases can currently be explained by known genetic causes, but researchers haven’t yet discovered all of the genes responsible [25].

Low or absent GnRH signaling can lead to Kallmann syndrome or normosmic idiopathic hypogonadotropic hypogonadism (nIHH). The primary difference between the two is that people with Kallman syndrome may completely lack their sense of smell [25].

People with these disorders do not go through normal puberty; thus, they may not be diagnosed until well after puberty would otherwise have begun. The most common treatment is hormone replacement therapy (HRT), which restores the appropriate sex hormones [25, 26].

If a person with IGD wants to have children, they will probably need a special kind of GnRH therapy as well. To restore fertility, doctors must administer GnRH in the same kind of pulses as the hypothalamus would normally produce. Without the pulses, the pituitary gland gets desensitized to GnRH and its overall effect decreases [25, 26, 27].

Congenital Combined Pituitary Hormone Deficiency

Congenital combined pituitary hormone deficiency, or CCPHD, is an inherited disorder that prevents the pituitary gland from producing its hormones, including LH and FSH. As a result, people with CCPHD do not grow very tall and may not go through puberty at all [28].

The mechanism and cause of CCPHD are currently unknown. However, 60% of men with CCPHD respond well to GnRH therapies, suggesting that GnRH may be involved in the pathology of the disease [28].

Other GnRH Disorders

PCOS

Polycystic ovarian syndrome (PCOS) is the most common reproductive disorder in women. Women with PCOS have cysts in their ovaries and often don’t ovulate or have periods [29].

PCOS is associated with an unusual hormone profile, including high testosterone and LH and relatively low FSH. In recent years, however, researchers have started to unravel the role of GnRH and various neurotransmitters in this disorder [29, 30, 31].

Women with PCOS tend to have high glutamate and low serotonin, dopamine, GABA, and acetylcholine. This neurotransmitter profile tends to increase the pulse rate of GnRH and LH, which would help explain the high LH to FSH ratio associated with the disorder [31].

GnRH Analogs

Do not under any circumstances use GnRH analogs without the prescription and supervision of a doctor.

GnRH analogs are a class of drugs that resemble GnRH and bind to its receptor. Some such drugs activate the receptor, and others block it; however, if they are taken for a long enough period, all GnRH analogs eventually reduce the effect of GnRH in the body [32].

GnRH antagonists block the GnRH receptor and decrease GnRH effects directly. These include abarelix, degarelix, and cetrorelix [32, 27].

By contrast, GnRH agonists activate the GnRH receptor. At first, this increases the effect of GnRH in a “flare” of LH and FSH. After about three or four weeks, the pituitary gland decreases the number of GnRH receptors and becomes desensitized to GnRH stimulation [32, 27].

GnRH agonists include buserelin, leuprorelin, nafarelin, and triptorelin [33].

In summary:

• GnRH antagonists block GnRH receptors and can only be used to decrease the effect of GnRH.
• GnRH agonists produce a “flare” of LH and FSH and then, over 3 – 4 weeks, also decrease GnRH effectiveness. These agonists can, therefore, be used to increase (short term) and decrease (long term) the effect of GnRH.

GnRH Therapy Uses

GnRH therapies are medical protocols which should only be undertaken with the prescription and supervision of a doctor. Do not under any circumstances attempt to administer GnRH therapy on your own.

GnRH Analogs

Remember that, over time, all GnRH analogs decrease the effect of GnRH. Antagonists bind to GnRH receptors and block them directly; agonists produce a “flare” of LH and FSH and then desensitize the pituitary gland to GnRH. Differently timed doses of GnRH agonists may have different results [32, 27].

GnRH analogs can be used in the following conditions:

1) Cancer

GnRH analogs are useful for preserving fertility and body image during chemotherapy and for sensitizing prostate cancer cells to treatment.

In women undergoing chemotherapy, GnRH agonists protect the function of the ovaries. In this way, women who achieve remission from their cancer can still become pregnant and have children without the need to freeze eggs or embryos [34, 35].

GnRH also has multiple roles in prostate cancer treatment. Prostate tumors require testosterone to grow, and GnRH antagonists dramatically decrease testosterone production. Artificially reducing testosterone – a therapy called “androgen deprivation” – may have a negative impact on people’s body image; treatment with GnRH analogs does not cause body image to deteriorate [36, 37].

More directly, GnRH agonists may sensitize prostate cancer cells to chemotherapy. Furthermore, in a mouse study, a GnRH vaccine delayed prostate tumor growth [38, 39].

2) Infertility and Subfertility

In women, GnRH agonists and antagonists can both be used to stimulate the ovaries and improve fertility. GnRH analogs suppress GnRH production and allow fertility doctors to fine-tune the hormones of the prospective mother. In this capacity, GnRH analogs prevent the ovaries from releasing any eggs until just the right time [27, 40].

GnRH agonists can also help to avoid ovarian hyperstimulation syndrome (OHSS). When women undergo fertility treatment, their ovaries sometimes become overstimulated and inflamed. OHSS can result in nausea, vomiting, severe abdominal pain, electrolyte imbalance, and even kidney failure [41, 42].

GnRH therapies are also used to improve the fertility of dairy cows impregnated by artificial insemination. In a study of Holstein cows, GnRH improved the efficiency of embryo production during early lactation [43, 44].

In dairy cows, GnRH can be used as a treatment option for animals with ovarian cysts. In a study of mice with polycystic ovaries, GnRH restored ovulation [45, 46].

3) Endometriosis

The endometrium is the inner lining of the uterus that grows and sheds during each menstrual cycle. Rarely, some of that endometrial tissue can implant and grow outside of the uterus, causing severe pelvic pain and infertility [47].

The best treatment for endometriosis is a reduction (but not complete elimination) of estrogen. When GnRH analogs decrease LH and FSH, they also reduce the production of sex steroids like estrogen. GnRH antagonists do not completely eliminate estrogen production; they, therefore, have fewer side effects and are better than agonists for this purpose [48].

After surgery to remove endometrial tissue, a combination of GnRH, estrogen, and progesterone therapy prevented the recurrence of pain [49].

4) Problems During Puberty

GnRH therapy suppresses and delays puberty, which can be helpful in conditions like gender dysphoria and precocious puberty.

Gender dysphoria is a condition in which a person does not feel like their body is the correct gender. Puberty delay can effectively help gender dysphoric adolescents by reducing testicular volume or breast development. In this way, young people can prevent unwanted development in advance of hormone replacement therapy [50, 51].

For girls with precocious (early) puberty, GnRH slows the progression of puberty and allows normal development; however, this therapy sometimes causes girls to mature at a shorter height than they would otherwise. A combination of GnRH and growth hormone benefitted the final height of the girls better than GnRH alone [52].

A GnRH analog treatment also helped reduce the number of seizures in a 7-year-old girl with precocious puberty [53].

Pulsatile GnRH

In order to increase the effects of GnRH over a long period of time, treatment has to mimic the natural pulses of GnRH from the hypothalamus. Pulsatile GnRH therapy is often effective for reduced pituitary function and delayed puberty [26, 32].

A reduced pituitary function can prevent puberty from getting started. Long-term pulsatile GnRH may be able to start puberty in adolescents with delayed puberty. It can also maintain sperm and egg production in some adults with pituitary deficiencies [32, 28, 54, 55].

Pulsatile GnRH therapy can restore fertility in people with severe pituitary disorders like Kallmann syndrome, congenital hypogonadotropic hypogonadism (CHH), and congenital combined pituitary hormone deficiency (CCPHD) [26, 28].

In a study of 40 men with CCPHD, three months of pulsatile GnRH therapy restored hormone function in the pituitary gland and testes in 60% of participants. Researchers currently don’t know why some people with CCPHD respond well to pulsatile GnRH therapy and some do not [28].

Inducing Ovulation

Pulses of GnRH can cause some women with hormonal disorders to produce a fertile egg. This type of therapy has been successful in women with hypogonadotropic hypogonadism [56].

Some fertility drugs work by triggering or increasing GnRH release from the hypothalamus. Among these is clomiphene citrate, a common fertility drug that competes with estrogen binding sites. In the hypothalamus, this appears to prevent estrogen from decreasing GnRH pulses [57].

GnRH Analog Side Effects

In Spanish girls with precocious puberty, GnRH therapy increased BMI relative to girls who did not undergo GnRH therapy [58].

GnRH antagonist and GnRH agonist treatments are associated with ectopic pregnancies. An ectopic pregnancy takes place when the embryo implants outside the uterus; this is a dangerous condition that never results in a healthy birth and often threatens the life of the mother [59, 60, 61].

GnRH during assisted reproductive technology cycles such as in-vitro fertilization (IVF) causes inflammation. More specifically, GnRH promotes the Th1 response and reduces the Th2 response. This change may trigger flare-ups in pregnant women with inflammatory conditions [62, 63].

Treatment with GnRH analogs rarely results in severe dysmotility, a condition whereby the muscles in the gut stop functioning correctly, causing digestion problems [64].

In advanced prostate cancer, GnRH treatment was associated with more severe cardiovascular side effects than degarelix treatment [65].

GnRH analog therapy is also associated with an increased risk of PCOS in girls with precocious puberty [66].