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Original Studies |
Geneva, Switzerland
Address all correspondence and requests for reprints to: Ares-Serono Scientific and Medical Communications Department, 15 bis Chemin des Mines, CH-1202 Geneva, Switzerland.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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1 follicle 17 mm; E2, 400
pmol/L; midluteal phase progesterone, 25 nmol/L) and maximal
endometrial growth. A minority of patients may require up to 225
IU/day. rhLH, given sc at a dose up to 225 IU/day, was not immunogenic
and was well tolerated. |
Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In women with HH and intact pituitary function, pulsatile GnRH therapy can be used to restore the periodic release of FSH and LH, resulting in ovulation (4, 5, 6, 7, 8). However, effective use of GnRH requires frequent administration (every 60–120 min) and the use of a portable pump injecting the drug either iv or sc for several weeks. The alternative therapeutic option is to give daily injections of human menopausal gonadotropin (hMG), which contains both FSH and LH (5, 7, 9, 10).
Although only FSH is required for follicular growth, some LH is necessary to achieve adequate follicular steroidogenesis and develop the capacity of the follicle to ovulate and luteinize when exposed to hCG (9, 10, 11). However, among the majority of patients for whom FSH therapy is indicated, no administration of LH is required to achieve follicular development, as sufficient endogenous LH is present, as shown in women with WHO group II anovulation (12, 13) and patients stimulated for Assisted Reproductive Technologies (14). In contrast, the majority of women with HH (WHO group I anovulation) (12) do not have the threshold level of endogenous LH required to achieve optimal follicular development and steroidogenesis during therapy with FSH alone. Among these women, urinary and recombinant FSH have been shown to stimulate considerably lower estradiol (E2) levels than those obtained with an hMG preparation containing both FSH and LH (9, 10, 11). It also appears that in this population, the follicles stimulated by FSH alone do not consistently rupture after hCG administration, they luteinize poorly (9, 10, 11), and oocytes may have a lower fertilization rate (9, 10, 11, 15). An exogenous supply of LH is required if an adequate follicular response is to be achieved.
Until recently, hMG, a urinary extract containing a fixed combination of LH and FSH, was the only source of exogenous LH for women with HH. However, recombinant human LH (rhLH) is now available for clinical use, providing a new treatment option. rhLH has indeed been shown 1) to have pharmacokinetic characteristics comparable to those of human pituitary LH (16), and 2) to promote E2 secretion by FSH-stimulated follicles in monkeys treated with a GnRH antagonist (17). Moreover, a few case reports have suggested that rhLH is effective and safe in humans (18, 19, 20, 21).
The aim of this first randomized, efficacy clinical study with rhLH was to determine the minimal effective dose of rhLH for supporting rhFSH-induced follicular development in LH- and FSH-deficient anovulatory women (HH) in addition to assessing the safety and tolerability of this treatment.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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A total of 38 infertile women with HH were enrolled in the study: 28 with primary and 10 with secondary HH. Of these, 28 patients wanted to conceive, and the remaining 10 were volunteers.
For inclusion in the study, each patient had to fulfill all of the
following criteria: aged 18–35 yr; have a clinical history of HH; have
received no treatment with pulsatile GnRH, gonadotropins, or
estrogen-progesterone (P4) replacement therapy for at least
1 month before screening; have a negative P4 challenge
test; have a body mass index between 18.4–31.4; and be using
mechanical contraception if not wishing to conceive. Patients were also
required to have a blood sample taken within 6 months before the start
of treatment, which was analyzed in a central laboratory, showing the
following results: LH, less than 1.2 IU/L; FSH, less than 5 IU/L; TSH,
less than 6.5 µIU/mL; testosterone, less than 3.5 nmol/L;
T4, more than 11 and less than 24 pmol/L; and PRL, less
than 1040 mIU/L. The ultrasound criteria were: have a uterus with a
midline echo, no ovarian tumor or cyst, and 13 or fewer (if using a
vaginal probe) or 10 or fewer (if using an abdominal probe) small
follicles (mean diameter, 
10 mm) on the largest section through each
ovary. Exclusion criteria included a known allergy to gonadotropin
preparations, a previous history of severe ovarian hyperstimulation
syndrome (OHSS), and active substance abuse.
Patients were enrolled at 10 university clinical centers in 4 countries. The study was conducted in accordance with European Union Good Clinical Practice Guidelines, which include obtaining written informed consent from each patient.
Treatment protocol
Eligible patients were to be allocated a unique patient identification number in sequential, chronological order. On the day when FSH and LH treatment was begun, the investigator was to open the envelope provided by the sponsor, carrying the patient’s number and containing details of her LH dose. The computer-generated randomization lists were created using a BASIC program RANPRO (Applied Logic Associates, Houston, TX).
Patients were randomly assigned to receive 0, 25, 75, or 225 IU rhLH (LHadi, Ares-Serono, Aubonne, Switzerland) once daily in addition to 150 IU rhFSH (Gonal-F, Ares-Serono) once daily for up to 20 days. Gonadotropins were injected sc into the abdomen. Patients in the 0 IU rhLH category only received daily injections of 150 IU rhFSH. No dose adaptation occurred for either of the gonadotropins during a given cycle.
Follicular growth was monitored by ultrasound and serum E2 measurements. Gonadotropin therapy did not exceed 14 days unless serum E2 rose and/or follicular growth (follicle >10 mm) indicated ongoing follicular development. In this situation, rhLH/rh FSH treatment could be continued up to a maximum of 20 days.
Ovulation was induced on the day after the last rhLH/rhFSH administration with a single im injection of 10,000 IU hCG (Profasi, Ares-Serono) as soon as one follicle reached a diameter of 17 mm or more and if risk of developing OHSS was judged to be low, i.e. three or fewer follicles with a diameter of 15 mm or more and/or a serum E2 level below 4000 pmol/L in patients willing to conceive, and six or fewer follicles with a diameter of 15 mm or more and/or a serum E2 level below 4000 pmol/L in patients not willing to conceive. Corpus luteum function was assessed by midluteal phase serum P4 measurement. For those patients wanting to conceive, luteal support in the form of an injection of 2500 IU hCG 8 days after the initial injection of hCG could be given.
Each patient was treated for one cycle (cycle A). However, patients who consented could receive treatment for up to two additional cycles (cycles B and C). The dose of rhFSH remained unchanged (150 IU/day), but the dose of rhLH was adjusted depending on the patient’s response in the previous cycle.
Efficacy end points
Based on previous experience with FSH in HH patients, follicular development was judged to be optimal if three criteria were all met during the cycle, i.e. having at least one follicle with a mean diameter of 17 mm or more, a preovulatory serum E2 level of 400 pmol/L or more, and a midluteal phase P4 level of 25 nmol/L or more.
Other assessments included serum LH, FSH, E2, P4, and androstenedione levels and endometrial thickness on days 5 and 10 of rhLH/rhFSH treatment and on the day of hCG administration.
All hormonal measurements were carried out at a certified central laboratory (SCL Bioscience Services, Cambridge, UK) using commercially available immunoassays for which assay validation includes determination of limit of quantification (LOQ) and intra- and interassay coefficients of variation (CVs; for a concentration close to the LOQ): Diagnostic Products Corp. Coat-a-Count, RIA solid phase coated tube separation (Diagnostic Products Corp., Los Angeles, CA) for E2 (intraassay CV, 7.0%; interassay CV, 8.1%; LOQ, 60 pmol/L), testosterone (interassay CV, 12.9%; LOQ, 0.5 nmol/L), androstenedione (intraassay CV, 3.6%; interassay CV, 5.6%), and P4 (intraassay CV, 8.8%; interassay CV, 9.7%; LOQ, <1.0 nmol/L); Serono MAIAclone immunoradiometric assay (Serono, Coinsins, Switzerland) for FSH (intraassay CV, 4.7%; interassay CV, 5.2%; LOQ, 1.0 IU/L), LH (intraassay CV, 11.4%; interassay CV, 13.3%; LOQ, 1.0 IU/L), and PRL (intraassay CV, 5.4%; interassay CV, 6.0%; LOQ, <40 mIU/L); Amersham immunoradiometric assay (Amersham, Aylesbury, UK) for TSH (intraassay CV, 3.2%; interassay CV, 5.7%; LOQ, <0.1 µIU/mL); and Amersham monoclonal antibody for free T4 (intraassay CV, 8.2%; interassay CV, 9.1%; LOQ, <4.0 pmol/L). Dehydroepiandrosterone sulfate (DHEA-S) was assayed with a DSL double antibody RIA (interassay CV, 15.8%; Diagnostic Systems, Webster, TX).
Safety assessment
Drug safety was assessed by monitoring adverse events and the incidence of local reactions at the injection site and through laboratory tests, including hematology, clinical chemistry, and urinalysis. Serum levels of antibodies to rhLH and rhFSH were measured at the central laboratory using immunoassays developed and validated by the sponsor. Briefly, the assay used either [125I]hFSH or [125I]hLH tracer and a set of calibrators (either anti-FSH antiserum or anti-LH antiserum). The separation of bound from free tracer was performed by polyethylene glycol precipitation, and the radioactivity bound was counted. Measurements of samples were expressed as the ratio of T/N, where T is the counts of sample and N is the blank count. The cut-off for positive:negative was T:N = 2.
Statistical analysis
All data were collected in case report forms designed by the
sponsor, and double data entry was performed using a database created
under ORACLE version 7.1.3. for SUN/SOLARIS (Oracle Corp., Redwood
City, CA). A Cochran-Armitage trend test was performed to detect a
trend in the relationship between the rhLH dose in cycle A and the
primary efficacy variable of follicular development as defined above.
As some patients overresponded (risk of OHSS), resulting in
cancellation of hCG administration, the trend analysis of follicular
development rates per protocol was repeated, including overstimulation
as a success for an end point. Secondary efficacy variables recorded in
cycle A were also analyzed statistically for evidence of a relationship
with the rhLH dose. For comparison of continuous variables, two-sided
t tests were used, assuming unequal variances.
P 0.05 was considered statistically significant.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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).
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The efficacy analysis was conducted on 34 A cycles: 10 patients treated with 225 IU rhLH, 9 treated with 75 IU rhLH, 7 treated with 25 IU rhLH, and 8 treated with 0 IU rhLH. Four patients (2 treated with 75 IU rhLH, 1 with 25 IU rhLH, and 1 with 0 IU rhLH) were excluded from the efficacy analysis for major protocol violations, i.e. 2 patients had serum LH levels incompatible with HH before the first injection of study medication, 1 patient was lost for follow-up after the first injection of study medication, and 1 patient received 300 IU rhFSH daily instead of 150 IU.
The endocrine responses of individual patients to therapy and
follicular development are summarized in Table 1
.
Among women receiving rhLH (75 or 225 IU once daily), the majority
showed follicular growth (15 of 19 patients), in contrast to those
receiving rhLH (0 or 25 IU, once daily), in whom a minority had
significant follicular growth (4 of 15 patients; Table 1). Because the
dose of rhFSH was fixed and identical for all patients, this strongly
suggests that rhLH enhances the ovarian response to FSH.
The proportion of patients who fulfilled all 3 efficacy criteria (1
follicle 17 mm; E2, 400 pmol/L; midluteal phase
P4, 25 nmol/L) increased with the dose of rhLH, both when
excessive follicular development was not included as a success
(P = 0.0124) and when excessive follicular development
was included as a success (P = 0.0001; Table 2). Of the 38 patients who started cycle
A, 9 entered the optional cycle B, and 5 entered cycle C. Although not
analyzed statistically, the proportion of patients meeting the primary
efficacy end point in all 3 cycles also increased with increasing dose
of rhLH (Table 2).
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).
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shows the mean number of
follicles greater than 10 mm during the course of cycle A in each of
the treatment groups.
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and Fig. 2; on the last day of FSH/LH treatment:
225 vs. 0 IU groups, P = 0.03; 75
vs. 0 IU groups, P = 0.05; on the day of hCG
treatment: 225 vs. 25 and 0 IU groups, P =
0.05; 75 vs. 25 and 0 IU groups, P < 0.01).
The difference in serum E2 levels between rhLH groups not
only reflected a difference in the number of follicles, but resulted
from a significant difference in the output of E2 per
follicles, as summarized in Table 4 (on
day of hCG treatment: 225 vs. 25 and 0 IU groups,
P = 0.12; 75 vs. 25 and 0 IU groups,
P = 0.03). Difference in serum E2 levels
resulted in different endometrial growth between the treatment groups.
Endometrial growth was similar in the 75 and 225 IU rhLH treatment
groups, even though serum E2 levels were twice as high in
the 225 IU group (Fig. 3; on the last day
of FSH/LH treatment: 225 vs. 0 IU group, P
< 0.01; 75 vs. 0 IU group, P < 0.01; on
the day of hCG treatment: 225 vs. 25 and 0 IU groups,
P = 0.04; 75 vs. 25 and 0 IU groups,
P = 0.07). Androstenedione levels were also higher
among patients treated with the higher doses of LH, i.e. on
the day of hCG treatment, androstenedione levels were 1.0 ± 0.0,
3.2 ± 1.5, 7.8 ± 2.1, and 6.7 ± 0.9 nmol/L in the 0,
25, 75, and 225 IU rhLH groups, respectively (225 vs. 25 and
0 IU groups, P = 0.04; 75 vs. 25 and 0 IU
groups, P = 0.08; see also Table 1). Due to the
administration of rhFSH, similar serum FSH levels were recorded in all
groups (Table 1). Serum LH levels remained below the limit of
quantification (1.0 IU/L) in all but three patients who received 225
IU/day (Table 1). In the midluteal phase, despite hCG administration,
three of four patients treated with 0 or 25 IU rhLH during the
follicular phase had not luteinized, and one had elevated serum
P4 levels, whereas all patients who were treated with 75 or
225 IU rhLH during the follicular phase were highly luteinized (Table 1).
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Safety assessment
A total of 42 adverse events (AEs) were reported in 14 (26%) of the 53 cycles in this study. Thirty-two AEs occurred in 11 (26.2%) of the 42 cycles treated with rhLH, and 10 occurred in 3 (27.2%) of the 11 cycles not treated with rhLH. The most frequent AEs were pelvic and abdominal pain, headache, breast pain, nausea, ovarian enlargement, and somnolence. These AEs are similar to those reported during therapy with FSH alone. No differences were observed in the incidence or type of AEs between patients who did not receive rhLH (0 LH group) and those who did receive rhLH treatment, regardless of the dose.
More than 80% of patients administered the medication themselves. No local reaction or only a mild reaction was reported in 95.6% of injections of rhLH and 96.3% of injections of rhFSH. Anti-LH and anti-FSH antibodies were not detected in any of the posttreatment serum samples. In addition, no symptoms suggesting immune reactions were reported. The assessment of hematology, biochemistry, and urinalysis parameters before and after therapy did not show any differences between treatment groups.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Although there is individual variation in the dose of rhLH required to promote optimal follicular development, the majority of patients with HH receiving 75 IU/day showed an adequate response. With 75 IU rhLH and a fixed dose of 150 IU FSH/day, sufficient, but not excessive, follicular development and steroidogenesis were obtained in 46% of the treatment cycles. Furthermore, among the subset of patients in the 75 IU/day treatment group who received hCG, rhLH promoted appropriate E2 and P4 secretion in 75–80% of the cycles. In addition, with that rhLH dose, the serum E2 threshold for promoting maximal endometrium growth had been achieved.
Although the dose of 75 IU rhLH was sufficient in the majority of patients for promoting optimal follicular development, trough levels of serum LH remained below the LOQ of the assay (1.0 IU/L). This further confirms that, as shown in pituitary down-regulated patients, minimal circulating levels of LH are required to initiate follicle steroidogenesis, and measurements of serum immunoactive LH levels are of limited value (if any) for identifying whether a patient has enough endogenous LH secretion to respond adequately to stimulation with FSH alone (22, 23).
The number of patients fulfilling the three efficacy criteria that defined optimal follicular growth was partly limited by the rigidity of the dose schedule for rhFSH. It is highly probable that if the dose of FSH had been adapted during the stimulation phase, more patients could have received hCG.
As discussed above, the dose of rhLH affects the ovarian response to a fixed dose of FSH, and patients who received 75 and 225 IU were more sensitive to FSH than patients who received no rhLH or a low dose of rhLH. Although not statistically significant, these data also show that the group that received 225 IU rhLH may have a smaller number of growing follicles than the group who received 75 IU rhLH/day. This could reflect a LH ceiling effect, i.e. some secondary follicles underwent atresia due to their high sensitivity to LH (24). This hypothesis requires further investigation.
Table 5 compares the results of the
present study with pivotal parameters of efficacy in large studies on
hMG and GnRH treatment of HH published within the last 15 yr. This
comparison suggests the efficacy of the combination of rhLH and rhFSH
to be similar to that of hMG or pulsatile administration of GnRH in
hypogonadotropic patients.
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95%) of nonspecific
copurified urinary proteins, which can cause hypersensitivity reactions
(25). Furthermore, only a once daily injection of rhFSH and rhLH is
required in comparison with GnRH, which has to be administered every
60–120 min. In this study more than 80% of the rhLH injections were
self-administered, and local tolerance to sc administration was
excellent. This study has confirmed the pivotal role of LH in normal follicular function. It has also demonstrated that a daily dose of 75 IU rhLH is sufficient for promoting optimal follicular development in the majority of HH patients, as measured by E2 secretion and the ability to luteinize when exposed to hCG. Interestingly, such a low dose does not lead to a measurable change in serum LH trough levels. A higher dose may be required by a minority of patients. In this population, LH was shown to modulate the ovarian threshold for FSH. Finally, these data suggest that increasing exposure to LH during the follicular phase reduces the number of growing follicles. This hypothesis requires further investigation.
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Acknowledgments |
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Footnotes |
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2 The following people from Ares-Serono, Medical Affairs Department,
contributed to the conception, conduct, and analysis of the study:
Ernest Loumaye, M.D., Ph.D.; Angela Piazzi; David Warne, Ph.D.; Muana
Kalubi; Paul Cox; Susan Lancaster, Ph.D.; Sara Rotem; Michèle
Sauvage; and Gianna Ursicino, Pharm.D. The following clinical
investigators participated in the conception and conduct of the study:
David Baird, M.D., University of Edinburgh (Edinburgh, UK); Ettore
Cittadini, M.D., and Roberto Palermo, M.D., Università degli
Studi di Palermo (Palermo, Italy); Roy Homburg, M.D., Hasharon Hospital
(Petah Tikva, Israel); Zeev Shoham, M.D., and Vaclav Insler, M.D.,
Kaplan Hospital (Rehovot, Israel); Carlo Flamigni, M.D., and Eleonora
Porcu, M.D., Università degli Studi di Bologna (Bologna, Italy);
Gilbert Schaison, M.D., Hôpital Kremlin Bicêtre (Kremlin
Bicêtre, France); Philippe Bouchard, M.D., Hôpital Saint
Antoine (Paris, France); Stephen Franks, M.D., St. Mary’s Hospital
(London, UK); Michael Hull, M.D., University of Bristol (Bristol, UK);
and Howard Jacobs, M.D., Middlesex Hospital (London, UK).
Received October 10, 1997.
Revised December 22, 1997.
Accepted January 15, 1998.
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References |
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C. K. Welt, Z. A. Smith, D. K. Pauler, and J. E. Hall Differential Regulation of Inhibin A and Inhibin B by Luteinizing Hormone, Follicle-Stimulating Hormone, and Stage of Follicle Development J. Clin. Endocrinol. Metab., June 1, 2001; 86(6): 2531 - 2537. [Abstract] [Full Text] [PDF]
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The European Recombinant LH Study Group Human Recombinant Luteinizing Hormone Is as Effective as, But Safer Than, Urinary Human Chorionic Gonadotropin in Inducing Final Follicular Maturation and Ovulation in in Vitro Fertilization Procedures: Results of a Multicenter Double-Blind Study J. Clin. Endocrinol. Metab., June 1, 2001; 86(6): 2607 - 2618. [Abstract] [Full Text] [PDF]
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