Homerton Fertility Centre, Homerton University Hospital, London, UK
Gonadotrophin therapy is a highly successful way of inducing ovulation and pregnancy for women who have anovulation associated with PCOS who have failed to conceive with anti-oestrogens. The complications of gonadotrophin therapy are multiple pregnancies and ovarian hyperstimulation syndrome (OHSS), both almost entirely dependent on a large number of follicles that develop as a result of ovarian stimulation. The principle of the classic chronic low dose regimen is to employ a low starting dose (maximum 75 IU) for a minimum of 14 days with no dose change and then use small incremental dose rises ( usually 25–37.5 IU) when necessary, at intervals of not less than 7 days, until follicular development is initiated. The purpose of this form of therapy is to achieve the development of a single dominant follicle rather than the development of many large follicles and so avoid the complications of OHSS and multiple pregnancies. It produces a remarkably consistent rate of uniovulatory cycles of around 70 %, a pregnancy rate of 40 % and an extraordinarily low prevalence of OHSS which was almost completely eliminated and a multiple pregnancy rate of 5.7 %. The majority of patients (90 %) on a low dose protocol develop a single large follicle meeting hCG administration criteria within 14–16 days without any change in the initial dose for 14 days.
GonadotrophinOvulation inductionPregnancyAnovulatoryHypogonadotrophic-hypogonadodismEu-oestrogenic anovulationPCOSAnti-oestrogensOvarian hyperstimulation syndromeOHSShCGClomipheneDominant folliclePolycystic ovariesFSHIn-vitro fertilizationEmbryo transferSuperovulationMonofollicular ovulationAntral folliclesGonadotrophinFollicular growth
Gonadotrophin therapy is a highly successful way of inducing ovulation and pregnancy for women who are anovulatory due to hypogonadotrophic-hypogonadodism (WHO Group I) (See Chap. 6) or eu-oestrogenic anovulation (WHO Group II) associated with PCOS who have failed to conceive with anti-oestrogens. The complications of gonadotrophin therapy in the latter group are multiple pregnancies and ovarian hyperstimulation syndrome (OHSS).
The prevalence of both multiple pregnancy and OHSS during ovulation induction is almost entirely dependent on the number of follicles that develop as a result of ovarian stimulation. The problem is that, the larger the number of follicles over 15 mm on the day of hCG, usually the higher the pregnancy rate and this tempts many practitioners to ‘go for it’ and hope for the best. However, the prevalence of multiple pregnancy increases from 12 % with 2 large follicles, 20 % with 3 and 50 % for >3 large follicles (Ares-Serono 1995, internal data, with permission). The first course of action, apparent from this data, is that if hCG is withheld when three or more large follicles develop or intercourse postponed, the multiple pregnancy rate during any form of ovulation induction, be it with clomiphene or gonadotrophins, can be severely reduced. Much the same can be said for OHSS in which the number of intermediate and small follicles also contribute to its prevalence.
The best course of action to prevent these complications of gonadotrophin therapy for anovulation, would be to encourage the growth of one dominant follicle only. This can be largely achieved today by using a chronic low dose protocol in preference to the conventional protocol widely used up to some years ago. Conventional ‘step-up’ treatment with gonadotrophins for women with PCOS who failed to conceive with clomiphene citrate yields an acceptable cumulative conception rate. However, because of the peculiarly high sensitivity of polycystic ovaries to gonadotrophin stimulation, this form of treatment, mostly 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. Regarding ovulation induction with gonadotrophins, a collection of data from 14 large published series which was reported in 1990  revealed a mean multiple pregnancy rate of 34 % and a rate of severe OHSS of 4.6 %. This rate of complications is entirely unacceptable today. All women in these series had undergone gonadotrophin induction of ovulation, using a conventional protocol, due to either WHO Group I or Group II anovulation.
Supraphysiological doses of FSH (as used in the conventional protocol) provoke an initial development of a large cohort, stimulate additional follicles, and even rescue those follicles destined for atresia. Multiple follicular development is induced by levels of FSH well above the threshold. This statement holds true for gonadotrophin stimulation of the ovaries in all groups of anovulatory patients and is actually utilized for the induction of superovulation for in-vitro fertilization and embryo transfer. However, for the induction of ovulation in women with PCOS, the problem of achieving the desired monofollicular ovulation is particularly difficult and acute due to the extreme sensitivity of the polycystic ovary to gonadotrophic stimulation. The reason for this does not lie in a difference of FSH threshold levels of the polycystic ovaries but is probably due to the fact that they contain about 6-times the number of available FSH-sensitive antral follicles in their cohort compared with the normal ovary . Any dose of FSH overstepping the threshold of the polycystic ovary will, therefore, produce multifollicular development and impending danger of multiple pregnancy and OHSS. The basic thinking behind this regimen of chronic low-dose gonadotrophin therapy is the ‘threshold theory’, which demands the attainment and maintenance of follicular development with exogenous FSH without exceeding the threshold requirement of the ovary.
9.2 Chronic Low-Dose Regimen
The principle of the classic chronic low dose regimen, shown in Fig. 9.1, is to employ a low starting dose for a minimum of 14 days with no dose change and then use small incremental dose rises ( usually 25–37.5 IU) when necessary, at intervals of not less than 7 days, until follicular development is initiated . The dose that initiates follicular development is continued until the criteria for giving hCG are attained. The purpose of this form of therapy is to achieve the development of a single dominant follicle rather than the development of many large follicles and so avoid the complications of OHSS and multiple pregnancies.
A recommended scheme for the first cycle of low-dose, step-up, FSH administration
A compilation of reported results from the literature (updated from Homburg and Howles ), using a chronic low dose protocol identical to that described above, is presented in Table 9.1. The prominent features include a remarkably consistent rate of uniovulatory cycles of around 70 % in each series. The pregnancy rate of 40 % of the patients and 20 % per cycle are acceptable judging from past experiences with conventional therapy and taking into account that many of the patients comprising these series received only one cycle of therapy. However, the justification for the adoption of the chronic low dose protocol may be seen in the extraordinarily low prevalence of OHSS which was almost completely eliminated and a multiple pregnancy rate of 5.7 %. The majority of patients (90 %) on a low dose protocol develop a single large follicle meeting hCG administration criteria within 14–16 days without any change in the initial dose for 14 days . In the relatively unusual case (often in very obese women) where a treatment cycle is abandoned after 28–35 days due to lack of response, a larger starting dose may, of course, be employed in a further attempt, starting the next cycle with the last dose used in the previous cycle.
Results of treatment of clomiphene resistant patients with low dose, step-up FSH
No. of patients
No. of cycles
Pregnancies (% patients)
320 (38 %)
Updated from Homburg and Howles 
9.4 Variations on a Theme
One variation of the chronic low dose step-up regimen is the step-down dose regimen which attempts to mimic more closely the events of the normal ovulatory cycle. The step-down dose regimen uses a starting dose of 150 IU FSH with a dose decrease of 37.5 IU ampoules when a follicle of 10 mm ensues and a decrease of the same amount every 3 days if follicular growth continues . A comparison of this regimen with the classic step-up regimen demonstrated a significant reduction in the median duration of treatment and a mean of 450 IU less were needed with the step-down dose regimen. This was achieved, however, at the expense of a reduced rate of mono-ovulatory cycles. Initial enthusiasm for this method was tempered by the results of a randomized, French multicenter study comparing the step-up with the step-down protocol which demonstrated superiority of the step-up regimen as regards the rates of monofollicular development, overstimulation and ovulation  clearly indicating the preferential use of the step-up protocol in terms of safety and efficiency.
9.5 Starting Dose
From a large, single-centre series of chronic low dose step-up therapy , the comparison of a starting dose of 75 IU with that of 52.5 IU for an initial 14-day period with an incremental dose rise of 37.5 or 22.5 IU respectively demonstrated a pregnancy rate/patient, uni-ovulatory cycle rate and miscarriage rate slightly in favour of the smaller starting dose.
A further study  demonstrated no difference in clinical outcome whether the starting dose was 37.5 or 50 IU of FSH.
9.6 Incremental Dose Rise
While employing a step-up protocol starting with doses of 50 IU/day of recombinant FSH for a minimum of 7 days, an RCT compared an incremental dose rise of 25 with 50 IU when needed . The smaller incremental dose rise was significantly more beneficial in terms of monofollicular development, ovulation rates and cancellation rates.
We have had very successful results using a starting dose of 50 IU FSH and an incremental dose rise of just 8.3 IU of FSH after 7 days of stimulation when needed . This regimen produced a mono-follicular ovulation in 83 % of the 69 cycles, a pregnancy rate of 80 % (20/25 subjects) with just one cycle cancelled and one set of twins.
Similarly, the low-dose protocol may be adapted for specific populations. In a series from Vietnam  where the average BMI of the patients is obviously much smaller than that seen in Western countries, a starting dose of 25 IU FSH was employed for a minimum of 14 days with an incremental dose of 25 IU when needed. This regimen produced very satisfactory results in terms of pregnancy rates and lack of complications.
9.7 Patience Is a Virtue
Not infrequently, patients and practitioners alike have objected to the apparently protracted length of the initial phase of the classic chronic low-dose protocol of 14 days without a change of dose . Many have reverted to an initial phase of 7 days instead. However, a few facts should be borne in mind. The FSH administered has a cumulative effect and the majority of patients (about 90 %) on the classic low dose protocol develop a single large follicle meeting hCG administration criteria within 14–16 days without any change in the initial dose for 14 days . In a study we performed , 50 patients were divided into a group which allowed a dose rise after 7 days and a group with an allowed dose rise after 14 days only. Although the 7-day starter group had a shorter duration of stimulation and a reduced amount of FSH needed, this was at the expense of a number of multiple pregnancies in this group compared with none in the 14-day starters.
9.8 Gonadotrophin Preparations
Much has been studied and published regarding the comparison of the many gonadotrophin preparations on the market today (See Chap. 13). Whether recombinant or urinary, FSH alone or containing LH activity, regarding low-dose therapy, I have found little to choose between them as far as clinical results are concerned. The importance lies in how you give it rather than what you give!
There is now sufficient evidence to demonstrate that low-dose, step-up, gonadotrophin therapy is virtually the only correct way to utilize gonadotrophins for anovulatory patients with PCOS. Small starting doses in the first cycle, preferably for a 14-day initial period without a dose change and then a small incremental dose rise if required, produce the best results.
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