gn rh analogues in gynaecology

Disclosure

Nothing to disclose

GnRH Analogues in Gynaecology

beyond fertility

Poonam Loomba, M.D.

Native Gnrh The structure of

Gonadotropin -releasing hormone (GnRH) was discovered by Guillemin and Schally in 1967

Neurohormone GnRH is considered a 

neurohormone

 A key area for production of GNRH is the preoptic area of the hypothalamus, which contains most of the GnRH-secreting neurons.

GnRH is found in organs outside the hypothalamus and pituitary e.g.Placenta,Gonads

GnRH Receptors

Breast Prostate

Ovary Endometrium

Action The portal blood carries the GnRH to

the pituitary gland, which contains the gonadotropecells, where GnRH activates its own receptor, gonadotropin-releasing hormone receptor (GnRHR).

This results in the activation of proteins involved in the synthesis and secretion of the gonadotropins LH and FSH. GnRH is degraded by proteolysis within a few minutes.Process is regulated by GnRH pulses and estrogen /androgen feedback

Low-frequency GnRH pulses are required for FSH release, whereas high-frequency GnRH pulses stimulate LH pulses in a one to one manner.[3]

GnRH Analogues Development of

clinically safe agonist was simple by changing one or two amino acids

Required 30 years of trial to develop antagonist by changing three or more amino acids

GnRH agonists are derived from native GnRH by substitution of a D-amino acid for the native L-amino acid at position 6 in the decapeptide

Modifications mainly at positions 6 and 10 gave rise to agonists with increased potency, extending the half life from minutes to hours and raising the binding capacity more than 100-fold

1 2 43 65 98 100

7

pyro (Glu) – His – Trp – Ser – Tyr – Gly – Leu – Arg – Pro – Gly – NH2

activation of the

GnRH receptor

regulation of

GnRHrecepto

raffinity

regulation of

biologic activity

GnRHa switch off ovaries temporarily

Mechanism of action Follicle-stimulating hormone and luteinizing

hormone (LH) secretion from the pituitary requires a pulsatile secretion of GnRH from hypothalamus, which allows receptor concentrations to be replenished between pulses.

A constant infusion of GnRH causes an initial agonistic action or the “flare” response, followed by downregulation of receptor concentrations, which desensitizes the pituitary to continued stimulation

Action of GnRH agonists

LH + FSH

post-receptor-cascade

GnRH - receptor

GnRH

GnRH - agonistflare up effect

Downregulation

pituitary suppression

The “flare” response is because of the release of the gonadotropins which are already produced and stored in pituitary, and indeed “flare” is greatest in the early follicular phase when GnRH and estradiol have combined to create a large reserve pool of gonadotropins.

Within 3 to 4 weeks, it induces a hypogonadotropic - hypogonadal state, a situation simulating WHO Group-1 anovulation (hypogonadotropic hypogonadal anovulation

Initially, this response is due to desensitization and downregulation and the same is sustained because of gradual loss of receptors and the uncoupling of the receptor from its effector system.

In addition, postreceptor mechanisms lead to secretion of biologically inactive gonadotropins, which may still be detected by immunoassay..

Action of GnRH antagonists

LH + FSH

post-receptor-cascade

GnRH - receptor

GnRH

GnRH - antagonist

pituitary suppression

Mechanism of action GnRH antagonist Competitive blockage of native GnRH receptors

and block their ability to initiate dimer formation and signal transduction

Cause immediate,rapid,reversible suppression of gonadotropin secreation

Since there is no receptor loss a constant supply of antagonist is required to ensure that all receptors are blocked

Consequently, they produce an immediate decline in gonadotropin levels and provide a therapeutic effect within 24 to 72 hours

GnRH agonists preperations• Agonists with 2 substitutions include:• leuprolide (Lupron) 3.75mg 11.25mg

22.5mg• buserelin (Suprefact)• nafarelin (Synarel)• histrelin (Supprelin )• goserelin (Zoladex)• deslorelin (Suprelorin)• Triptorelin

• Available as daily injections,depot prep,nasal sprays,implants(historelin)

Preparations of Gnrh antagonists Third generation preparations Cetrorelix Ganirelix Ramorelix Antarelix Abarelix

Therapeutic Uses of Synthetic GnRH Analogues

• Female and male infertility• Diagnosis of LH responsiveness

• Endometriosis

• Uterine Fibroids

• Prostate Cancer

Central Precocious Puberty

use in sex reassignment of male to female transsexuals,

management of final height in cases of congenital adrenal hyperplasia,

and preserving ovarian function in women undergoing cytotoxic chemotherapy

Endometriosis

EndometriosisEffective in relieving pain in women with endometriosis.

However, once the treatment is stopped, pain of lesser or equal intensity may recur and the recurrence rate is at around 10 to 20% per year.

The overall cumulative recurrence rate 5 years after treatment with a GnRH agonist is approximately 55%; it is around 37% for women with minimal and mild endometriosis but double the rate, i.e., 74%, for those with advanced disease.

Currently considered as second line therapy when ocp and progesterones fail or are contraindicated

Fibroids

Submucous fibroids –grading :

T0- whole in endometrial cavity

T1 - >50% in endometrial cavity

T2- < 50% in endometrial cavity

Fibroids

It has been shown that treatment with GnRH agonist for a 3-month duration results in a 40% to 60% decrease in the mean uterine volume.

The maximum reduction in uterine volume is usually noted by the third month of treatment.

 Premenstrual dysphoric disorderLong-term treatment with Gnrh analogues was limited because of hypoestrogenic side effects, loss of bone mineral density, and cost.

With the advent of add-back therapy, there has been a resurgence of interest in treating this condition with GnRH agonists and as expected has been found to be very useful in markedly alleviating the symptoms of PMDD and PMS.

Abnormal uterine bleeding

GnRH agonists given for 8 wks have been found to be effective in producing desired endometrial thinning before ablation

PRECOCIOUS PUBERTY• Appearance of secondary sexual characteristics before the age of 8

years in girls and before the age of 9 years in boys

• The overall incidence has been estimated to be 1:5,000 to 1:10,000 children

• The female to male ratio is approximately 10:1

A GnRH challenge test that demonstrates the pubertal response of gonadotropin (i.e., LH response > FSH response) is the hallmark of this diagnosis as is the usual ability to suppress pubertal development with GnRH agonists

This results from early maturation of the hypothalamic- pituitary-gonadal axis

Idiopathic precocious puberty seems to be the most common cause of CPP

GnRH agonists in precocious puberty: effects on stature growth

• Predicted height has been shown to improve with long-term GnRH agonist therapy and the absence of treatment is associated with reductions of these height predications

• Studies consistently demonstrate that girls presenting under age six are able to subsequently achieve normal adult height because of the GnRH agonist therapy

•Girls treated in childhood with GnRH a have normal BMI, BMD, body composition, and ovarian function in early adulthood

•There is no evidence that GnRH a treatment predisposes to polycystic ovary syndrome or menstrual irregularities later after discontinuation of therapy

GONADAL PROTECTION Cellular apoptosis is prevented by direct

action of GnRH a on the gonads By suppression of HPO axis Decreased perfusion of ovaries Cause a higher spontaneous rate of menses

and ovulation Injections more effective than intranasal route Should be administered during the entire

course of chemotherapy treatment

Sex assignment from male to female

Hirsutism

 Along with reducing hirsutism, GnRH agonists also decreases serum levels of gonadotropins, total testosterone, free testosterone, and androstenedione.

Add-back therapy further decreases serum testosterone levels and also reduces the hypoestrogenic side effects of analogues

GnRH agonist therapy indicated in women with ovarian hyperandrogenism who do not respond adequately to oral contraceptive therapy with or without use of an antiandrogen.

Miscellaneous USES Intractable chronic abdominal pain from functional bowel disease

Management of severe porphyria Combination of GH and GnRH-a have

been found to improve final adult height in patients with CAH

Miscellaneous uses

GnRH agonists have been put to use in treatment of cancers that are hormonally sensitive and where a hypogonadal state decrease the chances of recurrence. This includes the medical management of prostate cancer in males and also patients with breast cancer.

GnRH agonists have also been found to offset the hyperprolactinemia fashioned by microprolactinomas.

.[

Diagnostic usages

injection of native GnRH in human beings elicits an immediate response that may be used to evaluate the status of hypothalamic-pituitary-gonadal function in a variety of neuroendocrine conditions associated with amenorrhea and infertility. This provocative test has been used in an attempt to differentiate hypothalamic disorders from primary pituitary deficiencies.[44–47] Some authorities have also advocated the use of GnRH-a in diagnosis of endometriosis by what is called as “therapeutic trial.”[48] This is based on the premise that empiric medical treatment in patients with chronic pelvic pain and a high probability of endometriosis often can avoid a diagnostic surgical procedure.[49]

SIDE EFFECTS hot flashes, (80% women) decreased libido (especially because androgen

production is also suppressed along with estrogen),arthralgia,myalgia

breakthrough bleeding, vaginal dryness,(30 % women) irritability, fatigue, frontal headache, depression, changes in

skin texture, and bone mineral depletion.(after 6 months of therapy)

Standard GnRH agonist treatment regimens of 6 months cause significant bone loss in both the trabecular and cortical bone which manifests typically at lumbar spine and femoral neck, respectively.

The bone loss may even exceed 1% per month. Once the treatment is discontinued, bone loss recovers slowly, but may not be completely recovered in all women.

ADD-BACK

Commonly employed "add back" regimens are as follows:

low-dose combined estrogen-progestin;estrogen-only, progestins alone; bisphosphonates; tibolone;raloxifene.

Combined estrogen-progestin add-back treatment regimens protect bone and have the added advantage of preventing hot flushes and the development of genitourinary atrophy.

Is it a wonder drug?

Conclusion Ongoing research is needed to identify

more indications Antagonist with better tolerance need to be

explored Injudicious use is not advocated Clinicians should be made aware to realise

the drug’s full potential. When used appropraitely with full potential

it can be labelled as “wonder drug”