Role of Exogenous Gonadotropins in Ovulation Induction

Role of Exogenous Gonadotropins in Ovulation Induction

Exogenous Gonadotropins:

Gonadotropins are used to treat infertility in anovulatory women, usually after other less complicated and costly methods have failed. They are also used to help women with Hypogonadotropic amenorrhea (HA) to treat infertility as there is inadequate amounts of endogenous circulating follicle stimulating hormone (FSH) and luteinizing hormone (LH) in such patients.

Additionally, gonadotropins are used to induce development of multiple follicles for fertility treatments, such as superovulation- intrauterine insemination (IUI) and in vitro fertilization (IVF).

How it acts !

Exogenous FSH stimulates proliferation of granulosa cells and follicular growth. LH stimulates the production of androgen in thecal cells that subsequently is converted to estrogen by granulosa cells via aromatization. The goal of treatment is to promote the growth and development of a single mature follicle.Gonadotropin therapy has significant risks and is costly, it should therefore be used only by clinicians having the requisite training and experience.

Indications !

Exogenous gonadotropins can be used for ovulation induction (OI) in women who are anovulatory and infertile, and they are indicated when OI cannot be achieved with less complex methods. Two groups of anovulatory disorders may require gonadotropin therapy:

  • Hypogonadotropic Amenorrhea (HA, also known as hypogonadotropic hypogonadism, hypothalamic amenorrhea, or World Health Organization [WHO] type I amenorrhea); and
  • Polycystic Ovary Syndrome (PCOS, also known as hyperandrogenic amenorrhea or WHO type II amenorrhea)

In women with HA, optimal clinical results are achieved by the combined administration of FSH and LH , accomplished by administration of hMG or a combination of FSH and either recombinant LH or low-dose hCG. There are no established gonadotropin regimens for OI of HA patients and no prospective studies that assess treatment outcomes with different gonadotropin dosages.

In women with PCOS, only FSH activity is required, because endogenous LH levels are adequate, although added LH does not appear to be harmful. There is no significant advan- tage to using any specific gonadotropin preparation. A meta-analysis concluded that the outcomes of treatment achieved with hMG and with FSH alone were similar. Others have observed that treatment with rFSH or urinary FSH yields similar results. The risk of OHSS and multiple pregnancy is greater among women with PCOS than among those with HA, primarily be- cause gonadotropin treatment generally stimulates development of larger follicular cohorts in women with PCOS. Consequently, exogenous gonadotropins must be administered judiciously. The recommended approach in the first dose-finding cycle is to begin with a low dose of gonadotropin, typically 37.5–75 IU/day, increasing after 7 days or more if no follicle >10 mm has yet emerged, in small increments, at intervals, until evidence of progressive follicular development is observed. The maximum required daily dose of FSH/hMG seldom exceeds 225 IU/day.


PRETREATMENT EVALUATION:

 Given the risks and cost of exogenous gonadotropin therapy, treatment should be offered only by clinicians having the requisite training or experience.

Before treatment begins, other potential coexisting causes of infertility, such as uterine cavity abnormalities (myomas, adhesions), tubal obstruction, advanced endometriosis (ovarian endometrioma), pelvic adhesions, or poor semen quality, should be excluded. Pretreatment evaluation generally should exclude abnormalities of thyroid function and hyperprolactinemia and should include hysterosalpingography, transvaginal ultrasonography, and semen analysis.


OVULATION INDUCTION with EXOGENOUS GONADOTROPINS:

There are a number of protocols for the type, dosing, and timing of ovulation induction with gonadotropins. The protocol used will depend on the woman’s situation and the clinician’s preferences. Exogenous gonadotropins are given by injections.

According to the Practice Committee of the American Society for Reproductive Medicine on Use of exogenous gonadotropins in anovulatory women (2008), in women with PCOS, OI usually begins after a menses induced by a brief interval of treatment with an exogenous progestogen. In women with HA, OI may begin at any convenient time. Baseline ultrasonography is prudent to exclude pre-existing ovarian cysts. Among women not previously treated with exogenous gonadotropins, treatment generally should begin at a relatively low dose (e.g., 37.5–75 IU/day). In subsequent cycles, treatment generally begins at the threshold of response previously determined. Although 7–12 total days of treatment is typical, longer durations of treatment may be required.

The final stages of follicle/oocyte maturation and ovum re- lease can be induced by administration of hCG extracted from urine, recombinant hCG, recombinant LH, or a GnRH agonist. Although there are no evidence-based specific guidelines for optimal timing, the ovulatory stimulus generally should be administered when at least one and, ideally, no more than two follicles greater than 16–18 mm in mean diameter are observed, so as to limit the risk for multiple pregnancy. Estradiol concentrations generally should range between approximately 150 and 300 pg/mL per dominant follicle. Human chorionic gonadotropin is administered in a single injection of 5,000–10,000 IU IM or SC; recombinant hCG is administered at a dose of 250 μg SC, which corresponds to approximately 6,000–7,000 IU hCG.

A GnRH agonist also can be used to induce oocyte release in OI, provided that an agonist has not been administered earlier during the course of gonadotropin treatment to prevent a spontaneous LH surge. The GnRH agonists are not effective in HA. For purposes of inducing ovum release, the recommended dose for leuprolide is 500 μg and for triptorelin is 200 μg; both are administered in a single SC injection. When a GnRH agonist is used to induce ovum release, progesterone supplementation during the luteal phase is required, because agonist treatment may adversely affect endogenous luteal function.

Routine treatment with supplemental exogenous progesterone or additional small doses of hCG (1,500–2,500 IU every 3–4 days) during the luteal phase of OI cycles is advocated by many. Luteal support after OI is most clearly indicated and recommended in women with HA whose endogenous gonadotropin secretion may be inadequate to support normal luteal function. Its necessity and effectiveness otherwise are unproven and controversial.

Ovulation can be expected to occur between 24 and 48 h after injection of hCG or a GnRH agonist. Consequently, intercourse within that interval can help to maximize the likelihood of conception. When specifically indicated, intra- uterine insemination generally should be planned for approx- imately 24–36 h after the injection.


TREATMENT MONITORING:

The follicle size is monitored with ultrasound, and the blood estrogen level (serum E2 measurements) which is measured frequently throughout treatment.

Ultrasonography provides a structural measure of follicular development and generally should be performed after the first 4–5 days of treatment and at intervals of 1–3 days thereafter according to response. Endometrial thickness and appearance provide an indirect measure of endometrial development and maturation and have some prognostic value for implantation.

Rapid serum E2 determinations (results available the same day and, ideally, 7 days/week) provide a functional measure of follicular maturation.

Together with ultrasonography, serum E2 levels provide an accurate gauge of response to treatment and guide the management of the OI cycle. If estradiol levels and follicular monitoring indicates that the ovaries are not responding to gonadotropins, the dose may be increased. The goal is to achieve one or more mature follicles and an appropriate estrogen level, so that ovulation can be triggered by an human chorionic gonadotropin (hCG) injection. If too many follicles develop, or if the estrogen level is too high, the physician may decide to withhold the hCG injection rather than risk the higher likelihood of ovarian hyperstimulation syndrome (OHSS) or a high-order multiple pregnancy.


RISKS/COMPLICATIONS IN OI WITH GONADOTROPINS:

There are potential risks and complications associated with the use of gonadotropins.

Multifetal gestation:

Despite intensive monitoring, up to 30% of gonadotropin-stimulated pregnancies are multiple. Of the multiple pregnancies, about two-thirds are twins and one-third are triplets or more.The greater the number of fetuses in the uterus, the greater the risk of premature delivery. Premature delivery can subject the newborn to complications such as severe respiratory distress, intracranial hemorrhage, infection, cerebral palsy, and death.

As mentioned in the technical bulletin Use of exogenous gonadotropins in anovulatory women (2008) by the practice committee of the American Society for reproductive medicine,

To minimize the risk of multifollicular ovulation and multiple pregnancy, cycle cancellation generally should be seriously considered when three or more mature follicles (>16–17 mm) or large numbers of intermediate-sized follicles (10–15 mm) are observed or when the serum E2 concentration exceeds 1,000–1,500 pg/mL. However, the increased risk for multiple pregnancy associated with gonadotropin treatment cannot be eliminated entirely, and even the low-dose gonadotropin regimens advocated here are associ- ated with five- to 10-fold increased risk.

Ovarian Hyperstimulation Syndrome (OHSS):

In OHSS, the ovaries become swollen and painful. In severe cases, fluid accumulates in the abdominal cavity and chest. In about 2% of gonadotropin cycles, hyperstimulation may be severe enough to require hospitalization. Careful monitoring of ovulation induction cycles with the use of ultrasound and/or measurement of serum estradiol levels, in conjunction with adjustment of gonadotropin dosage, will enable the physician to identify risk factors and prevent most cases of severe OHSS. When serum estradiol levels are rapidly rising and/or too high, or an excessive number of ovarian follicles develop, one method of best prevention is to withhold further gonadotropin stimulation and delay hCG administration until estradiol levels plateau or decline. Alternately, hCG can be withheld so that ovulation fails to occur, thereby lessening the severity of OHSS.

According to the technical bulletin Use of exogenous gonadotropins in anovulatory women (2008) by the practice committee of the American Society for reproductive medicine,

To minimize the risk for developing OHSS, a lower dose of hCG (5,000 IU) or a GnRH agonist is recommended for inducing ovum release when E2 levels have risen rapidly or are markedly elevated (>2,500 pg/ mL) and/or a large number of intermediate-sized follicles (10–14 mm) are observed.

Other potential side effects of gonadotropin treatment: These include breast tenderness, swelling or rash at the injection site, abdominal bloating, mood swings, and slight twinges of abdominal pain.

As mentioned in the technical bulletin Use of exogenous gonadotropins in anovulatory women (2008) by the practice committee of the American Society for reproductive medicine, earlier concerns that OI might be associated with an increased risk for cancer of the ovary and breast have not been corroborated by subsequent studies. Although the risk for ovarian cancer may be higher for infertile women than for fertile women, there is no compelling evidence to indicate that such risk is increased by OI.


RESULTS:

In a 2003 systematic review of 13 studies published between 1991 and 2000 including 1,269 cycles among 881 anovulatory infertile women (2.7 cycles per patient) who received gonadotropin treatment for OI, there were 366 pregnancies; the pregnancy rate was 15% per cycle and 41% per patient. Women who were obese or insulin resistant required increased total amounts of gonadotropins per cycle. Insulin resistance, but not obesity, was associated with a lower pregnancy rate.

Another study, not included in the 2003 systematic review, reported 18 pregnancies in 28 women with HA across 72 cycles of treatment (25% per cycle), but only 16 pregnancies in 61 hyperandrogenic women with PCOS across 205 cycles of treatment (8% per cycle).


SUMMARY AND RECOMMENDATIONS


  • Gonadotropin treatment for OI is indicated for anovulatory infertile women with HA and for those with PCOS who fail to respond to less complicated OI treatment regimens.
  • Before treatment with gonadotropins, evaluation generally should exclude abnormalities of thyroid function and hyperprolactinemia, and should include hysterosalpingography, transvaginal ultrasonography, and evaluation of the male partner by semen analysis.
  • Although sometimes difficult to achieve, the goal of gonadotropin treatment is to promote the growth and development of a single mature follicle.
  • Among women not previously treated with exogenous gonadotropins, treatment generally should begin at a relatively low dose (e.g., 37.5–75 IU/day). In subsequent cycles, treatment generally begins at the threshold of response previously determined.
  • Ovulation of a mature ovarian follicle may be triggered with either purified (5,000–10,000 IU IM or SC) or recombinant (250 μg SC) hCG. A GnRH agonist (leuprolide 500 μg SC; triptorelin 200 μg SC) also may be used to trigger ovulation, except in women with HA and those who have received GnRH agonist treatment earlier during the course of gonadotropin treatment.
  • Luteal support after OI is most clearly indicated and recommended in women with HA and those who receive treatment with a GnRH agonist, because, in these cases, endogenous gonadotropin secretion may be inadequate to support normal luteal function.
  • The increased risk of multiple pregnancy associated with gonadotropin treatment can be limited by judicious treatment and careful monitoring, but it cannot be elim- inated entirely.
  • Despite careful monitoring, OHSS can occur after OI in anovulatory women.