Gonadotropins (Gns)

GONADOTROPINS (Gns)

The anterior pituitary secretes two Gns viz. FSH and LH. Both are glycoproteins containing 23– 28% sugar and consist of two peptide chains having a total of 207 amino acid residues. FSH has MW 32,000 while LH has MW 30,000.

Physiological Functions

FSH and LH act in concert to promote gametogenesis and secretion of gonadal hormones.

FSH In the female it induces follicular growth, development of ovum and secretion of estrogens. In the male it supports spermatogenesis and has a trophic influence on seminiferous tubules. Ovarian and testicular atrophy occurs in the absence of FSH.

LH It induces preovulatory swelling of the ripe graafian follicle and triggers ovulation followed by luteinization of the ruptured follicle and sustains corpus luteum till the next menstrual cycle. It is also probably responsible for atresia of the remaining follicles. Progesterone secretion occurs only under the influence of LH. In the male LH stimulates testosterone secretion by the interstitial cells and is designated interstitial cell stimulating hormone (ICSH).

Distinct LH and FSH receptors are expressed on the target cells. Both are G protein coupled receptors which on activation increase cAMP production. This in turn stimulates gametogenesis and conversion of cholesterol to pregnenolone—the first step in progesterone, testosterone and estrogen synthesis. In the testes FSH receptor is expressed on seminiferous (Sertoli) cells while LH receptor is expressed on interstitial (Leydig) cells. In the ovaries FSH receptors are present only on granulosa cells, while LH receptors are widely distributed on interstitial cells, theca cells, preovulatory granulosa cells and luteal cells.

Regulation Of Secretion

A single releasing factor (decapeptide designated GnRH) is produced by the hypothalamus which stimulates synthesis and release of both FSH and LH from pituitary. It is, therefore, also referred to as FSH/LHRH or simply LHRH or gonadorelin. It has been difficult to explain how hypothalamus achieves a divergent pattern of FSH and LH secretion in menstruating women through a single releasing hormone. Since GnRH is secreted in pulses and the frequency as well as amplitude of the pulses differs during follicular (high frequency, low amplitude) and luteal (lower frequency, higher amplitude) phases, it has been proposed that frequency and amplitude of GnRH pulses determines whether FSH or LH or both will be secreted as well as the amount of each. Further, the feedback regulation of FSH and LH may be different. In general, feedback inhibition of LH is more marked than that of FSH. In females estradiol and progesterone inhibit both FSH and LH secretion mainly through hypothalamus, but also by direct action on pituitary. However, the preovulatory rise in estrogen level paradoxically stimulates LH and FSH secretion. In addition there are other regulatory substances, e.g. Inhibin—a peptide from ovaries and testes selectively inhibits FSH release: dopamine inhibits only LH release. Testosterone is weaker than estrogens in inhibiting Gn secretion, but has effect on both FSH and LH. GnRH acts on gonadotropes through a Gprotein coupled receptor which acts by increasing intracellular Ca2+ through PIP₂ hydrolysis.

The Gn secretion increases at puberty and is higher in women than in men. In men, the levels of FSH and LH remain practically constant (LH > FSH) while in menstruating women they fluctuate cyclically. During the follicular phase, moderate levels of FSH and low levels of LH prevail. There is a midcycle surge of both, but more of LH, just before ovulation, followed by progressive fall during the luteal phase. Gn levels are high in menopausal women due to loss of feedback inhibition by sex steroids and inhibin.

Pathological Involvement

Disturbances of Gn secretion from pituitary may be responsible for delayed puberty or precocious puberty both in girls and boys.

Inadequate Gn secretion results in amenorrhoea and sterility in women; oligozoospermia, impotence and infertility in men. Excess production of Gn in adult women causes polycystic ovaries.

Preparations

All gonadotropin preparations are administered by i.m. route. They are partly metabolized, but mainly excreted unchanged in urine: t½ 2–6 hours.

1. Menotropins (FSH + LH): is a preparation obtained from urine of menopausal women:

PREGNORM, PERGONAL, GYNOGEN 75/150; 75 IU FSH + 75 IU LH activity per amp, also 150 IU FSH + 150 IU LH per amp.

2. Urofollitropin or Menotropin (pure FSH): METRODIN, ENDOGEN, FOLICULIN, PUREGON 75 IU and 150 IU per amp. This preparation has been preferred over the combined FSH + LH preparation for induction of ovulation in women with polycystic ovarian disease: these patients have elevated LH/FSH ratio; use of FSH alone is considered advantageous. It is also claimed to improve chances of obtaining good quality ova for in vitro fertilization.

3. Human Chorionic Gonadotropin (HCG): is derived from urine of pregnant women.

CORION, PROFASI, PUBERGEN 1000 IU, 2000 IU, 5000 IU, 10,000 IU, all as dry powder with separate solvent for injection.

The foetal placenta secretes HCG which is absorbed in maternal circulation and maintains corpus luteum of pregnancy. It is a glycoprotein with 33% sugar and 237 amino acids in two chains, MW 38000. It is excreted in urine by the mother from which it is commercially obtained. HCG binds to LH receptor with equal avidity; action of HCG is indistinguishable from that of LH.

Recombinant human FSH (rFSH: Follitropin α and follitropin β) and recombinant human LH (rLH: Lutropin) as well as recombinant HCG (rHCG: Choriogonadotropin α) have become available in some countries, but are more expensive.

Uses

1. Amenorrhoea And Infertility  When it is due to deficient production of Gns by pituitary. Gns are generally tried when attempts to induce ovulation with clomiphene have failed or when nonovulation is due to polycystic ovaries. The

procedure is to give 1 injection of menotropins (75 IU FSH + 75 IU LH or 75 IU pure FSH)) i.m. daily for 10 days followed the next day by 10,000 IU of HCG. Ovulation occurs within the next 24–48 hours in upto 75% cases and the woman may conceive. However, rates of abortion and multiple pregnancy are high, but not of teratogenesis.

To improve predictability of time of ovulation (controlled ovarian hyperstimulation) most experts now concurrently suppress endogenous FSH/LH secretion either by continuous pretreatment with a superactive GnRH agonist or by a GnRH antagonist.

2. Hypogonadotrophic Hypogonadism In males manifesting as delayed puberty or defective spermatogenesis → oligozoospermia, male sterility — start with 1000–4000 IU of HCG i.m. 2–3 times a week (to stimulate testosterone secretion), add FSH 75 IU + LH 75 IU after 3–4 months (to stimulate spermatogenesis) and reduce dose of HCG; continue treatment for 6–12 months for optimum results, which nevertheless are not always impressive.

3. Cryptorchism Since undescended testes can cause infertility and predispose to testicular cancer, medical/surgical treatment is imperative. Descent of testes can be induced by androgens whose production is stimulated by LH. Treatment with HCG can be tried between the age of 1–7 years if there is no anatomical obstruction; 1000– 2000 IU is given i.m. 2–3 times a week till the testes descend. If 2–6 week treatment does not induce descent, surgery should be performed.

4. To Aid In Vitro Fertilization Menotropins (FSH + LH or pure FSH) have been used to induce simultaneous maturation of several ova and to precisely time ovulation so as to facilitate their harvesting for in vitro fertilization.

Adverse Effects And Precautions

Ovarian hyperstimulation—polycystic ovary, pain in lower abdomen and even ovarian bleeding and shock can occur in females.

Precocious puberty is a risk when given to children.

Allergic reactions have occurred and skin tests are advised. Hormone dependent malignancies (prostate, breast) must be excluded.

Other side effects are edema, headache, mood changes.

Gonadotropin Releasing Hormone (Gn RH): Gonadorelin

Synthetic Gn RH injected i.v. (100 μg) induces prompt release of LH and FSH followed by elevation of gonadal steroid levels. It has a short plasma t½ (4–8 min) due to rapid enzymatic degradation; has been used for testing pituitarygonadal axis in male as well as female hypogonadism.

Since only pulsatile exposure to GnRH induces FSH/ LH secretion, while continuous exposure desensitizes pituitary gonadotropes resulting in loss of Gn release, therapy with GnRH or its analogues is not useful in the treatment of hypogonadism.

Superactive / Long Acting GnRH Agonists

Many analogues of GnRH, e.g. Buserelin, Goserelin, Leuprolide, Nafarelin, Triptorelin, have been developed: are 15–150 times more potent than natural Gn RH and longer acting (t½ 2–6 hours) because of high affinity for GnRH receptor and resistance to enzymatic hydrolysis. They acutely increase Gn secretion, but after 1–2 weeks cause desensitization and down regulation of Gn RH receptors → inhibition of FSH and LH secretion → suppression of gonadal function. Spermatogenesis or ovulation cease and testosterone or estradiol levels fall to castration levels. Recovery occurs within 2 months of stopping treatment.

The superactive GnRH agonists are used as nasal spray or injected s.c. Longacting preparations for once a month s.c. injection have been produced (triptorelin, goserelin depot). The resulting reversible pharmacological oophorectomy/orchiectomy is being used in precocious puberty, prostatic carcinoma, endometriosis, premenopausal breast cancer, uterine leiomyoma, polycystic ovarian disease and to assist induced ovulation. It also has potential to be used as contraceptive for both males and females.

Nafarelin This longacting GnRH agonist is 150 times more potent than native GnRH; used as

NASAREL 2 mg/ml soln for nasal spray; 200 μg per actuation.

Down regulation of pituitary GnRH receptors occurs in10 days but peak inhibition of Gn release occurs at one month. It is broken down in the body to shorter peptide segments; plasma t½ is 2–3 hours. Uses are:

Assisted Reproduction: Endogenous LH surge needs to be suppressed when controlled ovarian hyperstimulation is attempted by exogenous FSH and LH injection, so that precisely timed mature oocytes can be harvested. This is achieved by 400 μg BD intranasal nafarelin, reduced to 200 μg BD when menstrual bleeding occurs.

Uterine Fibroids: Nafarelin 200 μg BD intranasal for 3–6 months can reduce the size of leiomyoma and afford symptomatic relief.

Endometriosis: 200 μg in alternate nostril BD for upto 6 months. As effective as danazol, but second course cannot be given due to risk of osteoporosis.

Central Precocious Puberty: 800 μg BD by nasal spray; breast and genital development is arrested in girls and boys. The effect is reversible; pubertal changes resume when therapy is discontinued.

Adverse Effects: Hot flashes, loss of libido, vaginal dryness, osteoporosis, emotional lability.

Triptorelin: This long-acting GnRH agonist can be injected i.m. at 4 week intervals; therefore preferred for indications where long-term Gn suppression is desired, such as carcinoma prostate, endometriosis, precocious puberty and uterine leiomyoma. For prostate cancer, it is combined with an androgen antagonist flutamide or bicalutamide to prevent the initial flare up of the tumour that occurs due to increase in Gn secretion for the first 1–2 weeks.

Dose: 2.5–3.5 mg i.m. at 3–4 week intervals.

TRYPLOG 2.5 mg/5 ml vial for inj.

GnRH Antagonists

Some more extensively substituted GnRH analogues act as GnRH receptor antagonists. They inhibit Gn secretion without causing initial stimulation. The early GnRH antagonists had the limitation of producing reactions due to histamine release. Newer agents like ganirelix and cetrorelix have low histamine releasing potential and are being clinically used in specialized centres for inhibiting LH surges during controlled ovarian stimulation in women undergoing in vitro fertilization. Their advantages over longacting GnRH agonists include:

·     They produce quick Gn suppression by competitive antagonism, need to be started only from 6th day of ovarian hyperstimulation.

·      They carry a lower risk of ovarian hyperstimulation syndrome.

·                They achieve more complete suppression of endogenous Gn secretion.

·          However, pregnancy rates are similar or may even be lower.