Gonadorelin

(British Approved Name, rINN)

Follicle Stimulating Hormone-releasing Factor; GnRH; Gonadoliberin; Gonadoreliini; Gonadorelina; Gonadoréline; Gonadorelinum; Gonadotrophin-releasing Hormone; Hoe-471; LH/FSH-RF;LH/FSH-RH; LH-RF; LH-RH; Luliberin; Luteinising Hormone-releasing Factor.

5-Oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosylglycyl-L-leucyl-L-arginyl-L-prolylglycinamide.

Гонадорелин

Gonadorelin Acetate

Drug Approvals

(BANM, US Adopted Name, rINNM)

Abbott-41070; Acetato de gonadorelina; Gonadolrelin-acetát;Gonadoreliiniasetaatti; Gonadorelinacetat; Gonadorelin-acetát; Gonadoréline, acétate de; Gonadorelini acetas; Gonadorelinoacetatas.

Гонадорелина Ацетат

Pharmacopoeias. In Europe, Japan, and US for veterinary use only.

The United States Pharmacopeia 31, 2008 (Gonadorelin Acetate). A white to slightly yellowish powder. Soluble in water sparingly soluble in methyl alcohol. Store in airtight containers at a temperature of not more than 8°.

European Pharmacopoeia, 6th ed. (Gonadorelin Acetate). The acetate form of a hypothalamic peptide that stimulates the release of follicle-stimulating hormone and luteinising hormone from the pituitary gland. It is obtained by chemical synthesis. A white or slightly yellowish powder soluble in water and in 1% v/v glacial acetic acid sparingly soluble in methyl alcohol. Store in airtight containers at a temperature of 2° to 8°. Protect from light.

Gonadorelin Hydrochloride

Drug Approvals

(BANM, US Adopted Name, rINNM)

AY-24031; Gonadoréline, Chlorhydrate de; Gonadorelini Hydrochloridum; Hidrocloruro de gonadorelina.

Гонадорелина Гидрохлорид

Pharmacopoeias. In US.

The United States Pharmacopeia 31, 2008 (Gonadorelin Hydrochloride). A synthetic polypeptide hormone having the property of stimulating the release of the luteinising hormone from the hypothalamus. It is extremely hygroscopic. Protect from exposure to moisture and store in airtight well-sealed containers, in a desiccator.

Adverse Effects

Gonadorelin and its analogues are generally well tolerated but may cause gastrointestinal adverse effects, usually nausea and abdominal pain or discomfort. There may be headache or lightheadedness, and an increase in menstrual bleeding. Continued therapy with gonadorelin analogues results in paradoxical suppression of the pituitary gonadal axis in premenopausal women this may produce menopausal symptoms, including vaginal dryness, hot flushes, and loss of libido.

If sufficiently prolonged the suppression of circulating oestrogens may lead to osteoporosis. In men, hot flushes and sexual dysfunction can occur, and breast swelling and tenderness have been reported infrequently with gonadorelin analogues. Long-term treatment can also cause a loss of bone mineral density in men. Other adverse effects reportedly associated with gonadorelin analogue therapy, and presumably related to changes in the hormonal milieu, include mood changes, nervousness, palpitations, acne and dry skin, changes in scalp and body hair, alterations in liver function tests and blood lipids, and decreased glucose tolerance. Arthral-gia and paraesthesias have been reported. Ovarian hyperstimulation (as seen with chorionic gonadotrophin), although rare, has occurred in women given gonadorelin.

Reactions or pain may occur at the site of injection with rash (local or generalised), thrombophlebitis, swelling, or pruritus. Hypersensitivity reactions, including bronchospasm and anaphylaxis, have been reported. Other effects may be a consequence of the particular use of gonadorelin or its analogues. Tumour flare, due to an initial surge in testosterone concentrations, has been reported in the initial stages of treatment for cancer of the prostate and prophylactic anti-androgen therapy may be added.

Flare may manifest as an increase in bone pain occasionally there has been spinal cord compression, or a worsening of urinary-tract symptoms with haematuria and urinary obstruction. Acute degeneration of submucous fibroids with severe bleeding has been reported following use of leuprorelin. An initial increase in signs and symptoms has also been reported in women with breast cancer receiving gonadorelin analogues hypercalcaemia has occurred in those with metastatic disease. In girls being treated for precocious puberty, vaginal bleeding may occur in the first month of treatment because of initial ovarian stimulation followed by treatment-induced oestrogen withdrawal.

Hypersensitivity

Acquired hypersensitivity led to an anaphylactic reaction after an intravenous dose of gonadorelin in a man who had been receiving pulsatile subcutaneous gonadorelin therapy for 10 weeks.

Osteoporosis

Long-term use of a gonadorelin analogue results in oestrogen deficiency-associated osteoporosis and various drugs have been investigated for their ability to reduce this effect. Parathyroid hormone has been reported to prevent bone loss in small studies ofyoung women receiving nafarelin. ‘Add-back’ therapy with tibolone or oestrogen plus progestogen has also had beneficial effects on bone mineral density in women receiving gonadorelin analogues. However, studies have used various combination regimens and it is not possible to determine which is most effective. There is less information available about the management of osteoporosis in men receiving gonadorelin analogues as androgen deprivation therapy, but measures have included supplemental calcium and vitamin D, and the use of bisphosphonates. Raloxifene is also under investigation in both women and men.

Pituitary apoplexy

Pituitary apoplexy has been reported after endocrine stimulation testing using gonadorelin. A review of 14 cases found that 2 patients had received gonadorelin alone but most had also received protirelin (thyrotropin-releasing hormone). The onset of initial symptoms was within 2 hours and pituitary tumour haemorrhage was much more common than infarction alone.

Precautions

Gonadorelin or its analogues should not generally be used in patients with pituitary adenoma as haemor-rhagic infarction (pituitary apoplexy) has sometimes occurred. It has also been recommended that patients with weight-related amenorrhoea should not receive these drugs until their weight is corrected. Although at least one manufacturer recommends that gonadorelin should not be used in women with polycystic ovary disease or with endometriotic cysts, gonadorelin and its analogues have been used for ovulation induction in polycystic disease and produced improvement in uterine fibroids gonadorelin analogues have also been used with benefit in endometriosis.

Gonadorelin analogues may increase cervical resistance, making it difficult to dilate the cervix for intra-uterine surgical procedures. Gonadorelin or its analogues should be stopped if the patient becomes pregnant. Contraceptive measures should be taken to protect against unwanted ovulation. Men at risk from tumour flare should be carefully monitored in the first month of therapy.

Interactions

Drugs affecting pituitary secretion of gonadotrophin s may alter the response to gonadorelin or its analogues other hormonal therapy and corticosteroids can affect the response. Spironolactone and levodopa can stimulate gonadotrophins while phenothiazines, dopamine antagonists, digoxin, and sex hormones can inhibit gonadotrophin secretion.

Pharmacokinetics

Gonadorelin is poorly absorbed from the gastrointestinal tract. It has a terminal plasma half-life of only 10 to 40 minutes after intravenous injection. It is hydrolysed in the plasma and excreted in the urine as inactive metabolites.

Gonadorelin analogues are absorbed after oral, intramuscular, intranasal, or rectal doses and have a longer half-life.

Uses and Administration

Gonadorelin is a synthetic form of hypothalamic gonadotrophin-releasing hormone. It stimulates the synthesis and release of follicle-stimulating hormone and, in particular, luteinising hormone in the anterior lobe of the pituitary. The secretion of endogenous gonado-trophin-releasing hormone is pulsatile and is controlled by several factors including circulating sex hormones. Gonadotrophic hormones (gonadotrophins), released from the pituitary gland in response to gonadorelin, stimulate secretion of sex hormones from the gonads.

A single dose of gonadorelin or one of its analogues has the effect of increasing circulating sex hormones continued use leads to down-regulation of gonadorelin-receptor synthesis in the pituitary and results in a paradoxical reduction in sex-hormone secretion. Gonadorelin may be given as the base, acetate, or hydrochloride, and the dose may be expressed in terms of any of these.

Gonadorelin is used in the diagnosis of hypothalamic-pituitary-gonadal dysfunction. Assessment is usually based on the response to a dose of gonadorelin of 100 micrograms by intravenous or subcutaneous injection. In females, where possible, it should be given early in the follicular stage of the menstrual cycle. In the UK, the BNFC includes a single dose of 2.5 micrograms/kg, to a maximum of 100 micrograms, for children from the age of 1 year. Gonadorelin is also used in the treatment of amenorrhoea and infertility associated with hypogonadotrophic hypogonadism. Weight-related amenorrhoea should have been corrected by diet.

Treatment in such conditions is based on an intermittent pulse pump providing 5 to 20 micrograms over one minute every 90 minutes, either subcutaneously or intravenously, for up to 6 months or until conception. Gonadorelin or, more usually, its analogues such as buserelin, goserelin, leuprorelin, nafarelin, and trip-torelin (which are more potent and have a longer duration of action) are used in cryptorchidism, malignant neoplasms (especially of the prostate), and in delayed and precocious puberty.

Benign prostatic hyperplasia

The gonadorelin analogues have been tried in the management of benign prostatic hyperplasia but are considered unsatisfactory for indefinite use. See also under Leuprorelin Acetate, and Nafarelin Acetate.

Cryptorchidism

Although surgery remains the treatment with the best success rate, primary hormonal therapy with gonadorelin or an analogue is widely used for cryptorchidism. Systematic reviews’ suggest a success rate of about 20% overall, although this may be reduced when care is taken to exclude retractile testes. There is some suggestion that medical treatment given either before or after surgery can improve the patient’s fertility index, a predictor of future fertility.

Delayed and precocious puberty

For mention of the use of gonadorelin or its analogues in delayed and precocious puberty, and respectively. Benefit in delayed puberty is most likely in those cases where it is secondary to hypogonadism.

Diagnosis of hypothalamic and pituitary dysfunction.

Gonadorelin may be used in the diagnosis of hypothalamic -pituitary -gonadal dysfunction such as in hypogonadism, delayed puberty, and precocious puberty.

Disturbed behaviour

Gonadorelin analogues such as leuprorelin or triptorelin may be tried in men with paraphilias.

Endometriosis

Gonadorelin analogues are effective in the management of endometriosis, but the need for long-term therapy to prevent recurrence limits their value, because of the risk of osteoporosis. ‘Add-back’ therapy (hormone replacement) may be given in an attempt to reduce bone mineral density loss and vasomotor symptoms.

Fibroids

Uterine fibroids (leiomyomas) are benign tumours of uterine smooth muscle. They are found in about 25% of women, most of whom are aged in their 30s or 40s when the condition becomes symptomatic. Fibroids may give rise to menstrual problems, particularly menorrhagia, pelvic discomfort, infertility, and miscarriage. Although small fibroids may not require treatment, the management of symptomatic fibroids has traditionally been surgical. However, because fibroids are oestrogen responsive, gonadorelin analogues have also been tried as medical treatment for their ability to induce a hypogonadotrophic hypogonadal state.

These drugs produce a significant reduction in uterine and fibroid volume, and amenorrhoea, but when treatment stops uterine and fibroid volume tend to return to pretreatment values. The hypoestrogenism produced during treatment also causes menopausal symptoms such as hot flushes and vaginal dryness, and bone loss may occur. Giving oestrogens or progestogens, once the uterine fibroid size has significantly reduced, has been tried as ‘add-back’ therapy to counteract these adverse effects. Tibolone has also been reported to reduce bone loss and vasomotor symptoms.

Subcutaneous injection of long-acting depot preparations of gonadorelin or its analogues appears to be the preferred method and is considered a valuable pre-operative adjunct to surgery, simplifying the procedure by reducing uterine and fibroid volume and intra-operative blood loss, as well as correcting pre-operative iron-deficiency anaemia. However, concern has been expressed that the use of gonadorelin analogues for treating fibroids may complicate the differentiation of benign and malignant growths.

Other drugs that are under investigation for fibroids include gonadorelin antagonists such as cetrorelix and ganirelix, and mife-pristone. Danazol and gestrinone have also been tried in a small number of patients.

Growth retardation

The use of a gonadorelin analogue to delay precocious puberty may improve the final height of children with the disorder. However, the use of a gonadorelin analogue with growth hormone in short but otherwise normal children is controversial — see under Triptorelin.

Infertility

Gonadorelin and its analogues are used in the management of infertility related to hypogonadotrophic hypogonadism in both women and men. Some further references are given below. See also under Buserelin Acetate, Leuprorelin Acetate, and Nafarelin Acetate. For mention of the use of gonadorelin and its analogues in the management of infertility in polycystic ovary syndrome, see below.

Malignant neoplasms

Gonadorelin analogues are used in the treatment of prostatic cancer where they provide an alternative to orchidectomy in the management of advanced disease. They may also be used for ovarian ablation in premenopausal women with breast cancer. Gonadorelin analogues have been tried in neoplasms of the endometrium and ovary, but their use is much less well established. Analogues used include buserelin, goserelin, leuprorelin, and triptorelin.

Mastalgia

Gonadorelin analogues such as goserelin may be effective in severe refractory mastalgia.

Polycystic ovary syndrome

Gonadorelin and its analogues have been used in the management of infertility associated with polycystic ovary syndrome (see Infertility), even though some product information contra-indicates their use in this syndrome.

Pulsatile gonadorelin has been tried for ovulation induction but rates of ovulation and pregnancy are poor when it is used alone in women with polycystic ovary syndrome. Pretreatment with a gonadorelin analogue for pituitary desensitisation before starting pulsatile gonadorelin has shown some benefit in patients with polycystic ovary syndrome who have high levels of luteinising hormone. However, there is only limited clinical data from small short-term trials and case series on the use of pulsatile gonadorelin in these women.

Gonadorelin analogues may be used for pituitary desensitisation before the use of gonadotrophins for ovulation induction, and there is a suggestion that this strategy may improve pregnancy rates compared with gonadotrophins alone in women with polycystic ovary syndrome. Gonadorelin analogues are used also in ovarian stimulation protocols for assisted reproduction techniques.

Women with polycystic ovary syndrome are at increased risk of ovarian hyperstimulation syndrome and must be carefully monitored throughout the use of ovulation induction regimens.

Porphyria

For mention of the use of gonadorelin analogues to suppress cyclic premenstrual exacerbations of acute porphyria, see Buserelin, Nafarelin, and Triptorelin.

Premenstrual syndrome

In women in whom other drug treatments for premenstrual syndrome are ineffective, use of a gonadorelin analogue, usually with HRT as ‘add-back’ therapy to prevent menopausal symptoms, may be considered. Short-term therapy (3 months) has been used to confirm the diagnosis of premenstrual syndrome, or to predict the response to bilateral oophorectomy when this is being considered. Some references to the use of gonadorelin analogues in premenstrual syndrome are given below.

Preparations

The United States Pharmacopeia 31, 2008: Gonadorelin for Injection.

Proprietary Preparations

Argentina: Luteoliberina

Austria: Kryptocur Lutrele Relefact LH-RH

Belgium: HR

Brazil: Parlib

Canada: Lutrepulse

Czech Republic: Relefact LH-RH

France: Lutrele Stimu-LH

Germany: Kryptocur Lutrele Relefact LH-RH

Greece: Relefact LH-RH

Hong Kong: Relisorm L

Hungary: Relisorm I

Israel: Lutrele Relefact LH-RH

Italy: Kryptocur Lutrele

The Netherlands: Cryptocur HR Lutrele Relefact LH-RH

New Zealand: HR

South Africa: HR

Spain: Luforan

Sweden: Lutrele

Switzerland: Kryptocur Lutrele Relisorm L

United Kingdom: HR

USA: Factrel