Homerton Fertility Centre, Homerton University Hospital, London, UK
The availability of injectable gonadotrophin preparations provides a direct route for ovarian stimulation and ovulation induction as opposed to the indirect route of provoking endogenous FSH release taken by clomifene and letrozole. As far as the outcome of treatment for anovulation is concerned, no clear clinical superiority has been demonstrated between urinary and recombinant products nor between hMG and pure FSH. Recombinant products are purer and therefore, theoretically at least, safer than urinary products. The one group of patients in which the addition of LH seems to be critical is that of women with hypogonadotrophic-hypogonadism who have no endogenous LH. These women need exogenous hCG or recombinant LH to maintain adequate oestradiol biosynthesis and follicle development.
GonadotrophinsOvulation inductionClomiphene citrateAromatase inhibitorsGnRHFSHLHAnovulatory womenOvarian stimulationHypogonadotrophic hypogonadismHypothalamic-pituitary failureEu-oestrogenic womenHypothalamic-pituitary dysfunctionFollicleOvarian hyperstimulationIn-vitro fertilizationOocyteshMGhCGRecombinant FSHPCOSOestrogenOestradiolFollicular developmentAtreticOHSSAntral follicles
Clomiphene citrate, aromatase inhibitors and pulsatile GnRH therapy all provoke an endogenous production and discharge of FSH in order to induce ovulation in anovulatory women. In contrast to this indirect stimulation of the ovaries, the availability of injectable gonadotrophin preparations provides a direct route for ovarian stimulation and ovulation induction.
Gonadotrophin therapy is indicated for hypogonadotrophic hypogonadism, (hypothalamic-pituitary failure, WHO Group I) where it can be regarded as substitution therapy for the absent endogenous stimulation by FSH and LH. More commonly, gonadotrophins are administered for ovulation induction for eu-oestrogenic women who have hypothalamic-pituitary dysfunction (WHO Group II) and who have failed to ovulate or conceive following the usual first-line treatment with clomiphene citrate.
In order to develop, mature and ovulate, follicles need FSH. When this is completely lacking (hypogonadotrophic hypogonadism) or does not attain a sufficient stimulatory threshold due to intrinsic inhibitors of action and/or a dysfunctional feedback mechanism (as in PCOS), exogenous FSH can provide the stimulus for follicle development. At any one time, these anovulatory women have a limited cohort of follicles which are sensitive to FSH. In order for a follicle to grow, the threshold of its sensitivity needs to be reached and in order to develop and mature, continued stimulation with FSH is required. Physiologically, in a normal ovulatory cycle, only one follicle will become dominant and ovulate due to a sophisticated mechanism which provides it with a great enough sensitivity to dwindling levels of FSH in order to maintain its development while, all around, smaller follicles do not achieve this level of sensitivity to FSH, are not stimulated and fall into atresia (Fig. 2.7). Stimulation with FSH for ovulation induction should follow similar principles i.e. enough FSH should be given exogenously to reach a threshold sufficient to initiate growth and development of a number of follicles but only overstepping the threshold sufficiently to maintain the growth of one follicle and certainly, not more than three. This principle should be separated from that of controlled ovarian hyperstimulation in which larger doses of FSH are administered with the very purpose of producing more follicles and oocytes in sufficient numbers for in-vitro fertilization.
The original gonadotrophin preparations, containing equal quantities of FSH and LH, were extracted from menopausal urine and purified. Although these preparations have been extremely successful in inducing ovulation, the production technique is laborious, requires enormous amounts of urine and includes some unwanted proteins. Improvements in purification techniques enabled the production of preparations containing more active ingredients, less undesirable proteins and almost no LH so that purified and highly purified urinary FSH became available from 1983. Later, a highly purified urinary preparation containing hMG (FSH:LH activity in a ratio of 1:1) became available in which hCG mainly acts as an LH surrogate .
However, successful as these compounds are, the large quantities of urine required and ever increasing production demands in the early 1990s led to the use of recombinant DNA technology to produce human recombinant FSH. Recombinant FSH (follitropin-α and follitropin-β) has been clinically available since 1996 and now dominates the market. Similar technology has now made both recombinant LH and recombinant hCG available for clinical use and a preparation containing both recombinant FSH and recombinant LH has recently come on to the market.
Technically, in comparison with the urinary preparations, recombinant FSH is purer allowing safe subcutaneous self-administration, is said to have an improved batch-to-batch consistency and contains no LH. In addition, the recombinant DNA technology should promise unlimited availability. Regarding clinical results, no significant differences between urinary and recombinant preparations of gonadotrophins have been demonstrated despite a multitude of studies and meta-analyses.
13.3 Urinary vs Recombinant: Safety
As far as safety is concerned, the recombinant products theoretically, should have the edge as they contain less protein and other contaminants. However, in more than 40 years of use, not a single case of infection by prions or slow viruses has been reported . The theoretically immunogenic potential of the contamination in urinary products has been expressed in the very occasional local allergic reaction with intramuscular administration. Uneven biological potency of the urinary products has been quoted as a safety factor to the advantage of the recombinant products. However, similar concerns regarding uneven biopotency of the recombinant products have also been raised. Using the Steelman-Pohley ovarian weight augmentation assay for FSH has shown that an ampoule labeled to contain 75 IU may range in true activity from 50 to 120 IU FSH ! This has prompted the production of a “filled by mass” packaging of recombinant FSH employing size exclusion high performance liquid chromatography . Whatever the case, it has been clearly shown several times that, unit for unit, recombinant FSH is more potent than urinary FSH and, therefore, slightly lower overall doses are required. If this is remembered, there should not be and neither has there been demonstrated, any difference in the incidence of ovarian hyperstimulation syndrome between the two products during ovulation induction.
13.4 Urinary FSH vs Recombinant FSH: Efficacy
For ovulation induction, a randomized trial failed to show a difference between these two preparations as regards ovulation and pregnancy rates, miscarriage, hyperstimulation or multiple pregnancy rates . A meta-analysis of randomized controlled trials comparing urinary and recombinant FSH for ovulation induction in women with PCOS has confirmed these findings . The only difference between the preparations seems to be an increased unit-to-unit potency of recombinant FSH.
13.5 FSH vs hMG
Both high and very low levels of LH have been suggested as interfering with potential fertility. The LH content of hMG and the absence of LH in recombinant FSH have therefore come under scrutiny. Firstly, the LH content of hMG does not have any detrimental effect compared with recombinant FSH in ovulation induction whether this is for patients with predominately high LH (PCOS) or any others. The fact is that the administration of both hMG and pure FSH decrease LH concentrations so hMG is certainly not capable of pushing LH levels up to a ‘danger’ zone. The hope that the redressing of a high LH:FSH ratio, prevalent in many women with PCOS, by giving pure FSH rather than hMG, would improve clinical results has also proved unfounded . As GnRH agonists or antagonists are rarely used for pure ovulation induction, very low concentrations of LH are not encountered in anovulatory women with normal oestrogen levels. The one group of patients in which the addition of LH seems to be critical is that of women with hypogonadotrophic-hypogonadism who have no endogenous LH. These women need exogenous hCG or recombinant LH to maintain adequate oestradiol biosynthesis and follicle development . This study found that a dose of 75 IU/day of recombinant LH to support recombinant FSH was effective in promoting optimal follicular development. Conversely, there is preliminary clinical evidence for an LH ‘ceiling’ effect. In a pilot study, the addition of relatively large doses of recombinant LH to FSH administration in the late follicular phase seemed to be capable of causing the arrest of growth of non-dominant follicles in a number of patients undergoing ovulation induction .
In summary, as far as the outcome of treatment for anovulation is concerned, no clear clinical superiority has been demonstrated between urinary and recombinant products nor between hMG and pure FSH. Recombinant products are purer and therefore, theoretically at least, safer than urinary products.
13.6 Treatment Protocols for Ovulation Induction
The main complications of gonadotrophin therapy in ovulation induction, ovarian hyperstimulation syndrome (OHSS) and multiple pregnancies, are both caused by multiple follicular development. Doses of FSH well above the threshold provoke an initial development of a large cohort, stimulate additional follicles, and even rescue those follicles that without stimulation would have become atretic. The conventional step-up treatment with gonadotrophins employing incremental dose rises of 75 IU every 5–7 days, characteristically induces multiple follicular development, resulting in a high frequency of multiple pregnancies and OHSS. A review by Hamilton-Fairley & Franks in 1990  reported a mean multiple pregnancy rate of 34 % and severe OHSS of 4.6 % using the conventional regimen in a large collection of WHO Group I and II anovulatory women. These results are unacceptable today. The problem is particularly acute in women who have polycystic ovaries due to the fact that these ovaries contain twice the number of available FSH-sensitive antral follicles in their cohort compared with the normal ovary .
The chronic low dose regimen of FSH administration, pioneered and developed by Franks and colleagues, is aimed to avoid over-stimulation of follicles, multiple follicle development and prevent the complications of OHSS and multiple pregnancies. The low-dose regimens, both step-up and step-down variations, are fully described in Chap. 9 but, briefly, the classic low dose regimen employs a low starting dose for 14 days and then uses small incremental dose rises when necessary, at intervals of not less than 7 days, until follicular development is initiated . Once follicular development is underway, the dose required is continued until the criteria for giving hCG are attained. The aim of achieving the development of a single dominant follicle can be accomplished in about 70 % of cycles, OHSS can be completely eliminated and the multiple pregnancy rate is <6 % while pregnancy rates are no different to those using the conventional protocol .
Many variations on the theme of low-dose therapy have been examined including a step-down rather than a step-up regimen , various different starting doses  and smaller dose rise increments. The results are fully described in Chap. 9 but whatever variation is employed, it is now very clear that low- dose, step-up gonadotrophin therapy should be preferred to the now outdated conventional therapy for anovulatory patients and particularly for those with PCOS. The classical low-dose protocol of small starting doses in the first cycle for a 14-day initial period without a dose change and then a small incremental dose rise if required, seem to give the best results.
The European and Israeli Study Group on Highly Purified Menotropin Versus Recombinant Follicle-Stimulating Hormone. Efficacy and safety of highly purified menotropin versus recombinant follicle-stimulating hormone in in vitro fetilization/intracytoplasmic sperm injection cycles: a randomized, comparative trial. Fertil Steril. 2002;78:520–8.CrossRef
Balen A. Bye-bye urinary gonadotrophins? Is there a risk of prion disease after administration of urinary-derived gonadotrophins? Hum Reprod. 2002;17:1676–80.PubMedCrossRef
European pharmacopoeia. 4th ed. 2002. p. 2101–3.
Driebergen R, Baer G. Quantification of follicle stimulating hormone (follitropin alfa): is in vivo bioassay still relevant in the recombinant age? Curr Med Res Opin. 2003;19:41–6.PubMedCrossRef
Yarali H, Bukulmez O, Gurgan T. Urinary follicle stimulating hormone (FSH) versus recombinant FSH in clomiphene citrate-resistant, normogonaotrophic, chronic anovulation: a prospective randomized study. Fertil Steril. 1999;72:276–81.PubMedCrossRef
Bayram N, van Wely M, van der Veen F. Recombinant FSH versus urinary gonadotrophins or recombinant FSH for ovulation induction in subfertility associated with polycystic ovary syndrome. Cochrane Database Syst Rev. 2002;(1):CD002121. Oxford: Update Software.
Hughes E, Collins J, Vandekerckhove P. Ovulation induction with urinary follicle stimulating hormone vs human menopausal gonadotrophin for clomiphene resistant polycystic ovary syndrome. Cochrane Library. 1996;(3). Oxford: Update Software.
The European Recombinant Human LH Study Group. Recombinant human luteinizing hormone (LH) to support human follicle-stimulating hormone (FSH)-induced follicular development in LH and FSH deficient anovulatory women: a dose-finding study. J Clin Endocrinol Metab. 1998;83:1507–14.
Loumaye E, Engrand P, Shoham Z, Hillier S, Baird D. Clinical evidence for an LH ‘ceiling’ effect induced by administration of recombinant human LH during the late follicular phase of stimulated cycles in WHO type I and type II anovulation. Hum Reprod. 2003;18:314–22.PubMedCrossRef
Hamilton-Fairley D, Franks S. Common problems in induction of ovulation. Baillieres Clin Obstet Gynaecol. 1990;4:609–25.PubMedCrossRef
Van der Meer M, Hompes P, de Boer J, Schats R, Schoemaker J. Cohort size rather than follicle-stimulating hormone threshold levels determines ovarian sensitivity in polycystic ovary syndrome. J Clin Endocrinol Metab. 1988;83:423–6.
Polson DW, Mason HD, Saldahna MBY, Franks S. Ovulation of a single dominant follicle during treatment with low-dose pulsatile FSH in women with PCOS. Clin Endocrinol (Oxf). 1987;26:205–12.CrossRef
Homburg R, Howles CM. Low dose FSH therapy for anovulatory infertility associated with polycystic ovary syndrome: rationale, reflections and refinements. Hum Reprod Update. 1999;5:493–9.PubMedCrossRef
Van Santbrink EJP, Fauser BCJM. Urinary follicle-stimulating hormone for normogonadotropic clomiphene resistant anovulatory infertility: prospective, randomized comparison between low dose step-up and step-down dose regimens. J Clin Endocrinol Metab. 1997;82:3597–602.PubMed
White DM, Polson DW, Kiddy D, et al. Induction of ovulation with low-dose gonadotrophins in polycystic ovary syndrome: an analysis of 109 pregnancies in 225 women. J Clin Endocrinol Metab. 1996;81:3821–4.PubMed