Gonadotropin releasing

hormone and the

Gonadotropins
Haftom G. (MSc)
Fig: The hypothalamic-
pituitary-gonadal axis.
 Gonadotropin-releasing hormone

• GnRH release is pulsatile and is governed by a hypothalamic neural pulse generator

• Shortly before puberty, CNS inhibition decreases and the amplitude and frequency of GnRH pulses
increase, particularly during sleep.

• As puberty progresses, the GnRH pulses increase further in amplitude and frequency until the normal
adult pattern is established.

• The intermittent release of GnRH is crucial for the proper synthesis and release of the
gonadotropins; the continuous administration of GnRH leads to desensitization and downregulation
of GnRH receptors on pituitary gonadotropes.
Clinical Disorders of the Hypothalamic-PituitaryGonadal Axis

• Clinical disorders of the hypothalamic-pituitary-gonadal axis can manifest either

as alterations in levels and effects of sex steroids (hyper- or hypogonadism) or as
impaired reproduction.
• Deficient sex steroid production resulting from hypothalamic or pituitary
defects is termed hypogonadotropic hypogonadism because circulating levels of
gonadotropins are either low or undetectable.
• Hypogonadotropic hypogonadism in some patients results from GnRH receptor
mutations
Clinical Disorders of the Hypothalamic-PituitaryGonadal Axis

• Reproductive disorders caused by processes that directly

impair gonadal function are termed hypergonadotropic
• Because the impaired production of sex steroids leads to a loss of negative-
feedback inhibition, thereby increasing the synthesis and secretion of
gonadotropins
 Clinical Disorders of the Hypothalamic-PituitaryGonadal Axis

 Precocious Puberty.

• Development of secondary sexual characteristics

• Breast dev’t in girls and testes enlargement in boys) do not occur before age 8 in girls or age 9 in boys

• Initiation of sexual maturation before this time is termed “precocious.”

• GnRH-dependent excessive secretion of gonadotropins ( rare)

• GnRH-independent precocious puberty results from peripheral production of sex steroids

in a manner not driven by pituitary gonadotropins
 Clinical Disorders of the Hypothalamic-Pituitary Gonadal Axis

 Sexual Infantilism
• The converse of precocious puberty is a failure to initiate the processes of pubertal development
at the normal time.

• This can reflect defects in the GnRH neurons or gonadotropes (secondary hypogonadism) or
primary dysfunction in the gonads.

• In either case, induction of sexual maturation using sex steroids (estrogen followed by
estrogen/progesterone in females, testosterone in males) is standard therapy.

• This suffices to direct sex differentiation in the normal manner.

 Clinical Disorders of the Hypothalamic-Pituitary Gonadal Axis

 Infertility:
• A failure to conceive after 12 months of unprotected intercourse, is seen in up to
10%–15% of couples and is increasing in frequency as women choose to delay
childbearing.
 When the infertility is due to impaired synthesis or secretion of gonadotropins
(hypogonadotropic hypogonadism), various pharmacological approaches are employed.

 In contrast, when infertility results from intrinsic processes affecting the gonads,
pharmacotherapy generally is less effective.
 Gonadotropin-releasing hormone
• Pulsatile secretion GnRH from the hypothalamus is essential for the release of the
gonadotropins: FSH and LH

• Continuous administration of GnRH inhibits gonadotropin release through down-

regulation of the GnRH receptors on the pituitary.

Continuous administration of synthetic GnRH analogs is effective in suppressing

production of the gonadotropins

Suppression of gonadotropins, in turn, leads to reduced production of gonadal

steroid hormones (androgens and estrogens).
Fig: Secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH).
 Gonadotropin-releasing hormone....

• Thus, these agents are effective in the treatment of prostate cancer,

endometriosis, and precocious puberty.

• In women, the GnRH analogs may cause hot flushes and sweating, as well as
diminished libido, depression, and ovarian cysts.

• In men, they initially cause a rise in testosterone that can result in bone pain.
Hot flushes, edema, gynecomastia, and diminished libido may also occur.
 GnRH and Its Synthetic Agonist Analogues

• GnRH is a decapeptide found in all mammals.

 Substitution of amino acids at the 6 position or replacement of the C-terminal glycineamide
produces synthetic agonists.
 Both modifications make them more potent and longer-lasting than native GnRH and
gonadorelin.

• Such analogs of GnRH include: goserelin, buserelin, histrelin, leuprolide,

nafarelin, and triptorelin.
• Gonadorelin is an acetate salt of synthetic human GnRH.
 Pharmacokinetics
• Gonadorelin can be administered intravenously or subcutaneously.

• Other GnRH agonists can be administered SC, IM, via nasal spray (nafarelin), or as a subcutaneous implant.

• The half-life of intravenous gonadorelin is 4 minutes, and

• The half-lives of subcutaneous and intranasal GnRH analogs are approximately 3 hours.

• The duration of clinical uses of GnRH agonists varies from a few days for controlled ovarian stimulation to a
number of years for treatment of metastatic prostate cancer.

• Therefore, preparations have been developed with a range of durations of action from several hours (for
daily administration) to 1, 4, 6, or 12 months (depot forms).
Table : Structures of gonadotropin-releasing hormone and gnrh analogues
 Clinical Uses
 Stimulation
1. Female infertility

• Gonadorelin or a GnRH agonist analog can be used to initiate an LH surge and ovulation
in women with infertility who are undergoing ovulation induction with gonadotropins.

• Traditionally, hCG has been used to initiate ovulation in this situation.

• However, there is some evidence that gonadorelin or a GnRH agonist is less likely than
hCG to cause OHSS
 Clinical Uses
2. Male infertility—It is possible to use pulsatile gonadorelin for infertility in men with
hypothalamic hypogonadotropic hypogonadism.

• A portable pump infuses gonadorelin intravenously every 90 minutes. Serum

testosterone levels and semen analyses must be done regularly. At least 3–6 months of
pulsatile infusions are required before significant numbers of sperm are seen.

• As described above, treatment of hypogonadotropic hypogonadism is more commonly

done with hCG and hMG or their recombinant equivalents.
 Clinical Uses
3. Diagnosis of LH responsiveness

• GnRH may be useful in determining whether delayed puberty in a hypogonadotropic adolescent

is due to constitutional delay or to hypogonadotropic hypogonadism.

• The LH response (but not the FSH response) to a single dose of GnRH may distinguish between
these two conditions; however, there can be significant individual overlap in the LH response
between the two groups. Serum LH levels are measured before and at several times after an
intravenous or subcutaneous bolus of GnRH. An increase in serum LH with a peak that is greater
than 5–8 mIU/mL suggests early pubertal status

• An impaired LH response suggests hypogonadotropic hypogonadism due to either pituitary or

hypothalamic disease, but does not rule out constitutional delay of puberty
 Clinical Uses
B. Suppression of Gonadotropin Production
1. Controlled ovarian stimulation—In the controlled ovarian stimulation that provides
multiple mature oocytes for assisted reproductive technologies such as in vitro fertilization,
it is critical to suppress an endogenous LH surge that could prematurely
trigger ovulation.

• This suppression is most commonly achieved by daily subcutaneous injections of

leuprolide or daily nasal applications of nafarelin.
 Clinical Uses
B. Suppression of Gonadotropin Production
2. Endometriosis—Endometriosis is defined as the presence of estrogen-sensitive endometrium
outside the uterus that results in cyclical abdominal pain in premenopausal women.

• The pain of endometriosis is often reduced by abolishing exposure to the cyclical changes in the
concentrations of estrogen and progesterone that are a normal part of the menstrual cycle.

• The ovarian suppression induced by continuous treatment with a GnRH agonist greatly reduces
estrogen and progesterone concentrations and prevents cyclical changes.

• The preferred duration of treatment with a GnRH agonist is limited to 6 months (↓ bone
mineral density).
 Clinical Uses
B. Suppression of Gonadotropin Production
3. Uterine leiomyomata (uterine fibroids)—Uterine leiomyomata are benign, estrogen-sensitive,
smooth muscle tumors in the uterus that can cause menorrhagia, with associated anemia and pelvic pain.

• The effects of GnRH agonists are temporary, with gradual recurrent growth of leiomyomas to previous
size within several months after cessation of treatment.

• GnRH agonists have been used widely for preoperative treatment of uterine leiomyomas, both for
myomectomy and hysterectomy.

• GnRH agonists have been shown to improve hematologic parameters, shorten hospital stay, and
decrease blood loss, operating time, and postoperative pain when given for 3 months preoperatively.
 Clinical Uses
B. Suppression of Gonadotropin Production
4. Prostate cancer—Androgen deprivation therapy is the primary medical therapy
for prostate cancer.
• Combined anti-androgen therapy with continuous GnRH agonist and an androgen
receptor antagonist is as effective as surgical castration in reducing serum
testosterone concentrations and effects
• Leuprolide, goserelin, histrelin, buserelin, and triptorelin are approved for this
indication
 Clinical Uses
B. Suppression of Gonadotropin Production

5. Central precocious puberty—Continuous administration of a GnRH agonist is

indicated for treatment of central precocious puberty (onset of secondary sex
characteristics before 7–8 years in girls or 9 years in boys).
• Synthetic GnRH analogues play important roles in the diagnosis and
treatment of GnRH-dependent precocious puberty.

• In contrast, drugs that interfere with the production of sex steroids,

including ketoconazole and aromatase inhibitors, are used in
patients with GnRH-independent precocious puberty, with varying
success.
 Clinical Uses

6. Other—The gonadal suppression provided by continuous GnRH agonist

treatment is used in the management of advanced breast and ovarian cancer.

• In addition, recently (2018 GC) published clinical practice guidelines recommend

the use of continuous GnRH agonist administration in early pubertal transgender
adolescents to block endogenous puberty prior to subsequent treatment with
cross-gender gonadal hormones
 Side effects of GnRH analogs

• Gonadorelin can cause headache, light-headedness, nausea, and flushing.

• Local swelling at SC injection sites.

• Gonadal steroidogenesis is inhibited (e.g., hot flashes and decreased bone

density in both sexes, vaginal dryness and atrophy in women, and erectile
dysfunction in men).

• Because of these effects, therapy in non–life-threatening diseases such as

endometriosis or uterine fibroids generally is limited to 6 months.

• GnRH agonists are contraindicated in pregnant women and breast-feeding.

 GnRH receptor antagonists

• Four synthetic decapeptides that function as competitive antagonists of GnRH

receptors are available for clinical use (2018 GC).

• Ganirelix, cetrorelix, abarelix, and degarelix inhibit the secretion of FSH

and LH in a dose-dependent manner.

• Ganirelix and cetrorelix are approved for use in controlled ovarian stimulation
procedures, whereas degarelix and abarelix are approved for men with advanced
prostate cancer.
 GnRH receptor antagonists
• Clinical use
A. Suppression of Gonadotropin Production

• GnRH antagonists are approved for preventing the LH surge during controlled ovarian
stimulation.

B. Advanced Prostate Cancer

• Degarelix and abarelix: approved for the Rx of symptomatic advanced prostate cancer.

• These GnRH antagonists reduce concentrations of gonadotropins and androgens more

rapidly than GnRH agonists and avoid the testosterone surge seen with GnRH agonist
therapy.
 GnRH receptor antagonists

• Adverse Effects

Injection site reactions

Hot flashes, Weight gain, decreased bone mineral density

Increases in transaminase and γ-glutamyltransaminase levels

Prolonged QT interval
 Gonadotropins
• The gonadotropins include LH, FSH, and CG.

• They are referred to as the gonadotropins because of their actions on the gonads.

• Together with TSH, they constitute the glycoprotein family of pituitary hormones

• LH and FSH were named initially based on their actions on the ovary;

appreciation of their roles in male reproductive function came later.

 Gonadotropins

• LH and FSH are synthesized and secreted by gonadotropes, which make up about

10% of the hormone-secreting cells in the anterior pituitary.

• CG is produced by the placenta only in primates and horses.

• GnRH stimulates pituitary gonadotropin production, which is further regulated by

feedback effects of the gonadal hormones

 Physiology of the Gonadotropins

• In men
LH acts on testicular Leydig cells to stimulate the de novo synthesis of

androgens, primarily testosterone, from cholesterol.

FSH acts on the Sertoli cells to stimulate the production of proteins and

nutrients required for sperm maturation.

 Physiology of the Gonadotropins
 In women, the actions of FSH and LH are more complex.
 FSH stimulates the growth of developing ovarian follicles and induces the expression of LH

receptors on theca and granulosa cells.

 FSH also regulates the expression of aromatase: synthesis of estradiol.

 LH acts on the theca cells to stimulate the de novo synthesis of androstenedione, the major

precursor of ovarian estrogens in premenopausal women.

 LH also is required for the rupture of the dominant follicle during ovulation and for the synthesis of

progesterone by the corpus luteum

 Gonadotropins & Human Chorionic
Gonadotropin
 Gonadotropins (FSH and LH) are

Glycoproteins that are produced in the anterior pituitary.

Produced by a single type of pituitary cell, the gonadotroph.

Serve complementary functions in the reproductive process.

In women, the principal function of FSH is to direct ovarian follicle development.

Both FSH and LH are needed for ovarian steroidogenesis.

 Gonadotropins & Human Chorionic
Gonadotropin….
 Gonadotropins (FSH and LH)…

In the ovary, LH stimulates androgen production by theca cells in the follicular stage of the
menstrual cycle, whereas FSH stimulates the conversion by granulosa cells of androgens to
estrogens.

In the luteal phase of the menstrual cycle, estrogen and progesterone production is
primarily under the control first of LH and then, if pregnancy occurs, under the control of
human chorionic gonadotropin (hCG).

Human chorionic gonadotropin is a placental protein nearly identical with LH; its actions
are mediated through LH receptors.
 Gonadotropins & Human Chorionic
Gonadotropin….
 Gonadotropins (FSH and LH)…

In men, FSH is the primary regulator of spermatogenesis, whereas LH is the main
stimulus for testosterone synthesis in Leydig cells.

FSH helps maintain high local androgen concentrations in the vicinity of developing
sperm by stimulating the production of androgen-binding protein in Sertoli cells.

FSH also stimulates the conversion by Sertoli cells of testosterone to estrogen.

 Gonadotropins & Human Chorionic
Gonadotropin….
 FSH, LH, and hCG

Used in states of infertility to stimulate spermatogenesis in men and to induce

ovulation in women.
 Menotropins

• The first commercial gonadotropin product was extracted from the

urine of postmenopausal women, which contains a substance with
FSH-like properties (but with 4% of the potency of FSH) and an LH-like
substance.

• This purified extract of FSH and LH is known as menotropins, or

human menopausal gonadotropins (hMG).
 Follicle-Stimulating Hormone
• Three forms of purified FSH are available.

• Urofollitropin, also known as uFSH, is a purified preparation of human FSH extracted from the
urine of postmenopausal women.

• Two recombinant forms of FSH (rFSH) are also available: follitropin alfa and follitropin beta.

• The amino acid sequences of these two products are identical to that of human FSH.

• They differ from each other and urofollitropin in the composition of carbohydrate side chains.

• The rFSH preparations have a shorter half-life than preparations derived from human urine
but stimulate estrogen secretion at least as efficiently and, in some studies, more efficiently.

• The rFSH preparations are considerably more expensive.

 Luteinizing Hormone
• Lutropin alfa: recombinant form of human LH

• When given SC: t1/2~ 10 hours.

• Lutropin has only been approved for use in combination with follitropin alfa for
stimulation of follicular development in infertile women with profound LH
deficiency.
 Human Chorionic Gonadotropin

• hCG is produced by the human placenta and excreted into the urine, whence it
can be extracted and purified.

• It is a glycoprotein consisting of a 92-amino-acid α chain virtually identical to that

of FSH, LH, and TSH, and a β chain of 145 amino acids that resembles that of LH
except for the presence of a carboxyl terminal sequence of 30 amino acids not
present in LH.
 Human Chorionic Gonadotropin….
• Choriogonadotropin alfa (rhCG) is a recombinant form of hCG.

• Because of its greater consistency in biologic activity, rhCG is packaged and dosed on
the basis of weight rather than units of activity.

• All of the other gonadotropins, including rFSH, are packaged and dosed on the basis of
units of activity.

• The preparation of hCG that is purified from human urine is administered by

intramuscular injection, whereas rhCG is administered by subcutaneous injection.
 Cont’d……
• The gonadotropins and hCG exert their effects through GPCRs

• LH and FSH have complex effects on reproductive tissues in both sexes.

• In women, these effects change over the time course of a menstrual cycle as a
result of a complex interplay between concentration-dependent effects of the
gonadotropins, cross-talk between LH, FSH, and gonadal steroids, and the
influence of other ovarian hormones.
 Cont’d……
 Clinical indication
I. Ovulation Induction

• Gonadotropins are used to induce ovulation in women with anovulation that is

secondary to hypogonadotropic hypogonadism, polycystic ovary syndrome,
obesity, and other causes.

• Because of the high cost of gonadotropins and the need for close monitoring
during their administration, they are generally reserved for anovulatory women
who fail to respond to other less complicated forms of treatment (eg, clomiphene)
Fig: Controlled ovarian hyperstimulation in preparation for an assisted reproductive
technology such as in vitro fertilization.
 Cont’d……
 Clinical indication…..
II. Male Infertility

• Most of the signs and symptoms of hypogonadism in males can be adequately

treated with exogenous androgen; however, treatment of infertility in hypogonadal
men requires the activity of both LH and FSH.

• In men with hypogonadal hypogonadism, it takes an average of 4–6 months of

treatment with hCG for sperm to appear in the ejaculate.

• Urofollitropin, rFSH, and rLH are also used

 Cont’d……
 Adverse effects
Two most serious complications are the ovarian hyperstimulation syndrome

and multiple pregnancies.

 Ovarian hyperstimulation is characterized by ovarian enlargement, ascites,

hydrothorax, and hypovolemia, sometimes resulting in shock.

Other reported adverse effects of gonadotropin treatment are headache,

depression, edema, precocious puberty, and (rarely) production of antibodies to
hCG.
Thank you!!