, Volume 9, Issue 3, pp 235-260
Date: 13 Aug 2012

Follitropin Alpha in Infertility

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Summary

Synopsis

Follitropin alpha (recombinant human follicle- stimulating hormone; follitropin alfa) is a recombinant form of follicle- stimulating hormone (FSH), an endogenous gonadotrophin. Unlike FSH products derived from urine [menotropins (human menopausal gonadotrophins), urofollitropin and highly purified urofollitropin], follitropin alpha is readily available and shows batch-to-batch consistency. As well, it is free of luteinising hormone (LH) activity and contaminant urinary proteins and can be self- administered subcutaneously.

In women undergoing in vitro fertilisation-embryo transfer (IVF- ET), follitropin alpha appears to have a greater stimulatory effect on follicular development than urine-derived FSH products as a group. In direct comparisons it had similar effects to urofollitropin but produced more oocytes per stimulated cycle than highly purified urofollitropin and menotropins. Preliminary results of 1 small trial indicate similar efficacy for follitropin alpha and follitropin beta. Rates of pregnancy, live births and multiple births have been similar among all treatment groups.

As ovulation induction in women with clomifene- resistant WHO group II anovulation, follitropin alpha produces rates of ovulation, follicular development and pregnancy resembling those seen with urofollitropin or highly purified urofollitropin. A long term low-dose regimen of follitropin alpha is associated with a lower number of follicles and a trend toward fewer multiple births compared with conventional follitropin alpha or urofollitropin regimens. Data from women with WHO group I anovulation and from infertile men are scant.

Tolerability has not differed between follitropin alpha and other FSH products. The incidence of general events (e.g. headache, nausea, ovarian cyst), local irritations at injection site and ovarian hyperstimulation syndrome resembled those for comparator FSH products. However, it appears that follitropin alpha can be tolerated in instances of severe allergic reaction to urine- derived products.

Conclusions. In women undergoing IVF- ET, follitropin alpha appears to have a greater stimulatory effect on follicle development than urine-derived FSH products as a group and is at least as well tolerated as these preparations; preliminary data indicate similar efficacy to follitropin beta. At present, its efficacy in women with WHO group II anovulation disorder has been shown to be similar to that of the older products.

Compared with urinary FSH products, the benefits of follitropin alpha lie in its reliable supply, consistency of production, lack of contaminant urinary proteins and ease of self-administration. Given these practical advantages, and the apparently greater effect onfollicular development overall in women undergoing IVF-ET, recombinant products such as follitropin alpha are expected to eventually replace older urine-derived FSH preparations and claim a prominent position in the treatment of infertility.

Role of FSH in Fertility

Follicle-stimulating hormone (FSH) and luteinising hormone (LH) are synthesised in the anterior pituitary gland. Their secretion is controlled by gonadorelin [gonadotrophin-releasing hormone (GnRH)].

In Women. During a typical ovarian/menstrual cycle, FSH levels are elevated in the first few days, decline around day 6, then rise sharply on days 12 to 14. FSH stimulates granulosa cell proliferation and differentiation and contributes to development of the mature follicle. Estrogen secreted by the follicle initiates endometrial proliferation and cervical changes favouring sperm entry. Feedback loops involving estrogen, progesterone and inhibin suppress additional FSH release, preventing development of other follicles.

In usual circumstances, a single dominant follicle develops while the others undergo atresia. Estrogen levels peak about a day before ovulation, prompting a surge in LH levels which triggers ovum release. The ruptured follicle becomes the corpus luteum and secretes progesterone to prepare the endometrium for implantation. After fertilisation, placental human chorionic gonadotrophin (hCG) maintains pregnancy.

In Men. Both FSH and LH are required for spermatogenesis. LH stimulates Leydig cells to produce testosterone which, together with FSH, stimulates seminiferous tubules and promotes spermatogenesis. FSH acts at the Sertoli cells in the seminiferous tubules and is regulated by inhibin within these cells, although testosterone and estradiol also inhibit FSH secretion.

Pharmacodynamic Properties

Follitropin alpha (recombinant human follicle-stimulating hormone; follitropin alfa) is a recombinant FSH product expressed in Chinese hamster ovary cells. It is structurally identical to endogenous FSH, a complex heterodimeric glycoprotein comprising an α and a β subunit. Follitropin alpha is free of potentially allergenic urinary proteins, has a higher specific activity (10 000 IU/mg) than urine-derived FSH preparations other than highly purified urofollitropin and shows similar biological activity to these products in standard animal assays.

Native FSH exists in many isoforms mainly distinguished by differences in the number of terminal sialic acid residues attached to the carbohydrate moiety. Follitropin alpha has a slightly narrower isoelectric point (pI) band than follitropin beta (mainly 4 to 5 vs 3.5 to 5.5) and contains fewer isoforms with a pI <4 (9 vs <24%). The clinical importance, if any, of differences in the FSH isoforms present in commercial preparations is undetermined.

In most patients, follitropin alpha is sufficient to stimulate follicular development without the addition of exogenous LH (see Clinical Efficacy summary).

There are few data on the influence of follitropin alpha on hormones other than estradiol. A comparative trial found insulin levels to be increased in follicular fluid in the follitropin alpha group and in serum in the follitropin beta group. Levels of human growth hormone in follicular fluid and serum were twice as high with follitropin alpha as with follitropin beta.

The effects of endogenous FSH on spermatogenesis in humans are well known; data on the effects of follitropin alpha are sparse at present. In rodents, follitropin alpha contributes to the maintenance of early spermatogenesis.

As shown in standard in vivo and in vitro models, follitropin alpha in doses up to 100 times greater than those used therapeutically exerts no important effects on the central or autonomic nervous system, cardiovascular or respiratory systems, gastrointestinal system or renal function.

Pharmacokinetic Properties

The pharmacokinetics of follitropin alpha resemble those of the endogenous hormone. After subcutaneous administration to healthy female volunteers given the GnRH agonist goserelin as pituitary down-regulation, follitropin alpha pharmacokinetics are described by a 2-compartment model with first-order absorption. Steady state is achieved within 4 days.

At steady state, mean peak plasma concentrations are 3-fold higher than after a single dose and the volume of distribution is similar to that of extracellular water. Serum FSH levels after follitropin alpha administration do not correlate with pharmacodynamic or clinical effects and are not useful predictors or monitors of treatment outcome.

Endogenous FSH is eliminated via renal and hepatic routes. Terminal elimination half-life (t½β) values for follitropin alpha vary by up to 70% among individuals: at steady state t½⨿ is about 24 hours. Renal clearance accounts for 10% of total clearance.

The pharmacokinetics of follitropin alpha and urofollitropin are similar after intravenous administration, except that renal urofollitropin clearance is faster (by about 30%).

Clinical Efficacy

Superovulation for Assisted Reproduction Techniques (ART). In women undergoing in vitro fertilisation-embryo transfer (IVF-ET), about 8 to 12 oocytes are collected per cycle stimulated with follitropin alpha, fertilisation rate is about 55 to 68% and the mean number of embryos obtained ranges from about 4 to 8. Clinical pregnancy rates are in the range of 10 to 45% per cycle and 14 to 48% per embryo transfer. The live birth rate in 1 trial was 34% per cycle and 36% per embryo transfer.

Follitropin alpha appears to be more beneficial than urine-derived FSH products as a group in stimulating follicle development. In direct comparisons it was similar in efficacy to urofollitropin, but in generally larger comparisons follitropin alpha yielded significantly more oocytes and embryos when given in a lower dosage for a shorter period than highly purified urofollitropin and more oocytes than menotropins. Rates of pregnancy, live births and multiple births did not differ among groups receiving any of these agents; however, these rates are difficult to interpret because of factors such as small sample size and differences in methods of reporting. Follitropin alpha had similar effects to follitropin beta in a small comparative study.

The type of follitropin alpha regimen used has not affected outcome, but the role of a GnRH agonist in ART protocols containing pure FSH is now recognised.

Ovulation Induction in Ovulatory Disorders. In women with WHO group II anovulation, who commonly have polycystic ovary syndrome, levels of FSH and other gonadotrophins are often asynchronous with estrogen production. In these patients, follitropin alpha produces high rates of ovulation (about 64 to 93%) and follicular development (about 60 to 88%) after the first cycle, while the mean number of developed follicles remains within the desired range of 1 to 3. Pregnancy rates per cycle are about 20 to 33%.

No significant differences in any of these outcomes have eventuated between patients receiving follitropin alpha, urofollitropin or highly purified urofollitropin. On the other hand, a long term low-dose regimen of follitropin alpha is associated with a reduced number of follicles and a trend toward fewer multiple births compared with conventional regimens of follitropin alpha or urofollitropin. In women with a history of severe ovarian hyperstimulation syndrome (OHSS) given follitropin alpha, fewer cycles were cancelled but pregnancy rates were similar to those in women given menotropins: no episodes of OHSS recurred.

Women with WHO group I anovulation, who have abnormally low gonado-trophin levels and negligible estrogen levels, require LH as well as FSH for conception. A protocol including follitropin alpha 150 IU/day and recombinant human LH in a dosage of 75 or 225 IU/day resulted in follicular development in 79% and pregnancy in 16% of 19 such women in the only clinical trial reported to date.

Male Infertility. One case report has described increased sperm density within 3 months of follitropin alpha therapy in a man with azoospermia and, subsequently, 2 successful pregnancies in his partner. A phase III trial of follitropin alpha in infertile men is ongoing.

Tolerability

Clinical trials have provided few specific details on adverse events during follitropin alpha therapy. However, the drug appears well tolerated. General events such as headache, nausea and ovarian cyst are most common but may be related to increased estrogen levels rather than to the drug per se.

Tolerability has not differed between follitropin alpha and other FSH products. Local irritations at the injection site were mild or infrequent in most trials regardless of which FSH formulation was used. The drug was successfully administered to a patient with a severe allergic reaction to urofollitropin. Subcutaneous formulation of follitropin alpha improves the ease of self-administration.

OHSS, the most serious complication, has occurred in 0 to 10% of cycles stimulated with follitropin alpha in clinical trials. OHSS was severe in 1.7% of 540 cycles, an incidence similar to that documented with other FSH products. Preliminary data indicate that implementation of a long term low-dose regimen may reduce the risk of OHSS.

Dosage and Administration

Follitropin alpha is administered subcutaneously. Patients may self-administer this agent after training and only if expert advice is easily available. Dosage is individualised to patient response as monitored by serum estradiol levels and transvaginal ultrasonography.

As ovulation induction in women with anovulation, follitropin alpha is started at a dosage of 75 IU/day. This may be increased by 37.5 IU/day after 14 days, then every 7 days to a maximum of 300 IU/day. Treatment should not exceed 35 days. One injection of hCG 5000IU is given intramuscularly or subcutaneously to induce ovulation after the last follitropin alpha injection.

If response is excessive in women with anovulation, treatment should be stopped, hCG withheld and treatment restarted at a lower dose in the next cycle.

For ovarian stimulation prior to IVF-ET, follitropin alpha should be started once down-regulation has been achieved with a GnRH agonist. The starting dose of 150 or 225 IU/day may be adjusted by 75 to 150 IU/day every 3 to 5 days. Subcutaneous or intramuscular hCG 5000 to 10 000IU is given once after the last day of follitropin alpha therapy.

Follitropin alpha is contraindicated in women with a variety of disorders, including primary ovarian failure, abnormal uterine haemorrhage of undetermined origin, and pituitary and sex hormone-dependent tumours.