A 31 year old patient with primary amenorrhea, primary infertility and long-standing hypogonadotrophic hypogonadism presented to our infertility unit in June 2003. Immediately prior to her referral to our clinic, the patient was on sequential hormone replacement therapy for one year in view of moderate lumbar spine osteopenia detected on DEXA bone densitometry, which she discontinued because she wished to conceive. In the past, the patient used oral contraceptive pills to induce regular withdrawal bleeding.
A routine series of infertility investigations was performed. Hormonal profile revealed follicle-stimulating hormone of 0.9 IU/L, luteinising hormone of 0.5 IU/L, hypoestrogenaemia, normal prolactin level, testosterone and DHEA-sulphate at the upper range of normal. Hysterosalpingography showed normal bilateral spillage of dye through the tubes, and a small uterine filling defect. Hysteroscopy was therefore arranged and a small benign uterine polyp was removed. Pelvic ultrasound scan revealed small inactive ovaries. Semen analysis of the male partner was normal.
Management options of GnRH pump or gonadotrophin injections were discussed with the patient. She opted for gonadotrophin injections and was therefore commenced on recombinant follicle-stimulating hormone 50 IU (Follitropin beta, Puregon, Organon, The Netherlands) and recombinant luteinising hormone 75 IU (Lutropin alpha, Luveris, Serono, Switzerland) on day two of a withdrawal bleed, induced by a course of oral contraceptive pills. Serial transvaginal ultrasound measurements of follicular growth and endometrial thickness, together with hormonal determination of the levels of estradiol (E2) and luteinising hormone, were used for monitoring of her cycle. The dose of recombinant follicle-stimulating hormone was increased to 75 IU on day 12 of the treatment cycle as there was no obvious follicular growth. Follow up was continued until on day 26 of treatment, when ultrasound scan showed a dominant follicle of 23 mm in diameter, endometrial thickness of 9.1 mm, E2 level of 3155 pmol/L and luteinising hormone level of 3.3 IU/L. Human chorionic gonadotrophin (hCG, 5000 units; Profasi, Serono, Switzerland) was then administered and sexual intercourse was advised. A week later, a serum progesterone of 127 nmol/L confirmed ovulation. The patient became pregnant in this cycle. Unfortunately, the patient miscarried after the six week ultrasound scan and was managed by surgical evacuation of the uterus.
Two months later, the patient was very keen to start another treatment cycle. A similar treatment protocol was followed in the second cycle except that the starting dose of recombinant follicle-stimulating hormone was increased to 75 IU. This time, she developed a dominant follicle of 24 mm on day 19 of treatment, endometrial thickness of 10.1 mm, E2 and luteinising hormone level of 2231 pmol/L and 2.4 IU/L, respectively. Serum progesterone was also suggestive of ovulation at 64 nmol/L. Luteal phase support in the form of progesterone suppositories 400 mg daily (Cyclogest, Shire, United Kingdom) was commenced until the day of the pregnancy test. Subsequently, the patient became pregnant, and ultrasound scan performed six weeks later revealed a single viable intrauterine pregnancy. Luteal support was continued until 12 weeks of an ongoing pregnancy.
WHO group I anovulation, or hypogonadotrophic hypogonadism, is a rare condition, characterised by reduced hypothalamic or pituitary activity.1 It can be caused by a number of abnormalities of endogenous hypothalamic gonadotrophin releasing hormone (GnRH) secretion, all of which are incompatible with normal folliculogenesis and subsequent ovulation.1,2 Depending on the age of onset, patients may present with delayed puberty, amenorrhea or infertility. Biochemically, low serum levels of sex steroids occur in the presence of low luteinising hormone and follicle-stimulating hormone serum levels.3
In women with hypogonadotrophic hypogonadism desiring fertility, ovulation induction can be achieved either with exogenous gonadotrophins or GnRH therapy. The obvious advantage of pulsatile GnRH infusion is that, if effective, it is more likely to result in development and ovulation of a single follicle, thereby reducing the risks to the mother of ovarian hyperstimulation syndrome and to the fetus of multiple pregnancy. Ovulation induction with gonadotrophins is frequently complicated by multiple pregnancy and accounts for nearly a third of high order (triplet and above) admissions to neonatal intensive care units in the United Kingdom.4 Nevertheless, GnRH therapy may be ineffective, inappropriate and, in practice, more than 50% of women with organic pituitary disease will require gonadotrophin treatment.5 Moreover, effective use of GnRH requires frequent administration (every 60–120 minutes) and the use of a portable pump injecting the drug either intravenous or subcutaneous for several weeks.
According to two-cell, two-gonadotrophin concept, both follicle-stimulating hormone and luteinising hormone are required for normal follicular development and steroidogenesis.6 However, among the majority of patients for whom follicle-stimulating hormone therapy is indicated, administration of luteinising hormone is not required to achieve follicular development, as sufficient endogenous luteinising hormone is present, as shown in women with WHO group II anovulation,1,7 and patients stimulated for assisted reproductive technologies.1,8 In contrast, the majority of women with hypogonadotrophic hypogonadism (as our case) do not have the threshold level of endogenous luteinising hormone required to achieve optimal follicular development and steroidogenesis during therapy with follicle-stimulating hormone alone. Among these women, highly purified urinary and recombinant follicle-stimulating hormone have been shown to stimulate considerably lower E2 and inhibins levels than those obtained with an hMG preparation. It also appears that in this population, the follicles stimulated by follicle-stimulating hormone alone do not consistently rupture after hCG administration, they luteinise poorly, and oocytes may have a lower fertilisation rate.1,9 An exogenous supply of luteinising hormone is required if an adequate follicular response is to be achieved.1
Until recently, hMG, a urinary extract containing a fixed combination of follicle-stimulating hormone and luteinising hormone, was the only source of exogenous luteinising hormone for women with hypogonadotrophic hypogonadism.1 Recombinant luteinising hormone (Luveris, Serono) is the only available stand-alone preparation of luteinising hormone, and has been described in association with follicle-stimulating hormone for stimulating follicular development in luteinising hormone and follicle-stimulating hormone deficient women.10 Compared with hMG treatment, the use of recombinant luteinising hormone offers a number of advantages. Its characteristics are a high specific activity making it suitable for subcutaneous injection allowing self-administration by the patient, the absence of undesirable proteins which can cause hypersensitivity reactions in case of hMG, and an excellent batch-to-batch consistency. hMG can be given intramuscularly, and its highly purified preparation is suitable for subcutaneous injection.10 Overall, recombinant luteinising hormone has been shown to have pharmacokinetic characteristics comparable to those of human pituitary luteinising hormone.11 Moreover, the efficacy of the combination of recombinant follicle-stimulating horomone and recombinant luteinising hormone has been shown to be similar to that of hMG or GnRH in hypogonadotrophic patients.1
Our case chose to have recombinant gonadotrophins in preference to GnRH and hMG as alternative treatment options, for the convenience of administration, and considering the anticipated advantageous effects. We opted for lower starting doses of recombinant follicle-stimulating hormone (50 and 75 IU, respectively) for her treatment than those used in The European Recombinant Human Luteinising Hormone Study1 to avoid the multiple follicular growth encountered in their study. The patient has shown a rather consistent response to stimulation protocol in both treatment cycles as evidenced by adequate monofollicular development, appropriate thickening of the endometrium and a concomitant rise of her E2. The case has confirmed the pivotal role of luteinising hormone in normal follicular function, and that a daily dose of 75 IU recombinant luteinising hormone is sufficient for promoting optimal monofollicular development, adequate endometrial growth and appropriate E2 secretion in accordance with the findings of The European Recombinant Human Luteinising Hormone Study.1
In our case, the level of luteinising hormone increased above the limit of quantification (1.0 IU/L) and led to a measurable change in serum luteinising hormone trough levels, similar to a minority of patients in The European Recombinant Human Luteinising Hormone Study.1 This is an interesting finding considering the suggestion made by some studies1,12,13 that trough levels of serum luteinising hormone remain below the limit of quantification of the assay in the majority of patients with optimal follicular development. Also, it has previously been suggested that minimal circulating levels of luteinising hormone are required to initiate follicular steroidogenesis in pituitary down-regulated patients, and that measurements of serum immunoactive luteinising hormone levels are of limited value for identifying whether these patients have endogenous luteinising hormone secretion to respond adequately to stimulation with follicle-stimulating hormone alone.1,12,13
We have opted for luteal phase support in the second treatment cycle of our case, taking in consideration the early pregnancy loss the patient suffered in the first course of therapy. We are aware that the best dose, duration or type of luteal phase support in infertility treatment is controversial,14 and that the importance of luteal support in women with hypogonadotrophic hypogonadism was previously questioned in a study of two patients receiving hMG and hCG for ovulation induction proposing that 75 IU of luteinising hormone applied during the stimulation phase is sufficient to establish a normal follicular phase, normal luteal phase and even pregnancy.15
Agrawal et al.16 reported the first pregnancy after the use of recombinant follicle-stimulating hormone, luteinising hormone and hCG in a patient with hypogonadotrophic hypogonadism following initial unsuccessful attempts using GnRH. Yet the case they reported did not ovulate in her first treatment cycle, over-responded to the same doses of ovulation induction agents in her second cycle and developed severe ovarian hyperstimulation syndrome in her third cycle in which she eventually conceived. In contrast, recombinant gonadotrophins were used as a first line of therapy in our case, and they were judiciously tailored to the individual needs of our patient not only leading to good ovarian response with monofollicular ovulation induction, but to the establishment of two consecutive conceptions with avoidance of the serious complications of ovarian hyperstimulation syndrome and multiple pregnancy as well.
Our case is also different from that of a recent prospective multicentre observational study of 38 patients with type I WHO anovulation, in which a starting dose of 150 IU recombinant follicle-stimulating hormone and 75 IU recombinant luteinising hormone was used, and was thereafter adjusted according to the individual's response. The study reported sufficient dominant follicular development in the majority of the treatment cycles with a pregnancy rate of 39.5% without the use of luteal phase support. However, using this regimen had resulted in a high cancellation rate (14%) due to ovarian hyper-responsiveness or insufficient follicular growth, as well as a high multiple pregnancy rate (26%).17
It has been postulated that refinements in terms of the appropriate starting doses and/or increments of gonadotrophins (mainly follicle-stimulating hormone but also luteinising hormone) during ovarian stimulation are necessary when using recombinant preparations.17 As shown in this case, a novel dose as low as 50 IU of recombinant follicle-stimulating hormone can be sufficient to induce monofollicular ovulation. As far as we know, the described stimulation regimen using lower dose of recombinant follicle-stimulating hormone (50 IU) to initiate monofollicular recruitment has not been reported before. Further evaluation of this dosage regime merits study in large numbers of patients. The use of this and perhaps even lower doses of recombinant follicle-stimulating hormone is well recognised in patients with type II WHO anovulation.5
To conclude, this case demonstrates that low dose recombinant gonadotrophins therapy is a safe and successful ovulation induction regimen in an amenorrheic patient with hypogonadotrophic hypogonadism desiring fertility, resulting in a viable pregnancy using timed sexual intercourse. This line of treatment is acceptable, effective and increases the treatment options available to this group of patients.