Extended LH Administration

Primary objective The primary endpoint of the study will be to confirm that the pre-treatment with rhLH at the dose of 187.5 IU/day for 60 days may improve ovarian reserve as indicated by an increase in basal AMH.

The primary endpoint of the study will be to confirm that the pre-treatment with rhLH at the dose of 187.5 IU/day for 60 days may improve ovarian reserve as indicated by an increase in basal AMH. The chosen dose and duration for the study was based on a recent published article. In particular in this study women who presented for fertility treatment with very low functional ovarian reserve, showed that the administration of LH 187.5 IU/day for 60 days, contributed to a clinically evident increase in the functional ovarian reserve (AFC and AMH levels). The use of recombinant LH in women with gonadotrophin deficiency has been already investigated in two very well known randomized trials. In these two trials a dose of rec LH up to 225IU daily has been tested.

The objective of the European Recombinant Human LH study group was to conduct a randomized, efficacy clinical study with rLH in order to determine the minimal effective dose of rLH for supporting rFSH-induced follicular development in LH- and FSH-deficient anovulatory women (HH) in addition to assessing the safety and tolerability of this treatment. Patients were randomized to receive rLH (0, 25, 75, or 225IU/day) in addition to a fixed dose of rFSH (150 IU/day). rhLH was found 1) to promote dose-related increases in estradiol (E2) and androstenedione secretion by rFSH-induced follicles, 2) to increase ovarian sensitivity to FSH, as demonstrated by the proportion of patients who developed follicles after the administration of a fixed dose of FSH, and 3) to enhance theability of these follicles to luteinize when exposed to hCG. Recombinant LH, given sc at a dose up to 225 IU/day, was not immunogenicand was well tolerated.

In one study two double-blind, placebo-controlled, multicentre pilot studies were conducted. Study A was conducted in hypogonadotrophic hypogonadal women (WHO group I anovulation) with severe deficiency in LH and who were willing to conceive. Study B was conducted in WHO group II anovulatory patients (PCO) willing to conceive and who over-responded to FSH therapy. In the study A women received FSH plus LH at a dose of 225 IU daily. In the study B women were randomized to receive a dose of 225 IU or 450 IU daily. Authors reported that the Treatment with rLH was well tolerated. There were no serious or signficant adverse events during the study. No patient developed anti-LH antibodies.

Secondary objectives

The secondary endpoints will be:

• Change from baseline for basal AFC (antral follicle count) after 60 days of LH prolonged treatment or no treatment
• Change from baseline for basal AMH after 30 days of LH prolonged treatment or no treatment
• Change from baseline for basal AFC (antral follicle count) after 30 days of LH prolonged treatment or no treatment
• Ovarian response to controlled ovarian stimulation in IVF/ICSI cycles (number of follicles >16 mm at the end of stimulation, number of retrieved oocytes, FORT index- follicles to oocyte ratio, number of mature oocytes)
• Evaluate the safety of rLH throughout the treatment period
• cycles discontinued/cancelled before rhCG administration due to poor or excessive ovarian response
• percent of missed transfer of fresh embryos
• implantation rate
• biochemical pregnancy rate
• clinical pregnancy rate
• early (≤9 days after triggering) and late (12-17 days after triggering) OHSS onset (according to Golan's Classification System) rate
• miscarriage rate
• preterm birth rate
• low birth weight rate
• congenital anomalies rate
• gestational age at delivery
• mean neonatal weight

This is a multicenter clinical trial. The coordinating center is the Mother-Infant Department of University Hospital of Modena and Reggio Emilia (Principal investigator [PI]: Prof. La Marca Antonio)

This two-arm, multicenter, prospective, RCT (proof of concept) trial with two treatment arms at 2:1 ratio will involve couples attending an IVF/ICSI cycle, phase II study.

Inclusion criteria

• AFC of at least 5 in the 3 months prior to the study cycle
• Basal AMH levels of at least 1 ng/ml in the 3 months prior to the study cycle
• Age 25-38 at the moment of the study cycle
• D3 Basal LH: 1-6 IU/L in the 3 months prior to the study cycle
• D3 Basal FSH: < 8 IU/L in the 3 months prior to the study cycle 13
• D3 Estradiol < 70 pg/ml in the 3 months prior to the study cycle
• Willing to participate
• Capable to understand and follow the study procedure
• eumenorrheic women with low LH levels candidate to IVF/ICSI cycle for tubal factor, male factor or for idiopathic infertility
• Acceptance and signature of the informed consent

Exclusion criteria

• PCOS patients according to Rotterdam's criteria
• Patients with irregular cycles (shorter than 25 days or longer than 35 days)
• Patients already treated with LH priming
• Patients planning to undergo duo/double stimulation
• Patients with ASRM Stage III or IV endometriosis
• Patients with prior surgery significantly affecting ovary (ie ovariectomy, cystectomy significantly reducing ovarian volume or others) as assessed by the responsible gynecologist
• Previous cycle with less than 4 oocytes recovered
• Patients treated with hormones in the 3 months before the study
• Patients with an already known endocrinological disease including hypothyroidism (defined by TSH < 4 mIU/L), adrenocortical deficiency (ACTH stimulation test (250 mcg) with basal cortisol <3 mcg or, if basal cortisol is 3-18 mcg serum level, cortisol serum level 30 minutes after the stimulation test <18 mcg) and hyperprolactinemia (PLR > 25mcg/l)
• previous episode of OHSS or exuberant ovarian response to gonadotropins
• hypersensitivity to the study drug
• contraindication for pregnancy
• porphyria or a family history of porphyria
• history of ovarian torsion
• BMI > 30 kg/m2
• ovarian enlargement or ovarian cyst
• gynecological bleeding of unknown origin
• history of ovarian, breast or endometrial cancer.