{'fraction_non_alphanumeric': 0.024151571934207788, 'fraction_numerical': 0.0037476577139287947, 'mean_word_length': 5.509485094850948, 'pattern_counts': {'":': 0, '<': 1, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Exogenous luteinizing hormone supplementation in controlled ovarian stimulation: why, when and to whom?

Follicle stimulating hormone (FSH) and luteinizing hormone (LH) play an important role in assisted reproductive technology during ovarian stimulation. These hormones execute different but complementary functions in the control of ovarian folliculogenesis and steroidogenesis but, while the role of FSH is well understood, the need for LH supplementation in controlled ovarian stimulation (COS) is still debated and controversial. Several confounding factors (e.g. different exogenous LH formulations, different stimulation protocols, different study populations, difficulty in identifying a threshold value below which an LH add-back could be beneficial) contribute to the continuing uncertainty reported in the literature concerning exogenous LH supplementation, despite the large number of trials that have been published. LH is produced by the anterior pituitary gland and its synthesis and secretion are controlled by gonadotropin-releasing hormone (GnRH). LH is required for follicular growth, ovulation, luteinization of the dominant follicle and progesterone production after ovulation. LH receptors (LHCGRs) are mainly located on the theca cells of human antral follicles. According to the classical “two cell – two gonadotropin” theory, LH is responsible for the production of androgen precursors, which are essential for estradiol biosynthesis ruled by FSH in granulosa cells. During COS patients undergo daily injection of GnRH analogues (GnRH agonist or GnRH antagonist) in order to prevent a premature LH surge. It is important to underline that with the long GnRH agonist protocol a complete pituitary desensitization is obtained only after 2–3 weeks of treatment and that it is preceded by an initial production of gonadotropins (flare up effect). On the other hand, during downregulation with GnRH antagonists LH secretion remains present, although reduced due to the supra-physiological levels of estradiol related to FSH administration, and it is completely blocked during the periovulatory phase for 3–5 days following GnRH antagonist injections. Until a few years ago, the only available form of exogenous LH has been human menopausal gonadotropins (HMGs). HMGs are urinary derived gonadotropins that contain FSH, LH and human chorionic gonadotropin (hCG), showing biological activity of FSH and LH in a 1:1 ratio. Despite their widespread use, the administration of these compounds has shown several limitations related to the extraction processing (protein contamination, wide fluctuation in LH concentration and activity). Different studies have compared the use of HMG and recombinant FSH (rFSH) to rFSH-only cycles reporting an increase in live birth rate (3% to 4%), especially when using the long GnRH agonist protocol, with fewer ampoules of rFSH administered to the patient. Recently, new highly purified HMG preparations have been developed and have shown comparable results in terms of safety and efficacy but, despite the encouraging results, the available evidence is too limited to make definitive conclusions. Recombinant LH (rLH) has been introduced in clinical practice since its approval in 1994. The structure and functionality of rLH are analogous to human endogenous LH, with higher purity and precision of dosing, and similar volume of distribution and half-life when compared to urinary products. According to the threshold theory, optimal folliculogenesis requires a minimal amount of LH for adequate steroidogenesis (<1% of rLH should be occupied), but on the other hand excessive LH could inhibit cell growth and suppress granulosa aromatase activity. However, the identification of a minimal threshold LH value below which LH supplementation during COS could be beneficial in terms of treatment outcomes still remains a matter of concern. Several studies investigating GnRH agonist and GnRH antagonist protocols have employed sporadic single serum LH dosage on different days during ovarian stimulation (e.g. day 1–3 after agonists initiation, day of hCG administration, day 8 in antagonist protocols) in order to justify LH supplementation to increase pregnancy outcomes, with inconsistent results. Other authors suggest that it is not the absolute LH value that affects the final outcome, but it is rather the dynamic decrease ( 50%) in LH level following GnRH analogue administration that impacts the ultimate live birth rates the most. In addition to that, in some cases similar LH levels or comparable LH dynamic changes do not correspond to similar patients’ response during COS. The differences in ovarian response may be related to different LH isoforms or to LHCGR polymorphisms, the expression of which varies from one individual to another.